WO2023085894A1 - Nouveau dérivé de thio-urée utilisé en tant qu'activateur de rorα et composition pharmaceutique le comprenant - Google Patents

Nouveau dérivé de thio-urée utilisé en tant qu'activateur de rorα et composition pharmaceutique le comprenant Download PDF

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WO2023085894A1
WO2023085894A1 PCT/KR2022/017924 KR2022017924W WO2023085894A1 WO 2023085894 A1 WO2023085894 A1 WO 2023085894A1 KR 2022017924 W KR2022017924 W KR 2022017924W WO 2023085894 A1 WO2023085894 A1 WO 2023085894A1
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substituted
group
unsubstituted
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pharmaceutically acceptable
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박형근
이미옥
오대현
김현지
최해나
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서울대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
    • C07C335/08—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to a novel thiourea derivative as an activator of ROR ⁇ and a pharmaceutical composition containing the same.
  • ROR ⁇ (also called NR1F1, RORA, RZR) is a member of the steroid hormone receptor superfamily and is a transcription factor that regulates gene expression.
  • ROR ⁇ consists of an N-terminal transactivation domain, a DNA-binding domain and a C-terminal ligand binding domain.
  • ROR ⁇ binds to the ROR-binding response element (RORE) in the promoter of the target gene, and RORE has a hexanucleotide motif (5'-AGGTCA-3') and the A/T rich of 6 base pairs preceding this hexanucleotide. contains sequence.
  • ROR ⁇ The activity of ROR ⁇ is regulated by the ligand binding to the C-terminal ligand binding domain, and known ligands include cholesterol and cholesterol derivatives, melatonin, and CGP52608, one of thiazolidinedione.
  • known ligands include cholesterol and cholesterol derivatives, melatonin, and CGP52608, one of thiazolidinedione.
  • X-ray crystallization analysis revealed that cholesterol and cholesterol derivatives bind to the ligand binding domain of ROR ⁇ , and melatonin also specifically binds to ROR ⁇ to cause ROR ⁇ -mediated gene activity regulation. It has been reported that it is a synthetic ligand that competitively binds to ROR ⁇ .
  • JC1-40 that is selectively active against ROR ⁇ by conducting a primary structural activity study using the thiazolidinedione-based compound CGP52608 as a lead material (Patent Document 1).
  • Patent Document 1 When JC1-40 was administered to mice, non-alcoholic fatty liver was suppressed by inhibition of lipid accumulation through activation of AMPK, and anti-oxidation, anti-inflammatory effects, and anti-alcoholic steatohepatitis were shown through activation of Kupffer cell M2 polarity.
  • Non-alcoholic fatty liver disease is one of the chronic liver diseases that can progress from simple fatty liver to cirrhosis.
  • Liver fibrosis in non-alcoholic steatohepatitis and liver cirrhosis is a state in which extracellular matrix accumulation occurs due to chronic liver damage. Liver fibrosis can lead to cirrhosis and progress to liver cancer, a major pathological condition that increases liver-related mortality and requires liver transplantation.
  • ROR ⁇ deficient mice showed increased collagen deposition along with increased expression of fibrosis markers such as ⁇ -SMA and TGF ⁇ 1 when fed a high-fat diet, suggesting that ROR ⁇ has an inhibitory effect on liver fibrosis and can be applied to related diseases. suggested.
  • the present inventors not only discovered a novel compound with significantly better ROR ⁇ transcriptional activity enhancing effect than the compound of Patent Document 1, but also made diligent efforts to develop a candidate substance for treating metabolic diseases.
  • the present inventors discovered novel compounds that directly bind to ROR ⁇ protein and increase transcriptional activity, thereby completing the present invention.
  • an object of the present invention is to provide a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
  • X is a C 1 -C 5 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group, or combined with Z to form a substituted or unsubstituted C forms a 3 -C 20 cycloalkyl ring, a substituted or unsubstituted C 3 -C 20 heterocycloalkyl ring, a substituted or unsubstituted C 6 -C 20 aryl ring, or a substituted or unsubstituted C 3 -C 20 heteroaryl ring;
  • Y is hydrogen, hydroxy group, halogen, OR 1 , CO 2 R 2 , NR 3 R 4 , substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, substituted or unsubstituted a C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group;
  • Z is N, O, or S
  • R 1 to R 4 are each independently hydrogen, a C 1 -C 5 alkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group,
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic or inflammatory diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide an anti-inflammatory composition
  • an anti-inflammatory composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present inventors discovered compounds that increase the transcriptional activity of ROR ⁇ , and confirmed the therapeutic effect of metabolic diseases based on the effect of promoting the transcriptional activity of ROR ⁇ , thereby completing the present invention.
  • the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
  • X is a C 1 -C 5 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group, or combined with Z to form a substituted or unsubstituted C forms a 3 -C 20 cycloalkyl ring, a substituted or unsubstituted C 3 -C 20 heterocycloalkyl ring, a substituted or unsubstituted C 6 -C 20 aryl ring, or a substituted or unsubstituted C 3 -C 20 heteroaryl ring;
  • Y is hydrogen, hydroxy group, halogen, OR 1 , CO 2 R 2 , NR 3 R 4 , substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, substituted or unsubstituted a C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group;
  • Z is N, O, or S
  • R 1 to R 4 are each independently hydrogen, a C 1 -C 5 alkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group,
  • R 1 or R 2 when R 1 or R 2 is a substituted aryl group or a substituted heteroaryl group, an aromatic ring is a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a tree It may be substituted with a fluoromethyl group or a t-butyl group, but is not limited thereto.
