WO2021096314A1 - Nouveau dérivé de benzimidazole et son utilisation - Google Patents

Nouveau dérivé de benzimidazole et son utilisation Download PDF

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WO2021096314A1
WO2021096314A1 PCT/KR2020/016038 KR2020016038W WO2021096314A1 WO 2021096314 A1 WO2021096314 A1 WO 2021096314A1 KR 2020016038 W KR2020016038 W KR 2020016038W WO 2021096314 A1 WO2021096314 A1 WO 2021096314A1
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benzo
imidazol
piperidine
carboxamide
mmol
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Korean (ko)
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서승용
김선여
맹한주
이재혁
이산하
이빛
이정은
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Industry Academic Cooperation Foundation of Gachon University
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Industry Academic Cooperation Foundation of Gachon University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to novel benzimidazole-based compounds and uses thereof.
  • the novel benzimidazole-based compound of the present invention inhibits the production of advanced glycation end products (AGEs) and decomposes the resulting final glycation products, so it is suitable for the prevention or treatment of diseases caused by the final glycation products. It can be usefully used.
  • AGEs advanced glycation end products
  • Diabetes is a metabolic disease in which insulin secretion is insufficient or high blood sugar levels persist for a long period of time due to insulin resistance. As the state of elevated blood sugar in the body persists for a long time, the product of glycosylation invades large and small blood vessels in the retina, kidneys, nerves, or whole body, leading to chronic complications. Because diabetes is more dangerous for complications than itself, the primary goal of diabetes treatment today is to prevent the initiation or progression of diabetic complications. Typical diabetic complications include ulcerative colitis, inflammatory bowel disease, diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart disease, diabetic osteoporosis, diabetic atherosclerosis, and sarcopenia. .
  • the mechanisms that induce these diabetes complications are largely due to oxidative stress caused by free radicals, non-enzymatic glycation of protein, and osmotic pressure due to changes in the mechanisms of the polyol pathway. It is explained by stress, etc.
  • Oxidative stress which is the cause of diabetes complications, refers to a reaction that occurs when the removal function of free radicals occurring in the human body decreases or the production of free radicals is rapidly increased due to environmental factors.
  • oxidative stress increases due to hyperglycemia, increases insulin resistance, and causes cell damage such as blood vessels, kidneys, and retinas.
  • advanced glycation end products (AGEs) produced by oxidative stress are a major cause of diabetes complications.
  • the saccharification 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 disease
  • the pathogenesis of non-alcoholic steatohepatitis has not been fully elucidated, but it is widely accepted that at least it is closely related to insulin resistance.
  • FAA free fatty acid
  • Free fatty acids are converted into non-toxic triglycerides (TG) in hepatocytes, leading to a state of simple steatosis (Hepatology, 2007 Jun:45(6):1366-74; Hepatology, 2004 Jul:40(1)). :185-94).
  • non-alcoholic steatohepatitis is often accompanied by type 2 diabetes, another insulin resistance-related disease, which suggests a link between the final glycated product, which is known to be a major causative agent of diabetic complications, and non-alcoholic steatohepatitis.
  • glyceraldehyde (GA)-derived final glycosylation products (GAAGEs) are the most toxic among final glycosylation products produced in the body, so they are called TAGEs (toxic AGEs).
  • TAGEs are the serum and liver of patients with non-alcoholic steatohepatitis. It has been found to be present in high concentrations in the tissues.
  • Aminoguanidine is a nucleophilic hydrazine that binds to the product of the condensation reaction and inhibits the production of the final glycated product and prevents the development of diabetes complications. This is the most promising drug for the prevention and treatment of diabetic complications, and has been conducted up to phase 3 clinical trials, but there is a problem that toxicity is induced when administered for a long period of time, so the development of a safer drug is required.
  • Korean Patent Registration No. 10-1899234 discloses a fir extract for the treatment of diabetes complications, which is a disease related to the final glycation product
  • Korean Patent Publication No. 10-2018-0024825 discloses homoiso, which has inhibitory and crushing activity of final glycation products Flavonoid compounds are disclosed.
  • the present invention was completed by developing a novel substance having an activity to inhibit or decompose the formation of a final saccharified product.
  • An object of the present invention is to provide a novel compound having excellent inhibition or decomposition activity of the final glycation product.
