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WO2021118318A2 - Novel indole derivative and use thereof - Google Patents

Novel indole derivative and use thereof Download PDF

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Publication number
WO2021118318A2
WO2021118318A2 PCT/KR2020/018213 KR2020018213W WO2021118318A2 WO 2021118318 A2 WO2021118318 A2 WO 2021118318A2 KR 2020018213 W KR2020018213 W KR 2020018213W WO 2021118318 A2 WO2021118318 A2 WO 2021118318A2
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Prior art keywords
alkyl
hydrogen
diabetic
disease
substituted
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PCT/KR2020/018213
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French (fr)
Korean (ko)
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WO2021118318A3 (en
Inventor
박명규
이은주
서승용
이산하
이정은
김선여
홍성민
이재혁
강민철
Original Assignee
주식회사 메타센테라퓨틱스
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Publication of WO2021118318A2 publication Critical patent/WO2021118318A2/en
Publication of WO2021118318A3 publication Critical patent/WO2021118318A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/132—Heterocyclic compounds containing only one nitrogen as hetero atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/32—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the digestive tract
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/328—Foods, ingredients or supplements having a functional effect on health having effect on glycaemic control and diabetes

Definitions

  • the present invention relates to novel indole derivatives and uses thereof. Since the novel indole derivative of the present invention captures methylglyoxal (MGO), a major precursor of the final glycated product, it can be usefully used for the prevention or treatment of diseases related to the final glycated product.
  • MGO methylglyoxal
  • Diabetes mellitus is a metabolic disease in which high blood sugar levels persist for a long time due to insufficient insulin secretion or insulin resistance. As the blood sugar level in the body continues for a long time, chronic complications occur as glycation products invade the retina, kidneys, nerves, or large and small blood vessels throughout the body. Since diabetes is more dangerous than diabetes itself, the biggest goal in diabetes treatment today is to suppress the occurrence or progression of diabetes complications. Typical complications of diabetes include diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart disease, diabetic osteoporosis, diabetic atherosclerosis, and the like.
  • Mechanisms that induce these complications of diabetes are largely oxidative stress caused by free radicals, non-enzymatic glycation of protein, and osmotic pressure caused by a change in the mechanism of the polyol pathway. stress, etc.
  • Oxidative stress the cause of diabetes complications, refers to a reaction caused by a decrease in the ability to remove free radicals generated in the body or a rapid increase in the production of active oxygen due to environmental factors.
  • oxidative stress rises due to high blood sugar, which increases insulin resistance and damages cells such as blood vessels, kidneys, and retina.
  • advanced glycation end products (AGEs) produced by oxidative stress are a major cause of diabetic complications.
  • the glycation reaction is a non-enzymatic reaction between the aldehyde group of sugars present in blood or cell fluid and the free amino group of proteins inside and outside the cell.
  • nonalcoholic steatohepatitis NASH
  • nonalcoholic steatohepatitis NASH
  • FAA free fatty acid
  • TG non-toxic triglycerides
  • Nonalcoholic steatohepatitis is often accompanied by type 2 diabetes, another insulin resistance-related disease.
  • Methylglyoxal is a major precursor of the final glycosylation product that causes complications due to diabetes.
  • Experimental results have shown that MGO formation by cellular metabolism is increased at high glucose concentrations in vitro, and the abnormal accumulation of MGO affects the occurrence of diabetic complications in various tissues and organs.
  • MGO is produced through several pathways, including as a by-product of glycolysis, and several mechanisms may influence MGO detoxification.
  • MGO increased due to detoxification disorders within the organism is directly toxic to tissues and leads to the gradual development of obesity, hyperglycemia and insulin resistance. This suggests that an increase in MGO may result in and cause insulin resistance and hyperlipidemia, creating a potential vicious cycle (Moraru et al., 2018).
  • the production of the final glycated product is suppressed by trapping the MGO before the final glycated product is produced, the resulting diabetic complications can be prevented.
  • obesity and coronary artery disease act as risk factors, so treatment of hyperglycemia and treatment of these diseases can be performed at the same time to prevent the progression of complications. Capture is also expected to help manage obesity in people with type 2 diabetes.
  • the present inventors developed a novel material capable of capturing MGO and completed the present invention.
  • An object of the present invention is to provide a novel compound having excellent capture ability of methylglyoxal (MGO).
  • the present invention also seeks to provide a composition comprising the novel compound.
  • the present invention also intends to provide a composition for improving, preventing or treating diseases related to final glycation products comprising the novel compound.
  • the composition may be a pharmaceutical composition, a food composition, or a feed composition for animals.
  • the present invention provides a compound of the following formula (I) (hereinafter also referred to as 'indole derivative' or 'compound of formula I') or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen, halo, alkyl, alkenyl, or alkynyl,
  • R 2 is hydrogen; -N(Ra)(Rb) unsubstituted or substituted alkyl; or - aryl unsubstituted or substituted with N(Ra)(Rb) or alkyl;
  • Ra or Rb is each independently hydrogen or alkyl
  • Rc is hydrogen or alkyl
  • Rf is hydrogen; alkyl unsubstituted or substituted with an aryl group; or —NH-alkyl-NH-alkyl-NH 2 ,
  • R 4 is hydrogen, halo, alkyl, alkenyl, or alkynyl
  • R 6 or R 7 are each independently hydrogen, halo, alkyl, alkenyl, alkynyl, —OH or —Oalkyl;
  • a, b, n or m is an integer from 1 to 10;
  • the present invention provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably a composition for preventing, ameliorating, or treating a disease related to a final glycated product.
  • the composition may be a pharmaceutical composition, a food composition, or a feed composition for animals.
  • the final glycation product-related disease is aging, diabetes, diabetic complications, hyperlipidemia, hyperglycemia, cardiovascular disease, degenerative brain disease, autism spectrum disorder, arteriosclerosis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, skin fibrosis, lung It may be selected from the group consisting of fibrosis, renal fibrosis, and cardiac fibrosis. Preferably, it is diabetes (particularly preferably type 2 diabetes) or a diabetic complication.
  • the diabetic complications are diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, diabetic osteoporosis, diabetic sarcopenia. And it may be selected from the group consisting of obesity.
  • the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia, It may be selected from the group consisting of progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, early-stage dementia, temporal lobe epilepsy, and stroke.
  • the present invention relates to a novel indole derivative or a pharmaceutically acceptable salt thereof.
  • the indole derivative according to the present invention exhibits an effect of capturing methylglyoxal, a major precursor of the final glycation product, and an excellent cytoprotective effect. It can be usefully used as a pharmaceutical composition for preventing or treating diseases related to glycation products.
  • novel indole derivative of the present invention is particularly useful for preventing or treating type 2 diabetes and diabetic complications resulting therefrom.
  • Figure 3 shows the results of analyzing the cytoprotective activity according to the concentration of the compound 10 in the N2a cell line after treatment with methylglyoxal (MGO) and the compound 10 of the present invention.
  • MGO methylglyoxal
  • FIG. 11 shows the results of analyzing the cytoprotective activity of the compound 10 of the present invention with respect to cytotoxicity caused by free L-DOPA treatment.
  • FIG. 13 shows the results of analyzing the cytoprotective activity of the compound 10 of the present invention with respect to cytotoxicity caused by MGO + L-DOPA treatment.
  • Figure 14 shows the results of analyzing the cytoprotective activity of the compound 11 of the present invention with respect to the cytotoxicity caused by MGO + L-DOPA treatment.
  • the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen, halo, alkyl, alkenyl, or alkynyl,
  • R 2 is hydrogen; -N(Ra)(Rb) unsubstituted or substituted alkyl; or - aryl unsubstituted or substituted with N(Ra)(Rb) or alkyl;
  • Ra or Rb is each independently hydrogen or alkyl
  • Rc is hydrogen or alkyl
  • Rf is hydrogen; alkyl unsubstituted or substituted with an aryl group; or —NH-alkyl-NH-alkyl-NH 2 ,
  • R 4 is hydrogen, halo, alkyl, alkenyl, or alkynyl
  • R 6 or R 7 are each independently hydrogen, halo, alkyl, alkenyl, alkynyl, —OH or —Oalkyl,
  • a, b, n or m is an integer from 1 to 10;
  • R 1 is hydrogen, or C 1 -C 6 alkyl
  • R 2 is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with —N(Ra)(Rb); or - aryl unsubstituted or substituted with N(Ra)(Rb) or C 1 -C 6 alkyl,
  • Ra or Rb is each independently hydrogen or C 1 -C 6 alkyl
  • Rc is hydrogen or C 1 -C 6 alkyl
  • Rf is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with an aryl group; or -NH-C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 ,
  • R 4 is hydrogen or C 1 -C 6 alkyl
  • R 6 or R 7 are each independently hydrogen, C 1 -C 6 alkyl, —OH or —OC 1 -C 6 alkyl,
  • a, b, n or m may be an integer from 1 to 5.
  • R 1 is hydrogen
  • R 2 is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with NH 2 ; or aryl unsubstituted or substituted with NH 2 or C 1 -C 6 alkyl,
  • Rf is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with an aryl group; or -NH-C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 ,
  • R 4 is hydrogen or C 1 -C 6 alkyl
  • R 6 or R 7 are each independently hydrogen, C 1 -C 6 alkyl, —OH or —OC 1 -C 6 alkyl,
  • n or m may be an integer from 1 to 5.
  • R 1 is hydrogen
  • R 2 is hydrogen; -C 1 -C 6 alkyl-NH 2 ; Or NH 2 substituted or unsubstituted phenyl,
  • Rf is hydrogen, C 1 -C 6 alkyl, benzyl or —NH-C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 ,
  • R 4 is hydrogen
  • R 6 is hydrogen, —OH or —OC 1 -C 6 alkyl
  • R 7 is hydrogen
  • n or m may be an integer from 1 to 5.
  • R 1 is hydrogen
  • R 2 is hydrogen, —CH 2 NH 2 , or phenyl substituted with NH 2 ,
  • R 3 is hydrogen, , , , or ego,
  • R 4 is hydrogen
  • R 5 is hydrogen, -OH, -OCH 3 , , , , , , , or ego,
  • R 6 is hydrogen, -OH, -OCH 3
  • R 7 is hydrogen
  • R 2 and R 3 may not be hydrogen at the same time.
  • the present invention also provides a compound selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention is suitable not only for human medical use, but also for veterinary use in animals.
  • the animal is a mammal, warm-blooded animals including companion animals (eg, dogs, cats, horses, etc.), and guinea pigs, mice, rats, gerbils, cattle, goats, sheep, monkeys, pigs, rodents, rabbits, primates, and the like.
  • the pharmaceutical composition of the present invention can be used for the prevention or treatment of diseases related to final glycation products.
  • the pharmaceutical composition may further include conventional pharmaceutically acceptable additives, such as excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or extenders.
  • conventional pharmaceutically acceptable additives such as excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or extenders.
  • the final glycation product-related disease is aging, diabetes, diabetic complications, hyperlipidemia, hyperglycemia, cardiovascular disease, degenerative brain disease, autism spectrum disorder, arteriosclerosis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, skin fibrosis, lung It may be selected from the group consisting of fibrosis, renal fibrosis, and cardiac fibrosis. Preferably, it is diabetes (particularly preferably type 2 diabetes) or a diabetic complication.
  • the diabetic complications are diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, diabetic osteoporosis, diabetic sarcopenia. And it may be selected from the group consisting of obesity.
  • the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia, It may be selected from the group consisting of progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, early-stage dementia, temporal lobe epilepsy, and stroke.
  • the present invention provides a food composition
  • a food composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably, a food composition for preventing or ameliorating diseases related to final glycated products.
  • the food composition may be a health functional food, dairy product, fermented product or food additive.
  • the food composition comprises various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and It may further include salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.
  • pectic acid and its salts alginic acid and It may further include salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • the present invention provides a feed composition for animals comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, preferably, a feed composition for animals for preventing or improving diseases related to final glycated products.
  • the animal feed composition may further include one or more carriers, excipients, diluents, fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents or preservatives.
  • Alkyl as used herein is a hydrocarbon having primary, secondary, tertiary and/or quaternary carbon atoms, substituted or unsubstituted, and saturated aliphatic, which may be straight chain, branched, cyclic, or combinations thereof. includes the group.
  • an alkyl group may have 1 to 20 carbon atoms (ie, C 1 -C 20 alkyl), 1 to 10 carbon atoms (ie, C 1 -C 10 alkyl), or 1 to 6 carbon atoms (ie, C 1 -C 10 alkyl). C 1 -C 6 alkyl).
  • alkyl refers to C 1 -C 6 alkyl.
  • alkyl groups examples include methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i -Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl ( t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH
  • alkyl as used throughout the specification, examples and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which are trifluoromethyl and 2,2,2-tri refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as fluoroethyl, and the like.
  • C xy or "C x -C y ", when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, refers to a group containing x to y carbons in the chain. considered to include For example, a (C 1 -C 6 )alkyl group contains 1 to 6 carbon atoms in the chain.
  • Alkenyl has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and includes one or more regions of unsaturation, i.e., carbon- It is a hydrocarbon with a carbon sp 2 double bond.
  • an alkenyl group has 2 to 20 carbon atoms (ie, C 2 -C 20 alkenyl), 2 to 12 carbon atoms (ie, C 2 -C 12 alkenyl), 2 to 10 carbon atoms ( ie, C 2 -C 10 alkenyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkenyl).
  • Alkynyl has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and contains one or more carbon-carbon sp triple bonds.
  • hydrocarbons with For example, an alkynyl group has 2 to 20 carbon atoms (ie, C 2 -C 20 alkynyl), 2 to 12 carbon atoms (ie, C 2 -C 12 alkynyl), 2 to 10 carbon atoms ( ie, C 2 -C 10 alkynyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkynyl).
  • suitable alkynyl groups include, but are not limited to, acetylenic (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
  • Cycloalkyl refers to a monovalent or divalent, saturated or partially saturated non-aromatic ring, which may be monocyclic, bicyclic or polycyclic, substituted or unsubstituted, and wherein each atom of the ring is carbon. .
  • a “cycloalkyl” may also have 3 to 7 carbon atoms when monocyclic, 7 to 12 carbon atoms when bicyclic, and up to about 20 carbon atoms when polycyclic.
  • Bicyclic or polycyclic ring systems may be fused, bridged, or spiro ring systems.
  • heterocycloalkyl refers to monocyclic, bicyclic or containing one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms in the ring. polycyclic, substituted or unsubstituted monovalent or divalent, saturated or partially saturated non-aromatic ring.
  • heterocycloalkyl is a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is heterocyclic, and at the other
  • the click ring can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl.
  • Bicyclic or polycyclic ring systems may be fused, bridged, or spiro ring systems.
  • “Heterocycloalkyl” includes, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like, each of which may be substituted or unsubstituted.
  • halo means halogen and includes chloro, fluoro, bromo, and iodo.
  • aryl includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups wherein each atom of the ring is carbon, monocyclic, bicyclic or polycyclic.
  • Aryl is a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is aromatic and the other cyclic rings are, for example, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl.
  • Aryl can be, for example, benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline, and the like, each of which may be substituted or unsubstituted.
  • substituted refers to a particular moiety of a compound of the present invention having one or more substituents.
  • substituted with respect to alkyl, heterocycloalkyl, etc., for example "substituted alkyl” or “substituted heterocycloalkyl” means that one or more hydrogen atoms of the alkyl or heterocycloalkyl are each independently replaced by a non-hydrogen substituent. meant to be replaced.
  • the term "pharmaceutically acceptable salt” is used herein to refer to an acid or base addition salt suitable or compatible with the treatment of a patient.
  • exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Exemplary organic acids that form suitable salts include mono-, di- and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid acids, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, as well as sulfonic acids such as p-toluene sulfonic acid and methanesulfonic acid.
  • Monoacid or diacid salts may be formed, and such salts may exist in hydrated, solvated or substantially anhydrous form.
  • acid addition salts of compounds of the present invention are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base form. The selection of appropriate salts is known to those skilled in the art.
  • diabetes refers to a group of metabolic diseases in which high blood sugar levels persist for a long time. Diabetes can be caused by the pancreas not making enough insulin or the body's cells not responding properly to the insulin made. Diabetes is largely divided into type 1 diabetes, which is caused by not producing enough insulin, type 2 diabetes, which results from insulin resistance in which cells do not respond properly to insulin, and gestational diabetes.
  • diabetes complications refers to symptoms caused when diabetes persists for a long time. "Diabetic complications” is evaluated by criteria different from the criteria for the onset and judgment of diabetes.
  • ASD Autism Spectrum Disorder
  • Autism spectrum disorders include, but are not limited to, autism, Asperger's Syndrome, Pervasive Developmental Disorder Not Elsewhere Classified (PDD-NOS), Childhood Disintegrative Disorder, Rett Syndrome, and Fragile X Syndrome.
  • Step 2 N1-(3-(2-ammonio-3-(5-hydroxy-1) H -Indol-3-yl)propanamido)propyl)butane-1,4-diaminium chloride
  • Step 1 Benzyl ( S )-3-(5-(((3-(( tert -butoxycarbonyl) (4-(( tert -Butoxycarbonyl)amino)butyl)amino)propyl)carbamoyl)oxy)-1 H -Indol-3-yl)-2-(( tert -Preparation of butoxycarbonyl)amino)propanoate
  • Step 2 3-(5-(((3-(( tert -butoxycarbonyl) (4-(( tert -Butoxycarbonyl)amino)butyl)amino)propyl)carbamoyl)oxy)-1 H -Indol-3-yl)-2-(( tert Preparation of -butoxycarbonyl)amino)propanoic acid (intermediate)
  • Step 3 2-Amino-3-(5-(((3-((4-aminobutyl)amino)propyl)carbamoyl)oxy)-1 H -Indol-3-yl)propanoic acid
  • Examples compounds 22 to 51 of Table 1 were synthesized in a manner similar to Examples 1 to 21 above.
  • Methylglyoxal is a major precursor of final glycation products that cause complications due to diabetes. have. Therefore, in this example, it was attempted to confirm whether the compound of the present invention has the ability to capture methylglyoxal (MGO), a precursor before the formation of the final glycation product.
  • Methylglyoxal was added to phosphate buffered saline (PBS, Cat no. 10010023, pH 7.4) to prepare a mixture.
  • the mixture (MGO+PBS) was treated with the compound of each of Examples at a concentration of 1.0 mM, and then cultured at 37°C for 7 days. On days 1 and 7 after incubation, the fluorescence intensity of the reaction product was measured at an excitation wavelength of 355 nm and an emission wavelength of 460 nm using a VICTOR TM X3 multilabel plate reader. The fluorescence intensity obtained for each compound is shown in Table 2.
  • the reaction product produced by the reaction of the compound with methylglyoxal exhibits fluorescence.
  • the fluorescence intensity is 10 X 10 3 or more, it was determined that the compound has the ability to capture methylglyoxal.
  • the compounds of the present invention were confirmed to have excellent methylglyoxal capture ability.
  • methylglyoxal was added to phosphate buffered saline (PBS, Cat no. 10010023, pH 7.4) to prepare a mixture.
  • PBS phosphate buffered saline
  • Each compound of Examples was added to the mixture (MGO+PBS) at a concentration of 1:1 with methylglyoxal (MGO) to react, and then cultured at 37°C for 7 days. On days 1 and 7 after incubation, the concentration of free methylglyoxal (free MGO) unreacted with the example compound was measured by HPLC. The results are shown in FIGS. 1 and 2 .
  • the compound of the present invention was confirmed to reduce the concentration of free methylglyoxal (free MGO) by almost half or less as compared to the control (N: PBS + MGO).
  • the concentration of free methylglyoxal on the 7th day after culture was reduced to about 10% to 15% of the control group, and about 4% when the compound of Example 13 was treated. was reduced to
  • N2a cells were seeded in a 96-well plate at 2 x 10 4 cells/well. Each cell line was pretreated with 500 nM of the compound for 1 hour, followed by post-treatment with 500 ⁇ M MGO and cultured for 24 hours. After removing the medium, 0.5 mg/ml 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution was treated for 1 hour, and the reduced formazan was dissolved in 150 ⁇ l of DMSO to 570 nm Cell viability was measured with a microspectrophotometer at wavelength. Cell viability in the case of treatment with each substance was evaluated by setting the cell viability of the normal control untreated to 100%. The results are shown in Table 3, Figures 3 and 4 below.
  • Example compounds 10 and 11 have excellent protective efficacy against MGO.
  • SH-SY5Y cells were seeded in a 96-well plate at 2 x 10 4 cells/well. Each cell line was pretreated with 500 nM of the compound for 1 hour, followed by post-treatment with 500 ⁇ M MGO and cultured for 24 hours. After removing the medium, 0.5 mg/ml 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution was treated for 1 hour, and the reduced formazan was dissolved in 150 ⁇ l of DMSO to 570 nm Cell viability was measured with a microspectrophotometer at wavelength. Cell viability in the case of treatment with each substance was evaluated by setting the cell viability of the normal control untreated to 100%. The results are shown in Table 4, FIGS. 5 and 6 .
  • FIGS. 5 and 6 the cell viability in the treatment groups of Example compounds 4, 5, 10, 11 and 13 was confirmed to be higher than that of the control group (500 ⁇ M MGO).
  • the cell viability was significantly decreased in the group treated with 500 ⁇ M MGO in each cell line compared to that of the normal control group (Control).
  • the cell viability increased in a concentration-dependent manner. Therefore, it can be seen that the compound of the present invention has excellent protective efficacy against MGO.
  • cytotoxicity was induced by treatment with free methylglyoxal (MGO), and the methylglyoxal (MGO) protective ability of the compound of the present invention was confirmed using CyQUANTTM LDH Cytotoxicity Assay kit (Invitrogen).
  • SH-SY5Y cells were seeded in a 96-well plate at 2 x 10 4 cells/well and stabilized for 24 hours. Thereafter, cells were pre/post-treated with Example Compounds 10 and 11 at a concentration of 500 nM for 1 hour, followed by pre/post-treatment with 500 ⁇ M MGO and cultured for 24 hours. 50 ⁇ L of the medium was mixed with the substrate mix solution in the same amount and reacted for 30 minutes in the dark at room temperature, 50 ⁇ L stop solution was added, and absorbance was measured at 490 nm. The change in LDH content according to each sample treatment was calculated by setting the LDH content of the normal control untreated to 100%. The results are shown in FIGS. 7 and 8 below.
  • cell proliferation inhibition was induced due to free methylglyoxal (MGO) treatment, and the protective ability of the compound of the present invention to methylglyoxal (MGO) was confirmed using the BrdU cell proliferation assay kit (Cell signalin). .
  • SH-SY5Y cells were seeded in a 96-well plate at 2 x 10 4 cells/well and stabilized for 24 hours. Thereafter, cells were pre/post-treated with compounds 10 and 11 at a concentration of 500 nM for 1 hour, followed by pre/post-treatment with 500 ⁇ M MGO and cultured for 24 hours. After 24 hours, 200 ⁇ L of the fixing solution was treated and reacted at room temperature for 30 minutes. After washing 3 times with washing buffer, the BrdU primary antibody was treated and reacted for 1 hour. After washing with washing buffer, TMB peroxidase substrate was added and reacted for 30 minutes. After 30 minutes, the reaction was stopped using a stop solution. Absorbance was measured at 450/550 nm with a microspectrophotometer. With the cell proliferation rate of the normal control untreated as 100%, the change in cell proliferation according to each sample treatment was calculated, and the results are shown in FIGS. 9 and 10 .
  • the cell proliferation rate was significantly decreased in the group treated with 500 ⁇ M MGO in each cell line compared to the normal group (control). In contrast, in the group treated with compounds 10 and 11, the cell proliferation rate was increased.
  • SH-SY5Y cells were seeded in a 96-well plate at 2 x 104 cells/well and stabilized for 24 hours. Thereafter, the cells were pre/post-treated with compounds 10 and 11 at concentrations of 1, 5, and 10 ⁇ M for 1 hour, and then treated with 100 ⁇ M L- DOPA before/after and cultured for 24 hours. After removing the medium, 0.5 mg/ml MTT solution was treated for 1 hour after removing the medium, and the reduced formazan was dissolved in 150 ⁇ l of DMSO to measure cell viability with a microspectrophotometer at 570 nm wavelength. did. A change in cell protection according to each sample treatment was measured with the cell viability of the normal control untreated as 100%, and the results are shown in FIGS. 11 and 12 .
  • the cell proliferation rate was significantly reduced compared to that of the normal group (control).
  • the cell viability was significantly increased in the compounds 10 and 11 treatment groups.
  • MGO + L-DOPA Inducing cytotoxicity due to treatment, MGO + L- DOPA of the compounds of the present invention It was intended to confirm the protective ability.
  • SH-SY5Y cells were seeded in a 96-well plate at 2 x 10 4 cells/well and stabilized for 24 hours. Thereafter, cells were pre/post-treated with compounds 10 and 11 at a concentration of 500 nM for 30 minutes, followed by pre/post-treatment with 500 ⁇ M MGO and cultured for 24 hours. After removing the medium, 0.5 mg/ml MTT solution was treated for 1 hour after removing the medium, and the reduced formazan was dissolved in 150 ⁇ l of DMSO to measure cell viability with a microspectrophotometer at 570 nm wavelength. did. The cell viability of the untreated normal control group (Control) was set to 100%, and the cell viability when treated with MGO was measured and shown in FIGS. 13 and 14 .
  • the cell proliferation rate was significantly decreased in the group treated with MGO + L-DOPA compared to the normal group (control).
  • the cell viability increased in a concentration-dependent manner in the groups treated with compounds 10 and 11 of the present invention.
  • RTPCR reverse transcription polymerase chain reaction
  • RNA was isolated from liver and adipose tissue using Trizol (Invitrogen), and cDNA was synthesized using rimeScript TM RT Master Mix synthesis kit (Takara).
  • Real-time PCR was performed in triplicate using TB Green® Premix Ex Taq TM II (Takara) in Mx3000/Mx3005P Real-Time PCR System (Agilent).
  • the expression of the target gene was proportionally measured using the delta cycle threshold method for the expression of the endogenous standard gene actin, and the results are shown in FIG. 15 .

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Abstract

The present invention relates to a novel indole derivative and a use thereof. The novel indole derivative of the present invention captures methylglyoxal (MGO), which is a major precursor of advanced glycation end products, and exhibits an excellent cytoprotective effect, thus finding advantageous applications in preventing or treating diseases associated with advanced glycation end products.

Description

신규한 인돌 유도체 및 이의 용도Novel indole derivatives and uses thereof
본 발명은 신규한 인돌 유도체 및 이의 용도에 관한 것이다. 본 발명의 신규한 인돌 유도체는 최종당화산물의 주요 전구체인 메틸글리옥살(methylglyoxal: MGO)을 포획하므로, 최종당화산물과 관련된 질병의 예방 또는 치료에 유용하게 사용될 수 있다.The present invention relates to novel indole derivatives and uses thereof. Since the novel indole derivative of the present invention captures methylglyoxal (MGO), a major precursor of the final glycated product, it can be usefully used for the prevention or treatment of diseases related to the final glycated product.
당뇨병은 인슐린의 분비량이 부족하거나 인슐린 저항성으로 인해 높은 혈당 수치가 오랜 기간 지속되는 대사 질환이다. 체내 혈당이 높아진 상태가 장기간 지속됨에 따라, 당화 산물이 망막, 신장, 신경 또는 전신의 크고 작은 혈관들을 침범하면서 만성 합병증이 발병하게 된다. 당뇨병은 그 자체보다 당뇨 합병증이 더 위험하기 때문에, 오늘날 당뇨병 치료에 있어서 가장 큰 목표는 당뇨 합병증의 유발이나 진행을 억제하는 데에 있다. 대표적인 당뇨 합병증으로는 당뇨병성 망막증, 당뇨병성 백내장, 당뇨병성 신장병증, 당뇨병성 신경병증, 당뇨병성 심장병, 당뇨병성 골다공증, 당뇨병성 아테롬성 동맥경화 등이 있다.Diabetes mellitus is a metabolic disease in which high blood sugar levels persist for a long time due to insufficient insulin secretion or insulin resistance. As the blood sugar level in the body continues for a long time, chronic complications occur as glycation products invade the retina, kidneys, nerves, or large and small blood vessels throughout the body. Since diabetes is more dangerous than diabetes itself, the biggest goal in diabetes treatment today is to suppress the occurrence or progression of diabetes complications. Typical complications of diabetes include diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart disease, diabetic osteoporosis, diabetic atherosclerosis, and the like.
이러한 당뇨 합병증을 유발하는 기전으로는 크게 자유라디칼에 의한 산화적 스트레스(oxidative stress), 단백질의 비효소적 당화 반응(non-enzymatic glycation of protein)과 폴리올 경로(polyol pathway)의 기작 변화에 의한 삼투압 스트레스 등이 설명되고 있다.Mechanisms that induce these complications of diabetes are largely oxidative stress caused by free radicals, non-enzymatic glycation of protein, and osmotic pressure caused by a change in the mechanism of the polyol pathway. stress, etc.
