[go: up one dir, main page]

WO2021118318A2 - Nouveau dérivé d'indole et son utilisation - Google Patents

Nouveau dérivé d'indole et son utilisation Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
diabetic
disease
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2020/018213
Other languages
English (en)
Korean (ko)
Other versions
WO2021118318A3 (fr
Inventor
박명규
이은주
서승용
이산하
이정은
김선여
홍성민
이재혁
강민철
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Metacen Therapeutics
Original Assignee
Metacen Therapeutics
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Metacen Therapeutics filed Critical Metacen Therapeutics
Publication of WO2021118318A2 publication Critical patent/WO2021118318A2/fr
Publication of WO2021118318A3 publication Critical patent/WO2021118318A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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 .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Food Science & Technology (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Zoology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Mycology (AREA)
  • Animal Husbandry (AREA)
  • Nutrition Science (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau dérivé d'indole et une utilisation de celui-ci. Le nouveau dérivé d'indole de la présente invention capture le méthylglyoxal (MGO)), qui est un précurseur majeur de produits finaux de glycation avancée, et présente un excellent effet cytoprotecteur, ce qui lui permet de trouver des applications avantageuses dans la prévention ou le traitement de maladies associées à des produits finaux de glycation avancée.
PCT/KR2020/018213 2019-12-13 2020-12-11 Nouveau dérivé d'indole et son utilisation Ceased WO2021118318A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2019-0166432 2019-12-13
KR20190166432 2019-12-13

Publications (2)

Publication Number Publication Date
WO2021118318A2 true WO2021118318A2 (fr) 2021-06-17
WO2021118318A3 WO2021118318A3 (fr) 2021-07-29

Family

ID=76330224

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2020/018213 Ceased WO2021118318A2 (fr) 2019-12-13 2020-12-11 Nouveau dérivé d'indole et son utilisation

Country Status (2)

Country Link
KR (1) KR102323893B1 (fr)
WO (1) WO2021118318A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20220167804A (ko) * 2021-06-11 2022-12-22 주식회사 메타센테라퓨틱스 인돌 유도체를 포함하는 최종당화산물 관련 질환의 치료용 조성물
KR20220167441A (ko) * 2021-06-11 2022-12-21 주식회사 메타센테라퓨틱스 신규한 인돌 유도체 및 이의 최종당화산물 관련 질환의 치료 용도
KR20230168288A (ko) 2022-06-03 2023-12-14 주식회사 메타센테라퓨틱스 메틸글리옥살에 대한 내성을 갖는 신규한 균주 및 이의 용도

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2013391A6 (es) * 1989-02-08 1990-05-01 Consejo Superior Investigacion Procedimiento para la preparacion de derivados acetilenicos y alenicos de 2-aminometil -5-metoxiindoles.
US7084154B2 (en) * 2003-02-11 2006-08-01 Pharmacopeia Drug Disclovery, Inc. 2-(aminomethyl) arylamide analgesics
KR100807718B1 (ko) * 2006-10-17 2008-02-28 한국생명공학연구원 인돌 유도체를 유효성분으로 함유하는 대사성 질환 예방 및치료용 약학적 조성물
WO2015050984A1 (fr) * 2013-10-01 2015-04-09 New York University Composés amino, amido, et hétérocycliques à titre de modulateurs de l'activité rage et leurs utilisations
CN103755686B (zh) * 2014-01-23 2016-05-11 中国药科大学 具有抗血小板聚集活性的哌啶基取代5-羟色氨酸衍生物

Also Published As

Publication number Publication date
KR102323893B1 (ko) 2021-11-10
KR20210076857A (ko) 2021-06-24
WO2021118318A3 (fr) 2021-07-29