  • the present invention is also to provide a pharmaceutical composition comprising the novel compound.
  • the present invention also aims to provide a pharmaceutical composition for preventing or treating diseases related to final glycosylated products comprising the novel compound.
  • the present invention also aims to provide a food composition comprising the novel compound.
  • the present invention also aims to provide a food composition for preventing or improving diseases related to final saccharification products comprising the novel compound.
  • the present invention provides a compound of the following formula (I) (hereinafter also referred to as a'benzimidazole compound') or a pharmaceutically acceptable salt thereof.
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl;
  • R 1 , R 2 , and R 3 may each independently be one or more;
  • Ra or Rb are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -N(Rc) 2 , -ORc, -SRc, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and Each Rc is independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0 to 4.
  • the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition for preventing or treating diseases related to final glycosylated products comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the present invention provides a food composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a food composition for preventing or improving diseases related to final saccharification products comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the final glycated product-related disease is a group consisting of aging, diabetes, diabetes complications, degenerative brain disease, arteriosclerosis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, skin fibrosis, pulmonary fibrosis, renal fibrosis, and heart fibrosis. It may be selected from. Preferably, it is a diabetic complication or non-alcoholic steatohepatitis.
  • the diabetic complication is ulcerative colitis, inflammatory bowel disease, diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, It may be selected from the group consisting of diabetic osteoporosis, and sarcopenia.
  • the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Peak's disease, Creutzfeldt-Jakob's 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, early stage dementia, temporal lobe epilepsy, and stroke.
  • the present invention relates to a novel benzimidazole compound or a pharmaceutically acceptable salt thereof, and the benzimidazole compound according to the present invention has the effect of inhibiting the production of final saccharified products and decomposing the resulting final saccharified products. , It can be usefully used as a pharmaceutical composition for the prevention or treatment of diseases caused by the final glycation product.
  • novel benzimidazole compounds of the present invention are particularly useful for the prevention or treatment of diabetic complications or non-alcoholic steatohepatitis.
  • 1A and 1B are graphs showing the decomposition effect of the compounds of the present invention on the final glycosylated products MGO-AGEs and GO-AGEs, respectively.
  • 2A and 2B are graphs showing the decomposition effects of the compounds of the present invention on the final glycosylated products GA-AGEs and GC-AGEs, respectively.
  • 3 is a graph showing the result of measuring the amount of lipid droplets in the cell.
  • 4A to 4D are graphs showing results of measuring the generated NO concentration.
  • Figure 4e is a graph showing the expression level of iNOS to GAPDH as a ratio to the normal group.
  • Figure 4f is a graph showing the expression level of COX2 to GAPDH as a ratio to the normal group.
  • 5A to 5E are graphs showing the results of measuring cell viability.
  • 6A shows the results of confirming the expression level of ⁇ -SMA by immunoblotting.
  • 6B is a graph showing the expression level of ⁇ -SMA to ⁇ -Tubulin as a ratio of the normal group.
  • 8A and 8B are graphs showing the results of measuring blood glucose concentration and AUC according to time during the oral glucose tolerance test (OGTT).
  • 8C and 8D are graphs showing the results of measuring blood glucose concentration and AUC according to time during the insulin resistance test (ITT).
  • 9 is a graph showing the results of measuring GO values.
  • 10A shows the results of confirming the expression levels of p-ACC and ACC by immunoblotting.
  • Figure 10b is a graph showing the expression levels of p-ACC and ACC.
  • 11A shows the results of confirming the expression levels of FAS, SREBP1C, and C/EBP ⁇ by immunoblotting.
  • 11B is a graph showing the expression levels of FAS, SREBP1C, and C/EBP ⁇ .
  • 12B is a graph showing the expression level of PPAR ⁇ as a ratio of the normal group.
  • 13A shows the result of confirming the expression level of SIRT1 by immunoblotting.
  • 13B is a graph showing the expression level of SIRT1 to ⁇ -Tubulin as a ratio of the normal group.
  • 15A is a photograph showing lipid droplets, lipid accumulation, and collagen expression in liver tissue by staining.
  • 15B is a graph showing the results of measuring the area of lipid droplets in liver tissue.
  • 15C is a graph showing the results of measuring the degree of lipid accumulation in liver tissue.