당뇨 합병증을 일으키는 원인인 산화적 스트레스란 인체 내에서 발생하는 활성산소의 제거기능이 저하되거나 환경적인 요인으로 활성산소 생성이 급격하게 증가되어 일어나는 반응을 일컫는다. 당뇨 환자의 경우 고혈당에 의해 산화적 스트레스가 상승하여 인슐린 저항성을 증가시키고 혈관, 신장, 망막 등의 세포 손상을 발생시킨다고 알려져 있다. 이뿐만 아니라 산화적 스트레스로 인하여 생성되는 최종당화산물 (advanced glycation end products, AGEs)은 당뇨합병증의 주요한 원인이 되고 있다. 당화 반응은 혈액이나 세포액에 존재하는 당류의 aldehyde group과 세포 내외의 단백질의 free amino group 사이의 비효소적 반응으로, 당과 단백질이 반응하여 초기당화산물이 생성되고 이 초기당화산물이 분해되지 않고 재배열된 후 다른 단백질과 교차 결합하여 최종당화산물을 생성하는 일련의 반응을 일컫는다. 이 반응은 반응 시작 단계에서 에너지 공급 없이 거의 자연발생적으로 일어나므로 식품이나 우리의 신체 내에서 일어나며, 일정단계 이후 비가역적인 특징을 가진다. 따라서 최종당화산물은 일단 생성되면 혈당이 정상으로 회복되어도 분해되지 않고, 단백질 생존 기간 동안 조직에 축적되어 조직의 구조와 기능을 비정상적으로 변화시킨다. 이처럼 비효소적 단백질 당화반응에 의하여 기저막, 혈장 알부민, 수정체 단백질, 피브린, 콜라겐 등의 단백질에서 당화가 일어나며, 생성된 최종당화산물은 조직의 구조와 기능을 비정상적으로 변화시켜 만성 당뇨 합병증을 유발시킨다.Oxidative stress, the cause of diabetes complications, refers to a reaction caused by a decrease in the ability to remove free radicals generated in the body or a rapid increase in the production of active oxygen due to environmental factors. In diabetic patients, it is known that oxidative stress rises due to high blood sugar, which increases insulin resistance and damages cells such as blood vessels, kidneys, and retina. In addition, advanced glycation end products (AGEs) produced by oxidative stress are a major cause of diabetic complications. The glycation reaction is a non-enzymatic reaction between the aldehyde group of sugars present in blood or cell fluid and the free amino group of proteins inside and outside the cell. It refers to a series of reactions that cross-link with other proteins after rearrangement to produce final glycosylation products. Since this reaction occurs almost spontaneously without energy supply in the reaction initiation stage, it occurs in food or our body, and has irreversible characteristics after a certain stage. Therefore, once the final glycation product is generated, it is not decomposed even when blood sugar is restored to normal, but accumulates in the tissue during the protein survival period, abnormally changing the structure and function of the tissue. As such, glycosylation occurs in proteins such as basement membrane, plasma albumin, lens protein, fibrin, and collagen by non-enzymatic protein glycation, and the resulting final glycation product abnormally changes the structure and function of the tissue, causing chronic diabetes complications. .
따라서, 당뇨 합병증의 발병을 지연시키거나 예방 또는 치료하기 위해서는 산화적 스트레스를 막는 역할을 하거나 최종당화산물의 생성 억제 또는 분해 효과를 가지는 것이 중요하다.Therefore, in order to delay, prevent, or treat the onset of diabetic complications, it is important to prevent oxidative stress or to inhibit the production of final glycated products or to have a decomposition effect.
최종당화산물은 당뇨 합병증 외에도 비알코올성 지방간염(nonalcoholic steatohepatitis, NASH) 질환과 관련이 있다고 최근 밝혀졌다. 비알코올성 지방간염의 발병 기전은 완전히 밝혀지지는 않았지만, 적어도 인슐린 저항성과 밀접한 관련이 있는 것으로 널리 받아들여지고 있다. 유전적 요인과 더불어 식이 및 운동 등 생활습관과 관련된 환경적 요인의 복합 작용으로 인슐린 저항이 증가하면, 간에서 과도한 유리 지방산(free fatty acid, FAA)이 생성된다. 유리 지방산은 간세포 안에서 독성이 없는 중성 지방(triglyceride, TG)으로 전환되어 일차적으로 단순 지방증의 상태가 된다 (Hepatology, 2007 Jun:45(6):1366-74; Hepatology, 2004 Jul:40(1):185-94). 이후에 다양한 산화적 스트레스가 추가되면서 지방과산화와 염증 사이토카인의 과생성으로 간세포 손상 및 염증반응이 일어나 비알코올성 지방간염으로 발전한다. 비알코올성 지방간염은 또다른 인슐린 저항성 관련 질환인 제2형 당뇨병을 흔히 동반하는데, 이러한 사실은 당뇨 합병증의 주요 원인 물질로 알려진 최종당화산물과 비알코올성 지방간염의 연관성을 시사한다.It was recently discovered that the final glycation product is related to nonalcoholic steatohepatitis (NASH) disease in addition to diabetic complications. Although the pathogenesis of nonalcoholic steatohepatitis is not fully elucidated, it is widely accepted that it is at least closely related to insulin resistance. When insulin resistance increases due to the complex action of lifestyle-related environmental factors such as diet and exercise along with genetic factors, excess free fatty acid (FAA) is produced in the liver. Free fatty acids are converted into non-toxic triglycerides (TG) in hepatocytes, primarily resulting in simple steatosis (Hepatology, 2007 Jun:45(6):1366-74; Hepatology, 2004 Jul:40(1)) :185-94). Thereafter, as various oxidative stresses are added, hepatocyte damage and inflammatory reaction occur due to fat peroxidation and overproduction of inflammatory cytokines, which develops into nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis is often accompanied by type 2 diabetes, another insulin resistance-related disease.
메틸글리옥살(methylglyoxal: MGO)은 당뇨병으로 인한 합병증을 유발시키는 최종당화산물의 주요 전구체이다. 시험관 내 높은 포도당 농도에서 세포 대사에 의한 MGO 형성이 증가한다는 실험 결과가 있으며, MGO의 비정상적인 축적은 다양한 조직 및 기관에서 당뇨 합병증의 발생에 영향을 준다. 또한, MGO 수치를 증가시키자 초파리에서 비만과 고혈당증이 유발되었다는 실험결과도 존재한다. MGO는 해당 분해의 부산물을 비롯해 여러 경로를 통해 생성되며 여러 메커니즘이 MGO 해독에 영향을 줄 수 있다. 유기체 내에서 해독 장애로 인해 증가한 MGO는 조직에 직접 독성을 가지고 있으며 비만, 고혈당증 및 인슐린 저항성의 점진적인 발달로 이어진다. 이는 MGO의 증가가 인슐린 저항성 및 고지혈증의 결과이자 원인이 되어 잠재적 악순환을 일으킬 수 있음을 뜻한다 (Moraru et al., 2018). Methylglyoxal (MGO) is a major precursor of the final glycosylation product that causes complications due to diabetes. Experimental results have shown that MGO formation by cellular metabolism is increased at high glucose concentrations in vitro, and the abnormal accumulation of MGO affects the occurrence of diabetic complications in various tissues and organs. In addition, there are experimental results showing that increasing MGO levels induced obesity and hyperglycemia in fruit flies. MGO is produced through several pathways, including as a by-product of glycolysis, and several mechanisms may influence MGO detoxification. MGO increased due to detoxification disorders within the organism is directly toxic to tissues and leads to the gradual development of obesity, hyperglycemia and insulin resistance. This suggests that an increase in MGO may result in and cause insulin resistance and hyperlipidemia, creating a potential vicious cycle (Moraru et al., 2018).
따라서 최종당화산물 생성 이전에 MGO를 포획(trapping)함으로서 최종당화산물의 생성을 억제한다면 그로 인한 당뇨 합병증을 예방할 수 있다. 제2형 당뇨병 환자에서는 비만과 관상 동맥 질환 등이 위험 인자로 작용함으로써 고혈당의 치료와 더불어 이들 질환의 치료가 동시에 이루어져야 합병증의 진행을 막을 수 있는데, MGO의 축적은 비만에도 영향을 미치는 바, MGO 포획은 제2형 당뇨병 환자의 비만 관리에도 도움이 될 것으로 예상된다.Therefore, if the production of the final glycated product is suppressed by trapping the MGO before the final glycated product is produced, the resulting diabetic complications can be prevented. In type 2 diabetes patients, obesity and coronary artery disease act as risk factors, so treatment of hyperglycemia and treatment of these diseases can be performed at the same time to prevent the progression of complications. Capture is also expected to help manage obesity in people with type 2 diabetes.
이에 본 발명자들은 MGO를 포획할 수 있는 신규한 물질을 개발하여 본 발명을 완성하였다.Accordingly, the present inventors developed a novel material capable of capturing MGO and completed the present invention.
[선행기술문헌][Prior art literature]
[비특허문헌][Non-patent literature]
Yamaguchi K, et al., Hepatology. 2007 Jun;45(6):1366-74Yamaguchi K, et al., Hepatology. 2007 Jun;45(6):1366-74
Feldstein AE et al., Hepatology. 2004 Jul;40(1):185-94Feldstein AE et al., Hepatology. 2004 Jul;40(1):185-94
Moraru et al., Cell Metabolism 27, 926-934, April 3, 2018Moraru et al., Cell Metabolism 27, 926-934, April 3, 2018
본 발명은 메틸글리옥살(methylglyoxal: MGO)의 포획능이 우수한 신규한 화합물을 제공하고자 한다.An object of the present invention is to provide a novel compound having excellent capture ability of methylglyoxal (MGO).
본 발명은 또한 상기 신규한 화합물을 포함하는 조성물을 제공하고자 한다. The present invention also seeks to provide a composition comprising the novel compound.
본 발명은 또한 상기 신규한 화합물을 포함하는 최종당화산물 관련 질환의 개선, 예방 또는 치료용 조성물을 제공하고자 한다.The present invention also intends to provide a composition for improving, preventing or treating diseases related to final glycation products comprising the novel compound.
상기 조성물은 약학 조성물, 식품 조성물 또는 동물용 사료 조성물일 수 있다.The composition may be a pharmaceutical composition, a food composition, or a feed composition for animals.
본 발명은 하기 화학식 I의 화합물 (이하 '인돌 유도체' 또는 '화학식 I의 화합물'이라고도 한다) 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound of the following formula (I) (hereinafter also referred to as 'indole derivative' or 'compound of formula I') or a pharmaceutically acceptable salt thereof.
[화학식 I] [Formula I]
Figure PCTKR2020018213-appb-img-000001
Figure PCTKR2020018213-appb-img-000001
상기 식에서,In the above formula,
R 1은 수소, 할로, 알킬, 알케닐, 또는 알키닐이고,R 1 is hydrogen, halo, alkyl, alkenyl, or alkynyl,
R 2는 수소; -N(Ra)(Rb)로 치환되거나 비치환된 알킬; 또는 - N(Ra)(Rb) 또는 알킬로 치환되거나 비치환된 아릴이고,R 2 is hydrogen; -N(Ra)(Rb) unsubstituted or substituted alkyl; or - aryl unsubstituted or substituted with N(Ra)(Rb) or alkyl;
Ra 또는 Rb는 각각 독립적으로 수소 또는 알킬이고,Ra or Rb is each independently hydrogen or alkyl,
R 3은 수소; -(CH 2)n-C(Rc)(N(Rd)(Re))(COORf); 또는 -(CH 2)n-C(Rc)(N(Rd)(Re))(C(=O)Rf)이고,R 3 is hydrogen; -(CH 2 )nC(Rc)(N(Rd)(Re))(COORf); or -(CH 2 )nC(Rc)(N(Rd)(Re))(C(=O)Rf),
Rc는 수소 또는 알킬이고,Rc is hydrogen or alkyl,
Rd 또는 Re는 각각 독립적으로 수소, -C(=O)알킬 , -C(=O)알킬-O-알킬, C(=O)알킬-시클로알킬, C(=O)알킬-알케닐, -C(=O)O-알킬, 또는 -NH-알킬-NH-알킬-NH 2이고,Rd or Re are each independently hydrogen, -C(=O)alkyl , -C(=O)alkyl-O-alkyl, C(=O)alkyl-cycloalkyl, C(=O)alkyl-alkenyl, - C(=O)O-alkyl, or -NH-alkyl-NH-alkyl-NH 2 ,
Rf는 수소; 아릴기로 치환되거나 비치환된 알킬; 또는 -NH-알킬-NH-알킬-NH 2이고,Rf is hydrogen; alkyl unsubstituted or substituted with an aryl group; or —NH-alkyl-NH-alkyl-NH 2 ,
R 4는 수소, 할로, 알킬, 알케닐, 또는 알키닐이고,R 4 is hydrogen, halo, alkyl, alkenyl, or alkynyl;
R 5는 수소, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, 또는 -OC(=O)(CH 2)aS(CH2)bCH(Rg)(Rh)이고,R 5 is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or - OC(=O)(CH 2 )aS(CH2)bCH(Rg)(Rh),
Rk는 수소; 아미노기 또는 카르복실기로 치환되거나 비치환된 알킬; 또는 -CH 2NHC(=O)CH(CH 2SH)이고,Rk is hydrogen; alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH 2 NHC(=O)CH(CH 2 SH),
Rg 또는 Rh는 각각 독립적으로 수소, 알킬, 헤테로시클로알킬, -S(=O)알킬, Rg or Rh is each independently hydrogen, alkyl, heterocycloalkyl, -S(=O)alkyl,
Figure PCTKR2020018213-appb-img-000002
,
Figure PCTKR2020018213-appb-img-000003
,
Figure PCTKR2020018213-appb-img-000004
, 또는 -NH(CH 2)mNH 2이고,
Figure PCTKR2020018213-appb-img-000002
,
Figure PCTKR2020018213-appb-img-000003
,
Figure PCTKR2020018213-appb-img-000004
, or —NH(CH 2 )mNH 2 ,
R 6 또는 R 7은 각각 독립적으로 수소, 할로, 알킬, 알케닐, 알키닐, -OH 또는 -O알킬이고,R 6 or R 7 are each independently hydrogen, halo, alkyl, alkenyl, alkynyl, —OH or —Oalkyl;
a, b, n 또는 m은 1 내지 10의 정수이다. a, b, n or m is an integer from 1 to 10;
본 발명은 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 조성물, 바람직하게는, 최종당화산물 관련 질환의 예방, 개선 또는 치료용 조성물을 제공한다.The present invention provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably a composition for preventing, ameliorating, or treating a disease related to a final glycated product.
상기 조성물은 약학 조성물, 식품 조성물, 또는 동물용 사료 조성물일 수있다. The composition may be a pharmaceutical composition, a food composition, or a feed composition for animals.
일 실시태양에서, 상기 최종당화산물 관련 질환은 노화, 당뇨병, 당뇨 합병증, 고지혈증, 고혈당증, 심혈관질환, 퇴행성 뇌질환, 자폐 스펙트럼 장애, 동맥경화, 비알코올성 지방간, 비알코올성 지방간염, 피부섬유증, 폐섬유증, 신장섬유증, 및 심장섬유증으로 이루어진 군으로부터 선택되는 것일 수 있다. 바람직하게는, 당뇨 (특히 바람직하게는 제2형 당뇨) 또는 당뇨 합병증이다.In one embodiment, the final glycation product-related disease is aging, diabetes, diabetic complications, hyperlipidemia, hyperglycemia, cardiovascular disease, degenerative brain disease, autism spectrum disorder, arteriosclerosis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, skin fibrosis, lung It may be selected from the group consisting of fibrosis, renal fibrosis, and cardiac fibrosis. Preferably, it is diabetes (particularly preferably type 2 diabetes) or a diabetic complication.
일 실시태양에서, 상기 당뇨 합병증은 당뇨병성 신장병증, 당뇨병성 망막증, 당뇨병성 백내장, 당뇨병성 신경병증, 당뇨병성 족부궤양, 당뇨병성 심혈관 질환, 당뇨병성 동맥경화, 당뇨병성 골다공증, 당뇨병성 근감소증 및 비만으로 이루어진 군으로부터 선택되는 것일 수 있다.In one embodiment, the diabetic complications are diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, diabetic osteoporosis, diabetic sarcopenia. And it may be selected from the group consisting of obesity.
일 실시태양에서, 상기 퇴행성 뇌질환은 알츠하이머, 파킨슨병, 헌팅턴병, 피크병, 크로이츠펠트-야콥병, 루게릭병, 척수소뇌변성증, 프리드리히 운동실조증, 척수소뇌 실조증, 마카도-조셉병, 근육긴장이상, 진행성 핵상 마비, 인지기능장애, 노인성 치매, 루이소체 치매, 전두측두엽 치매, 혈관성 치매, 알코올성 치매, 초로기 치매, 측두엽 간질, 및 뇌졸중으로 이루어진 군으로부터 선택되는 것일 수 있다.In one embodiment, the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia, It may be selected from the group consisting of progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, early-stage dementia, temporal lobe epilepsy, and stroke.
본 발명은 신규한 인돌 유도체 또는 이의 약학적으로 허용가능한 염에 관한 것으로, 본 발명에 따른 인돌 유도체는 최종당화산물의 주요 전구체인 메틸글리옥살을 포획하는 효과 및 우수한 세포보호 효과를 나타내므로, 최종당화산물과 관련된 질환의 예방 또는 치료용 약학 조성물로 유용하게 사용될 수 있다.The present invention relates to a novel indole derivative or a pharmaceutically acceptable salt thereof. The indole derivative according to the present invention exhibits an effect of capturing methylglyoxal, a major precursor of the final glycation product, and an excellent cytoprotective effect. It can be usefully used as a pharmaceutical composition for preventing or treating diseases related to glycation products.
본 발명의 신규한 인돌 유도체는 특히 제2형 당뇨 및 그로부터 발생되는 당뇨 합병증의 예방 또는 치료에 유용하다.The novel indole derivative of the present invention is particularly useful for preventing or treating type 2 diabetes and diabetic complications resulting therefrom.
도 1 및 2는 메틸글리옥살(MGO)을 본 발명의 화합물로 처리하고 배양한 후 1일 및 7일째의 유리 메틸글리옥살(MGO) 농도를 고성능 액체크로마토그래피(HPLC)로 분석한 결과를 나타낸다. 1 and 2 show the results of analyzing the free methylglyoxal (MGO) concentration on days 1 and 7 by high-performance liquid chromatography (HPLC) after methylglyoxal (MGO) is treated with the compound of the present invention and cultured. .
도 3은 메틸글리옥살(MGO) 및 본 발명의 화합물 10을 처리한 후, N2a 세포주에서 화합물 10의 농도에 따른 세포보호 활성을 분석한 결과를 나타낸다.Figure 3 shows the results of analyzing the cytoprotective activity according to the concentration of the compound 10 in the N2a cell line after treatment with methylglyoxal (MGO) and the compound 10 of the present invention.
도 4는 메틸글리옥살(MGO) 및 본 발명의 화합물 11을 처리한 후, N2a 세포주에서 화합물 10의 농도에 따른 세포보호 활성을 분석한 결과를 나타낸다.4 shows the results of analyzing the cytoprotective activity according to the concentration of the compound 10 in the N2a cell line after treatment with methylglyoxal (MGO) and the compound 11 of the present invention.
도 5는 메틸글리옥살(MGO) 및 본 발명의 화합물 10을 처리한 후, SH-SY5Y 세포주에서 화합물 10의 농도에 따른 세포보호 활성을 분석한 결과를 나타낸다.5 shows the results of analysis of cytoprotective activity according to the concentration of compound 10 in SH-SY5Y cell line after treatment with methylglyoxal (MGO) and compound 10 of the present invention.
도 6은 메틸글리옥살(MGO) 및 본 발명의 화합물 11을 처리한 후, SH-SY5Y 세포주에서 화합물 10의 농도에 따른 세포보호 활성을 분석한 결과를 나타낸다.6 shows the results of analyzing the cytoprotective activity according to the concentration of the compound 10 in the SH-SY5Y cell line after treatment with methylglyoxal (MGO) and the compound 11 of the present invention.
도 7은 화합물 10 및 11을 전처리 군에서는 LDH 생산을 분석한 결과를 나타낸다. 7 shows the results of analyzing the LDH production in the group pretreated with compounds 10 and 11.
도 8은 화합물 10 및 11을 후처리 군에서는 LDH 생산을 분석한 결과를 나타낸다. 8 shows the results of analysis of LDH production in the post-treatment group with compounds 10 and 11.
도 9은 BrdU 1차 항체을 이용하여 본 발명의 화합물 10 및 11의 전처리 후 세포보호 활성을 분석한 결과를 나타낸다.9 shows the results of analyzing the cytoprotective activity after pretreatment of the compounds 10 and 11 of the present invention using the BrdU primary antibody.
도 10은 BrdU 1차 항체을 이용하여 본 발명의 화합물 10 및 11의 후처리후 세포보호 활성을 분석한 결과를 나타낸다.10 shows the results of analysis of cytoprotective activity after post-treatment of compounds 10 and 11 of the present invention using the BrdU primary antibody.
도 11은 유리 L-DOPA 처리로 인한 세포독성에 대해 본 발명의 화합물 10의 세포보호 활성을 분석한 결과를 나타낸다.11 shows the results of analyzing the cytoprotective activity of the compound 10 of the present invention with respect to cytotoxicity caused by free L-DOPA treatment.
도 12은 은 유리 L-DOPA 처리로 인한 세포독성에 대해 본 발명의 화합물 11의 세포보호 활성을 분석한 결과를 나타낸다.12 shows the results of analyzing the cytoprotective activity of compound 11 of the present invention with respect to cytotoxicity caused by silver-free L-DOPA treatment.
도 13은 MGO + L-DOPA 처리로 인한 세포독성에 대해 본 발명의 화합물 10의 세포보호 활성을 분석한 결과를 나타낸다.13 shows the results of analyzing the cytoprotective activity of the compound 10 of the present invention with respect to cytotoxicity caused by MGO + L-DOPA treatment.
도 14은 MGO + L-DOPA 처리로 인한 세포독성에 대해 본 발명의 화합물 11의 세포보호 활성을 분석한 결과를 나타낸다.Figure 14 shows the results of analyzing the cytoprotective activity of the compound 11 of the present invention with respect to the cytotoxicity caused by MGO + L-DOPA treatment.
도 15는 본 발명의 화합물 10 및 11의 처리 후, MGO로 유도된 염증성 사이토카인 수치를 측정한 결과를 나타낸다.15 shows the results of measuring the levels of MGO-induced inflammatory cytokines after treatment with compounds 10 and 11 of the present invention.
이하, 첨부한 도면을 참조하여 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본원의 실시태양 및 실시예를 상세히 설명한다. 그러나 본원은 여러 가지 형태로 구현될 수 있으며 여기에서 설명하는 실시태양 및 실시예에 한정되지 않는다. Hereinafter, with reference to the accompanying drawings, embodiments and examples of the present invention will be described in detail so that those of ordinary skill in the art to which the present invention pertains can easily carry out. However, the present application may be embodied in various forms and is not limited to the embodiments and examples described herein.
본원 명세서 전체에서, 어떤 부분이 어떤 구성 요소를 "포함" 한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.Throughout this specification, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.
본 발명은 하기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof.
[화학식 I][Formula I]
Figure PCTKR2020018213-appb-img-000005
Figure PCTKR2020018213-appb-img-000005
상기 식에서,In the above formula,
R 1은 수소, 할로, 알킬, 알케닐, 또는 알키닐이고,R 1 is hydrogen, halo, alkyl, alkenyl, or alkynyl,
R 2는 수소; -N(Ra)(Rb)로 치환되거나 비치환된 알킬; 또는 - N(Ra)(Rb) 또는 알킬로 치환되거나 비치환된 아릴이고,R 2 is hydrogen; -N(Ra)(Rb) unsubstituted or substituted alkyl; or - aryl unsubstituted or substituted with N(Ra)(Rb) or alkyl;
Ra 또는 Rb는 각각 독립적으로 수소 또는 알킬이고,Ra or Rb is each independently hydrogen or alkyl,
R 3은 수소; -(CH 2)n-C(Rc)(N(Rd)(Re))(COORf); 또는 -(CH 2)n-C(Rc)(N(Rd)(Re))(C(=O)Rf)이고, R 3 is hydrogen; -(CH 2 )nC(Rc)(N(Rd)(Re))(COORf); or -(CH 2 )nC(Rc)(N(Rd)(Re))(C(=O)Rf),
Rc는 수소 또는 알킬이고,Rc is hydrogen or alkyl,
Rd 또는 Re는 각각 독립적으로 수소, -C(=O)알킬 , -C(=O)알킬-O-알킬, C(=O)알킬-시클로알킬, C(=O)알킬-알케닐, -C(=O)O-알킬, 또는 -NH-알킬-NH-알킬-NH 2이고,Rd or Re are each independently hydrogen, -C(=O)alkyl , -C(=O)alkyl-O-alkyl, C(=O)alkyl-cycloalkyl, C(=O)alkyl-alkenyl, - C(=O)O-alkyl, or -NH-alkyl-NH-alkyl-NH 2 ,
Rf는 수소; 아릴기로 치환되거나 비치환된 알킬; 또는 -NH-알킬-NH-알킬-NH 2이고,Rf is hydrogen; alkyl unsubstituted or substituted with an aryl group; or —NH-alkyl-NH-alkyl-NH 2 ,
R 4는 수소, 할로, 알킬, 알케닐, 또는 알키닐이고,R 4 is hydrogen, halo, alkyl, alkenyl, or alkynyl;
R 5는 수소, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, 또는 -OC(=O)(CH 2)aS(CH2)bCH(Rg)(Rh)이고,R 5 is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or - OC(=O)(CH 2 )aS(CH2)bCH(Rg)(Rh),
Rk는 수소; 아미노기 또는 카르복실기로 치환되거나 비치환된 알킬; 또는 -CH 2NHC(=O)CH(CH 2SH)이고,Rk is hydrogen; alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH 2 NHC(=O)CH(CH 2 SH),
Rg 또는 Rh는 각각 독립적으로 수소, 알킬, 헤테로시클로알킬, -S(=O)알킬, Rg or Rh is each independently hydrogen, alkyl, heterocycloalkyl, -S(=O)alkyl,
Figure PCTKR2020018213-appb-img-000006
,
Figure PCTKR2020018213-appb-img-000007
,
Figure PCTKR2020018213-appb-img-000008
, 또는 -NH(CH 2)mNH 2이고,
Figure PCTKR2020018213-appb-img-000006
,
Figure PCTKR2020018213-appb-img-000007
,
Figure PCTKR2020018213-appb-img-000008
, or —NH(CH 2 )mNH 2 ,
R 6 또는 R 7은 각각 독립적으로 수소, 할로, 알킬, 알케닐, 알키닐, -OH 또는 -O알킬이고,R 6 or R 7 are each independently hydrogen, halo, alkyl, alkenyl, alkynyl, —OH or —Oalkyl,
a, b, n 또는 m은 1 내지 10의 정수다. a, b, n or m is an integer from 1 to 10;
바람직한 실시태양에서, In a preferred embodiment,
R 1은 수소, 또는 C 1-C 6알킬이고,R 1 is hydrogen, or C 1 -C 6 alkyl,
R 2는 수소; -N(Ra)(Rb)로 치환되거나 비치환된 C 1-C 6알킬; 또는 - N(Ra)(Rb) 또는 C 1-C 6알킬로 치환되거나 비치환된 아릴이고,R 2 is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with —N(Ra)(Rb); or - aryl unsubstituted or substituted with N(Ra)(Rb) or C 1 -C 6 alkyl,
Ra 또는 Rb는 각각 독립적으로 수소 또는 C 1-C 6알킬이고,Ra or Rb is each independently hydrogen or C 1 -C 6 alkyl,
R 3은 수소; -(CH 2)n-C(Rc)(N(Rd)(Re))(COORf); 또는 -(CH 2)n-C(Rc)(N(Rd)(Re))(C(=O)Rf)이고, R 3 is hydrogen; -(CH 2 )nC(Rc)(N(Rd)(Re))(COORf); or -(CH 2 )nC(Rc)(N(Rd)(Re))(C(=O)Rf),
Rc는 수소 또는 C 1-C 6알킬이고,Rc is hydrogen or C 1 -C 6 alkyl,
Rd 또는 Re는 각각 독립적으로 수소, -C(=O)C 1-C 6알킬 , -C(=O)C 1-C 6알킬-O-C 1-C 6알킬, -C(=O)C 1-C 6알킬-C 3-C 7시클로알킬, -C(=O)C 1-C 6알킬-C 2-C 6알케닐, -C(=O)O-C 1-C 6알킬, 또는 -NH-C 1-C 6알킬-NH-C 1-C 6알킬-NH 2이고,Rd or Re is each independently hydrogen, -C(=O)C 1 -C 6 alkyl , -C(=O)C 1 -C 6 alkyl-OC 1 -C 6 alkyl, -C(=O)C 1 -C 6 alkyl-C 3 -C 7 cycloalkyl, -C(=O)C 1 -C 6 alkyl-C 2 -C 6 alkenyl, -C(=O)OC 1 -C 6 alkyl, or -NH -C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 and
Rf는 수소; 아릴기로 치환되거나 비치환된 C 1-C 6알킬; 또는 -NH-C 1-C 6알킬-NH-C 1-C 6알킬-NH 2이고,Rf is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with an aryl group; or -NH-C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 ,
R 4는 수소 또는 C 1-C 6알킬이고,R 4 is hydrogen or C 1 -C 6 alkyl,
R 5는 수소, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, 또는 -OC(=O)(CH 2)aS(CH2)bCH(Rg)(Rh)이고,R 5 is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or - OC(=O)(CH 2 )aS(CH2)bCH(Rg)(Rh),
Rk는 수소; 아미노기 또는 카르복실기로 치환되거나 비치환된 C 1-C 6알킬; 또는 -CH 2NHC(=O)CH(CH 2SH)이고,Rk is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH 2 NHC(=O)CH(CH 2 SH),
Rg 또는 Rh는 각각 독립적으로 수소; C 1-C 6알킬; N, O, 또는 S에서 선택된 헤테로원자를 갖는 C 3-C 10헤테로시클로알킬; -S(=O)C 1-C 6알킬;
Figure PCTKR2020018213-appb-img-000009
;
Figure PCTKR2020018213-appb-img-000010
;
Figure PCTKR2020018213-appb-img-000011
; 또는 -NH(CH 2)mNH 2이고Rg or Rh are each independently hydrogen; C 1 -C 6 alkyl; C 3 -C 10 heterocycloalkyl having a heteroatom selected from N, O, or S; -S(=O)C 1 -C 6 alkyl;
Figure PCTKR2020018213-appb-img-000009
;
Figure PCTKR2020018213-appb-img-000010
;
Figure PCTKR2020018213-appb-img-000011
; or -NH(CH 2 )mNH 2 and
R 6 또는 R 7은 각각 독립적으로 수소, C 1-C 6알킬, -OH 또는 -O-C 1-C 6알킬이고,R 6 or R 7 are each independently hydrogen, C 1 -C 6 alkyl, —OH or —OC 1 -C 6 alkyl,
a, b, n 또는 m은 1 내지 5의 정수일 수 있다.a, b, n or m may be an integer from 1 to 5.