Similar Documents

Publication Publication Date Title
WO2011043568A2 (fr) Nouveaux composés efficaces comme inhibiteurs de la xanthine oxydase, leur procédé de préparation et composition pharmaceutique les contenant
WO2021118318A2 (fr) Nouveau dérivé d'indole et son utilisation
WO2021066608A1 (fr) Composé destiné à induire l'expression d'un gène klotho anti-âge et son utilisation
EP3827004A1 (fr) Composés dérivés de 1,3,4-oxadiazole utilisés en tant qu'inhibiteur de l'histone désacétylase 6, et composition pharmaceutique les comprenant
WO2019168237A1 (fr) Nouveau composé et composition pour la prévention, l'amélioration ou le traitement de la fibrose ou de la stéatohépatite non alcoolique le comprenant en tant que principe actif
WO2012161518A2 (fr) Nouveaux dérivés de thio-urée utilisés en tant qu'activateurs de rorα, et composition pharmaceutique les contenant
WO2011122815A2 (fr) Nouveaux dérivés de quinoxaline
WO2013105753A1 (fr) Dérivés de pipéridine substituée et procédés pour les préparer
WO2016093554A2 (fr) Nouveau dérivé de 4-(aryl)-n-(2-alkoxythiéno[3,2-b]pyrazin-3-yl)-pipérazine-1-carboxamide et effet antiprolifératif de celui-ci
WO2022211420A1 (fr) Composition pour la prévention ou le traitement d'une maladie neurodégénérative comprenant un composé induisant l'expression d'un gène klotho antivieillissement
WO2021215624A1 (fr) Nouveau dérivé de 2-arylthiazole ou sel de celui-ci, procédé de préparation associé et composition pharmaceutique les comprenant
WO2022050749A1 (fr) Nouveau dérivé biaryle utile en tant qu'inhibiteur de la diacylglycérol acyltransférase 2, et son utilisation
WO2012148140A2 (fr) Dérivés d'alcaloïdes à base d'imidazole ayant des effets d'inhibition de l'angiogenèse et antioxydants et leur procédé de préparation
WO2020017878A1 (fr) Nouveaux dérivés de catéchol ou sel de ceux-ci, leurs procédés de préparation et compositions pharmaceutiques les comprenant
WO2017131425A1 (fr) Nouveau dérivé d'imidazole présentant une activité inhibitrice de la jnk et son utilisation
WO2023224371A1 (fr) Nouveau composé dérivé d'oxadiazole, et composition pharmaceutique pour la prévention ou le traitement de maladies neuroinflammatoires le comprenant
WO2021096314A1 (fr) Nouveau dérivé de benzimidazole et son utilisation
WO2023059121A1 (fr) Nouveau composé dérivé de benzofuranyl-hydroxyphényl-méthanone ou sel pharmaceutiquement acceptable associé
WO2017217741A1 (fr) Nouveau dérivé de furanone bromé, son procédé de préparation, et composition pharmaceutique comprenant le nouveau dérivé de furanone bromé en tant que principe actif
WO2022010328A1 (fr) 1-alkyl-5-arylidène-2-sélénooxoimidazolidine-4-one et son dérivé, son procédé de préparation et composition le comprenant pour prévenir, soulager ou traiter des maladies neurodégénératives
WO2021112626A1 (fr) Nouveau dérivé d'indirubine et son utilisation
WO2019194556A1 (fr) Nouveau composé 6-hétéroarylamino-2,4,5-triméthylpyridine-3-ol, ou composition pharmaceutique pour la prévention ou le traitement de maladies intestinales inflammatoires et de maladies auto-immunes le comprenant
WO2014185561A1 (fr) Nouveau composé ou son sel pharmaceutiquement acceptable et composition pharmaceutique pour la prévention ou le traitement de maladies associées à uch-l1, le contenant en tant que principe actif
WO2020045982A1 (fr) DÉRIVÉ D'INDOLE SUBSTITUÉ, SON PROCÉDÉ DE PRÉPARATION, ET COMPOSITION PHARMACEUTIQUE LE COMPRENANT EN TANT QUE COMPOSANT ACTIF POUR PRÉVENIR OU TRAITER DES MALADIES ASSOCIÉES À PPARα, PPARγ ET PPARδ
WO2023085894A1 (fr) Nouveau dérivé de thio-urée utilisé en tant qu'activateur de rorα et composition pharmaceutique le comprenant

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20897686

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20897686

Country of ref document: EP

Kind code of ref document: A2