  • 15D is a graph showing the results of measuring the level of collagen expression in liver tissue.
  • 16A is a photograph showing the shape of the glomerulus, the number of mesangial matrices, and the expression of collagen in kidney tissue by staining.
  • 16B is a graph showing the number of mesangial matrices in kidney tissue as a ratio of the normal group.
  • 16C is a graph showing the results of measuring the level of collagen expression in kidney tissue.
  • 17A and 17B show the results of measuring cell viability in C2C12 cells, which are muscle cells.
  • HIEC-6 cells which are human small intestine epithelial cells.
  • HIEC-6 cells which are human small intestine epithelial cells.
  • 19B to 19D show results of measuring cell mobility related factors (relative wound density, wound confluence, and wound width).
  • the present invention provides a compound of the following formula (I) or a pharmaceutically acceptable salt thereof.
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl;
  • R 1 , R 2 , and R 3 may each independently be one or more;
  • Ra or Rb are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -N(Rc) 2 , -ORc, -SRc, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and Each Rc is independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0 to 4.
  • the present invention in one embodiment, the present invention
  • the present invention in one embodiment, the present invention
  • Ring A is 5- or 6-membered heterocycloalkyl
  • Ring B is or ego
  • X is C or N
  • R 3 is hydrogen, halo, -N(Ra)(Rb), -NO 2 , or -ORa;
  • the present invention provides a compound of the following formula (II) or a pharmaceutically acceptable salt thereof.
  • Ring B is or ego
  • X is C or N
  • One of Y and Z is N and the other is C;
  • R 3 is hydrogen, halo or -ORa
  • R 1 , R 2 , and R 3 may each independently be one or more;
  • Each Ra is independently C 1-6 alkyl unsubstituted or substituted with a halo group
  • n 1 or 2.
  • the present invention in one embodiment, the present invention
  • R3 is hydrogen, halo or -OCH 3 to provide a compound of formula II or a pharmaceutically acceptable salt thereof.
  • the present invention may be selected from the group consisting of the following compounds 1) to 49).
  • the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition for preventing or treating diseases related to final glycosylated products comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may further include conventional pharmaceutically acceptable additives, such as excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or bulking agents.
  • conventional pharmaceutically acceptable additives such as excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or bulking agents.
  • the formulation of the pharmaceutical composition may be selected from the group consisting of powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, and injections.
  • the final glycated product-related disease is a group consisting of aging, diabetes, diabetes complications, degenerative brain disease, arteriosclerosis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, skin fibrosis, pulmonary fibrosis, renal fibrosis, and heart fibrosis. It may be selected from. Preferably, it is a diabetic complication or non-alcoholic steatohepatitis.
  • the diabetic complication is ulcerative colitis, inflammatory bowel disease, diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, It may be selected from the group consisting of diabetic osteoporosis, and sarcopenia.
  • the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Peak's disease, Creutzfeldt-Jakob's 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, early stage dementia, temporal lobe epilepsy, and stroke.
  • the present invention provides a food composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a food composition for preventing or improving diseases related to final saccharification products comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the food composition may be a health functional food, a dairy product, a fermented product or a food additive.
  • the food composition is a variety of nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid, and Salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like may further be included.
  • nutrients vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid, and Salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like may further be included.
  • Alkyl as used herein is a hydrocarbon having substituted or unsubstituted primary, secondary, tertiary and/or quaternary carbon atoms, and saturated aliphatic, which may be straight chain, branched, cyclic, or a combination thereof. Includes a flag.
  • an alkyl group has 1 to 20 carbon atoms (i.e. C 1 -C 20 alkyl), 1 to 10 carbon atoms (i.e. C 1 -C 10 alkyl), or 1 to 6 carbon atoms (i.e. C 1 -C 6 alkyl).
  • alkyl refers to C 1 -C 6 alkyl.
  • alkyl groups are 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 It refers to an alkyl moiety having a substituent that replaces 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 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. It is believed to contain. 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, ie, carbon- It is a hydrocarbon with a carbon sp 2 double bond.
  • an alkenyl group has 2 to 20 carbon atoms (i.e. C 2 -C 20 alkenyl), 2 to 12 carbon atoms (i.e. C 2 -C 12 alkenyl), 2 to 10 carbon atoms ( That is, 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 has one or more carbon-carbon sp triple bonds. It is a hydrocarbon having.