또다른 바람직한 실시태양에서, In another preferred embodiment,
R 1은 수소이고,R 1 is hydrogen,
R 2는 수소; NH 2로 치환되거나 비치환된 C 1-C 6알킬; 또는 NH 2 또는 C 1-C 6알킬로 치환되거나 비치환된 아릴이고,R 2 is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with NH 2 ; or aryl unsubstituted or substituted with NH 2 or C 1 -C 6 alkyl,
R 3은 수소; -(CH 2)n-CH(N(Rd)(Re))(COORf); 또는 -(CH 2)n-CH(N(Rd)(Re))(C(=O)Rf)이고, R 3 is hydrogen; -(CH 2 )n-CH(N(Rd)(Re))(COORf); or -(CH 2 )n-CH(N(Rd)(Re))(C(=O)Rf),
Rd 또는 Re는 각각 독립적으로 수소, -C(=O)C 1-C 6알킬 , -C(=O)C 1-C 6알킬-O-C 1-C 6알킬, -C(=O)C 1-C 6알킬-C 3-C 7시클로알킬, -C(=O)C 1-C 6알킬-C 2-C 6알케닐, -C(=O)O-C 1-C 6알킬, 또는 -NH-C 1-C 6알킬-NH-C 1-C 6알킬-NH 2이고,Rd or Re is each independently hydrogen, -C(=O)C 1 -C 6 alkyl , -C(=O)C 1 -C 6 alkyl-OC 1 -C 6 alkyl, -C(=O)C 1 -C 6 alkyl-C 3 -C 7 cycloalkyl, -C(=O)C 1 -C 6 alkyl-C 2 -C 6 alkenyl, -C(=O)OC 1 -C 6 alkyl, or -NH -C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 and
Rf는 수소; 아릴기로 치환되거나 비치환된 C 1-C 6알킬; 또는 -NH-C 1-C 6알킬-NH-C 1-C 6알킬-NH 2이고,Rf is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with an aryl group; or -NH-C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 ,
R 4는 수소 또는 C 1-C 6알킬이고,R 4 is hydrogen or C 1 -C 6 alkyl,
R 5는 수소, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, 또는
Figure PCTKR2020018213-appb-img-000012
이고,R 5 is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or
Figure PCTKR2020018213-appb-img-000012
ego,
Rk는 수소; 아미노기 또는 카르복실기로 치환되거나 비치환된 C 1-C 6알킬; 또는 -CH 2NHC(=O)CH(CH 2SH)이고,Rk is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH 2 NHC(=O)CH(CH 2 SH),
Rg 또는 Rh는 각각 독립적으로 수소; C 1-C 6알킬; S에서 선택된 헤테로원자를 갖는 C 3-C 7헤테로시클로알킬; -S(=O)C 1-C 6알킬;
Figure PCTKR2020018213-appb-img-000013
;
Figure PCTKR2020018213-appb-img-000014
;
Figure PCTKR2020018213-appb-img-000015
; 또는 -NH(CH 2)mNH 2이고Rg or Rh are each independently hydrogen; C 1 -C 6 alkyl; C 3 -C 7 heterocycloalkyl having a heteroatom selected from S; -S(=O)C 1 -C 6 alkyl;
Figure PCTKR2020018213-appb-img-000013
;
Figure PCTKR2020018213-appb-img-000014
;
Figure PCTKR2020018213-appb-img-000015
; or -NH(CH 2 )mNH 2 and
R 6 또는 R 7은 각각 독립적으로 수소, C 1-C 6알킬, -OH 또는 -O-C 1-C 6알킬이고,R 6 or R 7 are each independently hydrogen, C 1 -C 6 alkyl, —OH or —OC 1 -C 6 alkyl,
n 또는 m은 1 내지 5의 정수일 수 있다.n or m may be an integer from 1 to 5.
또다른 바람직한 실시태양에서, In another preferred embodiment,
R 1은 수소이고,R 1 is hydrogen,
R 2는 수소; -C 1-C 6알킬-NH 2; 또는 NH 2로 치환되거나 비치환된 페닐이고,R 2 is hydrogen; -C 1 -C 6 alkyl-NH 2 ; Or NH 2 substituted or unsubstituted phenyl,
R 3은 수소; -(CH 2)n-CH(N(Rd)(Re))(COORf); 또는 -(CH 2)n-CH(N(Rd)(Re))(C(=O)Rf)이고, R 3 is hydrogen; -(CH 2 )n-CH(N(Rd)(Re))(COORf); or -(CH 2 )n-CH(N(Rd)(Re))(C(=O)Rf),
Rd 또는 Re는 각각 독립적으로 수소, -C(=O)C 1-C 6알킬 , -C(=O)C 1-C 6알킬-O-C 1-C 6알킬, C(=O)C 1-C 6알킬-C 3-C 7시클로알킬, C(=O)C 1-C 6알킬-C 2-C 6알케닐, -C(=O)O-C 1-C 6알킬, 또는 -NH-C 1-C 6알킬-NH-C 1-C 6알킬-NH 2이고,Rd or Re is each independently hydrogen, -C(=O)C 1 -C 6 alkyl , -C(=O)C 1 -C 6 alkyl-OC 1 -C 6 alkyl, C(=O)C 1 - C 6 alkyl-C 3 -C 7 cycloalkyl, C(=O)C 1 -C 6 alkyl-C 2 -C 6 alkenyl, -C(=O)OC 1 -C 6 alkyl, or -NH-C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 and
Rf는 수소, C 1-C 6알킬, 벤질 또는 -NH-C 1-C 6알킬-NH-C 1-C 6알킬-NH 2이고,Rf is hydrogen, C 1 -C 6 alkyl, benzyl or —NH-C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 ,
R 4는 수소이고,R 4 is hydrogen,
R 5는 수소, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, 또는
Figure PCTKR2020018213-appb-img-000016
이고,R 5 is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or
Figure PCTKR2020018213-appb-img-000016
ego,
Rk는 수소; 아미노기 또는 카르복실기로 치환되거나 비치환된 C 1-C 6알킬; 또는 -CH 2NHC(=O)CH(CH 2SH)이고,Rk is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH 2 NHC(=O)CH(CH 2 SH),
Rg 또는 Rh는 각각 독립적으로 수소; C 1-C 6알킬; S에서 선택된 헤테로원자를 갖는 C 3-C 7헤테로시클로알킬; -S(=O)C 1-C 6알킬;
Figure PCTKR2020018213-appb-img-000017
;
Figure PCTKR2020018213-appb-img-000018
;
Figure PCTKR2020018213-appb-img-000019
; 또는 -NH(CH 2)mNH 2이고Rg or Rh are each independently hydrogen; C 1 -C 6 alkyl; C 3 -C 7 heterocycloalkyl having a heteroatom selected from S; -S(=O)C 1 -C 6 alkyl;
Figure PCTKR2020018213-appb-img-000017
;
Figure PCTKR2020018213-appb-img-000018
;
Figure PCTKR2020018213-appb-img-000019
; or -NH(CH 2 )mNH 2 and
R 6은 수소, -OH 또는 -O-C 1-C 6알킬이고R 6 is hydrogen, —OH or —OC 1 -C 6 alkyl
R 7은 수소이고,R 7 is hydrogen,
n 또는 m은 1 내지 5의 정수일 수 있다.n or m may be an integer from 1 to 5.
또다른 바람직한 실시태양에서, In another preferred embodiment,
R 1은 수소이고,R 1 is hydrogen,
R 2는 수소, -CH 2NH 2, 또는 NH 2로 치환된 페닐이고, R 2 is hydrogen, —CH 2 NH 2 , or phenyl substituted with NH 2 ,
R 3은 수소,
Figure PCTKR2020018213-appb-img-000020
,
Figure PCTKR2020018213-appb-img-000021
,
Figure PCTKR2020018213-appb-img-000022
,
Figure PCTKR2020018213-appb-img-000023
또는
Figure PCTKR2020018213-appb-img-000024
이고,R 3 is hydrogen,
Figure PCTKR2020018213-appb-img-000020
,
Figure PCTKR2020018213-appb-img-000021
,
Figure PCTKR2020018213-appb-img-000022
,
Figure PCTKR2020018213-appb-img-000023
or
Figure PCTKR2020018213-appb-img-000024
ego,
R 4는 수소이고,R 4 is hydrogen,
R 5는 수소, -OH, -OCH 3,
Figure PCTKR2020018213-appb-img-000025
,
Figure PCTKR2020018213-appb-img-000026
,
Figure PCTKR2020018213-appb-img-000027
,
Figure PCTKR2020018213-appb-img-000028
,
Figure PCTKR2020018213-appb-img-000029
,
Figure PCTKR2020018213-appb-img-000030
, 또는
Figure PCTKR2020018213-appb-img-000031
이고, R 5 is hydrogen, -OH, -OCH 3 ,
Figure PCTKR2020018213-appb-img-000025
,
Figure PCTKR2020018213-appb-img-000026
,
Figure PCTKR2020018213-appb-img-000027
,
Figure PCTKR2020018213-appb-img-000028
,
Figure PCTKR2020018213-appb-img-000029
,
Figure PCTKR2020018213-appb-img-000030
, or
Figure PCTKR2020018213-appb-img-000031
ego,
R 6은 수소, -OH, -OCH 3이고, R 6 is hydrogen, -OH, -OCH 3
R 7은 수소이고,R 7 is hydrogen,
단, R 2 및 R 3은 동시에 수소가 아닐 수 있다.However, R 2 and R 3 may not be hydrogen at the same time.
본 발명은 또한 하기 화합물로 이루어진 군으로부터 선택되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention also provides a compound selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof.
Figure PCTKR2020018213-appb-img-000032
Figure PCTKR2020018213-appb-img-000032
Figure PCTKR2020018213-appb-img-000033
Figure PCTKR2020018213-appb-img-000033
Figure PCTKR2020018213-appb-img-000034
Figure PCTKR2020018213-appb-img-000034
Figure PCTKR2020018213-appb-img-000035
Figure PCTKR2020018213-appb-img-000035
Figure PCTKR2020018213-appb-img-000036
Figure PCTKR2020018213-appb-img-000036
Figure PCTKR2020018213-appb-img-000037
Figure PCTKR2020018213-appb-img-000037
Figure PCTKR2020018213-appb-img-000038
Figure PCTKR2020018213-appb-img-000038
Figure PCTKR2020018213-appb-img-000039
Figure PCTKR2020018213-appb-img-000039
본 발명은 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 약학 조성물을 제공한다. 본 발명의 약학 조성물은 인간을 대상으로 한 의학적 용도뿐 아니라, 동물을 대상으로 한 수의학적 용도에도 적합하다. 바람직하게는 상기 동물은 포유동물이며, 반려 동물 (예를 들어, 개, 고양이, 말 등)을 포함하는 온혈동물, 및 기니 피그, 마우스, 래트, 저빌, 소, 염소, 양, 원숭이, 돼지, 설치류, 토끼류, 영장류 등을 비제한적으로 포함한다. The present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention is suitable not only for human medical use, but also for veterinary use in animals. Preferably, the animal is a mammal, warm-blooded animals including companion animals (eg, dogs, cats, horses, etc.), and guinea pigs, mice, rats, gerbils, cattle, goats, sheep, monkeys, pigs, rodents, rabbits, primates, and the like.
바람직하게는, 본 발명의 약학 조성물은 최종당화산물 관련 질환의 예방 또는 치료용으로 사용될 수 있다.Preferably, the pharmaceutical composition of the present invention can be used for the prevention or treatment of diseases related to final glycation products.
일 실시태양에서 상기 약학 조성물에 약제학적으로 허용 가능한 통상의 첨가제, 예를 들어 부형제, 결합제, 붕해제, 활택제, 가용화제, 현탁화제, 보존제 또는 증량제 등이 더 포함될 수 있다.In one embodiment, the pharmaceutical composition may further include conventional pharmaceutically acceptable additives, such as excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or extenders.
일 실시태양에서, 상기 최종당화산물 관련 질환은 노화, 당뇨병, 당뇨 합병증, 고지혈증, 고혈당증, 심혈관질환, 퇴행성 뇌질환, 자폐 스펙트럼 장애, 동맥경화, 비알코올성 지방간, 비알코올성 지방간염, 피부섬유증, 폐섬유증, 신장섬유증, 및 심장섬유증으로 이루어진 군으로부터 선택되는 것일 수 있다. 바람직하게는, 당뇨 (특히 바람직하게는 제2형 당뇨) 또는 당뇨 합병증이다.In one embodiment, the final glycation product-related disease is aging, diabetes, diabetic complications, hyperlipidemia, hyperglycemia, cardiovascular disease, degenerative brain disease, autism spectrum disorder, arteriosclerosis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, skin fibrosis, lung It may be selected from the group consisting of fibrosis, renal fibrosis, and cardiac fibrosis. Preferably, it is diabetes (particularly preferably type 2 diabetes) or a diabetic complication.
일 실시태양에서, 상기 당뇨 합병증은 당뇨병성 신장병증, 당뇨병성 망막증, 당뇨병성 백내장, 당뇨병성 신경병증, 당뇨병성 족부궤양, 당뇨병성 심혈관 질환, 당뇨병성 동맥경화, 당뇨병성 골다공증, 당뇨병성 근감소증 및 비만으로 이루어진 군으로부터 선택되는 것일 수 있다.In one embodiment, the diabetic complications are diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, diabetic osteoporosis, diabetic sarcopenia. And it may be selected from the group consisting of obesity.
일 실시태양에서, 상기 퇴행성 뇌질환은 알츠하이머, 파킨슨병, 헌팅턴병, 피크병, 크로이츠펠트-야콥병, 루게릭병, 척수소뇌변성증, 프리드리히 운동실조증, 척수소뇌 실조증, 마카도-조셉병, 근육긴장이상, 진행성 핵상 마비, 인지기능장애, 노인성 치매, 루이소체 치매, 전두측두엽 치매, 혈관성 치매, 알코올성 치매, 초로기 치매, 측두엽 간질, 및 뇌졸중으로 이루어진 군으로부터 선택되는 것일 수 있다.In one embodiment, the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia, It may be selected from the group consisting of progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, early-stage dementia, temporal lobe epilepsy, and stroke.
본 발명은 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 식품 조성물, 바람직하게는, 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물을 제공한다. The present invention provides a food composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably, a food composition for preventing or ameliorating diseases related to final glycated products.
일 실시태양에서 상기 식품 조성물은 건강기능식품, 유제품, 발효제품 또는 식품첨가물일 수 있다.In one embodiment, the food composition may be a health functional food, dairy product, fermented product or food additive.
일 실시태양에서 상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 추가로 포함할 수 있다.In one embodiment, the food composition comprises various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and It may further include salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
본 발명은 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 동물용 사료 조성물, 바람직하게는, 최종당화산물 관련 질환의 예방 또는 개선용 동물용 사료 조성물을 제공한다.The present invention provides a feed composition for animals comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, preferably, a feed composition for animals for preventing or improving diseases related to final glycated products.
일 실시태양에서 상기 동물용 사료 조성물에 하나 이상의 담체, 부형제, 희석제, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 또는 방부제 등이 더 포함될 수 있다. In one embodiment, the animal feed composition may further include one or more carriers, excipients, diluents, fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents or preservatives.
정의Justice
달리 정의되지 않는 한, 본원에서 사용되는 모든 기술용어는 본 발명이 속한 분야의 당업자가 일반적으로 이해하는 바와 동일한 의미를 갖는다. 더욱이, 본원에 기재된 수치는 명백히 언급되지 않는 한 "약"의 의미를 포함하는 것으로 간주한다. 본원에서 사용되는 잔기 및 치환기의 정의를 하기 제공한다. 달리 명시하지 않는 한, 각각의 잔기는 하기 정의를 가지며, 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다.Unless defined otherwise, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Moreover, numerical values recited herein are intended to include the meaning of “about” unless explicitly stated otherwise. Definitions of residues and substituents as used herein are provided below. Unless otherwise specified, each residue has the following definitions and is used in the sense commonly understood by one of ordinary skill in the art.
당업계에서 사용되는 관습에 따라, 본원의 화학식에 사용된 "
Figure PCTKR2020018213-appb-img-000040
"은 잔기 또는 치환기 "R"이 골격 구조에 부착되어 있는 것을 나타내는데 사용된다.In accordance with the convention used in the art, "" is used in the formulas herein.
Figure PCTKR2020018213-appb-img-000040
"A" is used to indicate that a moiety or substituent "R" is attached to the backbone structure.
본원에 사용된 "알킬"은 치환 또는 비치환된 1차, 2차, 3차 및/또는 4차 탄소 원자를 갖는 탄화수소이며, 직쇄형, 분지형, 환형, 또는 이들의 조합일 수 있는 포화 지방족기를 포함한다. 예를 들어, 알킬 기는 1 내지 20개의 탄소 원자 (즉, C 1-C 20 알킬), 1 내지 10개의 탄소 원자 (즉, C 1-C 10 알킬), 또는 1 내지 6개의 탄소 원자 (즉, C 1-C 6 알킬)를 가질 수 있다. 달리 정의되지 않는 한, 바람직한 실시양태에서, 알킬은 C 1-C 6 알킬을 지칭한다. 적합한 알킬 기의 예로는 메틸 (Me, -CH 3), 에틸 (Et, -CH 2CH 3), 1-프로필 (n-Pr, n-프로필, -CH 2CH 2CH 3), 2-프로필 (i-Pr, i-프로필, -CH(CH 3) 2), 1-부틸 (n-Bu, n-부틸, -CH 2CH 2CH 2CH 3), 2-메틸-1-프로필 (i-Bu, i-부틸, -CH 2CH(CH 3) 2), 2-부틸 (s-Bu, s-부틸, -CH(CH 3)CH 2CH 3), 2-메틸-2-프로필 (t-Bu, t-부틸, -C(CH 3) 3), 1-펜틸 (n-펜틸, -CH 2CH 2CH 2CH 2CH 3), 2-펜틸 (-CH(CH 3)CH 2CH 2CH 3), 3-펜틸 (-CH(CH 2CH 3) 2), 2-메틸-2-부틸 (-C(CH 3) 2CH 2CH 3), 3-메틸-2-부틸 (-CH(CH 3)CH(CH 3) 2), 3-메틸-1-부틸 (-CH 2CH 2CH(CH 3) 2), 2-메틸-1-부틸 (-CH 2CH(CH 3)CH 2CH 3), 1-헥실 (-CH 2CH 2CH 2CH 2CH 2CH 3), 2-헥실 (-CH(CH 3)CH 2CH 2CH 2CH 3), 3-헥실 (-CH(CH 2CH 3)(CH 2CH 2CH 3)), 2-메틸-2-펜틸 (-C(CH 3) 2CH 2CH 2CH 3), 3-메틸-2-펜틸 (-CH(CH 3)CH(CH 3)CH 2CH 3), 4-메틸-2-펜틸 (-CH(CH 3)CH 2CH(CH 3) 2), 3-메틸-3-펜틸 (-C(CH 3)(CH 2CH 3) 2), 2-메틸-3-펜틸 (-CH(CH 2CH 3)CH(CH 3) 2), 2,3-디메틸-2-부틸 (-C(CH 3) 2CH(CH 3) 2), 3,3-디메틸-2-부틸 (-CH(CH 3)C(CH 3) 3), 및 옥틸 (-(CH 2) 7CH 3)을 들 수 있으나 이에 제한되는 것은 아니다."Alkyl" as used herein is a hydrocarbon having primary, secondary, tertiary and/or quaternary carbon atoms, substituted or unsubstituted, and saturated aliphatic, which may be straight chain, branched, cyclic, or combinations thereof. includes the group. For example, an alkyl group may have 1 to 20 carbon atoms (ie, C 1 -C 20 alkyl), 1 to 10 carbon atoms (ie, C 1 -C 10 alkyl), or 1 to 6 carbon atoms (ie, C 1 -C 10 alkyl). C 1 -C 6 alkyl). Unless otherwise defined, in a preferred embodiment, alkyl refers to C 1 -C 6 alkyl. Examples of suitable alkyl groups include methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i -Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl ( t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl ( -CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 ) )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl ( -CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (- CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C (CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C( CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), and octyl (-(CH 2 ) 7 CH 3 ). may, but is not limited thereto.
더욱이, 명세서, 실시예 및 청구항 전반에 걸쳐 사용되는 용어 "알킬"은 비치환된 및 치환된 알킬 기 모두를 포함하는 것으로 의도되며, 이들 중 후자는 트리플루오로메틸 및 2,2,2-트리플루오로에틸과 같은 할로알킬 기 등을 포함하는, 탄화수소 골격의 1개 이상의 탄소 상의 수소를 대체하는 치환기를 갖는 알킬 잔기를 지칭한다. Moreover, the term “alkyl” as used throughout the specification, examples and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which are trifluoromethyl and 2,2,2-tri refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as fluoroethyl, and the like.
용어 "C x-y" 또는 "C x-C y"는, 아실, 아실옥시, 알킬, 알케닐, 알키닐 또는 알콕시와 같은 화학적 잔기와 함께 사용되는 경우, 사슬 내에 x 내지 y개의 탄소를 함유하는 기를 포함하는 것으로 여겨진다. 예를 들어, (C 1-C 6)알킬 기는 사슬 내에 1 내지 6개의 탄소 원자를 함유한다.The term "C xy " or "C x -C y ", when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, refers to a group containing x to y carbons in the chain. considered to include For example, a (C 1 -C 6 )alkyl group contains 1 to 6 carbon atoms in the chain.
"알케닐"은 1차, 2차, 3차 및/또는 4차 탄소 원자를 갖고, 직쇄형, 분지형 및 환형 기, 또는 이들의 조합을 포함하고, 1개 이상의 불포화 영역, 즉, 탄소-탄소 sp 2 이중 결합을 갖는 탄화수소이다. 예를 들어, 알케닐 기는 2 내지 20개의 탄소 원자 (즉, C 2-C 20 알케닐), 2 내지 12개의 탄소 원자 (즉, C 2-C 12 알케닐), 2 내지 10개의 탄소 원자 (즉, C 2-C 10 알케닐), 또는 2 내지 6개의 탄소 원자 (즉, C 2-C 6 알케닐)를 가질 수 있다. 적합한 알케닐 기의 예로는 비닐 (-CH=CH 2), 알릴 (-CH 2CH=CH 2), 시클로펜테닐 (-C 5H 7), 및 5-헥세닐 (-CH 2CH 2CH 2CH 2CH=CH 2)을 들 수 있으나 이에 제한되는 것은 아니다."Alkenyl" has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and includes one or more regions of unsaturation, i.e., carbon- It is a hydrocarbon with a carbon sp 2 double bond. For example, an alkenyl group has 2 to 20 carbon atoms (ie, C 2 -C 20 alkenyl), 2 to 12 carbon atoms (ie, C 2 -C 12 alkenyl), 2 to 10 carbon atoms ( ie, C 2 -C 10 alkenyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkenyl). Examples of suitable alkenyl groups include vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), cyclopentenyl (-C 5 H 7 ), and 5-hexenyl (-CH 2 CH 2 CH). 2 CH 2 CH=CH 2 ), but is not limited thereto.
"알키닐"은 1차, 2차, 3차 및/또는 4차 탄소 원자를 갖고, 직쇄형, 분지형 및 환형 기, 또는 이들의 조합을 포함하고, 1개 이상의 탄소-탄소 sp 삼중 결합을 갖는 탄화수소이다. 예를 들어, 알키닐 기는 2 내지 20개의 탄소 원자 (즉, C 2-C 20 알키닐), 2 내지 12개의 탄소 원자 (즉, C 2-C 12 알키닐), 2 내지 10개의 탄소 원자 (즉, C 2-C 10 알키닐), 또는 2 내지 6개의 탄소 원자 (즉, C 2-C 6 알키닐)를 가질 수 있다. 적합한 알키닐 기의 예로는 아세틸레닉 (-C≡CH)및 프로파르길 (-CH 2C≡CH)을 들 수 있으나 이에 제한되는 것은 아니다."Alkynyl" has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and contains one or more carbon-carbon sp triple bonds. hydrocarbons with For example, an alkynyl group has 2 to 20 carbon atoms (ie, C 2 -C 20 alkynyl), 2 to 12 carbon atoms (ie, C 2 -C 12 alkynyl), 2 to 10 carbon atoms ( ie, C 2 -C 10 alkynyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C≡CH) and propargyl (-CH 2 C≡CH).
본원에 사용된 "시클로알킬"은 치환 또는 비치환된 모노시클릭, 바이시클릭 또는 폴리시클릭일 수 있고 고리의 원자 각각이 탄소인 1가 또는 2가, 포화 또는 부분 포화 비방향족 고리를 지칭한다. 또한 "시클로알킬"은 모노시클릭일 때 3 내지 7개의 탄소 원자, 바이시클릭일 때 7 내지 12개의 탄소 원자, 및 폴리시클릭일 때 약 20개 이하의 탄소 원자를 가질 수 있다. 바이시클릭 또는 폴리시클릭 고리계는 융합, 다리, 또는 스피로 고리계일 수 있다."Cycloalkyl," as used herein, refers to a monovalent or divalent, saturated or partially saturated non-aromatic ring, which may be monocyclic, bicyclic or polycyclic, substituted or unsubstituted, and wherein each atom of the ring is carbon. . A “cycloalkyl” may also have 3 to 7 carbon atoms when monocyclic, 7 to 12 carbon atoms when bicyclic, and up to about 20 carbon atoms when polycyclic. Bicyclic or polycyclic ring systems may be fused, bridged, or spiro ring systems.
본원에 사용된 "헤테로시클로알킬"은 고리 내에 1개 이상의 헤테로원자, 바람직하게는 1 내지 4개의 헤테로원자, 보다 바람직하게는 1 내지 2개의 헤테로원자를 함유하는, 모노시클릭, 바이시클릭 또는 폴리시클릭인, 치환 또는 비치환된 1가 또는 2가, 포화 또는 부분 포화 비방향족 고리를 지칭한다. 또한 "헤테로시클로알킬"은 2개 이상의 탄소가 2개의 인접한 고리에 공통인 2개 이상의 시클릭 고리를 갖는 바이시클릭 또는 폴리시클릭 고리계일 경우, 고리 중 1개 이상은 헤테로시클릭이고, 다른 시클릭 고리는 예를 들어, 시클로알킬, 시클로알케닐, 시클로알키닐, 아릴, 헤테로아릴, 및/또는 헤테로시클로알킬일 수 있다. 바이시클릭 또는 폴리시클릭 고리계는 융합, 다리, 또는 스피로 고리계일 수 있다. "헤테로시클로알킬"은 예를 들어, 피페리딘, 피페라진, 피롤리딘, 모르폴린, 락톤, 락탐 등 (이들 각각은 치환되거나 또는 비치환된 것일 수 있음)을 포함한다.As used herein, "heterocycloalkyl" refers to monocyclic, bicyclic or containing one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms in the ring. polycyclic, substituted or unsubstituted monovalent or divalent, saturated or partially saturated non-aromatic ring. Also "heterocycloalkyl" is a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is heterocyclic, and at the other The click ring can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl. Bicyclic or polycyclic ring systems may be fused, bridged, or spiro ring systems. “Heterocycloalkyl” includes, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like, each of which may be substituted or unsubstituted.
본원에 사용된 "할로"는 할로겐을 의미하고, 클로로, 플루오로, 브로모, 및 요오도를 포함한다.As used herein, “halo” means halogen and includes chloro, fluoro, bromo, and iodo.
본원에 사용된 용어 "아릴"은 고리의 원자 각각이 탄소인, 모노시클릭, 바이시클릭 또는 폴리시클릭인, 치환 또는 비치환된 1가 또는 2가 방향족 탄화수소기를 포함한다. "아릴"은 2개 이상의 탄소가 2개의 인접한 고리에 공통인 2개 이상의 시클릭 고리를 갖는 바이시클릭 또는 폴리시클릭 고리계일 경우, 고리 중 1개 이상은 방향족이고, 다른 시클릭 고리는 예를 들어, 시클로알킬, 시클로알케닐, 시클로알키닐, 아릴, 헤테로아릴, 및/또는 헤테로시클로알킬일 수 있다. "아릴"은 예를 들어, 벤젠, 나프탈렌, 페난트렌, 안트라센, 인덴, 인단, 페놀, 아닐린 등 (이들 각각은 치환되거나 또는 비치환된 것일 수 있음)일 수 있다.As used herein, the term “aryl” includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups wherein each atom of the ring is carbon, monocyclic, bicyclic or polycyclic. "Aryl" is a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is aromatic and the other cyclic rings are, for example, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl. “Aryl” can be, for example, benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline, and the like, each of which may be substituted or unsubstituted.