  • an alkynyl group has 2 to 20 carbon atoms (i.e. C 2 -C 20 alkynyl), 2 to 12 carbon atoms (i.e. C 2 -C 12 alkynyl), 2 to 10 carbon atoms ( That is, 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 substituted or unsubstituted monocyclic, bicyclic or polycyclic and each atom of the ring is carbon. . Further, “cycloalkyl” may 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, bridging, or spiro ring systems.
  • heterocycloalkyl is monocyclic, bicyclic or containing one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms within the ring It refers to a 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, at least one of the rings is heterocyclic, and
  • the click ring can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl.
  • Bicyclic or polycyclic ring systems may be fused, bridging, 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, at least one of the rings is aromatic, and the other cyclic ring is for example For example, it may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl.
  • Aryl may be, for example, benzene, naphthalene, phenanthrene, anthracene, indene, indan, phenol, aniline, and the like, each of which may be substituted or unsubstituted.
  • heteroaryl refers to a substituted or unsubstituted monovalent or divalent aromatic group, which is monocyclic, bicyclic or polycyclic, containing one or more heteroatoms within the ring.
  • suitable heteroatoms include oxygen, sulfur and nitrogen.
  • Heteroaryl 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, at least one of the rings is heteroaromatic, and the other cyclic ring is For example, it may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl.
  • Heteroaryl is, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyra Sol, pyridine, pyrazine, pyridazine, and pyrimidine, and the like, each of which may be substituted or unsubstituted.
  • substituted refers to a specific moiety of a compound of the present invention having one or more substituents.
  • substituted for example "substituted alkyl” or “substituted heterocycloalkyl” for alkyl, heterocycloalkyl, etc. means that one or more hydrogen atoms of the alkyl or heterocycloalkyl are each independently by a non-hydrogen substituent. Means 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 these salts may exist in hydrated, solvated or substantially anhydrous form.
  • the acid addition salts of the compounds of the present invention are more soluble in water and in various hydrophilic organic solvents compared to their free base form, and generally exhibit a higher melting point.
  • suitable salts is known to those skilled in the art.
  • diabetes complication refers to a symptom that occurs when diabetes lasts for a long time.
  • the "diabetic complication” is evaluated on a criterion different from the criteria for onset and judgment of diabetes.
  • the benzimidazole-based compound according to the present invention can be synthesized using the synthesis protocol of Scheme 1 below or a modification thereof. All starting materials and reagents were commercially available and did not undergo further purification. Reactions sensitive to air and moisture were carried out under a nitrogen atmosphere. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck) with the indicated solvents. Thin film chromatography was performed using a 0.25 mm silica gel plate (Merck). 1 H and 13 C NMR spectra were recorded on a Bruker 600 MHz spectrometer with a solution in dimethylsulfoxide-d6, chloroform-d or methanol-d4.
  • N- (3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-amine (20 mg, 0.1 mmol) in a CH 2 Cl 2 solution (5 mL) of 1-( N , N -dimethylsulfamoyl ) Piperidine-4-carboxylic acid (26 mg, 0.1 mmol), EDCI (40 mg, 0.2 mmol), HOBt (6 mg, 40 ⁇ mol), DIPEA (40 ⁇ L, 0.3 mmol), and DMAP (2 mg , 8 ⁇ mol) was added. After stirring for 17 hours, the reaction mixture was diluted with CH 2 Cl 2 and the organic layer was washed with distilled water and brine.
  • the benzimidazole-based compound according to the present invention can be synthesized using the synthesis protocol of Scheme 2 below or a modification thereof.
  • the benzimidazole-based compound according to the present invention can be synthesized using the synthesis protocol of Scheme 3 below or a modification thereof.
  • the final glycated product is produced through a non-enzymatic reaction in which the free amine end of the protein is covalently modified by reactive glucose or other carbonyl-containing molecules. Therefore, in this experimental example, by measuring the amount of free amine, which is a decomposition product of the final saccharified product, using a TNBSA (2,4,6-trinitrobenzene sulfonic acid) assay, the final saccharified product (AGEs ) The decomposition effect was evaluated.
  • TNBSA 2,4,6-trinitrobenzene sulfonic acid
  • Methylglyoxal (MGO) or glyoxal (GO) is mixed with bovine serum albumin (BSA) and sodium azide, and then stored at 37°C for 7 days to produce final glycation products (AGEs).
  • BSA bovine serum albumin
  • AGEs final glycation products
  • MGO-AGEs or GO-AGEs 1 mg/ml of the final glycosylated product was treated with the compound of the present invention at a concentration of 0.4 mM for 24 hours.
  • aminoguanidine AG
  • AGEs an inhibitor of final glycosylated products
  • TNBSA 2,4,6-trinitrobenzene sulfonic acid
  • sodium bicarbonate reagent were added to react, followed by 10% sodium dedecyl sulfate and 1N hydrochloric acid solution. Stopped.
  • the compound of the present invention increased the amount of free amine compared to the negative control (MGO-AGEs or GO-AGEs) treated with only the final glycosylated product.
  • MGO-AGEs or GO-AGEs the negative control
  • SA the compound of Example 11
  • the compound of the present invention increased the amount of free amine compared to the negative control group (MGO-AGEs) treated with only the final glycosylated product.
  • the compounds of Examples 56 and 60 exhibited similar values when compared to the positive control (aminoguanidine 1 nM), and the compound (SA) of Example 11 was 0.4 mM at a lower concentration when compared to the positive control (aminoguanidine 1 nM). It was reconfirmed that the degree of decomposition of the final glycation product MGO-AGEs was very good.
  • the benzimidazole compound of the present invention increased the amount of free amine compared to the negative control, in particular compared to the positive control Alagebrium using the same concentration as the compound of the present invention. It indicated a higher amount of free amine. From this, it was confirmed that the compound (SA) of the present invention has excellent resolution of the final saccharified product.
  • Glyceraldehyde (GA) or glycoaldehyde (GC) is mixed with bovine serum albumin (BSA) and sodium azide, and then stored at 37°C for 7 days to final glycated product (AGEs).
  • BSA bovine serum albumin
  • AGEs final glycated product
  • the final glycated product derived from glyceraaldehyde (GA) was referred to as GA-AGEs
  • the final glycated product derived from glycoaldehyde (GC) was referred to as GC-AGEs.
  • the benzimidazole compound (SA) of the present invention increased the amount of free amine compared to the negative control, and in particular, when comparing the degree of decomposition of GA-AGEs with the positive control, the present Treatment with the inventive compound (SA) showed a higher amount of free amine even at a lower concentration. From this, it was confirmed that the benzimidazole compound of the present invention has excellent resolution of the final saccharified product.
  • the benzimidazole compound (SA) of the present invention reduced the amount of lipid accumulation compared to the negative control, and in particular, when 10 ⁇ M was treated, the amount of lipid accumulation was at the level of the normal group. Decreased.
  • the compound of the present invention inhibits lipid accumulation.
  • Raw 264.7 cells which are macrophages, were seeded in a 96-well plate at 5 ⁇ 10 4 each and incubated in an incubator at 37° C. and 5% CO 2 for 24 hours, followed by pretreatment with 10 ⁇ M of the compound (SA) of Example 11 for 30 minutes, and then 100 It was stimulated with ng/ml LPS for 24 hours. After 24 hours, 50 ⁇ l of the supernatant was taken and transferred to a 96-well plate, and then Griess reagent (50 ⁇ l,% sulfanilamide in 5% phosphoric acid and 50 ⁇ l 0.1% N-1-napthylethylenediamine dihydrochloride in water) was added 1:1.
  • SA compound
  • Raw 264.7 cells were seeded in a 60 ⁇ dish with 1 ⁇ 10 6 each and incubated for 24 hours in a 37° C., 5% CO 2 incubator, and then the compound (SA) of Example 11 was pretreated for each concentration and incubated for 30 minutes, and LPS was It was treated at a concentration of 100 ng/ml and incubated for 24 hours.
  • After collecting the cultured cells spin down the cell pellet with a centrifuge (5,000 rpm, 5 min, 4°C), add lysis buffer, dissolve for 1 day, and then centrifuge (12,000 rpm, 25 min, 4°C) Cell membrane components and the like were removed. After denatured separation by SDS-PAGE, it was transferred to a PVDF membrane. Thereafter, after reacting with the primary antibody overnight, the secondary antibody was bound and the expression of iNOS and COX2 was measured using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA).