본원에 사용된 용어 "Bn"은 벤질(-CH 2C 6H 5)을 지칭하고, "Boc"는 tert-부틸옥시카보닐(-C(=O)OC(CH 3) 3)을 지칭한다.As used herein, the term “Bn” refers to benzyl (—CH 2 C 6 H 5 ) and “Boc” refers to tert -butyloxycarbonyl (—C(=O)OC(CH 3 ) 3 ) .
본원에 사용된 용어 "치환된"은 1개 이상의 치환기를 갖는 본 발명의 화합물의 특정 잔기를 지칭한다. 알킬, 헤테로시클로알킬 등에 대하여 용어 "치환된", 예를 들어 "치환된 알킬" 또는 "치환된 헤테로시클로알킬"은 알킬 또는 헤테로시클로알킬의 1개 이상의 수소 원자가 각각 독립적으로 비-수소 치환기에 의해 대체된 것을 의미한다. As used herein, the term “substituted” refers to a particular moiety of a compound of the present invention having one or more substituents. The term "substituted" with respect to alkyl, heterocycloalkyl, etc., for example "substituted alkyl" or "substituted heterocycloalkyl" means that one or more hydrogen atoms of the alkyl or heterocycloalkyl are each independently replaced by a non-hydrogen substituent. meant to be replaced.
본원에 사용된 용어 "약학적으로 허용가능한 염"은 본원에서 환자의 치료에 적합한 또는 상용성이 있는 산부가염 또는 염기부가염을 지칭하는데 사용된다. 적합한 염을 형성하는 예시적 무기산으로는 염산, 브롬화수소산, 황산 및 인산, 뿐만 아니라 금속 염, 예컨대 오르토인산 일수소 나트륨 및 황산수소칼륨을 들 수 있다. 적합한 염을 형성하는 예시적 유기산으로는 모노-, 디- 및 트리카르복실산, 예컨대 글리콜산, 락트산, 피루브산, 말론산, 숙신산, 글루타르산, 푸마르산, 말산, 타르타르산, 시트르산, 아스코르브산, 말레산, 벤조산, 페닐아세트산, 신남산 및 살리실산, 뿐만 아니라 술폰산, 예컨대 p-톨루엔 술폰산 및 메탄술폰산을 들 수 있다. 일산 또는 이산 염이 형성될 수 있으며, 이러한 염은 수화, 용매화 또는 실질적으로 무수 형태로 존재할 수 있다. 일반적으로, 본 발명의 화합물의 산부가염은 이의 유리 염기 형태와 비교하여 물 및 다양한 친수성 유기 용매에 더욱 가용성이고, 일반적으로 더 높은 융점을 나타낸다. 적절한 염의 선택은 당업자에게 공지되어 있다.As used herein, the term "pharmaceutically acceptable salt" is used herein to refer to an acid or base addition salt suitable or compatible with the treatment of a patient. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di- and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid acids, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, as well as sulfonic acids such as p-toluene sulfonic acid and methanesulfonic acid. Monoacid or diacid salts may be formed, and such salts may exist in hydrated, solvated or substantially anhydrous form. In general, acid addition salts of compounds of the present invention are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base form. The selection of appropriate salts is known to those skilled in the art.
본원에 사용된 용어 "당뇨병(diabetes mellitus: DM, 또는 diabetes)"은 높은　혈당　수치가 오랜 기간 지속되는 대사 질환군을 지칭한다. 당뇨병은　췌장이 충분한　인슐린을 만들어 내지 못하거나 몸의 세포가 만들어진 인슐린에 적절하게 반응하지 못하는 것으로 인해 발생할 수 있다. 당뇨병은 크게 충분한 인슐린을 만들어내지 못하는 것에 기인하는 제1형 당뇨병, 세포가 인슐린에 적절하게 반응하지 못하는 인슐린저항으로부터 나타나는 제2형 당뇨병, 및 임신성 당뇨병으로 나뉜다. As used herein, the term “diabetes mellitus (DM, or diabetes)” refers to a group of metabolic diseases in which high blood sugar levels persist for a long time. Diabetes can be caused by the pancreas not making enough insulin or the body's cells not responding properly to the insulin made. Diabetes is largely divided into type 1 diabetes, which is caused by not producing enough insulin, type 2 diabetes, which results from insulin resistance in which cells do not respond properly to insulin, and gestational diabetes.
본원에 사용된 용어 "당뇨 합병증"은, 당뇨병이 장기간 지속되는 경우 유발되는 증상을 의미한다. "당뇨 합병증"은, 당뇨병의 발병 기준 및 판단 기준과 상이한 기준으로 평가된다.As used herein, the term “diabetic complications” refers to symptoms caused when diabetes persists for a long time. "Diabetic complications" is evaluated by criteria different from the criteria for the onset and judgment of diabetes.
본원에 사용된 용어 "자폐 스펙트럼 장애(Autism Spectrum Disorder; ASD)"는 사회적 의사소통과 상호작용이 결핍되거나 제한적이고 반복적인 패턴의 행동, 관심사 또는 활동을 특징으로 하는 신경발달 장애 계열을 포함한다. 자폐 스펙트럼 장애는 자폐증, 아스퍼거 증후군, 달리 분류되지 않는 전반적 발달 장애(PDD-NOS), 소아기 붕괴성 장애, 렛트 증후군 및 취약 X 증후군을 포함하나 이에 한정되지 않는다.As used herein, the term "Autism Spectrum Disorder (ASD)" includes a class of neurodevelopmental disorders characterized by a deficit in social communication and interaction or a restricted or repetitive pattern of behaviors, interests or activities. Autism spectrum disorders include, but are not limited to, autism, Asperger's Syndrome, Pervasive Developmental Disorder Not Elsewhere Classified (PDD-NOS), Childhood Disintegrative Disorder, Rett Syndrome, and Fragile X Syndrome.
이하 실시예를 통하여 본 발명을 더욱 상세하게 설명하고자 하나, 하기의 실시예는 단지 설명의 목적을 위한 것이며 본원 발명의 범위를 한정하고자 하는 것은 아니다.The present invention will be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
모든 출발 물질 및 시약은 상업적 공급 업체로부터 입수하였고 추가 정제없이 사용하였다. 공기 및 습기에 민감한 반응은 질소 대기 하에서 수행하였다. 표시된 용매와 함께 실리카겔 60(230-400 메쉬, Merck)을 사용하여 플래시 컬럼 크로마토그래피를 수행하였다. 0.25mm 실리카겔 플레이트(Merck)를 사용하여 박층 크로마토그래피(TLC)를 수행하였다. 1H 및 13C{ 1H} NMR 스펙트럼은 CDCl 3 또는 DMSO-d 6 중 용액으로서 Bruker 600 MHz 상에 기록되었다. 1H NMR 데이터는 화학적 이동, 다중도 (s, singlet; d, doublet; t, triplet; m, multiplet 및/또는 multiple 공명), 양성자 수 및 결합 상수( J; Hz)의 순서로 기록하였다.All starting materials and reagents were obtained from commercial suppliers and used without further purification. The reaction sensitive to air and moisture was carried out under a nitrogen atmosphere. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck) with the indicated solvents. Thin layer chromatography (TLC) was performed using a 0.25 mm silica gel plate (Merck). 1 H and 13 C{ 1 H} NMR spectra were recorded on a Bruker 600 MHz as solutions in CDCl 3 or DMSO-d 6 . 1 H NMR data were recorded in the order of chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet and/or multiple resonance), number of protons and binding constant ( J ; Hz).
[실시예 1] [Example 1]
메틸 (methyl ( SS )-2-아미노-3-(5-하이드록시-1)-2-amino-3-(5-hydroxy-1 HH -인돌-3-일)프로파노에이트(KST-11001)-Indol-3-yl)propanoate (KST-11001)
메탄올 (10 mL) 중 5-하이드록시 트립토판 (0.66 g, 3.0 mmol)의 용액을 0 °C로 냉각시켰다. 티오닐 클로라이드 (0.44 mL, 6.0 mmol)를 N 2 하에서 용액에 적가하고 40 °C에서 밤새 교반하였다. 반응 혼합물을 감압 하에서 농축시켰다. 잔류물을 에틸 아세테이트 (10 mL)에 첨가하고 상온에서 3시간 동안 교반하였다. 반응 혼합물을 셀라이트로 여과하고 감압 하에서 농축시켜, 메틸 ( S)-2-아미노-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (2) (0.70 g, 99%)를 수득하였다. A solution of 5-hydroxy tryptophan (0.66 g, 3.0 mmol) in methanol (10 mL) was cooled to 0 °C. Thionyl chloride (0.44 mL, 6.0 mmol) was added dropwise to the solution under N 2 and stirred at 40 °C overnight. The reaction mixture was concentrated under reduced pressure. The residue was added to ethyl acetate (10 mL) and stirred at room temperature for 3 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure, methyl ( S )-2-amino-3-(5-hydroxy-1 H -indol-3-yl)propanoate (2) (0.70 g, 99) %) was obtained.
1H NMR (600 MHz, DMSO-d6) δ 10.83 (d, 1H, J = 1.6 Hz), 8.66 (s, 3H), 7.15 (m, 2H), 6.78 (d, 1H, J = 2.1 Hz), 6.63 (m, 1H), 4.13 (s, 1H), 3.65 (s, 3H), 3.22 (m, 2H). 13C{ 1H} NMR (150 MHz, DMSO-d6) δ 169.8, 150.6, 130.7, 127.6, 125.4, 111.9, 111.6, 105.3, 101.9, 52.7, 52.5, 26.3. 1 H NMR (600 MHz, DMSO-d6) δ 10.83 (d, 1H, J = 1.6 Hz), 8.66 (s, 3H), 7.15 (m, 2H), 6.78 (d, 1H, J = 2.1 Hz), 6.63 (m, 1H), 4.13 (s, 1H), 3.65 (s, 3H), 3.22 (m, 2H). 13 C{ 1 H} NMR (150 MHz, DMSO-d6) δ 169.8, 150.6, 130.7, 127.6, 125.4, 111.9, 111.6, 105.3, 101.9, 52.7, 52.5, 26.3.
[실시예 2] [Example 2]
(( SS )-3-(5-하이드록시-1)-3-(5-hydroxy-1 HH -인돌-3-일)-2-(3-메틸부탄아미도)프로판산(KST-11002)-Indol-3-yl)-2-(3-methylbutanamido)propanoic acid (KST-11002)
디클로로메탄 (3 mL) 중 이소발레르산 (0.06 mL, 0.5 mmol) 및 HOBT (0.07 g, 0.5 mmol) 용액에 0 °C에서 EDCI (0.1 g, 0.5 mmol)을 첨가하고 30분 동안 교반하였다. 이후에, 5-하이드록시-트립토판 (1) (0.11 g, 0.5 mmol) 및 트리메틸 아민 (0.2 mL, 1.5 mmol)을 첨가하고, 상온에서 밤새 교반하였다. 반응 혼합물을 감압 하에서 농축시켰다. 잔류물을 실리카겔 (MeOH/CH 2Cl 2 = 1 : 20) 상에서 플래시 컬럼 크로마토그래피로 정제하여 ( S)-3-(5-하이드록시-1 H-인돌-3-일)-2-(3-메틸부탄아미도)프로판산 (0.03 g, 22%)을 수득하였다. To a solution of isovaleric acid (0.06 mL, 0.5 mmol) and HOBT (0.07 g, 0.5 mmol) in dichloromethane (3 mL) at 0 °C was added EDCI (0.1 g, 0.5 mmol) and stirred for 30 min. Then, 5-hydroxy-tryptophan (1) (0.11 g, 0.5 mmol) and trimethyl amine (0.2 mL, 1.5 mmol) were added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/CH 2 Cl 2 =1 : 20) (S )-3-(5-hydroxy-1 H -indol-3-yl)-2-(3) -Methylbutanamido)propanoic acid (0.03 g, 22%) was obtained.
1H NMR (600 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.49 (d, 1H, J = 1.8 Hz), 8.60 (s, 1H), 8.02 (d, 1H, J = 7.8 Hz), 7.11 (d, 1H, J = 8.6 Hz), 7.02 (d, 1H, J = 2.3 Hz), 6.83 (d, 1H, J = 2.2 Hz), 6.58 (m, 1H), 4.42 (m, 1H), 3.05 (m, 1H), 2.88 (m, 1H), 1.93 (m, 3H), 0.82 (d, 3H, J = 6.4 Hz), 0.78 (d, 3H, J = 6.4 Hz). 13C{1H} NMR (150 MHz, DMSO-d6) δ 173.8, 171.6, 150.3, 130.7, 127.8, 124.0, 111.7, 111.2, 109.0, 102.1, 52.6, 44.4, 27.2, 25.6, 22.3, 22.2. 1 H NMR (600 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.49 (d, 1H, J = 1.8 Hz), 8.60 (s, 1H), 8.02 (d, 1H, J = 7.8 Hz), 7.11 (d, 1H, J = 8.6 Hz), 7.02 (d, 1H, J = 2.3 Hz), 6.83 (d, 1H, J = 2.2 Hz), 6.58 (m, 1H), 4.42 (m, 1H), 3.05 (m, 1H), 2.88 (m, 1H), 1.93 (m, 3H), 0.82 (d, 3H, J = 6.4 Hz), 0.78 (d, 3H, J = 6.4 Hz). 13 C{1H} NMR (150 MHz, DMSO-d6) δ 173.8, 171.6, 150.3, 130.7, 127.8, 124.0, 111.7, 111.2, 109.0, 102.1, 52.6, 44.4, 27.2, 25.6, 22.3, 22.2.
[실시예 3] [Example 3]
메틸 (methyl ( SS )-2-(3-에톡시프로판아미도)-3-(5-하이드록시-1)-2-(3-ethoxypropanamido)-3-(5-hydroxy-1 HH -인돌-3-일)프로파노에이트 (KST-11003)-Indol-3-yl)propanoate (KST-11003)
THF (1.5 mL) 중 메틸 ( S)-2-아미노-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.07 g, 0.3 mmol), 3-에톡시프로판산 (0.037 mL, 0.33 mmol) 및 HBTU (0.13 g, 0.33 mmol)의 용액에 0 °C에서 DIPEA (0.16 mL, 0.9 mmol)을 첨가하였다. 생성된 혼합물을 상온에서 밤새 교반하였다. 용매를 감압 하에서 제거하였고, 잔류물을 에틸 아세테이트 (10 mL)로 희석하고, 물로 세척하였다. 유기층을 무수 Na 2SO 4로 건조하고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (MeOH/CH 2Cl 2 = 1 : 50) 상에서 플래시 컬럼 크로마토그래피로 정제시켜 목적 화합물 (0.05 g, 47%)을 수득하였다. Methyl ( S )-2-amino-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.07 g, 0.3 mmol), 3-ethoxypropanoic acid ( To a solution of 0.037 mL, 0.33 mmol) and HBTU (0.13 g, 0.33 mmol) at 0 °C was added DIPEA (0.16 mL, 0.9 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/CH 2 Cl 2 =1 : 50) to give the title compound (0.05 g, 47%).
1H NMR (600 MHz, CDCl 3) δ 7.89 (s, 1H), 7.19 (d, 1H, J = 8.7 Hz), 7.03 (d, 1H, J = 2.3 Hz), 6.90 (d, 1H, J = 2.3 Hz), 6.78 (m, 1H), 6.54 (d, 1H, J = 7.8 Hz), 6.02 (s, 1H), 5.00 (m, 1H), 3.83 (m, 1H), 3.70 (m, 4H), 3.55 (m, 2H), 3.39 (m, 1H), 3.22 (m, 1H), 2.44 (m, 2H), 1.19 (t, 3H, J = 7.0 Hz). 13C{ 1H} NMR (150 MHz, CDCl 3) δ 172.2, 170.7, 150.4, 131.2, 128.9, 123.5, 112.2, 112.0, 109.9, 103.9, 67.1, 66.2, 53.7, 52.4, 36.8, 27.9, 15.0. 1 H NMR (600 MHz, CDCl 3 ) δ 7.89 (s, 1H), 7.19 (d, 1H, J = 8.7 Hz), 7.03 (d, 1H, J = 2.3 Hz), 6.90 (d, 1H, J = 2.3 Hz), 6.78 (m, 1H), 6.54 (d, 1H, J = 7.8 Hz), 6.02 (s, 1H), 5.00 (m, 1H), 3.83 (m, 1H), 3.70 (m, 4H) , 3.55 (m, 2H), 3.39 (m, 1H), 3.22 (m, 1H), 2.44 (m, 2H), 1.19 (t, 3H, J = 7.0 Hz). 13 C{ 1 H} NMR (150 MHz, CDCl 3 ) δ 172.2, 170.7, 150.4, 131.2, 128.9, 123.5, 112.2, 112.0, 109.9, 103.9, 67.1, 66.2, 53.7, 52.4, 36.8, 27.9, 15.0.
[실시예 4] [Example 4]
메틸 (methyl ( SS )-2-(2-시클로펜틸아세트아미도)-3-(5-하이드록시-1)-2-(2-cyclopentylacetamido)-3-(5-hydroxy-1 HH -인돌-3-일)프로파노에이트 (KST-11004)-Indol-3-yl)propanoate (KST-11004)
드라이 DMF/CH 2Cl 2 (1/6, 1 mL) 중 메틸 ( S)-2-아미노-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.06 g, 0.25 mmol), 시클로펜틸 아세트산 (0.03 mL, 0.28 mmol) 및 HBTU (0.10 g, 0.28 mmol)의 용액에 0 °C에서 DIPEA (0.13 mL, 0.75 mmol)을 첨가하였다. 생성된 혼합물을 상온에서 밤새 교반하였다. 용매를 감압 하에서 제거하였고, 잔류물을 에틸 아세테이트 (10 mL)로 희석하고, 물로 세척하였다. 유기층을 무수 Na 2SO 4로 건조하고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (EtOAc/Hexane = 1 : 1) 상에서 플래시 컬럼 크로마토그래피로 정제시켜 메틸 ( S)-2-(2-시클로펜틸아세트아미도)-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.06 g, 64%)를 수득하였다. Methyl (S )-2-amino-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.06 g, 0.25) in dry DMF/CH 2 Cl 2 (1/6, 1 mL) mmol), cyclopentyl acetic acid (0.03 mL, 0.28 mmol) and HBTU (0.10 g, 0.28 mmol) at 0 °C was added DIPEA (0.13 mL, 0.75 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1:1) to methyl ( S )-2-(2-cyclopentylacetamido)-3-(5-hydroxy- 1H -indole) -3-yl)propanoate (0.06 g, 64%) was obtained.
1H NMR (600 MHz, CDCl 3) δ 8.01 (s, 1H), 7.20 (d, 1H, J = 8.6 Hz), 6.99 (d, 1H, J = 2.3 Hz), 6.93 (d, 1H, J = 2.4 Hz), 6.79 (m, 1H), 6.03 (d, 1H, J = 7.7 Hz), 5.69 (s, 1H), 4.95 (m, 1H), 3.70 (s, 3H), 3.24 (m, 2H), 2.18 (m, 3H), 1.74 (m, 2H), 1.57 (m, 2H), 1.49 (m, 2H), 1.07 (m, 2H). 13C{ 1H} NMR (150 MHz, CDCl 3) δ 172.9, 172.8, 150.3, 131.4, 128.6, 123.7, 112.4, 112.0, 109.7, 103.1, 60.6, 52.5, 42.9, 37.1, 32.7, 32.6, 28.0, 25.1, 14.3. 1 H NMR (600 MHz, CDCl 3 ) δ 8.01 (s, 1H), 7.20 (d, 1H, J = 8.6 Hz), 6.99 (d, 1H, J = 2.3 Hz), 6.93 (d, 1H, J = 2.4 Hz), 6.79 (m, 1H), 6.03 (d, 1H, J = 7.7 Hz), 5.69 (s, 1H), 4.95 (m, 1H), 3.70 (s, 3H), 3.24 (m, 2H) , 2.18 (m, 3H), 1.74 (m, 2H), 1.57 (m, 2H), 1.49 (m, 2H), 1.07 (m, 2H). 13 C{ 1 H} NMR (150 MHz, CDCl 3 ) δ 172.9, 172.8, 150.3, 131.4, 128.6, 123.7, 112.4, 112.0, 109.7, 103.1, 60.6, 52.5, 42.9, 37.1, 32.7, 32.6, 28.0, 25.1 , 14.3.
[실시예 5] [Example 5]
메틸 (methyl ( SS )-2-부티르아미도-3-(5-하이드록시-1)-2-butyramido-3-(5-hydroxy-1 HH -인돌-3-일)프로파노에이트 (KST-11005)-Indol-3-yl)propanoate (KST-11005)
드라이 DMF/CH 2Cl 2 (1/6, 1 mL) 중 메틸 ( S)-2-아미노-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.06 g, 0.25 mmol), 부티르산 (0.03 mL, 0.28 mmol) 및 HBTU (0.10 g, 0.28 mmol)의 용액에 0 °C에서 DIPEA (0.13 mL, 0.75 mmol)을 첨가하였다. 생성된 혼합물을 상온에서 밤새 교반하였다. 용매를 감압 하에서 제거하였고, 잔류물을 에틸 아세테이트 (10 mL)로 희석하고, 물로 세척하였다. 유기층을 무수 Na 2SO 4로 건조하고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (EtOAc/Hexane = 1 : 1) 상에서 플래시 컬럼 크로마토그래피로 정제시켜 메틸 ( S)-2-부티르아미도-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.05 g, 62%)를 수득하였다. Methyl (S )-2-amino-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.06 g, 0.25) in dry DMF/CH 2 Cl 2 (1/6, 1 mL) mmol), butyric acid (0.03 mL, 0.28 mmol) and HBTU (0.10 g, 0.28 mmol) at 0 °C was added DIPEA (0.13 mL, 0.75 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1:1) to methyl ( S )-2-butyramido-3-(5-hydroxy-1 H -indol-3-yl) Propanoate (0.05 g, 62%) was obtained.
1H NMR (600 MHz, CDCl 3) δ 8.01 (s, 1H), 7.20 (d, 1H, J = 8.6 Hz), 6.97 (d, 1H, J = 2.4 Hz), 6.93 (d, 1H, J = 2.4 Hz), 6.79 (m, 1H), 6.02 (d, 1H, J = 7.7 Hz), 5.59 (s, 1H), 4.95 (m, 1H), 3.70 (s, 3H), 3.24 (m, 2H), 2.15 (m, 2H), 1.62 (m, 2H), 0.89 (t, 3H, J = 7.4 Hz). 13C{ 1H} NMR (150 MHz, CDCl 3) δ 173.1, 172.7, 150.2, 131.4, 128.7, 123.7, 112.4, 112.0, 109.7, 103.1, 60.6, 52.5, 38.6, 27.9, 19.1, 13.8. 1 H NMR (600 MHz, CDCl 3 ) δ 8.01 (s, 1H), 7.20 (d, 1H, J = 8.6 Hz), 6.97 (d, 1H, J = 2.4 Hz), 6.93 (d, 1H, J = 2.4 Hz), 6.79 (m, 1H), 6.02 (d, 1H, J = 7.7 Hz), 5.59 (s, 1H), 4.95 (m, 1H), 3.70 (s, 3H), 3.24 (m, 2H) , 2.15 (m, 2H), 1.62 (m, 2H), 0.89 (t, 3H, J = 7.4 Hz). 13 C{ 1 H} NMR (150 MHz, CDCl 3 ) δ 173.1, 172.7, 150.2, 131.4, 128.7, 123.7, 112.4, 112.0, 109.7, 103.1, 60.6, 52.5, 38.6, 27.9, 19.1, 13.8.
[실시예 6] [Example 6]
메틸 (methyl ( SS )-2-헥산아미도-3-(5-하이드록시-1)-2-hexanamido-3-(5-hydroxy-1 HH -인돌-3-일)프로파노에이트 (KST-11006)-Indol-3-yl)propanoate (KST-11006)
드라이 DMF/CH 2Cl 2 (1/6, 1 mL) 중 메틸 ( S)-2-아미노-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.06 g, 0.25 mmol), 헥산산 (0.03 mL, 0.28 mmol) 및 HBTU (0.10 g, 0.28 mmol)의 용액에 0 °C에서 DIPEA (0.13 mL, 0.75 mmol)을 첨가하였다. 생성된 혼합물을 상온에서 밤새 교반하였다. 용매를 감압 하에서 제거하였고, 잔류물을 에틸 아세테이트 (10 mL)로 희석하고, 물로 세척하였다. 유기층을 무수 Na 2SO 4로 건조하고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (EtOAc/Hexane = 1 : 1) 상에서 플래시 컬럼 크로마토그래피로 정제시켜 메틸 ( S)-2-헥산아미도-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.08 g, 99%)를 수득하였다. Methyl (S )-2-amino-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.06 g, 0.25) in dry DMF/CH 2 Cl 2 (1/6, 1 mL) mmol), hexanoic acid (0.03 mL, 0.28 mmol) and HBTU (0.10 g, 0.28 mmol) at 0 °C was added DIPEA (0.13 mL, 0.75 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1:1) to methyl ( S )-2-hexanamido-3-(5-hydroxy- 1H -indol-3-yl)pro Fanoate (0.08 g, 99%) was obtained.
1H NMR (600 MHz, CDCl 3) δ 8.32 (s, 1H), 7.14 (d, 1H, J = 8.6 Hz), 6.98 (s, 1H), 6.94 (s, 1H), 6.87 (s, 1H), 6.78 (d, 1H, J = 8.6 Hz), 6.21 (d, 1H, J = 7.7 Hz), 4.92 (m, 1H), 3.20 (m, 2H), 2.14 (m, 2H), 1.53 (m, 2H), 1.18 (m, 4H), 0.80 (t, 3H, J = 7.0 Hz). 13C{ 1H} NMR (150 MHz, CDCl 3) δ 173.8, 172.9, 150.5, 131.3, 128.5, 123.8, 112.4, 112.1, 109.2, 102.9, 60.6, 52.5, 36.6, 31.4, 27.8, 25.3, 22.4, 14.0. 1 H NMR (600 MHz, CDCl 3 ) δ 8.32 (s, 1H), 7.14 (d, 1H, J = 8.6 Hz), 6.98 (s, 1H), 6.94 (s, 1H), 6.87 (s, 1H) , 6.78 (d, 1H, J = 8.6 Hz), 6.21 (d, 1H, J = 7.7 Hz), 4.92 (m, 1H), 3.20 (m, 2H), 2.14 (m, 2H), 1.53 (m, 2H), 1.18 (m, 4H), 0.80 (t, 3H, J = 7.0 Hz). 13 C{ 1 H} NMR (150 MHz, CDCl 3 ) δ 173.8, 172.9, 150.5, 131.3, 128.5, 123.8, 112.4, 112.1, 109.2, 102.9, 60.6, 52.5, 36.6, 31.4, 27.8, 25.3, 22.4, 14.0 .
[실시예 7] [Example 7]
메틸 (methyl ( SS )-2-(부트-3-엔아미도)-3-(5-하이드록시-1)-2-(but-3-enamido)-3-(5-hydroxy-1 HH -인돌-3-일)프로파노에이트 (KST-11007)-Indol-3-yl)propanoate (KST-11007)
드라이 DMF/CH 2Cl 2 (1/6, 1 mL) 중 메틸 ( S)-2-아미노-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.06 g, 0.25 mmol), 3-부텐산 (0.02 mL, 0.28 mmol) 및 HBTU (0.10 g, 0.28 mmol)의 용액에 0 °C에서 DIPEA (0.13 mL, 0.75 mmol)을 첨가하였다. 생성된 혼합물을 상온에서 밤새 교반하였다. 용매를 감압 하에서 제거하였고, 잔류물을 에틸 아세테이트 (10 mL)로 희석하고, 물로 세척하였다. 유기층을 무수 Na 2SO 4로 건조하고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (EtOAc/Hexane = 1 : 1) 상에서 플래시 컬럼 크로마토그래피로 정제시켜 메틸 ( S)-2-(부트-3-엔아미도)-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.05 g, 66%)를 수득하였다. Methyl (S )-2-amino-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.06 g, 0.25) in dry DMF/CH 2 Cl 2 (1/6, 1 mL) mmol), 3-butenoic acid (0.02 mL, 0.28 mmol) and HBTU (0.10 g, 0.28 mmol) at 0 °C was added DIPEA (0.13 mL, 0.75 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1:1) to methyl ( S )-2-(but-3-enamido)-3-(5-hydroxy-1 H -indole) -3-yl)propanoate (0.05 g, 66%) was obtained.
1H NMR (600 MHz, CDCl 3) δ 7.95 (s, 1H), 7.21 (d, 1H, J = 8.6 Hz), 6.93 (m, 1H), 6.78 (m, 1H), 6.15 (d, 1H, J = 7.5 Hz), 5.84 (m, 1H), 5.15 (m, 2H), 5.06 (s, 1H), 4.92 (m, 1H), 3.70 (d, 3H, J = 5.1 Hz), 3.28 (m, 1H), 3.23 (m, 1H), 2.99 (m, 2H). 13C{ 1H} NMR (150 MHz, CDCl 3) δ 172.4, 170.5, 150.0, 131.0, 128.7, 123.8, 120.2, 112.3, 112.0, 109.7, 103.3, 53.2, 52.6, 41.6, 27.8, 21.2. 1 H NMR (600 MHz, CDCl 3 ) δ 7.95 (s, 1H), 7.21 (d, 1H, J = 8.6 Hz), 6.93 (m, 1H), 6.78 (m, 1H), 6.15 (d, 1H, J = 7.5 Hz), 5.84 (m, 1H), 5.15 (m, 2H), 5.06 (s, 1H), 4.92 (m, 1H), 3.70 (d, 3H, J = 5.1 Hz), 3.28 (m, 1H), 3.23 (m, 1H), 2.99 (m, 2H). 13 C{ 1 H} NMR (150 MHz, CDCl 3 ) δ 172.4, 170.5, 150.0, 131.0, 128.7, 123.8, 120.2, 112.3, 112.0, 109.7, 103.3, 53.2, 52.6, 41.6, 27.8, 21.2.