  • the compound (SA) of Example 11 decreased the expression of iNOS and COX2 compared to the negative control.
  • the compound of the present invention has an excellent anti-inflammatory effect.
  • Raw 264.7 cells which are macrophages, were seeded in a 96-well plate at 5 ⁇ 10 4 each and incubated in an incubator at 37° C. and 5% CO 2 for 24 hours, and then compound (SA) of Example 11 0.1, 1, 10 ⁇ M and positive control L -NMMA (20 ⁇ M) was pretreated for 30 minutes and then stimulated with 100 ng/ml LPS for 24 hours. After incubation for 24 hours, 0.5 mg/ml MTT solution (3-[4,5-dimethylthiazol-2-yl]-2,5-bromide) was treated for 1 hour. Thereafter, cells were lysed using 100 ⁇ l of DMSO, and then the 570 nm wavelength value was measured with a microplated reader to evaluate the cytotoxicity.
  • SA compound
  • MTT solution 3-[4,5-dimethylthiazol-2-yl]-2,5-bromide
  • the LPS 100 ng / ml inducing group exhibited cytotoxicity, and the compounds of Examples 11, 44, 56 and 60 exhibited a cytoprotective effect.
  • LX2 cells Human stellate cells
  • SA compound 1 + 5 and 10 ⁇ M of Example 11
  • Pretreatment was performed and incubated for 1 hour, and TGF- ⁇ was treated at a concentration of 2 ng/ml and incubated for 24 hours.
  • spin down the cell pellet with a centrifuge (5,000 rpm, 5 min, 4°C), add lysis buffer, dissolve for 1 day, and then centrifuge (12,000 rpm, 25 min, 4°C)
  • a centrifuge 5,000 rpm, 5 min, 4°C
  • lysis buffer dissolve for 1 day
  • centrifuge (12,000 rpm, 25 min, 4°C
  • the compound of the present invention exhibits anti-fibrotic activity and can be used for the treatment of liver fibrosis, skin fibrosis, pulmonary fibrosis, renal fibrosis, or cardiac fibrosis.
  • OGTT Oral glucose tolerance test
  • ITT insulin tolerance test
  • an in vivo experiment was performed as shown in FIG. 7 using a male C57BL/6J mouse.
  • the negative control group (DMC; Diabetes mellitus control) and the experimental group were fed a high-fat diet containing 60% kcal of fat, and the normal group (CON or C) was fed a normal diet of tongue odors.
  • STZ streptozotocin 60 mg/kg was administered, and in the case of the normal group, only citrate buffer was administered.
  • 10 mg/kg of the compound of Example 11 (SA) was administered from the 11th week after the start of the experiment.
  • mice were subjected to an oral glucose tolerance test (OGTT) and an insulin resistance test (ITT) to measure blood glucose levels.
  • OGTT oral glucose tolerance test
  • ITT insulin resistance test
  • ITT insulin resistance test
  • Glyoxal is known to be one of the substances that cause diabetes complications. Accordingly, in this experimental example, the effect of reducing the GO level of the compound of the present invention was evaluated to determine whether the compound of the present invention can be used in the treatment of diabetic complications.
  • the GO level was decreased in the group treated with the compound (SA) of Example 11 of the present invention.
  • SA negative control
  • the GO level was reduced to a degree similar to that of the normal group. Accordingly, it was confirmed that the compound of the present invention can be effectively used in the treatment of diabetic complications.
  • Hepatic lipid metabolism related hepatic protein level measurement ( in vivo test)
  • liver protein related to liver lipid metabolism was measured. Specifically, it was attempted to determine whether the compound of the present invention can be effectively used in the treatment of fatty liver, especially non-alcoholic steatohepatitis, by measuring whether or not the protein expression related to adipogenesis or lipolysis is decreased.
  • Acetyl-CoA carboxylase is known to be a factor that oxidizes fatty acids and is reduced during adipogenesis, and FAS, SREBP1c, and C/EBP ⁇ are known to be highly expressed during adipogenesis as adipogenesis factors.
  • the liver tissues of the mice were homogenized, and the lysis buffer was added thereto for 24 hours to extract proteins.
  • a sample was prepared after quantification through the Bradford assay protein quantification method. Then, it was denatured and separated by SDS-PAGE, and it was transferred to the PVDF membrane. Thereafter, after reacting the primary antibody overnight, the secondary antibody is bound and Acetyl-CoA carboxylase (ACC), FAS, SREBP1c, C/EBP is used using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA). The expression of the ⁇ protein was measured.
  • Figs. 10 and 11 the ratio of p-ACC to ACC was increased in the group treated with the compound (SA) of Example 11 of the present invention (Figs. 10a and 10b), FAS, SREBP1c, C /EBP ⁇ protein expression was decreased (Figs. 11A and 11B).
  • the compounds of the present invention can be effectively used in the treatment of fatty liver, particularly non-alcoholic steatohepatitis, by reducing the expression of proteins associated with adipogenesis or lipolysis.
  • liver tissues of the mice were homogenized, and the lysis buffer was added thereto for 24 hours to extract proteins.
  • a sample was prepared after quantification through a Bradford assay protein quantification method. Then, it was denatured and separated by SDS-PAGE, and it was transferred to the PVDF membrane. Thereafter, after reacting with the primary antibody overnight, the secondary antibody was combined and the expression level of Sirt1 protein in liver tissue was measured using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA).
  • the expression level of the Sirt1 protein was increased in the group treated with the compound (SA) of Example 11 of the present invention. This confirmed the applicability of the compound of the present invention for the treatment of non-alcoholic steatohepatitis.
  • liver tissues of the mice were homogenized, and the lysis buffer was added thereto for 24 hours to extract proteins.
  • a sample was prepared after quantification through a Bradford assay protein quantification method. Then, it was denatured and separated by SDS-PAGE, and it was transferred to the PVDF membrane. Then, after reacting with the primary antibody overnight, the secondary antibody was combined and the expression levels of iNOS and COX2 in the liver tissue of mice were measured using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA).
  • the expression level of iNOS decreased in the group treated with the compound (SA) of Example 11 of the present invention. Accordingly, it was confirmed that the compound of the present invention can be effectively used in the treatment of non-alcoholic steatohepatitis, diabetes, and diabetic complications.
  • hepatic steatosis Representative features of hepatic steatosis are that lipid droplets are observed in liver tissue, lipid accumulation is confirmed, and collagen is expressed. Accordingly, in this experimental example, the degree of lipid droplets, accumulation of lipids, and collagen expression in liver tissues were checked to determine whether the compound of the present invention can be used for the treatment of hepatic steatosis, particularly non-alcoholic fatty liver or non-alcoholic steatohepatitis.
  • liver tissue of the mouse at 23 weeks of ingestion of the high fat diet of Experimental Example 6 was stained with hematoxylin eosin (H&E) or PAS to identify lipid droplets, stained with Oil Red O to confirm lipid accumulation, and stained with Masson's trichrome. Thus, collagen expression was confirmed.
  • H&E hematoxylin eosin
  • PAS hematoxylin eosin
  • lipid droplets, lipid accumulation, and collagen expression were decreased in the group administered with the compound (SA) of Example 11 of the present invention compared to the negative control group. From this, it was confirmed that the compound of the present invention can be effectively used in the treatment of hepatic steatosis, in particular, non-alcoholic fatty liver or non-alcoholic steatohepatitis.
  • a typical characteristic of diabetic nephropathy is that the shape of the glomerulus is deformed, and the number of mesangial matrix and the expression of collagen are increased. Therefore, in this experimental example, the shape of the glomerulus in the kidney tissue was observed, the number of mesangial matrices and the degree of collagen expression were checked to determine whether the compound of the present invention can be used in the treatment of diabetic nephropathy. I wanted to.
  • kidney tissue of the mouse at 23 weeks after ingestion of the high fat diet of Experimental Example 6 was stained with hematoxylin eosin (H&E) to confirm the glomerulus, stained with PAS to confirm the mesangial matrix, and with Masso' trichrome. By staining, collagen expression in the kidneys was confirmed.
  • H&E hematoxylin eosin
  • Diabetic complications are accompanied by sarcopenia.
  • cell viability and cell morphology are observed to confirm whether the compound of the present invention exhibits a cell protective effect due to treatment with methylglyoxal (MGO), which is highly toxic among glycotoxin substances.