[실시예 8] [Example 8]
2-아미노-3-(5-((부틸카바모일)옥시)-12-Amino-3-(5-((butylcarbamoyl)oxy)-1 HH -인돌-3-일)프로판산 (KST-11008)-Indol-3-yl)propanoic acid (KST-11008)
CH 2Cl 2 중 2-((((9 H-플루오렌-9-일)메톡시)카르보닐)아미노)-3-(5-하이드록시-1 H-인돌-3-일)프로판산 (0.09 g, 0.20 mmol)의 용액에 0 °C에서 메탄올 (1 mL) 중 부틸 이소시아네이트 (0.02 mL, 0.22 mmol) 및 TEA (0.08 mL, 0.60 mmol)를 적가하였다. 생성된 혼합물을 상온에서 밤새 교반하였다. 용매를 감압 하에서 제거하였고, C18 역상 컬럼 크로마토그래피 (용출액으로서 H 2O/MeOH)로 정제시켜 2-((((9 H-플루오렌-9-일)메톡시)카르보닐)아미노)-3-(5-((부틸카바모일)옥시)-1 H-인돌-3-일)프로판산 (22 mg, 20%)을 수득하였다. 프로판산 (0.01 g, 0.02 mmol)을 DMF (0.5 mL) 중 20% 피페리딘에 용해시켰다. 그 후 혼합물을 20분 동안 교반하고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (MeOH/CH 2Cl 2/TFA = 1 : 7 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제시켜 2-아미노-3-(5-((부틸카바모일)옥시)-1 H-인돌-3-일)프로판산(5.5 mg, 71%)을 수득하였다. 2-((((9 H -fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanoic acid in CH 2 Cl 2 ( 0.09 g, 0.20 mmol) was added dropwise butyl isocyanate (0.02 mL, 0.22 mmol) and TEA (0.08 mL, 0.60 mmol) in methanol (1 mL) at 0 °C. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and purified by C18 reverse phase column chromatography (H 2 O/MeOH as eluent) to 2-((((9 H -fluoren-9-yl)methoxy)carbonyl)amino)-3 - (5 - ((butyl-carbamoyl) oxy) -1 H-indol-3-yl) propanoic acid (22 mg, 20%) was obtained. Proanoic acid (0.01 g, 0.02 mmol) was dissolved in 20% piperidine in DMF (0.5 mL). The mixture was then stirred for 20 min and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/CH 2 Cl 2 / TFA = 1 : 7 : 0.1) to 2-amino-3-(5-((butylcarbamoyl)oxy)-1 H -indole -3-yl)propanoic acid (5.5 mg, 71%) was obtained.
1H NMR (600 MHz, DMSO- d6) δ 13.87 (s, 1H), 11.09 (s, 1H), 8.19 (s, 2H), 7.58 (t, 1H, J = 5.7 Hz), 7.32 (d, 1H, J = 8.7 Hz), 7.25 (s, 1H), 6.81 (dd, 1H, J = 8.7, 2.2 Hz), 4.13 (d, 1H, J = 5.0 Hz), 3.20 (m, 2H), 3.06 (m, 2H), 1.46 (m, 2H), 1.33 (m, 2H), 0.90 (t, 3H, J = 7.3 Hz). 1 H NMR (600 MHz, DMSO- d6 ) δ 13.87 (s, 1H), 11.09 (s, 1H), 8.19 (s, 2H), 7.58 (t, 1H, J = 5.7 Hz), 7.32 (d, 1H) , J = 8.7 Hz), 7.25 (s, 1H), 6.81 (dd, 1H, J = 8.7, 2.2 Hz), 4.13 (d, 1H, J = 5.0 Hz), 3.20 (m, 2H), 3.06 (m) , 2H), 1.46 (m, 2H), 1.33 (m, 2H), 0.90 (t, 3H, J = 7.3 Hz).
[실시예 9] [Example 9]
(( SS )-1-(벤질옥시)-3-(5-(부티릴옥시)-1)-1-(benzyloxy)-3-(5-(butyryloxy)-1 HH -인돌-3-일)-1-옥소프로판-2-아미늄 2,2,2-트리플루오로아세테이트 (KST-11009)-Indol-3-yl)-1-oxopropane-2-aminium 2,2,2-trifluoroacetate (KST-11009)
벤질 ( S)-2-(( tert-부톡시카르보닐)아미노)-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.08 g, 0.20 mmol)의 디클로로메탄 용액 (1 mL)에 부티르산 (0.02 mL, 0.23 mmol), EDCI (0.06 g, 0.29 mmol) 및 DMAP (2.3 mg, 0.02 mmol)를 첨가하였다. 17시간 동안 교반한 후, 반응 혼합물을 디클로로메탄으로 희석하고 물 및 염수로 세척한 후, MgSO 4로 건조시키고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (EtOAc/Hexane = 1 : 2) 상에서 플래시 컬럼 크로마토그래피로 정제하여 ( S)-3-(3-(벤질옥시)-2-(( tert-부톡시카르보닐)아미노)-3-옥소프로필)-1 H-인돌-5-일 부티레이트 (0.08 g, 81%)를 수득하였다. 인돌-5-일 부티레이트 (0.02 g, 0.03 mmol)의 CH 2Cl 2 용액 (2 mL)에 0 °C에서 TFA (0.5 mL)를 첨가하였다. 실온에서 2.5시간 동안 교반한 후에, 반응 혼합물을 감압 하에서 농축시켜 ( S)-1-(벤질옥시)-3-(5-(부티릴옥시)-1 H-인돌-3-일)-1-옥소프로판-2-아미늄 2,2,2-트리플루오로아세테이트 (0.05 g, quantitative)를 수득하였다. A dichloromethane solution of benzyl ( S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy- 1H -indol-3-yl)propanoate (0.08 g, 0.20 mmol) in dichloromethane To (1 mL) was added butyric acid (0.02 mL, 0.23 mmol), EDCI (0.06 g, 0.29 mmol) and DMAP (2.3 mg, 0.02 mmol). After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine , dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1 : 2) to ( S )-3-(3-(benzyloxy)-2-(( tert -butoxycarbonyl)amino)-3 - to give the indol-5-yl butyrate (0.08 g, 81%) - oxopropyl) -1 H. To a CH 2 Cl 2 solution (2 mL) of indol-5-yl butyrate (0.02 g, 0.03 mmol) at 0 °C was added TFA (0.5 mL). After stirring for 2.5 hours at room temperature, The reaction mixture was concentrated under reduced pressure to give (S) -1- (benzyloxy) -3- (5- (butyryl-oxy) -1 H - indol-3-yl) -1 Oxopropane-2-aminium 2,2,2-trifluoroacetate (0.05 g, quantitative) was obtained.
1H NMR (600 MHz, CDCl 3) δ 8.09 (bs, 1H), 7.34 (m, 3H), 7.28 (m, 3H), 7.22 (d, 1H, J = 1.8 Hz), 6.90 (d, 1H, J = 9 Hz), 6.80 (s, 1H), 5.12 (m, 3H), 4.68 (d, 1H, J = 7.8 Hz), 3.25 (d, 2H, J = 5.4 Hz), 2.56 (t, 2H, J = 7.8 Hz), 1.82 (q, 2H, J = 7.2 Hz), 1.42 (s, 9H), 1.08 (t, 3H, J = 7.8 Hz); 13C{ 1H} NMR (150 MHz, CDCl 3) δ 173.0, 172.0, 155.2, 144.4, 135.4, 133.9, 128.5, 128.4, 128.3, 128.1, 124.2, 116.5, 111.6, 110.9, 110.4, 79.9, 67.1, 54.3, 36.3, 28.3, 28.0, 18.6, 13.8. 1 H NMR (600 MHz, CDCl 3 ) δ 8.09 (bs, 1H), 7.34 (m, 3H), 7.28 (m, 3H), 7.22 (d, 1H, J = 1.8 Hz), 6.90 (d, 1H, J = 9 Hz), 6.80 (s, 1H), 5.12 (m, 3H), 4.68 (d, 1H, J = 7.8 Hz), 3.25 (d, 2H, J = 5.4 Hz), 2.56 (t, 2H, J = 7.8 Hz), 1.82 (q, 2H, J = 7.2 Hz), 1.42 (s, 9H), 1.08 (t, 3H, J = 7.8 Hz); 13 C{ 1 H} NMR (150 MHz, CDCl 3 ) δ 173.0, 172.0, 155.2, 144.4, 135.4, 133.9, 128.5, 128.4, 128.3, 128.1, 124.2, 116.5, 111.6, 110.9, 110.4, 79.9, 67.1, 54.3 , 36.3, 28.3, 28.0, 18.6, 13.8.
[실시예 10] [Example 10]
(( SS )-2-(5-(부티릴옥시)-1)-2-(5-(butyryloxy)-1 HH -인돌-3-일)-1-카르복시에탄-1-아미늄 2,2,2-트리플루오로아세테이트 (KST-11010)-Indol-3-yl)-1-carboxyethane-1-aminium 2,2,2-trifluoroacetate (KST-11010)
( S)-2-(( tert-부톡시카르보닐)아미노)-3-(5-(부티릴옥시)-1 H-인돌-3-일)프로판산 (0.02 g, 0.05 mmol)의 CH 2Cl 2 용액 (2 mL)에 0 °C에서 TFA (0.5 mL)를 첨가하였다. 실온에서 2.5시간 동안 교반한 후에, 반응 혼합물을 감압 하에서 농축시켜 ( S)-2-(5-(부티릴옥시)-1 H-인돌-3-일)-1-카르복시에탄-1-아미늄 2,2,2-트리플루오로아세테이트 (20 mg, quantitative)를 수득하였다. (S) -2 - ((tert - butoxycarbonyl) amino) - CH 2 of the (indol-3-yl 5- (butyryl-oxy) -1 H) propanoic acid (0.02 g, 0.05 mmol), 3- To a Cl 2 solution (2 mL) at 0 °C was added TFA (0.5 mL). After stirring for 2.5 hours at room temperature, The reaction mixture was concentrated under reduced pressure to give (S) -2- (5- (butyryl-oxy) -1 H - indol-3-yl) -1-carboxy-1-aminium ethane 2,2,2-trifluoroacetate (20 mg, quantitative) was obtained.
1H NMR (600 MHz, DMSO- d6) δ 11.18 (d, 1H, J = 1.8 Hz), 8.24 (s, 3H), 7.37 (d, 1H, J = 8.7 Hz), 7.28 (m, 2H), 6.83 (m, 1H), 5.75 (s, 2H), 4.13 (d, 1H, J = 5.0 Hz), 3.21 (m, 2H), 2.55 (t, 2H, J = 7.3 Hz), 1.68 (m, 2H), 0.99 (t, 3H, J = 7.4 Hz). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 172.4, 170.9, 143.6, 134.1, 127.2, 126.5, 115.8, 111.9, 110.4, 107.1, 54.9, 52.6, 35.4, 26.1, 18.1, 13.5. 1 H NMR (600 MHz, DMSO- d6 ) δ 11.18 (d, 1H, J = 1.8 Hz), 8.24 (s, 3H), 7.37 (d, 1H, J = 8.7 Hz), 7.28 (m, 2H), 6.83 (m, 1H), 5.75 (s, 2H), 4.13 (d, 1H, J = 5.0 Hz), 3.21 (m, 2H), 2.55 (t, 2H, J = 7.3 Hz), 1.68 (m, 2H) ), 0.99 (t, 3H, J = 7.4 Hz). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 172.4, 170.9, 143.6, 134.1, 127.2, 126.5, 115.8, 111.9, 110.4, 107.1, 54.9, 52.6, 35.4, 26.1, 18.1, 13.5.
[실시예 11] [Example 11]
(( SS )-1-(벤질옥시)-3-(5-(부티릴옥시)-1)-1-(benzyloxy)-3-(5-(butyryloxy)-1 HH -인돌-3-일)-1-옥소프로판-2-아미늄 2,2,2-트리플루오로아세테이트 (KST-11011)-Indol-3-yl)-1-oxopropane-2-aminium 2,2,2-trifluoroacetate (KST-11011)
( S)-3-(2-(( tert-부톡시카르보닐)아미노)-3-메톡시-3-옥소프로필)-1 H-인돌-5-일 부티레이트 (0.04 g, 0.09 mmol)의 CH 2Cl 2 용액 (2 mL)에 0 °C에서 TFA (0.5 mL)를 첨가하였다. 실온에서 2.5시간 동안 교반한 후에, 반응 혼합물을 감압 하에서 농축시켜 목적 화합물 (48 mg, quantitative)을 수득하였다. (S) 3-CH of indol-5-yl butyrate (0.04 g, 0.09 mmol) - (2 - ((tert - butoxycarbonyl) amino) -3-methoxy-3-oxopropyl) -1 H To a 2 Cl 2 solution (2 mL) at 0 °C was added TFA (0.5 mL). After stirring at room temperature for 2.5 hours, the reaction mixture was concentrated under reduced pressure to give the title compound (48 mg, quantitative).
1H NMR (600 MHz, DMSO- d6) δ 11.22 (s, 1H), 8.47 (s, 3H), 7.37 (d, 1H, J = 8.6 Hz), 7.26 (d, 1H, J = 21.9 Hz), 7.19 (s, 1H), 6.83 (m, 1H), 4.26 (s, 1H), 3.66 (s, 3H), 3.23 (m, 2H), 2.55 (t, 2H, J = 7.2 Hz), 1.68 (m, 2H), 0.99 (t, 3H, J = 7.4 Hz). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 172.4, 169.8, 143.6, 134.1, 127.0, 126.5, 115.7, 112.0, 110.2, 106.6, 52.6, 35.4, 26.1, 18.0, 13.4. 1 H NMR (600 MHz, DMSO- d6 ) δ 11.22 (s, 1H), 8.47 (s, 3H), 7.37 (d, 1H, J = 8.6 Hz), 7.26 (d, 1H, J = 21.9 Hz), 7.19 (s, 1H), 6.83 (m, 1H), 4.26 (s, 1H), 3.66 (s, 3H), 3.23 (m, 2H), 2.55 (t, 2H, J = 7.2 Hz), 1.68 (m) , 2H), 0.99 (t, 3H, J = 7.4 Hz). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 172.4, 169.8, 143.6, 134.1, 127.0, 126.5, 115.7, 112.0, 110.2, 106.6, 52.6, 35.4, 26.1, 18.0, 13.4.
[실시예 12] [Example 12]
(2(2 SS )-3-(5-((5-(1,2-디티올란-3-일)펜타노일)옥시)-1)-3-(5-((5-(1,2-dithiolan-3-yl)pentanoyl)oxy)-1 HH -인돌-3-일)-1-(벤질옥시)-1-옥소프로판-2-아미늄 클로라이드 (KST-11012)-Indol-3-yl)-1-(benzyloxy)-1-oxopropane-2-aminium chloride (KST-11012)
디클로로메탄 (1 mL) 중 벤질 ( S)-2-(( tert-부톡시카르보닐)아미노)-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.10 g, 0.24 mmol)의 용액에 α- D,L-리포산 (0.06 g, 0.29 mmol), EDCI (0.07 g, 0.36 mmol) 및 DMAP (2 mg, 0.01 mmol)을 첨가하였다. 17시간 동안 교반한 후에, 반응 혼합물을 디클로로메탄으로 희석하고 물 및 염수로 세척한 후, MgSO 4로 건조시키고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (EtOAc/Hexane = 1 : 2) 상에서 플래시 컬럼 크로마토그래피로 정제하여 3-(( S)-3-(벤질옥시)-2-(( tert-부톡시카르보닐)아미노)-3-옥소프로필)-1 H-인돌-5-일 5-(1,2-디티올란-3-일) 펜타노에이트를 수득하였다. CH 2Cl 2 중 인돌-5-일 5-(1,2-디티올란-3-일)펜타노에이트 (0.02 g, 0.03 mmol)의 용액 (2 mL)에 0 °C에서 디옥산 중 4N HCl (0.5 mL)을 첨가하였다. 실온에서 2.5시간 동안 교반한 후에, 반응 혼합물을 감압 하에서 농축시켜 (2 S)-3-(5-((5-(1,2-디티올란-3-일)펜타노일)옥시)-1 H-인돌-3-일)-1-(벤질옥시)-1-옥소프로판-2-아미늄 클로라이드 (5 mg, 35%)를 수득하였다. Benzyl ( S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.10 g, 0.24 mmol) was added α- D,L -lipoic acid (0.06 g, 0.29 mmol), EDCI (0.07 g, 0.36 mmol) and DMAP (2 mg, 0.01 mmol). After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine , dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1 : 2) to 3-(( S )-3-(benzyloxy)-2-(( tert -butoxycarbonyl)amino)-3 - to give the indol-5-yl 5- (1,2-dithiol olran-3-yl) pentanoate-oxopropyl) -1 H. To a solution (2 mL) of indol-5-yl 5-(1,2-dithiolan-3-yl)pentanoate (0.02 g, 0.03 mmol) in CH 2 Cl 2 at 0 °C 4N HCl in dioxane (0.5 mL) was added. After stirring at room temperature for 2.5 h, the reaction mixture was concentrated under reduced pressure to (2 S )-3-(5-((5-(1,2-dithiolan-3-yl)pentanoyl)oxy)-1 H Obtained -indol-3-yl)-1-(benzyloxy)-1-oxopropan-2-aminium chloride (5 mg, 35%).
1H NMR (600 MHz, DMSO- d6) δ 11.24 (s, 1H), 7.29 (m, 8H), 6.83 (m, 1H), 5.14 (m, 1H), 5.05 (m, 1H), 4.24 (m, 1H), 3.63 (m, 1H), 3.26 (m, 4H), 3.11 (m, 1H), 2.56 (t, 2H, J = 7.3 Hz) 2.42 (m, 1H), 1.87 (m, 1H), 1.59 (m, 8H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 172.4, 169.3, 150.6, 143.6, 134.9, 134.0, 130.8, 128.4, 128.3, 128.1, 128.0, 127.0, 126.6, 115.7, 112.0, 110.2, 106.7, 67.0, 56.1, 52.6, 38.1, 34.1, 33.4, 28.1, 24.2. 1 H NMR (600 MHz, DMSO- d6 ) δ 11.24 (s, 1H), 7.29 (m, 8H), 6.83 (m, 1H), 5.14 (m, 1H), 5.05 (m, 1H), 4.24 (m , 1H), 3.63 (m, 1H), 3.26 (m, 4H), 3.11 (m, 1H), 2.56 (t, 2H, J = 7.3 Hz) 2.42 (m, 1H), 1.87 (m, 1H), 1.59 (m, 8H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 172.4, 169.3, 150.6, 143.6, 134.9, 134.0, 130.8, 128.4, 128.3, 128.1, 128.0, 127.0, 126.6, 115.7, 112.0, 110.2, 106.7, 67.0, 56.1, 52.6, 38.1, 34.1, 33.4, 28.1, 24.2.
[실시예 13] [Example 13]
(2(2 SS )-3-(5-((5-(1,2-디티올란-3-일)펜타노일)옥시)-1)-3-(5-((5-(1,2-dithiolan-3-yl)pentanoyl)oxy)-1 HH -인돌-3-일)-1-메톡시-1-옥소프로판-2-아미늄 클로라이드 (KST-11013)-Indol-3-yl)-1-methoxy-1-oxopropane-2-aminium chloride (KST-11013)
디클로로메탄 (3 mL) 중 메틸 ( S)-2-(( tert-부톡시카르보닐)아미노)-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.06 g, 0.18 mmol)의 용액에 α- D,L-리포산 (0.05 g, 0.22 mmol), EDCI (0.05 g, 0.27 mmol) 및 DMAP (2 mg, 0.01 mmol)을 첨가하였다. 17시간 동안 교반한 후에, 반응 혼합물을 디클로로메탄으로 희석하고 물 및 염수로 세척한 후, MgSO 4로 건조시키고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (EtOAc/Hexane = 1 : 2)상에서 플래시 컬럼 크로마토그래피로 정제하여 3-(( S)-2-(( tert-부톡시카르보닐)아미노)-3-메톡시-3-옥소프로필)-1 H-인돌-5-일 5-(1,2-디티올란-3-일)펜타노에이트를 수득하였다. 인돌-5-일 5-(1,2-디티올란-3-일)펜타노에이트 (16.6 mg, 0.03 mmol)의 CH 2Cl 2 용액 (2 mL)에 0 °C에서 디옥산 중 4N HCl (0.5 mL)을 첨가하였다. 실온에서 2.5시간 동안 교반한 후에, 반응 혼합물을 감압 하에서 농축시켜 (2 S)-3-(5-((5-(1,2-디티올란-3-일)펜타노일)옥시)-1 H-인돌-3-일)-1-메톡시-1-옥소프로판-2-아미늄 클로라이드 (5 mg, 25%)를 수득하였다. methyl ( S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.06 g, 0.18 mmol) was added α- D,L -lipoic acid (0.05 g, 0.22 mmol), EDCI (0.05 g, 0.27 mmol) and DMAP (2 mg, 0.01 mmol). After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine , dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1 : 2) to 3-(( S )-2-(( tert -butoxycarbonyl)amino)-3-methoxy-3-oxo to give the indol-5-yl 5- (1,2-dithiol olran-3-yl) pentanoate-propyl) -1 H. Indol-5-yl 5-(1,2-dithiolan-3-yl)pentanoate (16.6 mg, 0.03 mmol) in a CH 2 Cl 2 solution (2 mL) at 0 °C in 4N HCl in dioxane ( 0.5 mL) was added. After stirring at room temperature for 2.5 h, the reaction mixture was concentrated under reduced pressure to (2 S )-3-(5-((5-(1,2-dithiolan-3-yl)pentanoyl)oxy)-1 H -Indol-3-yl)-1-methoxy-1-oxopropan-2-aminium chloride (5 mg, 25%) was obtained.
1H NMR (600 MHz, DMSO- d6) δ 11.25 (s, 1H), 7.25 (m, 3H), 6.72 (m, 2H), 4.17 (m, 1H), 3.65 (m, 4H), 3.19 (m, 4H), 2.59 (t, 2H, J = 7.3 Hz), 2.41 (m, 1H), 2.21 (t, 1H, J = 7.3 Hz), 1.75 (m, 8H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 172.4, 150.6, 143.6, 134.0, 127.0, 126.6, 125.4, 112.0, 110.2, 106.6, 105.2, 101.9, 56.1, 52.6, 38.2, 34.1, 33.4, 28.1, 24.3. 1 H NMR (600 MHz, DMSO- d6 ) δ 11.25 (s, 1H), 7.25 (m, 3H), 6.72 (m, 2H), 4.17 (m, 1H), 3.65 (m, 4H), 3.19 (m) , 4H), 2.59 (t, 2H, J = 7.3 Hz), 2.41 (m, 1H), 2.21 (t, 1H, J = 7.3 Hz), 1.75 (m, 8H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 172.4, 150.6, 143.6, 134.0, 127.0, 126.6, 125.4, 112.0, 110.2, 106.6, 105.2, 101.9, 56.1, 52.6, 38.2, 34.1, 33.4, 28.1, 24.3.
[실시예 14] [Example 14]
(5-메톡시-1(5-Methoxy-1 HH -인돌-2-일)메탄아민 (KST-41001)-Indol-2-yl)methanamine (KST-41001)
THF (2 mL) 중 5-메톡시-2-카르복실산 (0.05 g, 0.26 mmol)의 용액에 CDI (0.09 mg, 0.52 mmol)을 첨가하였다. 반응 혼합물을 2시간 동안 교반한 후, NH 4OH (28-30% 수용액, 0.5 mL)를 첨가하였다. 이어서 반응 혼합물을 2시간 동안 교반한 후, H 2O (5 mL)로 켄칭하였다. 층을 분리하고 에틸 아세테이트 (2 Х 10 mL)로 수상을 추출하였다. 결합된 유기 추출물은 염수로 세척하고, Na 2SO 4로 건조시킨 후 감압 하에서 농축시켰다. 조 잔류물을 THF (5 mL)에 용해시키고 0 °C로 냉각시켰다. LiAlH 4 (14 mg, 0.38 mmol)를 천천히 첨가하고 반응 혼합물을 상온으로 가온한 후, 가열하여 환류시키고 2시간 동안 교반하였다. 이어서 반응 혼합물을 H 2O (100 mL)로 켄칭하였다. 층을 분리하고 에틸 아세테이트 (2 Х 100 mL)로 수상을 추출하였다. 결합된 유기 추출물은 염수로 세척하고, Na 2SO 4로 건조시킨 후 감압 하에서 농축시켰다. 잔류물을 실리카겔 (MeOH 10% NH 4OH/CH 2Cl 2, 0:1 → 1:9 gradient run) 상에서 플래시 컬럼 크로마토그래피로 정제하여 (5-메톡시-1 H-인돌-2-일)메탄아민 (11 mg, 43%)을 백색 고체 형태로 수득하였다. To a solution of 5-methoxy-2-carboxylic acid (0.05 g, 0.26 mmol) in THF (2 mL) was added CDI (0.09 mg, 0.52 mmol). After the reaction mixture was stirred for 2 h, NH 4 OH (28-30% aqueous solution, 0.5 mL) was added. The reaction mixture was then stirred for 2 h, then quenched with H 2 O (5 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 Х 10 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude residue was dissolved in THF (5 mL) and cooled to 0 °C. LiAlH 4 (14 mg, 0.38 mmol) was added slowly and the reaction mixture was warmed to room temperature, heated to reflux, and stirred for 2 hours. The reaction mixture was then quenched with H 2 O (100 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 Х 100 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH 10% NH 4 OH/CH 2 Cl 2 , 0:1 to 1:9 gradient run) (5-methoxy-1 H -indol-2-yl) Methanamine (11 mg, 43%) was obtained in the form of a white solid.
1H NMR (600 MHz, DMSO- d6) δ 10.81 (s, 1H), 7.20 (d, 1H, J = 8.7 Hz), 6.95 (d, 1H, J = 2.4 Hz), 6.66 (m, 1H), 6.20 (s, 1H), 3.87 (s, 2H), 3.72 (s, 3H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 153.2, 140.4, 131.1, 128.4, 111.5, 110.4, 101.6, 98.5, 55.2, 38.5. 1 H NMR (600 MHz, DMSO- d6 ) δ 10.81 (s, 1H), 7.20 (d, 1H, J = 8.7 Hz), 6.95 (d, 1H, J = 2.4 Hz), 6.66 (m, 1H), 6.20 (s, 1H), 3.87 (s, 2H), 3.72 (s, 3H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 153.2, 140.4, 131.1, 128.4, 111.5, 110.4, 101.6, 98.5, 55.2, 38.5.
[실시예 15] [Example 15]
(6-메톡시-1(6-methoxy-1 HH -인돌-2-일)메탄아민 (KST-41002)-Indol-2-yl)methanamine (KST-41002)
THF (5 mL) 중 6-메톡시-2-카르복실산 (0.05 g, 0.26 mmol)의 용액에 CDI (0.09 g, 0.52 mmol)을 첨가하였다. 반응 혼합물을 2시간 동안 교반한 후 NH 4OH (28-30% 수용액, 0.5 mL)를 첨가하였다. 이어서 반응 혼합물을 2시간 동안 교반한 후 H 2O (5 mL)로 켄칭하였다. 층을 분리하고 에틸 아세테이트 (2 Х 10 mL)로 수상을 추출하였다. 결합된 유기 추출물은 염수로 세척하고, Na 2SO 4로 건조시킨 후 감압 하에서 농축시켰다. 조 잔류물을 THF (5 mL)에 용해시키고 0 °C로 냉각시켰다. LiAlH 4 (0.01 g, 0.38 mmol)를 천천히 첨가하고 반응 혼합물을 상온으로 가온한 후, 가열하여 환류시키고 2시간 동안 교반하였다. 이어서 반응 혼합물을 H 2O (10 mL)로 켄칭하였다. 층을 분리하고 에틸 아세테이트 (2 Х 10 mL)로 수상을 추출하였다. 결합된 유기 추출물은 염수로 세척하고, Na 2SO 4로 건조시킨 후 감압 하에서 농축시켰다. 잔류물을 실리카겔 (MeOH 10% NH 4OH/CH 2Cl 2, 0:1 → 1:9 radient run) 상에서 플래시 컬럼 크로마토그래피로 정제하여 (6-메톡시-1 H-인돌-2-일)메탄아민 (7.5 mg, 28%)을 백색 고체 형태로 수득하였다. To a solution of 6-methoxy-2-carboxylic acid (0.05 g, 0.26 mmol) in THF (5 mL) was added CDI (0.09 g, 0.52 mmol). The reaction mixture was stirred for 2 h before NH 4 OH (28-30% aqueous solution, 0.5 mL) was added. The reaction mixture was then stirred for 2 h and then quenched with H 2 O (5 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 Х 10 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude residue was dissolved in THF (5 mL) and cooled to 0 °C. LiAlH 4 (0.01 g, 0.38 mmol) was added slowly, and the reaction mixture was warmed to room temperature, heated to reflux, and stirred for 2 hours. The reaction mixture was then quenched with H 2 O (10 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 Х 10 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH 10% NH 4 OH/CH 2 Cl 2 , 0:1 to 1:9 radient run) (6-methoxy-1 H -indol-2-yl) Methanamine (7.5 mg, 28%) was obtained in the form of a white solid.