  • MGO methylglyoxal
  • C2C12 cells which are muscle cells, were seeded in a 6-well plate at 2.5 ⁇ 10 5 each, incubated in a 37° C., 5% CO 2 incubator for 24 hours, and then differentiated for 4 days after replacement with 2% horse serum medium. After 4 days, 10 ⁇ M of the compounds of Examples 11 (SA), 44, 56, and 60 were each pretreated for 1 hour, followed by stimulation with 1.5 mM MGO for 24 hours. After 24 hours, after observing the cell morphology using IncuCyte imaging program, 0.5 mg/ml MTT solution (3-[4,5-dimethylthiazol-2-yl]-2,5-bromide) was treated for 1 hour. Thereafter, cells were lysed using 100 ⁇ l of DMSO, and then the 570 nm wavelength value was measured with a microplated reader to evaluate the cytotoxicity.
  • SA compounds of Examples 11
  • MGO methylglyoxal
  • HIEC-6 cells which are human small intestine epithelial cells, were seeded in a 96-well plate at 2.0X10 4 and 8.0X10 4 , respectively, and cultured in an incubator at 37°C and 5% CO 2 for 24 hours. ), 10 ⁇ M of compounds of 44, 56 and 60 were pretreated for 1 hour and then stimulated with 1.0 mM MGO for 24 hours. After 24 hours, 0.5 mg/ml MTT solution (3-[4,5-dimethylthiazol-2-yl]-2,5- bromide) was treated for 1 hour. Thereafter, cells were lysed using 100 ⁇ l of DMSO, and then the 570 nm wavelength value was measured with a microplated reader to evaluate the cytotoxicity.
  • MTT solution 3-[4,5-dimethylthiazol-2-yl]-2,5- bromide
  • the effect of cell migration was evaluated as the effect of restoring the inhibition of cell migration by treatment with MGO, and it was confirmed that the compounds of Examples 11, 44, 56 and 60 exhibit the effect of restoring the suppressed cell migration to MGO, In particular, as shown in Figs. 19A to 19D, it was confirmed that the compounds of Examples 56 and 60 have excellent cell migration recovery effects.
  • the compound of the present invention can be effectively used for the treatment of ulcerative colitis and inflammatory bowel disease.

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Abstract

La présente invention concerne de nouveaux composés à base de benzimidazole et leurs utilisations. Les nouveaux composés à base de benzimidazole selon la présente invention inhibent la formation de produits finis de glycation avancée (AGE), et peuvent donc être utiles dans la prévention ou le traitement de maladies provoquées par des AGE.
PCT/KR2020/016038 2019-11-15 2020-11-13 Nouveau dérivé de benzimidazole et son utilisation Ceased WO2021096314A1 (fr)

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WO2014096388A2 (fr) * 2012-12-21 2014-06-26 Selvita S.A. Nouveaux dérivés de benzimidazole en tant qu'inhibiteurs de la kinase
WO2017040993A1 (fr) * 2015-09-03 2017-03-09 The Arizona Board Of Regents On Behalf Of The University Of Arizona Petites molécules inhibitrices de dyrk1a et leurs utilisations
WO2017143011A1 (fr) * 2016-02-16 2017-08-24 Chrysalis, Inc. Inhibiteurs d'histones déméthylases
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KR101899234B1 (ko) 2017-01-12 2018-09-17 가천대학교 산학협력단 전나무 메탄올 추출물, 이의 분획물 또는 이들로부터 분리한 화합물을 포함하는 최종당화산물 관련 질환의 예방 또는 치료용 조성물

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WO2014096388A2 (fr) * 2012-12-21 2014-06-26 Selvita S.A. Nouveaux dérivés de benzimidazole en tant qu'inhibiteurs de la kinase
WO2017040993A1 (fr) * 2015-09-03 2017-03-09 The Arizona Board Of Regents On Behalf Of The University Of Arizona Petites molécules inhibitrices de dyrk1a et leurs utilisations
WO2017143011A1 (fr) * 2016-02-16 2017-08-24 Chrysalis, Inc. Inhibiteurs d'histones déméthylases
WO2017144909A1 (fr) * 2016-02-25 2017-08-31 Gesynta Pharma Ab Méthodes de traitement de maladies caractérisées par une vasoconstriction

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US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11944622B2 (en) 2018-10-05 2024-04-02 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity

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