1H NMR (600 MHz, DMSO- d6) δ 10.74 (d, 2H, J = 12.9 Hz), 7.28 (m, 1H), 6.82 (m, 1H), 6.58 (m, 1H), 6.11 (d, 1H, J = 0.7 Hz), 4.43 (s, 1H), 3.78 (s, 2H), 3.73 (s, 3H). 1 H NMR (600 MHz, DMSO- d6 ) δ 10.74 (d, 2H, J = 12.9 Hz), 7.28 (m, 1H), 6.82 (m, 1H), 6.58 (m, 1H), 6.11 (d, 1H) , J = 0.7 Hz), 4.43 (s, 1H), 3.78 (s, 2H), 3.73 (s, 3H).
[실시예 16] [Example 16]
벤질 (2benzyl (2 SS )-2-(()-2-(( terttert -부톡시카르보닐)아미노)-3-(5-(((4-(메틸설피닐)부틸)카바모티오일)옥시)-1-Butoxycarbonyl)amino)-3-(5-(((4-(methylsulfinyl)butyl)carbamothioyl)oxy)-1 HH -인돌-3-일)프로파노에이트-Indol-3-yl)propanoate
THF (3 mL) 중 벤질 ( S)-2-(( tert-부톡시카르보닐)아미노)-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.2 g, 0.34 mmol)의 용액에 설포라판 (0.06 g, 0.34 mmol) 및 포타슘 t-부톡시드 (0.08 mg, 0.68 mmol)를 첨가하였다. 1시간 동안 교반한 후, 반응 혼합물을 디클로로메탄으로 희석하고 물 및 염수로 세척한 후, MgSO 4로 건조시키고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (CH 2Cl 2/CH 3OH= 20 : 1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 벤질 (2 S)-2-(( tert-부톡시카르보닐)아미노)-3-(5-(((4-(메틸설피닐)부틸)카바모티오일)옥시)-1 H-인돌-3-일)프로파노에이트 (0.08 g, 35%)를 수득하였다. Benzyl (S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.2 g, 0.34) in THF (3 mL) mmol) was added sulforaphane (0.06 g, 0.34 mmol) and potassium t-butoxide (0.08 mg, 0.68 mmol). After stirring for 1 hour, the reaction mixture was diluted with dichloromethane, washed with water and brine , dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH 2 Cl 2 /CH 3 OH= 20 : 1) to benzyl (2 S )-2-(( tert -butoxycarbonyl)amino)-3-(5) - (((4- (methyl sulfinyl) butyl) cover motif oil) oxy) -1 H-indole-3-yl) propanoate (0.08 g, 35%) was obtained.
1H NMR (600 MHz, CDCl 3) δ 7.95 (d, 1H, J = 42.2 Hz), 7.67 (m, 2H), 7.31 (d, 3H, J = 6.5 Hz), 6.89 (s, 1H), 6.71 (d, 1H, J = 8.7 Hz), 5.08 (d, 2H, J = 7.9 Hz), 4.62 (m, 1H), 3.80 (s, 2H), 3.05 (m, 2H), 2.68 (s, 2H), 2.50 (d, 3H, J = 5.9 Hz), 1.88 (s, 4H), 1.39 (d, 9H, J = 2.7 Hz). 13C{ 1H} NMR (150 MHz, CDCl 3) δ 171.9, 155.4, 152.3, 152.3, 135.1, 128.6, 128.4, 128.4, 114.2, 113.2, 104.8, 80.3, 67.4, 53.7, 53.1, 53.0, 45.2, 38.2, 38.1, 28.3, 28.0, 27.9, 20.3, 20.2. LRMS (ESI) m/z: [M + Na] + Calcd for C 29H 37N 3NaO 6S 2 610.2; found 610.2. 1 H NMR (600 MHz, CDCl 3 ) δ 7.95 (d, 1H, J = 42.2 Hz), 7.67 (m, 2H), 7.31 (d, 3H, J = 6.5 Hz), 6.89 (s, 1H), 6.71 (d, 1H, J = 8.7 Hz), 5.08 (d, 2H, J = 7.9 Hz), 4.62 (m, 1H), 3.80 (s, 2H), 3.05 (m, 2H), 2.68 (s, 2H) , 2.50 (d, 3H, J = 5.9 Hz), 1.88 (s, 4H), 1.39 (d, 9H, J = 2.7 Hz). 13 C{ 1 H} NMR (150 MHz, CDCl 3 ) δ 171.9, 155.4, 152.3, 152.3, 135.1, 128.6, 128.4, 128.4, 114.2, 113.2, 104.8, 80.3, 67.4, 53.7, 53.1, 53.0, 45.2, 38.2 , 38.1, 28.3, 28.0, 27.9, 20.3, 20.2. LRMS (ESI) m/z: [M + Na] + Calcd for C 29 H 37 N 3 NaO 6 S 2 610.2; found 610.2.
[실시예 17] [Example 17]
(2(2 SS )-1-(벤질옥시)-3-(5-(((4-(메틸설피닐)부틸)카바모티오일)옥시)-1)-1-(benzyloxy)-3-(5-(((4-(methylsulfinyl)butyl)carbamothioyl)oxy)-1 HH -인돌-3-일)-1-옥소프로판-2-아미늄 2,2,2-트리플루오로아세테이트-Indol-3-yl)-1-oxopropan-2-aminium 2,2,2-trifluoroacetate
벤질 2-(( tert-부톡시카르보닐)아미노)-3-(5-(((4-(메틸설피닐)부틸)카바모티오일)옥시)-1 H-인돌-3-일)프로파노에이트 (0.05 g, 0.08 mmol)의 CH 2Cl 2 용액 (3 mL)에 0 °C에서 TFA (0.1 mL)를 첨가하였다. 실온에서 3시간 동안 교반한 후에, 반응 혼합물을 디클로로메탄으로 희석하고 물 및 염수로 세척한 후, MgSO 4로 건조시키고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (CH 2Cl 2/CH 3OH= 15 : 1 내지 7 : 1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 (2 S)-1-(벤질옥시)-3-(5-(((4-(메틸설피닐)부틸)카바모티오일)옥시)-1 H-인돌-3-일)-1-옥소프로판-2-아미늄 2,2,2-트리플루오로아세테이트 (25 mg, 52%)를 수득하였다.Benzyl 2 - ((tert-butoxycarbonyl) amino) -3- (5 - (((4- (methyl sulfinyl) butyl) cover motif oil) oxy) -1 H-indol-3-yl) propanoate To a CH 2 Cl 2 solution (3 mL) of ate (0.05 g, 0.08 mmol) at 0 °C was added TFA (0.1 mL). After stirring at room temperature for 3 h, the reaction mixture was diluted with dichloromethane, washed with water and brine , dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH 2 Cl 2 /CH 3 OH= 15 : 1 to 7 : 1) to (2 S )-1-(benzyloxy)-3-(5-(((( 4- (methyl sulfinyl) butyl) cover motif oil) oxy) -1 H - indol-3-yl) -1-oxo-propane-2-aminium 2,2,2-trifluoro-acetate (25 mg, 52 %) was obtained.
1H NMR (600 MHz, DMSO- d6) δ 9.66 (t, 1H, J = 5.2 Hz), 9.29 (s, 1H), 8.10 (bs, 2H), 8.06 (d, 1H, J = 9.0 Hz), 7.72 (s, 1H), 7.34 (m, 3H), 7.25 (m, 2H), 6.89 (d, 1H, J = 2.4 Hz), 6.79 (m, 1H), 5.13 (m, 2H), 4.28 (t, 1H, J = 6.7 Hz), 3.72 (m, 2H), 3.16 (d, 2H, J = 7.2 Hz), 2.83 (m, 1H), 2.71 (m, 1H), 2.53 (s, 3H), 1.83 (m, 2H), 1.75 (m, 2H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 178.2, 169.7, 153.0, 134.9, 131.1, 129.1, 128.5, 128.3, 128.2, 127.6, 115.3, 112.8, 111.4, 103.4, 67.2, 52.8, 52.2, 48.6, 45.0, 38.0, 26.8, 26.3, 19.7.; LRMS (ESI) m/z: [M + Na] + Calcd for C 24H 29N 3NaO 4S 2 510.2; found 510.2. 1 H NMR (600 MHz, DMSO- d6 ) δ 9.66 (t, 1H, J = 5.2 Hz), 9.29 (s, 1H), 8.10 (bs, 2H), 8.06 (d, 1H, J = 9.0 Hz), 7.72 (s, 1H), 7.34 (m, 3H), 7.25 (m, 2H), 6.89 (d, 1H, J = 2.4 Hz), 6.79 (m, 1H), 5.13 (m, 2H), 4.28 (t) , 1H, J = 6.7 Hz), 3.72 (m, 2H), 3.16 (d, 2H, J = 7.2 Hz), 2.83 (m, 1H), 2.71 (m, 1H), 2.53 (s, 3H), 1.83 (m, 2H), 1.75 (m, 2H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 178.2, 169.7, 153.0, 134.9, 131.1, 129.1, 128.5, 128.3, 128.2, 127.6, 115.3, 112.8, 111.4, 103.4, 67.2, 52.8, 52.2, 48.6, 45.0, 38.0, 26.8, 26.3, 19.7.; LRMS (ESI) m/z: [M + Na] + Calcd for C 24 H 29 N 3 NaO 4 S 2 510.2; found 510.2.
[실시예 18] [Example 18]
메틸 (2methyl (2 SS )-2-(()-2-(( terttert -부톡시카르보닐)아미노)-3-(5-(((4-(메틸설피닐)부틸)카바모티오일)옥시)-1-Butoxycarbonyl)amino)-3-(5-(((4-(methylsulfinyl)butyl)carbamothioyl)oxy)-1 HH -인돌-3-일)프로파노에이트-Indol-3-yl)propanoate
THF (3 mL) 중 메틸 ( S)-2-(( tert-부톡시카르보닐)아미노)-3-(5-하이드록시-1 H-인돌-3-일)프로파노에이트 (0.08 g, 0.16 mmol)의 용액에 설포라판 (0.03 g, 0.16 mmol) 및 포타슘 t-부톡시드 (0.04 g, 0.32 mmol)를 첨가하였다. 1시간 동안 교반한 후에, 반응 혼합물을 디클로로메탄으로 희석하고 물 및 염수로 세척한 후, MgSO 4 로 건조시키고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (CH 2Cl 2/CH 3OH= 20 : 1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 메틸 (2 S)-2-(( tert-부톡시카르보닐)아미노)-3-(5-(((4-(메틸설피닐)부틸)카바모티오일)옥시)-1 H-인돌-3-일)프로파노에이트 (0.03 g, 36%)를 수득하였다. Methyl (S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.08 g, 0.16) in THF (3 mL) mmol) was added sulforaphane (0.03 g, 0.16 mmol) and potassium t-butoxide (0.04 g, 0.32 mmol). After stirring for 1 hour, the reaction mixture was diluted with dichloromethane, washed with water and brine , dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH 2 Cl 2 /CH 3 OH= 20 : 1) to methyl (2 S )-2-(( tert -butoxycarbonyl)amino)-3-(5) - (((4- (methyl sulfinyl) butyl) cover motif oil) oxy) -1 H-indole-3-yl) propanoate (0.03 g, 36%) was obtained.
1H NMR (600 MHz, CDCl 3) δ 8.13 (d, 1H, J = 21.6 Hz), 7.65 (m, 2H), 6.87 (s, 1H), 6.71 (s, 1H), 5.34 (m, 1H), 3.79 (s, 2H), 3.67 (s, 3H), 3.04 (m, 2H), 2.68 (s, 2H), 2.51 (s, 2H), 2.16 (s, 3H), 1.86 (s, 4H), 1.39 (s, 9H). 13C{ 1H} NMR (150 MHz, CDCl 3) δ 207.3, 179.5, 172.5, 155.4, 152.4, 132.4, 129.0, 127.9, 114.2, 113.2, 104.7, 80.3, 53.5, 53.1, 52.5, 45.2, 38.1, 31.0, 28.3, 20.2. LRMS (ESI) m/z: [M + Na] + Calcd for C 23H 33N 3NaO 6S 2 534.2; found 534.3. 1 H NMR (600 MHz, CDCl 3 ) δ 8.13 (d, 1H, J = 21.6 Hz), 7.65 (m, 2H), 6.87 (s, 1H), 6.71 (s, 1H), 5.34 (m, 1H) , 3.79 (s, 2H), 3.67 (s, 3H), 3.04 (m, 2H), 2.68 (s, 2H), 2.51 (s, 2H), 2.16 (s, 3H), 1.86 (s, 4H), 1.39 (s, 9H). 13 C{ 1 H} NMR (150 MHz, CDCl 3 ) δ 207.3, 179.5, 172.5, 155.4, 152.4, 132.4, 129.0, 127.9, 114.2, 113.2, 104.7, 80.3, 53.5, 53.1, 52.5, 45.2, 38.1, 31.0 , 28.3, 20.2. LRMS (ESI) m/z: [M + Na] + Calcd for C 23 H 33 N 3 NaO 6 S 2 534.2; found 534.3.
[실시예 19] [Example 19]
(2(2 SS )-1-메톡시-3-(5-(((4-(메틸설피닐)부틸)카바모티오일)옥시)-1)-1-methoxy-3-(5-(((4-(methylsulfinyl)butyl)carbamothioyl)oxy)-1 HH -인돌-3-일)-1-옥소프로판-2-아미늄 2,2,2-트리플루오로아세테이트-Indol-3-yl)-1-oxopropan-2-aminium 2,2,2-trifluoroacetate
메틸 (2 S)-2-(( tert-부톡시카르보닐)아미노)-3-(5-(((4-(메틸설피닐)부틸)카바모티오일)옥시)-1 H-인돌-3-일)프로파노에이트 (0.03 g, 0.06 mmol)의 CH 2Cl 2 용액 (3 mL)에 0 °C에서 TFA (0.1 mL)를 첨가하였다. 실온에서 3시간 동안 교반한 후에, 반응 혼합물을 디클로로메탄으로 희석하고 물 및 염수로 세척한 후, MgSO 4로 건조시키고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (CH 2Cl 2/CH 3OH= 15 : 1 내지 7 : 1)상에서 플래시 컬럼 크로마토그래피로 정제하여 (2 S)-1-메톡시-3-(5-(((4-(메틸설피닐)부틸)카바모티오일)옥시)-1 H-인돌-3-일)-1-옥소프로판-2-아미늄 2,2,2-트리플루오로아세테이트 (14 mg, 44%)를 수득하였다. Methyl (2 S) -2 - ((tert-butoxycarbonyl) amino) -3- (5 - (((4- (methyl sulfinyl) butyl) cover motif oil) oxy) -1 H-indol -3 To a CH 2 Cl 2 solution (3 mL) of -yl)propanoate (0.03 g, 0.06 mmol) at 0 °C was added TFA (0.1 mL). After stirring at room temperature for 3 h, the reaction mixture was diluted with dichloromethane, washed with water and brine , dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH 2 Cl 2 /CH 3 OH= 15 : 1 to 7 : 1) (2 S )-1-methoxy-3-(5-(((4- (methyl sulfinyl) butyl) cover motif oil) oxy) -1 H - indol-3-yl) acetate (14 mg, 44% l-oxo-propan-2-aminium 2,2,2-trifluoroethyl) was obtained.
1H NMR (600 MHz, DMSO- d6) δ 9.72 (s, 1H), 9.32 (d, 1H, J = 2.9 Hz), 8.11 (bs, 2H) 8.01 (d, 2H, J = 9.0 Hz), 7.72 (s, 1H), 6.84 (d, 1H, J = 2.3 Hz), 6.77 (m, 1H), 4.21 (t, 1H, J = 6.3 Hz), 3.71 (d, 2H, J = 6.0 Hz), 3.67 (s, 3H), 3.14 (d, 2H, J = 6.0 Hz), 2.83 (m, 1H), 2.71 (m, 1H), 2.53 (s, 3H), 1.83 (m, 2H), 1.74 (m, 2H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 178.3, 158.2, 158.0, 153.0, 131.1, 129.0, 127.8, 115.2, 112.8, 103.3, 52.8, 52.7, 52.2, 45.0, 38.0, 30.7, 26.8, 19.7.; LRMS (ESI) m/z: [M + Na] + Calcd for C 18H 25N 3NaO 4S 2 434.1; found 434.2. 1 H NMR (600 MHz, DMSO- d6 ) δ 9.72 (s, 1H), 9.32 (d, 1H, J = 2.9 Hz), 8.11 (bs, 2H) 8.01 (d, 2H, J = 9.0 Hz), 7.72 (s, 1H), 6.84 (d, 1H, J = 2.3 Hz), 6.77 (m, 1H), 4.21 (t, 1H, J = 6.3 Hz), 3.71 (d, 2H, J = 6.0 Hz), 3.67 (s, 3H), 3.14 (d, 2H, J = 6.0 Hz), 2.83 (m, 1H), 2.71 (m, 1H), 2.53 (s, 3H), 1.83 (m, 2H), 1.74 (m, 2H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 178.3, 158.2, 158.0, 153.0, 131.1, 129.0, 127.8, 115.2, 112.8, 103.3, 52.8, 52.7, 52.2, 45.0, 38.0, 30.7, 26.8, 19.7.; LRMS (ESI) m/z: [M + Na] + Calcd for C 18 H 25 N 3 NaO 4 S 2 434.1; found 434.2.
[실시예 20] [Example 20]
2-아미노-2-amino- NN -(3-((4-아미노부틸)아미노)프로필)-3-(5-히드록시-1-(3-((4-aminobutyl)amino)propyl)-3-(5-hydroxy-1 HH -인돌-3-일)프로판아미드-Indol-3-yl)propanamide
1 단계:Stage 1: tert tert -부틸(-Butyl ( SS )-(3-(2-(()-(3-(2-(( terttert -부톡시카르보닐)아미노)-3-(5-히드록시-1-Butoxycarbonyl)amino)-3-(5-hydroxy-1 HH -인돌-3-일)프로파나미도)프로필)(4-((-indol-3-yl)propanamido)propyl)(4-(( terttert -부톡시카르보닐)아미노)부틸)카바메이트의 제조Preparation of -butoxycarbonyl)amino)butyl)carbamate
( S)-2-(( tert-부톡시카르보닐)아미노)-3-(5-히드록시-1 H-인돌-3-일)프로판산(0.13 g, 0.4 mmol)의 CH 2Cl 2 용액에 N1, N5-비스-boc 스퍼미딘(0.17 g, 0.5 mmol)과 N-메틸모르폴린 (NMM) (0.13 mL, 0.4 mmol)을 첨가하였다. 0 °C에서 30분 교반한 후에 EDCI와 HOBt를 첨가하고 실온에서 15시간 동안 교반하였다. 반응 혼합물을 디클로로메탄으로 희석하고 물 및 염수로 세척한 후, Na 2SO 4로 건조시키고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 tert-부틸( S)-(3-(2-(( tert-부톡시카르보닐)아미노)-3-(5-히드록시-1 H-인돌-3-일)프로파나미도)프로필)(4-(( tert-부톡시카르보닐)아미노)부틸)카바메이트(0.17 g, 51%)를 수득하였다. CH 2 Cl 2 solution of ( S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanoic acid (0.13 g, 0.4 mmol) To N1, N5-bis-boc spermidine (0.17 g, 0.5 mmol) and N-methylmorpholine (NMM) (0.13 mL, 0.4 mmol) were added. After stirring at 0 °C for 30 minutes, EDCI and HOBt were added and stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane, washed with water and brine , dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to tert -butyl( S )-(3-(2-(( tert -butoxycarbonyl)amino )-3-(5-hydroxy- 1H -indol-3-yl)propanamido)propyl)(4-(( tert -butoxycarbonyl)amino)butyl)carbamate (0.17 g, 51%) was obtained.
1H NMR (600 MHz, MeOD) δ 7.15 (d, 1H, J = 8.6 Hz), 7.03 (s, 1H), 6.95 (d, 1H, J = 2.3 Hz), 6.66 (m, 1H), 4.24 (s, 1H), 3.11 (d, 4H, J = 10.4 Hz), 2.98 (m, 6H), 1.49 (s, 4H), 1.42 (m, 27H), 1.29 (m, 2H). 13C{ 1H} NMR (150 MHz, MeOD) δ 173.0, 158.6, 157.6, 151.4, 133.0, 129.5, 125.3, 112.7, 112.5, 110.2, 103.7, 80.9, 80.7, 79.9, 61.5, 57.3, 41.2, 28.8, 28.8, 28.7, 20.9, 14.4. 1 H NMR (600 MHz, MeOD) δ 7.15 (d, 1H, J = 8.6 Hz), 7.03 (s, 1H), 6.95 (d, 1H, J = 2.3 Hz), 6.66 (m, 1H), 4.24 ( s, 1H), 3.11 (d, 4H, J = 10.4 Hz), 2.98 (m, 6H), 1.49 (s, 4H), 1.42 (m, 27H), 1.29 (m, 2H). 13 C{ 1 H} NMR (150 MHz, MeOD) δ 173.0, 158.6, 157.6, 151.4, 133.0, 129.5, 125.3, 112.7, 112.5, 110.2, 103.7, 80.9, 80.7, 79.9, 61.5, 57.3, 41.2, 28.8, 28.8, 28.7, 20.9, 14.4.
2 단계: N1-(3-(2-암모니오-3-(5-히드록시-1Step 2: N1-(3-(2-ammonio-3-(5-hydroxy-1) HH -인돌-3-일)프로판아미도)프로필)부탄-1,4-디아미늄 클로라이드-Indol-3-yl)propanamido)propyl)butane-1,4-diaminium chloride
tert-부틸( S)-(3-(2-(( tert-부톡시카르보닐)아미노)-3-(5-히드록시-1 H-인돌-3-일)프로파나미도)프로필)(4-(( tert-부톡시카르보닐)아미노)부틸)카바메이트(0.04 g, 0.06 mmol)를 4.0 M HCl in dioxane (2 mL)에 녹인 후 실온에서 2 시간 동안 교반하였다. 반응 용매를 제거한 뒤 diethyl ether로 희석하고 2시간 동안 교반하여 석출된 고체를 수득하였다. (0.03 g, 98%) tert -Butyl( S )-(3-(2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy- 1H -indol-3-yl)propanamido)propyl)(4 -(( tert -butoxycarbonyl)amino)butyl)carbamate (0.04 g, 0.06 mmol) was dissolved in 4.0 M HCl in dioxane (2 mL) and stirred at room temperature for 2 hours. After removing the reaction solvent, it was diluted with diethyl ether and stirred for 2 hours to obtain a precipitated solid. (0.03 g, 98%)
1H NMR (600 MHz, MeOD) δ 7.23 (d, 1H, J = 8.6 Hz), 7.19 (s, 1H), 7.02 (d, 1H, J = 2.3 Hz), 6.72 (m, 1H), 4.11 (t, 1H, J = 7.3 Hz), 3.25 (m, 4H), 3.00 (d, 2H, J = 6.7 Hz), 2.93 (t, 2H, J = 6.7 Hz), 2.75 (m, 2H), 1.78 (m, 6H). 13C{ 1H} NMR (150 MHz, MeOD) δ 170.8, 151.7, 132.9, 129.2, 126.3, 113.1, 113.0, 107.3, 103.5, 55.1, 48.2, 46.2, 40.0, 37.3, 28.7, 27.0, 25.5, 24.3. 1 H NMR (600 MHz, MeOD) δ 7.23 (d, 1H, J = 8.6 Hz), 7.19 (s, 1H), 7.02 (d, 1H, J = 2.3 Hz), 6.72 (m, 1H), 4.11 ( t, 1H, J = 7.3 Hz), 3.25 (m, 4H), 3.00 (d, 2H, J = 6.7 Hz), 2.93 (t, 2H, J = 6.7 Hz), 2.75 (m, 2H), 1.78 ( m, 6H). 13 C{ 1 H} NMR (150 MHz, MeOD) δ 170.8, 151.7, 132.9, 129.2, 126.3, 113.1, 113.0, 107.3, 103.5, 55.1, 48.2, 46.2, 40.0, 37.3, 28.7, 27.0, 25.5, 24.3.
[실시예 21] [Example 21]
2-아미노-3-(5-(((3-((4-아미노부틸)아미노)프로필)카르바모일)옥시)-12-amino-3-(5-(((3-((4-aminobutyl)amino)propyl)carbamoyl)oxy)-1 HH -인돌-3-일)프로판산-Indol-3-yl)propanoic acid
1 단계: 벤질 (Step 1: Benzyl ( SS )-3-(5-(((3-(()-3-(5-(((3-(( terttert -부톡시카르보닐)(4-((-butoxycarbonyl) (4-(( terttert -부톡시카르보닐)아미노)부틸)아미노)프로필)카르바모일)옥시)-1-Butoxycarbonyl)amino)butyl)amino)propyl)carbamoyl)oxy)-1 HH -인돌-3-일)-2-((-Indol-3-yl)-2-(( terttert -부톡시카르보닐)아미노)프로파노에이트의 제조-Preparation of butoxycarbonyl)amino)propanoate
벤질 ( S)-2-(( tert-부톡시카르보닐)아미노)-3-(5-히드록시-1 H-인돌-3-일)프로파노에이트(0.15 g, 0.4 mmol)의 CH 2Cl 2 용액에 트리포스겐(0.05 g, 0.2 mmol)과 피리딘(0.03 mL, 0.4 mmol)을 첨가하였다. 실온에서 30분동안 교반한 후에 0 °C에서 N1, N5-비스-boc 스퍼미딘(0.13 g, 0.4 mmol)과 피리딘(0.04 mL, 0.4 mmol)을 첨가하였다. 실온에서 2시간 동안 교반한 후에, 반응 혼합물을 물로 quenching하였다. 디클로로메탄으로 희석하고 물 및 염수로 세척한 후, Na 2SO 4로 건조시키고 감압 하에서 농축시켰다. 잔류물을 실리카겔 (EtOAc/Hexane/CH 3OH = 1:3:0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 벤질 ( S)-3-(5-(((3-(( tert-부톡시카르보닐)(4-(( tert-부톡시카르보닐)아미노)부틸)아미노)프로필)카르바모일)옥시)-1 H-인돌-3-일)-2-(( tert-부톡시카르보닐)아미노)프로파노에이트(0.16 g, 55%)를 수득하였다. CH 2 Cl of benzyl ( S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy- 1H -indol-3-yl)propanoate (0.15 g, 0.4 mmol) 2 To the solution were added triphosgene (0.05 g, 0.2 mmol) and pyridine (0.03 mL, 0.4 mmol). After stirring at room temperature for 30 min, N1, N5-bis-boc spermidine (0.13 g, 0.4 mmol) and pyridine (0.04 mL, 0.4 mmol) were added at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was quenched with water. Diluted with dichloromethane, washed with water and brine , dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1:3:0.1) to benzyl ( S )-3-(5-(((3-(( tert -butoxycarbonyl) ) (4 - ((tert - butoxycarbonyl) amino) butyl) amino) propyl) carbamoyl) oxy) -1 H - indol-3-yl) -2 - ((tert - butoxycarbonyl) amino ) propanoate (0.16 g, 55%) was obtained.
1H NMR (600 MHz, CDCl 3) δ 7.31 (m, 3H), 7.23 (m, 4H), 6.92 (m, 1H), 6.77 (d, 1H, J = 2.0 Hz), 5.08 (d, 2H, J = 11.1 Hz), 4.64 (d, 1H, J = 7.0 Hz), 3.33 (s, 2H), 3.24 (s, 2H), 3.21 (d, 1H, J = 5.4 Hz), 3.16 (s, 2H), 3.13 (t, 2H, J = 6.9 Hz), 1.73 (m, 2H), 1.55 (m, 2H), 1.47 (s, 9H), 1.43 (d, 18H, J = 14.0 Hz), 1.37 (s, 1H), 1.31 (m, 1H). 13C{ 1H} NMR (150 MHz, CDCl 3) δ 172.2, 156.2, 155.3, 135.5, 128.7, 128.6, 128.6, 128.4, 128.1, 111.6, 111.2, 110.3, 80.0, 67.3, 67.2, 60.5, 54.4, 46.7, 31.7, 28.6, 28.6, 28.4, 28.1, 27.6, 21.2, 14.3, 14.3. 1 H NMR (600 MHz, CDCl 3 ) δ 7.31 (m, 3H), 7.23 (m, 4H), 6.92 (m, 1H), 6.77 (d, 1H, J = 2.0 Hz), 5.08 (d, 2H, J = 11.1 Hz), 4.64 (d, 1H, J = 7.0 Hz), 3.33 (s, 2H), 3.24 (s, 2H), 3.21 (d, 1H, J = 5.4 Hz), 3.16 (s, 2H) , 3.13 (t, 2H, J = 6.9 Hz), 1.73 (m, 2H), 1.55 (m, 2H), 1.47 (s, 9H), 1.43 (d, 18H, J = 14.0 Hz), 1.37 (s, 1H), 1.31 (m, 1H). 13 C{ 1 H} NMR (150 MHz, CDCl 3 ) δ 172.2, 156.2, 155.3, 135.5, 128.7, 128.6, 128.6, 128.4, 128.1, 111.6, 111.2, 110.3, 80.0, 67.3, 67.2, 60.5, 54.4, 46.7 , 31.7, 28.6, 28.6, 28.4, 28.1, 27.6, 21.2, 14.3, 14.3.
2 단계: 3-(5-(((3-((Step 2: 3-(5-(((3-(( terttert -부톡시카르보닐)(4-((-butoxycarbonyl) (4-(( terttert -부톡시카르보닐)아미노)부틸)아미노)프로필)카르바모일)옥시)-1-Butoxycarbonyl)amino)butyl)amino)propyl)carbamoyl)oxy)-1 HH -인돌-3-일)-2-((-Indol-3-yl)-2-(( terttert -부톡시카르보닐)아미노)프로판산 (중간체)의 제조Preparation of -butoxycarbonyl)amino)propanoic acid (intermediate)
벤질 ( S)-3-(5-(((3-(( tert-부톡시카르보닐)(4-(( tert-부톡시카르보닐)아미노)부틸)아미노)프로필)카르바모일)옥시)-1 H-인돌-3-일)-2-(( tert-부톡시카르보닐)아미노)프로파노에이트 (0.16 g, 0.2 mmol)의 에틸 아세테이트 용액 및 10% dry Pd/C (4 mg, 0.04 mmol)를 수소 대기 하에서 반응시켰다. 2 시간 동안 교반시킨 후, 반응 혼합물을 메틸 알코올로 희석시키고, celite pad로 여과한 후 갑압농축하였다. 잔여물을 MPLC(20-100% CH 3CN/H 2O over 1 h)로 정제하여 목적 화합물을 수득하였다(0.07 g, 47%). benzyl ( S )-3-(5-(((3-(( tert -butoxycarbonyl)(4-(( tert -butoxycarbonyl)amino)butyl)amino)propyl)carbamoyl)oxy) -1 H -indol-3-yl)-2-(( tert -butoxycarbonyl)amino)propanoate (0.16 g, 0.2 mmol) in ethyl acetate solution and 10% dry Pd/C (4 mg, 0.04) mmol) was reacted under a hydrogen atmosphere. After stirring for 2 hours, the reaction mixture was diluted with methyl alcohol, filtered through a celite pad, and concentrated under reduced pressure. The residue was purified by MPLC (20-100% CH 3 CN/H 2 O over 1 h) to obtain the target compound (0.07 g, 47%).
1H NMR (600 MHz, MeOD) δ 7.28 (m, 2H), 7.12 (s, 1H), 6.84 (d, 1H, J = 8.7 Hz), 4.38 (m, 1H), 3.23 (m, 7H), 3.13 (d, 1H, J = 7.2 Hz), 3.06 (t, 2H, J = 6.9 Hz), 1.79 (s, 2H), 1.56 (d, 2H, J = 14.4 Hz), 1.49 (m, 9H), 1.42 (d, 18H, J = 16.1 Hz), 1.24 (s, 2H). 13C{ 1H} NMR (150 MHz, MeOD) δ 158.6, 158.4, 157.7, 145.6, 135.6, 129.3, 126.0, 116.9, 112.4, 111.9, 111.6, 81.0, 80.5, 79.9, 56.2, 41.0, 28.8, 28.8, 28.7, 28.4. 1 H NMR (600 MHz, MeOD) δ 7.28 (m, 2H), 7.12 (s, 1H), 6.84 (d, 1H, J = 8.7 Hz), 4.38 (m, 1H), 3.23 (m, 7H), 3.13 (d, 1H, J = 7.2 Hz), 3.06 (t, 2H, J = 6.9 Hz), 1.79 (s, 2H), 1.56 (d, 2H, J = 14.4 Hz), 1.49 (m, 9H), 1.42 (d, 18H, J = 16.1 Hz), 1.24 (s, 2H). 13 C{ 1 H} NMR (150 MHz, MeOD) δ 158.6, 158.4, 157.7, 145.6, 135.6, 129.3, 126.0, 116.9, 112.4, 111.9, 111.6, 81.0, 80.5, 79.9, 56.2, 41.0, 28.8, 28.8, 28.7, 28.4.
3 단계: 2-아미노-3-(5-(((3-((4-아미노부틸)아미노)프로필)카르바모일)옥시)-1Step 3: 2-Amino-3-(5-(((3-((4-aminobutyl)amino)propyl)carbamoyl)oxy)-1 HH -인돌-3-일)프로판산-Indol-3-yl)propanoic acid
3-(5-(((3-(( tert-부톡시카르보닐)(4-(( tert-부톡시카르보닐)아미노)부틸)아미노)프로필)카르바모일)옥시)-1 H-인돌-3-일)-2-(( tert-부톡시카르보닐)아미노)프로판산 (0.05 g, 0.08 mmol)를 4.0 M HCl in dioxane (3 mL)에 녹인 후 실온에서 3 시간 동안 교반하였다. 반응 용매를 제거한 뒤 diethyl ether로 희석하고 2시간 동안 교반하여 석출된 고체를 수득하였다. (0.03 g, quantitive)3- (5 - (((3 - ((tert - butoxycarbonyl) (4 - ((tert - butoxycarbonyl) amino) butyl) amino) propyl) carbamoyl) oxy) -1 H - indole -3-yl)-2-(( tert -butoxycarbonyl)amino)propanoic acid (0.05 g, 0.08 mmol) was dissolved in 4.0 M HCl in dioxane (3 mL) and stirred at room temperature for 3 hours. After removing the reaction solvent, it was diluted with diethyl ether and stirred for 2 hours to obtain a precipitated solid. (0.03 g, quantitative)
1H NMR (600 MHz, MeOD) δ 7.38 (m, 2H), 7.29 (s, 1H), 6.91 (m, 1H), 4.27 (m, 1H), 3.46 (m, 1H), 3.33 (d, 3H, J = 5.8 Hz), 3.11 (d, 4H, J = 23.5 Hz), 2.98 (t, 2H, J = 6.6 Hz), 2.02 (m, 2H), 1.81 (d, 4H, J = 27.6 Hz). 13C{ 1H} NMR (150 MHz, MeOD) δ 171.5, 158.8, 145.8, 135.9, 128.5, 127.3, 117.4, 113.0, 111.6, 108.1, 54.6, 48.4, 46.8, 40.1, 38.9, 27.8, 27.3, 25.6, 24.3. 1 H NMR (600 MHz, MeOD) δ 7.38 (m, 2H), 7.29 (s, 1H), 6.91 (m, 1H), 4.27 (m, 1H), 3.46 (m, 1H), 3.33 (d, 3H) , J = 5.8 Hz), 3.11 (d, 4H, J = 23.5 Hz), 2.98 (t, 2H, J = 6.6 Hz), 2.02 (m, 2H), 1.81 (d, 4H, J = 27.6 Hz). 13 C{ 1 H} NMR (150 MHz, MeOD) δ 171.5, 158.8, 145.8, 135.9, 128.5, 127.3, 117.4, 113.0, 111.6, 108.1, 54.6, 48.4, 46.8, 40.1, 38.9, 27.8, 27.3, 25.6, 24.3.
Figure PCTKR2020018213-appb-img-000041
Figure PCTKR2020018213-appb-img-000041
Figure PCTKR2020018213-appb-img-000042
Figure PCTKR2020018213-appb-img-000042
Figure PCTKR2020018213-appb-img-000043
Figure PCTKR2020018213-appb-img-000043
Figure PCTKR2020018213-appb-img-000044
Figure PCTKR2020018213-appb-img-000044
Figure PCTKR2020018213-appb-img-000045
Figure PCTKR2020018213-appb-img-000045
표 1의 실시예 화합물 22 내지 51은 상기 실시예 1 내지 21과 유사한 방법으로 합성되었다.Examples compounds 22 to 51 of Table 1 were synthesized in a manner similar to Examples 1 to 21 above.
[실험예 1] [Experimental Example 1]
메틸글리옥살(methylglyoxal, MGO) 포획능 분석 (1) : 형광강도 분석Analysis of methylglyoxal (MGO) capture ability (1): analysis of fluorescence intensity
메틸글리옥살(methylglyoxal: MGO)은 당뇨병으로 인한 합병증을 유발시키는 최종당화산물의 주요 전구체로서, 메틸글리옥살(MGO)를 성공적으로 포획(trapping)하는 경우에는, 최종당화산물의 생성을 억제할 수 있다. 따라서 본 실시예에서는 본 발명의 화합물이 최종당화산물 생성 이전의 전구체인 메틸글리옥살(MGO)를 포획하는 능력을 갖는지를 확인하고자 하였다. Methylglyoxal (MGO) is a major precursor of final glycation products that cause complications due to diabetes. have. Therefore, in this example, it was attempted to confirm whether the compound of the present invention has the ability to capture methylglyoxal (MGO), a precursor before the formation of the final glycation product.
메틸글리옥살(MGO)을 phosphate buffered saline (PBS, Cat no. 10010023, pH 7.4)에 첨가하여 혼합물을 제조하였다. 상기 혼합물 (MGO+PBS)에 실시예 각각의 화합물을 1.0 mM 농도로 처리한 후, 37℃에서 7일간 배양하였다. 배양 후 1일 및 7일째에, 반응 생성물의 형광강도 (fluorescence intensity)를 VICTOR TMX3 multilabel plate reader를 이용하여 355nm의 여기 파장 및 460nm의 방출 파장에서 측정하였다. 각 화합물에 대해 얻어진 형광강도를 표 2에 나타내었다. Methylglyoxal (MGO) was added to phosphate buffered saline (PBS, Cat no. 10010023, pH 7.4) to prepare a mixture. The mixture (MGO+PBS) was treated with the compound of each of Examples at a concentration of 1.0 mM, and then cultured at 37°C for 7 days. On days 1 and 7 after incubation, the fluorescence intensity of the reaction product was measured at an excitation wavelength of 355 nm and an emission wavelength of 460 nm using a VICTOR TM X3 multilabel plate reader. The fluorescence intensity obtained for each compound is shown in Table 2.
화합물이 메틸글리옥살과 반응하여 생성된 반응 생성물은 형광을 나타내는데, 반응 생성물로부터 측정된 형광강도가 높을수록 해당 화합물이 메틸글리옥살을 포획(trapping)하는 능력이 높음을 나타낸다. 또한 본 실시예에서는 형광강도가 10 X 10 3 이상인 경우, 해당 화합물이 메틸글리옥살의 포획능을 갖는 것으로 판단하였다. The reaction product produced by the reaction of the compound with methylglyoxal exhibits fluorescence. The higher the fluorescence intensity measured from the reaction product, the higher the ability of the compound to trap methylglyoxal. In addition, in this example, when the fluorescence intensity is 10 X 10 3 or more, it was determined that the compound has the ability to capture methylglyoxal.
표 2에 나타낸 바와 같이, 본 발명의 화합물은 우수한 메틸글리옥살 포획능을 갖는 것으로 확인되었다.As shown in Table 2, the compounds of the present invention were confirmed to have excellent methylglyoxal capture ability.
Figure PCTKR2020018213-appb-img-000046
Figure PCTKR2020018213-appb-img-000046
[실험예 2] [Experimental Example 2]
메틸글리옥살 (methylglyoxal, MGO) 포획능 분석 (2) : HPLC 분석Analysis of methylglyoxal (MGO) capture capacity (2): HPLC analysis
본 실시예에서는 유리 메틸글리옥살(MGO) 농도를 고성능 액체크로마토그래피(high-performance liquid chromatography: HPLC)로 분석함으로써, 본 발명의 화합물의 메틸글리옥살(MGO) 포획능을 확인하고자 하였다. In this example, by analyzing the free methylglyoxal (MGO) concentration by high-performance liquid chromatography (HPLC), it was attempted to confirm the methylglyoxal (MGO) capture ability of the compound of the present invention.
구체적으로, 메틸글리옥살(MGO)을 phosphate buffered saline (PBS, Cat no. 10010023, pH 7.4)에 첨가하여 혼합물을 제조하였다. 상기 혼합물 (MGO+PBS)에 실시예 각각의 화합물을 메틸글리옥살(MGO)와 1:1의 농도가 되도록 첨가하여 반응시킨 후, 37℃에서 7일간 배양하였다. 배양 후 1일 및 7일째에, 실시예 화합물과 반응하지 않은 유리 메틸글리옥살(free MGO)의 농도를 HPLC로 측정하였다. 그 결과를 도 1 및 2에 나타내었다. Specifically, methylglyoxal (MGO) was added to phosphate buffered saline (PBS, Cat no. 10010023, pH 7.4) to prepare a mixture. Each compound of Examples was added to the mixture (MGO+PBS) at a concentration of 1:1 with methylglyoxal (MGO) to react, and then cultured at 37°C for 7 days. On days 1 and 7 after incubation, the concentration of free methylglyoxal (free MGO) unreacted with the example compound was measured by HPLC. The results are shown in FIGS. 1 and 2 .
도 1 및 2로부터 확인할 수 있는 바와 같이, 본 발명의 화합물은 대조군(N : PBS + MGO)와 비교하여, 유리 메틸글리옥살(free MGO)의 농도를 거의 절반 이하로 감소시키는 것으로 확인되었다. 특히, 실시예 9의 화합물을 처리하였을 때의 배양 후 7일째의 유리 메틸글리옥살의 농도는, 대조군의 약 10% 내지 15% 정도로 감소되었고, 실시예 13의 화합물을 처리시에는 약 4% 정도까지 감소되었다. As can be seen from Figures 1 and 2, the compound of the present invention was confirmed to reduce the concentration of free methylglyoxal (free MGO) by almost half or less as compared to the control (N: PBS + MGO). In particular, when the compound of Example 9 was treated, the concentration of free methylglyoxal on the 7th day after culture was reduced to about 10% to 15% of the control group, and about 4% when the compound of Example 13 was treated. was reduced to
[실험예 3] [Experimental Example 3]
메틸글리옥살 (methylglyoxal, MGO) 처리로 인한 N2a 세포주에서In the N2a cell line caused by methylglyoxal (MGO) treatment 세포독성 보호 효과 측정Measurement of cytotoxic protective effect
본 실시예에서는 유리 메틸글리옥살 (MGO) 처리로 인해 세포독성을 유도하여, 본 발명의 화합물의 메티글리옥살 (MGO) 보호능을 확인하고자 하였다.In this example, by inducing cytotoxicity due to free methylglyoxal (MGO) treatment, it was attempted to confirm the methylglyoxal (MGO) protective ability of the compound of the present invention.
구체적으로, N2a 세포를 2 x 10 4 cell/well로 96 well plate에 분주하였다. 각 세포주에 500 nM의 화합물을 1시간 동안 전처리한 후 500 μM MGO를 후처리하여 24시간 동안 배양하였다. 배지를 제거한 후 0.5 mg/ml 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) 용액을 1시간 처리하고, 환원된 formazan을 150 μl의 DMSO에 녹여 570 nm 파장에서 미세분광광도계 (microspectrophotometer)로 세포 생존율 (cell viability)을 측정하였다. 아무것도 처리하지 않은 정상 대조군(Control)의 세포 생존율을 100%로 하여, 각 물질을 처리한 경우의 세포 생존율을 평가하였다. 그 결과를 하기 표 3, 도 3 및 도 4에 나타내었다.Specifically, N2a cells were seeded in a 96-well plate at 2 x 10 4 cells/well. Each cell line was pretreated with 500 nM of the compound for 1 hour, followed by post-treatment with 500 μM MGO and cultured for 24 hours. After removing the medium, 0.5 mg/ml 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution was treated for 1 hour, and the reduced formazan was dissolved in 150 μl of DMSO to 570 nm Cell viability was measured with a microspectrophotometer at wavelength. Cell viability in the case of treatment with each substance was evaluated by setting the cell viability of the normal control untreated to 100%. The results are shown in Table 3, Figures 3 and 4 below.
Figure PCTKR2020018213-appb-img-000047
Figure PCTKR2020018213-appb-img-000047
상기 표 3, 도 3 및 도 4에 나타낸 바와 같이, 실시예 화합물 10 및 11 처리군에서의 세포 생존율은 대조군 (MGO+PBS)과 비교하여 높은 것으로 확인되었다. As shown in Table 3, FIGS. 3 and 4, it was confirmed that the cell viability in the groups treated with Example Compounds 10 and 11 was higher than that of the control group (MGO+PBS).
특히, 각 세포주에서 500 μM MGO로 후처리 한 군에서는 세포 생존률이 정상 대조군 (Control)에 비하여 유의적으로 감소하였다. 이에 반해, 실시예 화합물 10 및 11을 전처리 한 군에서는 농도의존적으로 세포 생존률이 증가하였다. 따라서, 실시예 화합물 10 및 11은 우수한 MGO에 대한 보호 효능을 갖는 것을 알 수 있다.In particular, the cell viability was significantly reduced in the group treated with 500 μM MGO in each cell line compared to the normal control group (Control). In contrast, in the group pretreated with Examples 10 and 11, the cell viability increased in a concentration-dependent manner. Therefore, it can be seen that Example compounds 10 and 11 have excellent protective efficacy against MGO.
[실험예 4] [Experimental Example 4]
메틸글리옥살 (methylglyoxal, MGO) 처리로 인한 SH-SY5Y 세포주에서 세포보호 효과 측정Measurement of cytoprotective effect in SH-SY5Y cell line caused by methylglyoxal (MGO) treatment
본 실시예에서는 유리 메틸글리옥살(MGO) 처리로 인해 세포독성을 유도하여, 본 발명의 화합물의 메티글리옥살(MGO) 보호능을 확인하고자 하였다.In this example, by inducing cytotoxicity due to free methylglyoxal (MGO) treatment, it was attempted to confirm the methylglyoxal (MGO) protective ability of the compound of the present invention.
구체적으로, SH-SY5Y 세포를 2 x 10 4 cell/well로 96 well plate에 분주하였다. 각 세포주에 500 nM의 화합물을 1시간 동안 전처리한 후 500 μM MGO를 후처리하여 24시간 동안 배양하였다. 배지를 제거한 후 0.5 mg/ml 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) 용액을 1시간 처리하고, 환원된 formazan을 150 μl의 DMSO에 녹여 570 nm 파장에서 미세분광광도계(microspectrophotometer)로 세포 생존율(cell viability)을 측정하였다. 아무것도 처리하지 않은 정상 대조군(Control)의 세포 생존율을 100%로 하여, 각 물질을 처리한 경우의 세포 생존율을 평가하였다. 그 결과를 표 4, 도 5 및 도 6에 나타내었다.Specifically, SH-SY5Y cells were seeded in a 96-well plate at 2 x 10 4 cells/well. Each cell line was pretreated with 500 nM of the compound for 1 hour, followed by post-treatment with 500 μM MGO and cultured for 24 hours. After removing the medium, 0.5 mg/ml 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution was treated for 1 hour, and the reduced formazan was dissolved in 150 μl of DMSO to 570 nm Cell viability was measured with a microspectrophotometer at wavelength. Cell viability in the case of treatment with each substance was evaluated by setting the cell viability of the normal control untreated to 100%. The results are shown in Table 4, FIGS. 5 and 6 .
Figure PCTKR2020018213-appb-img-000048
Figure PCTKR2020018213-appb-img-000048
상기 표 4, 도 5 및 도 6에 나타낸 바와 같이, 실시예 화합물 4, 5, 10, 11 및 13 처리군에서의 세포 생존율은 대조군(500 μM MGO)과 비교하여 높은 것으로 확인되었다. As shown in Table 4, FIGS. 5 and 6, the cell viability in the treatment groups of Example compounds 4, 5, 10, 11 and 13 was confirmed to be higher than that of the control group (500 μM MGO).
특히, 각 세포주에서 500 μM MGO로 후처리 한 군에서는 세포 생존률이 정상 대조군 (Control)에 비하여 유의적으로 감소하였다. 이에 반해, 실시예 화합물 10 및 11을 전처리 한 군에서는 농도의존적으로 세포 생존률이 증가하였다. 따라서, 본 발명의 화합물은 우수한 MGO에 대한 보호 효능을 갖는 것을 알 수 있다.In particular, the cell viability was significantly decreased in the group treated with 500 μM MGO in each cell line compared to that of the normal control group (Control). In contrast, in the group pretreated with Examples Compounds 10 and 11, the cell viability increased in a concentration-dependent manner. Therefore, it can be seen that the compound of the present invention has excellent protective efficacy against MGO.
[실험예 5] [Experimental Example 5]
메틸글리옥살 (methylglyoxal, MGO) 처리로 인한 LDH production 측정Measurement of LDH production by methylglyoxal (MGO) treatment
본 실시예에서는 유리 메틸글리옥살(MGO) 처리로 인해 세포독성을 유도하여, 본 발명의 화합물의 메티글리옥살(MGO) 보호능을 CyQUANTTM LDH Cytotoxicity Assay kit (Invitrogen)를 이용하여 확인하였다.In this example, cytotoxicity was induced by treatment with free methylglyoxal (MGO), and the methylglyoxal (MGO) protective ability of the compound of the present invention was confirmed using CyQUANT™ LDH Cytotoxicity Assay kit (Invitrogen).
구체적으로, SH-SY5Y 세포를 2 x 10 4 cell/well로 96-well plate에 분주하고 24시간 동안 안정화시켰다. 이후, 세포에 실시예 화합물 10 및 11을 500 nM 농도로 1시간 동안 전/후 처리한 뒤에, 500 μM MGO를 전/후 처리하여 24시간 동안 배양하였다. 배지 50 μL를 substrate mix 용액과 동량으로 혼합하여 실온암소에서 30분 동안 반응시킨 후, 50 μL stop 용액을 넣고 490 nm에서 흡광도를 측정하였다. 아무것도 처리하지 않은 정상 대조군 (Control)의 LDH 함량을 100%로 하여, 각 시료처리에 따른 LDH 함량의 변화를 계산하였다. 그 결과를 하기 도 7 및 도 8에 나타내었다.Specifically, SH-SY5Y cells were seeded in a 96-well plate at 2 x 10 4 cells/well and stabilized for 24 hours. Thereafter, cells were pre/post-treated with Example Compounds 10 and 11 at a concentration of 500 nM for 1 hour, followed by pre/post-treatment with 500 μM MGO and cultured for 24 hours. 50 μL of the medium was mixed with the substrate mix solution in the same amount and reacted for 30 minutes in the dark at room temperature, 50 μL stop solution was added, and absorbance was measured at 490 nm. The change in LDH content according to each sample treatment was calculated by setting the LDH content of the normal control untreated to 100%. The results are shown in FIGS. 7 and 8 below.
도 7 및 도 8에 나타낸 바와 같이, 화합물 10 및 11 처리군에서의 LDH production 수치를 대조군 (500 μM MGO)과 비교하여 낮은 것으로 확인되었다. 특히, 각 세포주에서 500 μM MGO로 전처리 및 후처리 한 군에서 세포 생존률이 정상 대조군 (control)에 비하여 유의적으로 증가하였다. 이에 반해, 화합물 10 및 11을 전처리 및 후처리한 군에서는 LDH production이 감소하였다. 7 and 8 , it was confirmed that the LDH production level in the compound 10 and 11 treatment groups was low compared to the control group (500 μM MGO). In particular, in each cell line, the cell viability was significantly increased in the groups pre-treated and post-treated with 500 μM MGO compared to the normal control group. On the other hand, LDH production was decreased in the groups pre-treated and post-treated with compounds 10 and 11.
[실험예 6] [Experimental Example 6]
메틸글리옥살 (methylglyoxal, MGO) 처리로 인한 BrdU 측정BrdU measurement with methylglyoxal (MGO) treatment
본 실시예에서는 유리 메틸글리옥살(MGO) 처리로 인해 세포증식 억제를 유도하여, 본 발명의 화합물의 메티글리옥살(MGO) 보호능을 BrdU cell proliferation assay kit (Cell signalin)를 이용하여 확인하고자 하였다.In this example, cell proliferation inhibition was induced due to free methylglyoxal (MGO) treatment, and the protective ability of the compound of the present invention to methylglyoxal (MGO) was confirmed using the BrdU cell proliferation assay kit (Cell signalin). .
구체적으로, SH-SY5Y 세포를 2 x 10 4 cell/well로 96-well plate에 분주하고 24시간 동안 안정화시켰다. 이후, 세포에 화합물 10 및 11을 500 nM 농도로 1시간 동안 전/후 처리한 뒤에, 500 μM MGO를 전/후 처리하여 24시간 동안 배양하였다. 24시간 후, fixing solution을 200 μL 처리하고 상온에서 30분 반응시켰다. Washing buffer로 3번 세척한 후, BrdU 1차 항체를 처리하여 1시간 반응시켰다. Washing buffer로 세척한 후, TMB peroxidase 기질을 첨가해 30분간 반응시켰다. 30분 후, stop solution을 이용해 반응을 중지시켰다. 미세분광광도계 (microspectrophotometer)로 450/550 nm에서 흡광도를 측정하였다. 아무것도 처리하지 않은 정상 대조군(Control)의 세포증식률을 100%로 하여, 각 시료처리에 따른 세포증식의 변화를 계산하여, 그 결과를 도 9 및 도 10에 나타내었다.Specifically, SH-SY5Y cells were seeded in a 96-well plate at 2 x 10 4 cells/well and stabilized for 24 hours. Thereafter, cells were pre/post-treated with compounds 10 and 11 at a concentration of 500 nM for 1 hour, followed by pre/post-treatment with 500 μM MGO and cultured for 24 hours. After 24 hours, 200 μL of the fixing solution was treated and reacted at room temperature for 30 minutes. After washing 3 times with washing buffer, the BrdU primary antibody was treated and reacted for 1 hour. After washing with washing buffer, TMB peroxidase substrate was added and reacted for 30 minutes. After 30 minutes, the reaction was stopped using a stop solution. Absorbance was measured at 450/550 nm with a microspectrophotometer. With the cell proliferation rate of the normal control untreated as 100%, the change in cell proliferation according to each sample treatment was calculated, and the results are shown in FIGS. 9 and 10 .
도 9 및 도 10에 나타낸 바와 같이, 화합물 10 및 11 처리군에서의 세포 증식률이 대조군 (500 μM MGO)과 비교하여 높은 것으로 확인되었다. As shown in FIGS. 9 and 10 , it was confirmed that the cell proliferation rate in the compound 10 and 11 treatment groups was higher than that of the control group (500 μM MGO).
특히, 각 세포주에서 500 μM MGO로 후처리 한 군에서는 세포 증식률이 정상군 (control)에 비하여 유의적으로 감소하였다. 이에 반해, 화합물 10 및 11을 후처리 한 군에서는 세포 증식률이 증가하였다.In particular, the cell proliferation rate was significantly decreased in the group treated with 500 μM MGO in each cell line compared to the normal group (control). In contrast, in the group treated with compounds 10 and 11, the cell proliferation rate was increased.
[실험예 7] [Experimental Example 7]
L-DOPA 처리로 인한 세포독성 보호효과 측정Measurement of cytotoxic protective effect due to L-DOPA treatment
본 실시예에서는 유리 L-DOPA 처리로 인해 세포독성을 유도하여, 본 발명의 화합물의 L-DOPA 보호능을 확인하고자 하였다.In this example, by inducing cytotoxicity due to free L- DOPA treatment, it was attempted to confirm the L- DOPA protective ability of the compound of the present invention.
구체적으로, SH-SY5Y 세포를 2 x 104 cell/well로 96-well plate에 분주하고 24시간 동안 안정화시켰다. 이후, 세포에 화합물 10 및 11을 1, 5 및 10 μM 농도로 1시간 동안 전/후 처리한 뒤에, 100 μM L-DOPA를 전/후 처리하여 24시간 동안 배양하였다. 배지를 제거한 후, 배지를 제거한 후 0.5 mg/ml MTT 용액을 1시간 처리하고, 환원된 formazan을 150 μl의 DMSO에 녹여 570 nm 파장에서 미세분광광도계(microspectrophotometer)로 세포 생존율(cell viability)을 측정하였다. 아무것도 처리하지 않은 정상 대조군(Control)의 세포생존률을 100%로 하여, 각 시료처리에 따른 세포보호의 변화를 측정하여 그 결과를 도 11 및 도 12에 나타내었다. Specifically, SH-SY5Y cells were seeded in a 96-well plate at 2 x 104 cells/well and stabilized for 24 hours. Thereafter, the cells were pre/post-treated with compounds 10 and 11 at concentrations of 1, 5, and 10 μM for 1 hour, and then treated with 100 μM L- DOPA before/after and cultured for 24 hours. After removing the medium, 0.5 mg/ml MTT solution was treated for 1 hour after removing the medium, and the reduced formazan was dissolved in 150 μl of DMSO to measure cell viability with a microspectrophotometer at 570 nm wavelength. did. A change in cell protection according to each sample treatment was measured with the cell viability of the normal control untreated as 100%, and the results are shown in FIGS. 11 and 12 .
도 11 및 도 12에 나타낸 바와 같이, 화합물 10 및 11 처리군에서의 세포독성 수치가 대조군 (500 μM MGO)에 비해 낮은 것으로 확인되었다. As shown in FIGS. 11 and 12 , it was confirmed that the cytotoxicity level in the compound 10 and 11 treatment groups was lower than that of the control group (500 μM MGO).
특히, 각 세포주에서 100 μM L-DOPA로 처리한 군에서는 세포 증식률이 정상군 (control)에 비하여 유의적으로 감소하였다. 이에 반해, 화합물 10 및 11 처리군에서는 세포 생존률이 유의적으로 증가하였다. In particular, in the group treated with 100 μM L- DOPA in each cell line, the cell proliferation rate was significantly reduced compared to that of the normal group (control). In contrast, the cell viability was significantly increased in the compounds 10 and 11 treatment groups.
[실험예 8] [Experimental Example 8]
MGO + L-DOPA 처리로 인한 세포독성 보호효과 측정Measurement of cytotoxic protective effect by MGO + L -DOPA treatment
본 실시예에서는 유리 MGO + L-DOPA 처리로 인해 세포독성을 유도하여, 본 발명의 화합물의 MGO + L-DOPA 보호능을 확인하고자 하였다.In this example, free MGO + L -DOPA Inducing cytotoxicity due to treatment, MGO + L- DOPA of the compounds of the present invention It was intended to confirm the protective ability.
SH-SY5Y 세포를 2 x 10 4 cell/well로 96-well plate에 분주하고 24시간 동안 안정화시켰다. 이후, 세포에 화합물 10, 및 11의 화합물을 500 nM 농도로 30분 동안 전/후 처리한 뒤에, 500 μM MGO를 전/후 처리하여 24시간 동안 배양하였다. 배지를 제거한 후, 배지를 제거한 후 0.5 mg/ml MTT 용액을 1시간 처리하고, 환원된 formazan을 150 μl의 DMSO에 녹여 570 nm 파장에서 미세분광광도계(microspectrophotometer)로 세포 생존율 (cell viability)을 측정하였다. 아무것도 처리하지 않은 정상 대조군 (Control)의 세포 생존율을 100%로 하여, MGO 처리한 경우의 세포 생존율을 측정하여 도 13 및 도 14에 나타내었다.SH-SY5Y cells were seeded in a 96-well plate at 2 x 10 4 cells/well and stabilized for 24 hours. Thereafter, cells were pre/post-treated with compounds 10 and 11 at a concentration of 500 nM for 30 minutes, followed by pre/post-treatment with 500 μM MGO and cultured for 24 hours. After removing the medium, 0.5 mg/ml MTT solution was treated for 1 hour after removing the medium, and the reduced formazan was dissolved in 150 μl of DMSO to measure cell viability with a microspectrophotometer at 570 nm wavelength. did. The cell viability of the untreated normal control group (Control) was set to 100%, and the cell viability when treated with MGO was measured and shown in FIGS. 13 and 14 .
도 13 및 도 14에 나타낸 바와 같이, 화합물 10 및 11 처리군에서의 세포 증식률이 대조군 (MGO + L-DOPA)에 비해 높은 것으로 확인되었다. 13 and 14 , it was confirmed that the cell proliferation rate in the compound 10 and 11 treatment groups was higher than that of the control group (MGO + L-DOPA).
특히, 각 세포주에서 MGO + L-DOPA로 처리군에서는 세포 증식률이 정상군 (control)에 비하여 유의적으로 감소하였다. 이에 반해, 본 발명의 화합물 10 및 11 처리군에 농도의존적으로 세포 생존률이 증가하였다. In particular, in each cell line, the cell proliferation rate was significantly decreased in the group treated with MGO + L-DOPA compared to the normal group (control). In contrast, the cell viability increased in a concentration-dependent manner in the groups treated with compounds 10 and 11 of the present invention.
[실험예 9] [Experimental Example 9]
MGO 처리로 인한 염증성 사이토카인 측정Measurement of inflammatory cytokines due to MGO treatment
본 실시예에서는 유리 MGO 처리로 인해 세포독성을 유도하여, 본 발명의 화합물의 MGO 보호능을 확인하고자 하였다.In this example, by inducing cytotoxicity due to free MGO treatment, it was attempted to confirm the MGO protective ability of the compound of the present invention.
단핵구세포 THP-1세포에서 CD14, CD68의 발현량을 비교하기 위하여, 역전사 중합효소연쇄반응(RTPCR)을 수행하였다. 트리졸(Invitrogen)을 이용하여 간 및 지방조직으로부터 RNA를 분리하고 rimeScript TM RT Master Mix 합성키트(Takara)를 이용하여 cDNA를 합성하였다. Real-time PCR은 Mx3000/Mx3005P Real-Time PCR System(Agilent)에서 TB Green® Premix Ex Taq TM II(Takara)를 이용하여 3회 반복으로 수행되었다. 내생 표준유전자 액틴의 발현에 delta cycle threshold method를 이용하여 비례적으로 타겟유전자의 발현을 측정하여 그 결과를 도 15에 나타내었다.To compare the expression levels of CD14 and CD68 in monocyte THP-1 cells, reverse transcription polymerase chain reaction (RTPCR) was performed. RNA was isolated from liver and adipose tissue using Trizol (Invitrogen), and cDNA was synthesized using rimeScript TM RT Master Mix synthesis kit (Takara). Real-time PCR was performed in triplicate using TB Green® Premix Ex Taq TM II (Takara) in Mx3000/Mx3005P Real-Time PCR System (Agilent). The expression of the target gene was proportionally measured using the delta cycle threshold method for the expression of the endogenous standard gene actin, and the results are shown in FIG. 15 .
도 15에 나타낸 바와 같이, 화합물 10 및 11 처리군에서의 염증성 사이토카인 수치가 대조군 (MGO)에 비해 낮은 것으로 확인되었다.As shown in FIG. 15 , it was confirmed that the levels of inflammatory cytokines in the compounds 10 and 11 treated groups were lower than in the control group (MGO).

Claims (19)

  1. 하기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염:A compound of formula (I): or a pharmaceutically acceptable salt thereof:
    [화학식 I][Formula I]
    Figure PCTKR2020018213-appb-img-000049
    Figure PCTKR2020018213-appb-img-000049
    상기 식에서,In the above formula,
    R 1은 수소, 할로, 알킬, 알케닐, 또는 알키닐이고,R 1 is hydrogen, halo, alkyl, alkenyl, or alkynyl,
    R 2는 수소; -N(Ra)(Rb)로 치환되거나 비치환된 알킬; 또는 - N(Ra)(Rb) 또는 알킬로 치환되거나 비치환된 아릴이고,R 2 is hydrogen; -N(Ra)(Rb) unsubstituted or substituted alkyl; or - aryl unsubstituted or substituted with N(Ra)(Rb) or alkyl;
    Ra 또는 Rb는 각각 독립적으로 수소 또는 알킬이고,Ra or Rb is each independently hydrogen or alkyl,
    R 3은 수소; -(CH 2)n-C(Rc)(N(Rd)(Re))(COORf); 또는 -(CH 2)n-C(Rc)(N(Rd)(Re))(C(=O)Rf)이고, R 3 is hydrogen; -(CH 2 )nC(Rc)(N(Rd)(Re))(COORf); or -(CH 2 )nC(Rc)(N(Rd)(Re))(C(=O)Rf),
    Rc는 수소 또는 알킬이고,Rc is hydrogen or alkyl,
    Rd 또는 Re는 각각 독립적으로 수소, -C(=O)알킬 , -C(=O)알킬-O-알킬, -C(=O)알킬-시클로알킬, -C(=O)알킬-알케닐, -C(=O)O-알킬, 또는 -NH-알킬-NH-알킬-NH 2이고,Rd or Re are each independently hydrogen, -C(=O)alkyl , -C(=O)alkyl-O-alkyl, -C(=O)alkyl-cycloalkyl, -C(=O)alkyl-alkenyl , -C(=O)O-alkyl, or -NH-alkyl-NH-alkyl-NH 2 ,
    Rf는 수소; 아릴기로 치환되거나 비치환된 알킬; 또는 -NH-알킬-NH-알킬-NH 2이고,Rf is hydrogen; alkyl unsubstituted or substituted with an aryl group; or —NH-alkyl-NH-alkyl-NH 2 ,
    R 4는 수소, 할로, 알킬, 알케닐, 또는 알키닐이고,R 4 is hydrogen, halo, alkyl, alkenyl, or alkynyl;
    R 5는 수소, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, 또는 -OC(=O)(CH 2)aS(CH2)bCH(Rg)(Rh)이고,R 5 is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or - OC(=O)(CH 2 )aS(CH2)bCH(Rg)(Rh),
    Rk는 수소; 아미노기 또는 카르복실기로 치환되거나 비치환된 알킬; 또는 -CH 2NHC(=O)CH(CH 2SH)이고,Rk is hydrogen; alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH 2 NHC(=O)CH(CH 2 SH),
    Rg 또는 Rh는 각각 독립적으로 수소, 알킬, 헤테로시클로알킬, -S(=O)알킬, Rg or Rh is each independently hydrogen, alkyl, heterocycloalkyl, -S(=O)alkyl,
    Figure PCTKR2020018213-appb-img-000050
    ,
    Figure PCTKR2020018213-appb-img-000051
    ,
    Figure PCTKR2020018213-appb-img-000052
    , 또는 -NH(CH 2)mNH 2이고,
    Figure PCTKR2020018213-appb-img-000050
    ,
    Figure PCTKR2020018213-appb-img-000051
    ,
    Figure PCTKR2020018213-appb-img-000052
    , or —NH(CH 2 )mNH 2 ,
    R 6 또는 R 7은 각각 독립적으로 수소, 할로, 알킬, 알케닐, 알키닐, -OH 또는 -O알킬이고,R 6 or R 7 are each independently hydrogen, halo, alkyl, alkenyl, alkynyl, —OH or —Oalkyl,
    a, b, n 또는 m은 1 내지 10의 정수이다. a, b, n or m is an integer from 1 to 10;
  2. 제1항에 있어서, According to claim 1,
    R 1은 수소, 또는 C 1-C 6알킬이고,R 1 is hydrogen, or C 1 -C 6 alkyl,
    R 2는 수소; -N(Ra)(Rb)로 치환되거나 비치환된 C 1-C 6알킬; 또는 - N(Ra)(Rb) 또는 C 1-C 6알킬로 치환되거나 비치환된 아릴이고,R 2 is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with —N(Ra)(Rb); or - aryl unsubstituted or substituted with N(Ra)(Rb) or C 1 -C 6 alkyl,
    Ra 또는 Rb는 각각 독립적으로 수소 또는 C 1-C 6알킬이고,Ra or Rb is each independently hydrogen or C 1 -C 6 alkyl,
    R 3은 수소; -(CH 2)n-C(Rc)(N(Rd)(Re))(COORf); 또는 -(CH 2)n-C(Rc)(N(Rd)(Re))(C(=O)Rf)이고, R 3 is hydrogen; -(CH 2 )nC(Rc)(N(Rd)(Re))(COORf); or -(CH 2 )nC(Rc)(N(Rd)(Re))(C(=O)Rf),
    Rc는 수소 또는 C 1-C 6알킬이고,Rc is hydrogen or C 1 -C 6 alkyl,
    Rd 또는 Re는 각각 독립적으로 수소, -C(=O)C 1-C 6알킬 , -C(=O)C 1-C 6알킬-O-C 1-C 6알킬, -C(=O)C 1-C 6알킬-C 3-C 7시클로알킬, -C(=O)C 1-C 6알킬-C 2-C 6알케닐, -C(=O)O-C 1-C 6알킬, 또는 -NH-C 1-C 6알킬-NH-C 1-C 6알킬-NH 2이고,Rd or Re is each independently hydrogen, -C(=O)C 1 -C 6 alkyl , -C(=O)C 1 -C 6 alkyl-OC 1 -C 6 alkyl, -C(=O)C 1 -C 6 alkyl-C 3 -C 7 cycloalkyl, -C(=O)C 1 -C 6 alkyl-C 2 -C 6 alkenyl, -C(=O)OC 1 -C 6 alkyl, or -NH -C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 and
    Rf는 수소; 아릴기로 치환되거나 비치환된 C 1-C 6알킬; 또는 -NH-C 1-C 6알킬-NH-C 1-C 6알킬-NH 2이고,Rf is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with an aryl group; or -NH-C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 ,
    R 4는 수소 또는 C 1-C 6알킬이고,R 4 is hydrogen or C 1 -C 6 alkyl,
    R 5는 수소, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, 또는 -OC(=O)(CH 2)aS(CH2)bCH(Rg)(Rh)이고,R 5 is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or - OC(=O)(CH 2 )aS(CH2)bCH(Rg)(Rh),
    Rk는 수소; 아미노기 또는 카르복실기로 치환되거나 비치환된 C 1-C 6알킬; 또는 -CH 2NHC(=O)CH(CH 2SH)이고,Rk is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH 2 NHC(=O)CH(CH 2 SH),
    Rg 또는 Rh는 각각 독립적으로 수소; C 1-C 6알킬; N, O, 또는 S에서 선택된 헤테로원자를 갖는 C 3-C 10헤테로시클로알킬; -S(=O)C 1-C 6알킬;
    Figure PCTKR2020018213-appb-img-000053
    ;
    Figure PCTKR2020018213-appb-img-000054
    ;
    Figure PCTKR2020018213-appb-img-000055
    ; 또는 -NH(CH 2)mNH 2이고    Rg or Rh are each independently hydrogen; C 1 -C 6 alkyl; C 3 -C 10 heterocycloalkyl having a heteroatom selected from N, O, or S; -S(=O)C 1 -C 6 alkyl;
    Figure PCTKR2020018213-appb-img-000053
    ;
    Figure PCTKR2020018213-appb-img-000054
    ;
    Figure PCTKR2020018213-appb-img-000055
    ; or -NH(CH 2 )mNH 2 and
    R 6 또는 R 7은 각각 독립적으로 수소, C 1-C 6알킬, -OH 또는 -O-C 1-C 6알킬이고,R 6 or R 7 are each independently hydrogen, C 1 -C 6 alkyl, —OH or —OC 1 -C 6 alkyl,
    a, b, n 또는 m은 1 내지 5의 정수인,a, b, n or m is an integer from 1 to 5;
    화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염.A compound of formula (I) or a pharmaceutically acceptable salt thereof.
  3. 제1항에 있어서, According to claim 1,
    R 1은 수소이고,R 1 is hydrogen,
    R 2는 수소; NH 2로 치환되거나 비치환된 C 1-C 6알킬; 또는 NH 2 또는 C 1-C 6알킬로 치환되거나 비치환된 아릴이고,R 2 is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with NH 2 ; or aryl unsubstituted or substituted with NH 2 or C 1 -C 6 alkyl,
    R 3은 수소; -(CH 2)n-CH(N(Rd)(Re))(COORf); 또는 -(CH 2)n-CH(N(Rd)(Re))(C(=O)Rf)이고, R 3 is hydrogen; -(CH 2 )n-CH(N(Rd)(Re))(COORf); or -(CH 2 )n-CH(N(Rd)(Re))(C(=O)Rf),
    Rd 또는 Re는 각각 독립적으로 수소, -C(=O)C 1-C 6알킬 , -C(=O)C 1-C 6알킬-O-C 1-C 6알킬, -C(=O)C 1-C 6알킬-C 3-C 7시클로알킬, -C(=O)C 1-C 6알킬-C 2-C 6알케닐, -C(=O)O-C 1-C 6알킬, 또는 -NH-C 1-C 6알킬-NH-C 1-C 6알킬-NH 2이고,Rd or Re is each independently hydrogen, -C(=O)C 1 -C 6 alkyl , -C(=O)C 1 -C 6 alkyl-OC 1 -C 6 alkyl, -C(=O)C 1 -C 6 alkyl-C 3 -C 7 cycloalkyl, -C(=O)C 1 -C 6 alkyl-C 2 -C 6 alkenyl, -C(=O)OC 1 -C 6 alkyl, or -NH -C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 and
    Rf는 수소; 아릴기로 치환되거나 비치환된 C 1-C 6알킬; 또는 -NH-C 1-C 6알킬-NH-C 1-C 6알킬-NH 2이고,Rf is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with an aryl group; or -NH-C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 ,
    R 4는 수소 또는 C 1-C 6알킬이고,R 4 is hydrogen or C 1 -C 6 alkyl,
    R 5는 수소, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, 또는
    Figure PCTKR2020018213-appb-img-000056
    이고,    R 5 is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or
    Figure PCTKR2020018213-appb-img-000056
    ego,
    Rk는 수소; 아미노기 또는 카르복실기로 치환되거나 비치환된 C 1-C 6알킬; 또는 -CH 2NHC(=O)CH(CH 2SH)이고,Rk is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH 2 NHC(=O)CH(CH 2 SH),
    Rg 또는 Rh는 각각 독립적으로 수소; C 1-C 6알킬; S에서 선택된 헤테로원자를 갖는 C 3-C 7헤테로시클로알킬; -S(=O)C 1-C 6알킬;
    Figure PCTKR2020018213-appb-img-000057
    ;
    Figure PCTKR2020018213-appb-img-000058
    ;
    Figure PCTKR2020018213-appb-img-000059
    ; 또는 -NH(CH 2)mNH 2이고    Rg or Rh are each independently hydrogen; C 1 -C 6 alkyl; C 3 -C 7 heterocycloalkyl having a heteroatom selected from S; -S(=O)C 1 -C 6 alkyl;
    Figure PCTKR2020018213-appb-img-000057
    ;
    Figure PCTKR2020018213-appb-img-000058
    ;
    Figure PCTKR2020018213-appb-img-000059
    ; or -NH(CH 2 )mNH 2 and
    R 6 또는 R 7은 각각 독립적으로 수소, C 1-C 6알킬, -OH 또는 -O-C 1-C 6알킬이고,R 6 or R 7 are each independently hydrogen, C 1 -C 6 alkyl, —OH or —OC 1 -C 6 alkyl,
    n 또는 m은 1 내지 5의 정수인,n or m is an integer from 1 to 5;
    화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염.A compound of formula (I) or a pharmaceutically acceptable salt thereof.
  4. 제1항에 있어서, According to claim 1,
    R 1은 수소이고,R 1 is hydrogen,
    R 2는 수소; -C 1-C 6알킬-NH 2; 또는 NH 2로 치환되거나 비치환된 페닐이고,R 2 is hydrogen; -C 1 -C 6 alkyl-NH 2 ; Or NH 2 substituted or unsubstituted phenyl,
    R 3은 수소; -(CH 2)n-CH(N(Rd)(Re))(COORf); 또는 -(CH 2)n-CH(N(Rd)(Re))(C(=O)Rf)이고, R 3 is hydrogen; -(CH 2 )n-CH(N(Rd)(Re))(COORf); or -(CH 2 )n-CH(N(Rd)(Re))(C(=O)Rf),
    Rd 또는 Re는 각각 독립적으로 수소, -C(=O)C 1-C 6알킬 , -C(=O)C 1-C 6알킬-O-C 1-C 6알킬, -C(=O)C 1-C 6알킬-C 3-C 7시클로알킬, -C(=O)C 1-C 6알킬-C 2-C 6알케닐, -C(=O)O-C 1-C 6알킬, 또는 -NH-C 1-C 6알킬-NH-C 1-C 6알킬-NH 2이고,Rd or Re is each independently hydrogen, -C(=O)C 1 -C 6 alkyl , -C(=O)C 1 -C 6 alkyl-OC 1 -C 6 alkyl, -C(=O)C 1 -C 6 alkyl-C 3 -C 7 cycloalkyl, -C(=O)C 1 -C 6 alkyl-C 2 -C 6 alkenyl, -C(=O)OC 1 -C 6 alkyl, or -NH -C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 and
    Rf는 수소, C 1-C 6알킬, 벤질 또는 -NH-C 1-C 6알킬-NH-C 1-C 6알킬-NH 2이고,Rf is hydrogen, C 1 -C 6 alkyl, benzyl or —NH-C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl-NH 2 ,
    R 4는 수소이고,R 4 is hydrogen,
    R 5는 수소, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, 또는
    Figure PCTKR2020018213-appb-img-000060
    이고,    R 5 is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or
    Figure PCTKR2020018213-appb-img-000060
    ego,
    Rk는 수소; 아미노기 또는 카르복실기로 치환되거나 비치환된 C 1-C 6알킬; 또는 -CH 2NHC(=O)CH(CH 2SH)이고,Rk is hydrogen; C 1 -C 6 alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH 2 NHC(=O)CH(CH 2 SH),
    Rg 또는 Rh는 각각 독립적으로 수소; C 1-C 6알킬; S에서 선택된 헤테로원자를 갖는 C 3-C 7헤테로시클로알킬; -S(=O)C 1-C 6알킬;
    Figure PCTKR2020018213-appb-img-000061
    ;
    Figure PCTKR2020018213-appb-img-000062
    ;
    Figure PCTKR2020018213-appb-img-000063
    ; 또는 -NH(CH 2)mNH 2이고    Rg or Rh are each independently hydrogen; C 1 -C 6 alkyl; C 3 -C 7 heterocycloalkyl having a heteroatom selected from S; -S(=O)C 1 -C 6 alkyl;
    Figure PCTKR2020018213-appb-img-000061
    ;
    Figure PCTKR2020018213-appb-img-000062
    ;
    Figure PCTKR2020018213-appb-img-000063
    ; or -NH(CH 2 )mNH 2 and
    R 6은 수소, -OH 또는 -O-C 1-C 6알킬이고R 6 is hydrogen, —OH or —OC 1 -C 6 alkyl
    R 7은 수소이고,R 7 is hydrogen,
    n 또는 m은 1 내지 5의 정수인,n or m is an integer from 1 to 5;
    화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염.A compound of formula (I) or a pharmaceutically acceptable salt thereof.
  5. 제1항에 있어서, According to claim 1,
    R 1은 수소이고,R 1 is hydrogen,
    R 2는 수소, -CH 2NH 2, 또는 NH 2로 치환된 페닐이고, R 2 is hydrogen, —CH 2 NH 2 , or phenyl substituted with NH 2 ,
    R 3은 수소,
    Figure PCTKR2020018213-appb-img-000064
    ,    R 3 is hydrogen,
    Figure PCTKR2020018213-appb-img-000064
    ,
    Figure PCTKR2020018213-appb-img-000065
    ,
    Figure PCTKR2020018213-appb-img-000066
    ,
    Figure PCTKR2020018213-appb-img-000067
    또는
    Figure PCTKR2020018213-appb-img-000068
    이고,
    Figure PCTKR2020018213-appb-img-000065
    ,
    Figure PCTKR2020018213-appb-img-000066
    ,
    Figure PCTKR2020018213-appb-img-000067
    or
    Figure PCTKR2020018213-appb-img-000068
    ego,
    R 4는 수소이고,R 4 is hydrogen,
    R 5는 수소, -OH, -OCH 3,
    Figure PCTKR2020018213-appb-img-000069
    ,
    Figure PCTKR2020018213-appb-img-000070
    ,
    Figure PCTKR2020018213-appb-img-000071
    ,
    Figure PCTKR2020018213-appb-img-000072
    ,
    Figure PCTKR2020018213-appb-img-000073
    ,
    Figure PCTKR2020018213-appb-img-000074
    , 또는
    Figure PCTKR2020018213-appb-img-000075
    이고,     R 5 is hydrogen, -OH, -OCH 3 ,
    Figure PCTKR2020018213-appb-img-000069
    ,
    Figure PCTKR2020018213-appb-img-000070
    ,
    Figure PCTKR2020018213-appb-img-000071
    ,
    Figure PCTKR2020018213-appb-img-000072
    ,
    Figure PCTKR2020018213-appb-img-000073
    ,
    Figure PCTKR2020018213-appb-img-000074
    , or
    Figure PCTKR2020018213-appb-img-000075
    ego,
    R 6은 수소, -OH, -OCH 3이고, R 6 is hydrogen, -OH, -OCH 3
    R 7은 수소이고,R 7 is hydrogen,
    단, R 2 및 R 3은 동시에 수소가 아닌 것을 특징으로 하는,with the proviso that R 2 and R 3 are not hydrogen at the same time,
    화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염.A compound of formula (I) or a pharmaceutically acceptable salt thereof.
  6. 하기 화합물로 이루어진 군으로부터 선택되는 화합물 또는 이의 약학적으로 허용가능한 염:A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof:
    Figure PCTKR2020018213-appb-img-000076
    Figure PCTKR2020018213-appb-img-000076
    Figure PCTKR2020018213-appb-img-000077
    Figure PCTKR2020018213-appb-img-000077
    Figure PCTKR2020018213-appb-img-000078
    Figure PCTKR2020018213-appb-img-000078
    Figure PCTKR2020018213-appb-img-000079
    Figure PCTKR2020018213-appb-img-000079
    Figure PCTKR2020018213-appb-img-000080
    Figure PCTKR2020018213-appb-img-000080
    Figure PCTKR2020018213-appb-img-000081
    Figure PCTKR2020018213-appb-img-000081
    Figure PCTKR2020018213-appb-img-000082
    Figure PCTKR2020018213-appb-img-000082
    Figure PCTKR2020018213-appb-img-000083
    Figure PCTKR2020018213-appb-img-000083
  7. 제1항 내지 제6항 중 어느 한 항에 따른 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 최종당화산물 관련 질환의 예방 또는 치료용 약학 조성물.A pharmaceutical composition for the prophylaxis or treatment of diseases related to final glycation products, comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
  8. 제7항에 있어서, 상기 최종당화산물 관련 질환은 노화, 당뇨병, 당뇨 합병증, 고지혈증, 고혈당증, 심혈관질환, 퇴행성 뇌질환, 자폐 스펙트럼 장애, 동맥경화, 비알코올성 지방간, 비알코올성 지방간염, 피부섬유증, 폐섬유증, 신장섬유증, 및 심장섬유증으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 약학 조성물.The method of claim 7, wherein the final glycation product-related disease is aging, diabetes, diabetic complications, hyperlipidemia, hyperglycemia, cardiovascular disease, degenerative brain disease, autism spectrum disorder, arteriosclerosis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, skin fibrosis, A pharmaceutical composition, characterized in that it is selected from the group consisting of pulmonary fibrosis, renal fibrosis, and cardiac fibrosis.
  9. 제7항에 있어서, 상기 최종당화산물 관련 질환은 당뇨병 또는 당뇨 합병증인 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 7, wherein the final glycation product-related disease is diabetes or a diabetic complication.
  10. 제9항에 있어서, 상기 당뇨병은 제2 당뇨병인 것을 특징으로 하는, 약학 조성물.The pharmaceutical composition according to claim 9, wherein the diabetes is second diabetes.
  11. 제9항에 있어서, 상기 당뇨 합병증은 당뇨병성 신장병증, 당뇨병성 망막증, 당뇨병성 백내장, 당뇨병성 신경병증, 당뇨병성 족부궤양, 당뇨병성 심혈관 질환, 당뇨병성 동맥경화, 당뇨병성 골다공증, 당뇨병성 근감소증, 및 비만으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 약학 조성물.10. The method of claim 9, wherein the diabetic complications are diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, diabetic osteoporosis, diabetic muscle. A pharmaceutical composition, characterized in that it is selected from the group consisting of hypothyroidism, and obesity.
  12. 제8항에 있어서, 상기 퇴행성 뇌질환은 알츠하이머, 파킨슨병, 헌팅턴병, 피크병, 크로이츠펠트-야콥병, 루게릭병, 척수소뇌변성증, 프리드리히 운동실조증, 척수소뇌 실조증, 마카도-조셉병, 근육긴장이상, 진행성 핵상 마비, 인지기능장애, 노인성 치매, 루이소체 치매, 전두측두엽 치매, 혈관성 치매, 알코올성 치매, 초로기 치매, 측두엽 간질, 및 뇌졸중으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 약학 조성물.The method of claim 8, wherein the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph disease, dystonia , progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, senile dementia, temporal lobe epilepsy, and a pharmaceutical composition, characterized in that selected from the group consisting of stroke.
  13. 제1항 내지 제6항 중 어느 한 항에 따른 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물.A food composition for preventing or ameliorating a disease related to the final glycation product, comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
  14. 제13항에 있어서, 상기 최종당화산물 관련 질환은 노화, 당뇨병, 당뇨 합병증, 고지혈증, 고혈당증, 심혈관질환, 퇴행성 뇌질환, 자폐 스펙트럼 장애, 동맥경화, 비알코올성 지방간, 비알코올성 지방간염, 피부섬유증, 폐섬유증, 신장섬유증, 및 심장섬유증으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 식품 조성물.The method of claim 13, wherein the final glycation product-related disease is aging, diabetes, diabetic complications, hyperlipidemia, hyperglycemia, cardiovascular disease, degenerative brain disease, autism spectrum disorder, arteriosclerosis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, skin fibrosis, A food composition, characterized in that it is selected from the group consisting of pulmonary fibrosis, renal fibrosis, and cardiac fibrosis.
  15. 제13항에 있어서, 상기 최종당화산물 관련 질환은 당뇨병 또는 당뇨 합병증인 것을 특징으로 하는, 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물.[Claim 14] The food composition for preventing or improving end-glycated product-related disease according to claim 13, wherein the end-glycated product-related disease is diabetes or a diabetic complication.
  16. 제15항에 있어서, 상기 당뇨병은 제2 당뇨병인 것을 특징으로 하는, 식품 조성물.The food composition according to claim 15, wherein the diabetes is second diabetes.
  17. 제15항에 있어서, 상기 당뇨 합병증은 당뇨병성 신장병증, 당뇨병성 망막증, 당뇨병성 백내장, 당뇨병성 신경병증, 당뇨병성 족부궤양, 당뇨병성 심혈관 질환, 당뇨병성 동맥경화, 당뇨병성 골다공증, 당뇨병성 근감소증 및 비만으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물.16. The method of claim 15, wherein the diabetic complications are diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, diabetic osteoporosis, diabetic muscle. A food composition for the prevention or improvement of diseases related to final glycation products, characterized in that it is selected from the group consisting of atrophy and obesity.
  18. 제14항에 있어서, 상기 퇴행성 뇌질환은 알츠하이머, 파킨슨병, 헌팅턴병, 피크병, 크로이츠펠트-야콥병, 루게릭병, 척수소뇌변성증, 프리드리히 운동실조증, 척수소뇌 실조증, 마카도-조셉병, 근육긴장이상, 진행성 핵상 마비, 인지기능장애, 노인성 치매, 루이소체 치매, 전두측두엽 치매, 혈관성 치매, 알코올성 치매, 초로기 치매, 측두엽 간질, 및 뇌졸중으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물.15. The method of claim 14, wherein the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia , progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, senile dementia, temporal lobe epilepsy, and stroke. Food composition for the prevention or improvement of.
  19. 제1항 내지 제6항 중 어느 한 항에 따른 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 최종당화산물 관련 질환의 예방 또는 개선용 동물용 사료 조성물.[Claim 7] A feed composition for animals for preventing or improving diseases related to final glycation products, comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
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