  • R 3 and R 4 are bonded to each other to form a substituted or unsubstituted C 3 -C 20 cycloalkyl ring, a substituted or unsubstituted C 6 -C 20 heterocycloalkyl ring, or a substituted or unsubstituted C It may form a 6 -C 20 aryl ring or a substituted or unsubstituted C 3 -C 20 heteroaryl ring, but is not limited thereto.
  • the aromatic ring is a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a trifluoromethyl group, or It may be substituted with a t-butyl group, but is not limited thereto.
  • X is a C 1 -C 4 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted C 3 -C 10 heteroaryl group, or Z Combined with each other to form a substituted or unsubstituted C 3 -C 10 heteroaryl ring;
  • Y is hydrogen, OR 1 , CO 2 R 2 , NR 3 R 4 , a substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 is a heteroaryl group;
  • Z is N or S
  • R 1 is hydrogen
  • R 2 is hydrogen or a t-butyl group
  • the R 3 and R 4 may each independently be hydrogen or a C 1 -C 5 alkyl group, but are not limited thereto.
  • the compound represented by Formula 1 may be selected from the group consisting of compounds having the following structural formula, but is not limited thereto.
  • the compound represented by Formula 1 may be an activator of ROR ⁇ protein, but is not limited thereto.
  • the present invention provides a pharmaceutical composition for preventing or treating metabolic or inflammatory diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the metabolic disease may be one or more selected from the group consisting of insulin resistance syndrome, hepatic fibrosis, fatty liver, steatohepatitis, liver cirrhosis, type 2 diabetes, hyperlipidemia, cardiovascular disease, and arteriosclerosis. It is not limited.
  • the metabolic disease may be a metabolic liver disease, but is not limited thereto.
  • the metabolic disease may be a lipid metabolism-related disease, but is not limited thereto.
  • the inflammatory disease is asthma, allergic and non-allergic rhinitis, gastritis, enteritis, ulcerative gastritis, nephritis, hepatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, irritable bowel syndrome, inflammatory pain, Migraine headache, headache, back pain, fibromyalgia, myofascial disease, viral infection (e.g.
  • hepatitis C infection bacterial infection
  • fungal infection fungal infection
  • burns surgical or dental wounds
  • gout arthritis
  • rheumatoid arthritis ankylosing It may be one or more selected from the group consisting of spondylitis, Hodgkin's disease, pancreatitis, conjunctivitis, ulceris, scleritis, uveitis, dermatitis (including atopic dermatitis), eczema, and multiple sclerosis, but is not limited thereto.
  • the present invention provides an anti-inflammatory composition
  • an anti-inflammatory composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound may inhibit or reduce inflammation by inhibiting the expression or secretion of pro-inflammatory cytokines or upregulating M2 macrophages, but is not limited thereto.
  • the present invention is directed to preventing or treating metabolic or inflammatory diseases, including administering a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof. provides a way
  • the present invention provides a use of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating metabolic or inflammatory diseases.
  • the present invention provides a use of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for preparing a drug for treating metabolic or inflammatory diseases.
  • the present invention provides a method for inhibiting inflammation, comprising the step of administering a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.
  • the present invention provides an anti-inflammatory use of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides the use of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for preparing an anti-inflammatory agent.
  • the present invention provides a method for preventing or treating a metabolic disease or an inflammatory disease, comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the present invention provides a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for preventing or treating metabolic or inflammatory diseases.
  • the present invention provides a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for preparing a drug for treating metabolic or inflammatory diseases.
  • the present invention provides a method for inhibiting inflammation, comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the present invention provides an anti-inflammatory use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for preparing an anti-inflammatory agent.
  • the compound according to the present invention is expected to be effective in the treatment and prevention of metabolic or inflammatory diseases through various in vivo functions of ROR ⁇ , and in particular, prevention and treatment of metabolic liver diseases including liver fibrosis through inhibition of hepatic stellate cell activity. is expected to be useful for
  • Figure 2 shows the effect of the new compounds on the transcriptional activity of ROR ⁇ .
  • FIG. 3 shows the change in RORa transcriptional activity according to the concentration of ODH-08.
  • Figure 4 shows the expected binding site of ODH-08 with ROR ⁇ through docking simulation analysis.
  • Figure 5 shows the binding force with ROR ⁇ according to the concentration of ODH-08 through a plasmon resonance experiment. According to the Fig. 5 graph
  • the line graph shows the RU values of 100 ⁇ , 75 ⁇ , 50 ⁇ , 20 ⁇ , 10 ⁇ , 5 ⁇ and 1 ⁇ concentrations in order from the top. corresponding to the graph shown.
  • 6a and 6b show the selectivity of ODH-08 for regulating RORa transcriptional activity through luciferase activity assay.
  • 7a and 7b show the results of Nile Red staining and neutral fat (triglyceride) quantification in order to confirm the effect of ODH-08 on lipid accumulation in hepatocytes.
  • 9a and 9b show the effect of ODH-08 on fibrosis gene expression in hepatic stellate cell lines.
  • 9a shows the expression of Pro-COL1A1 and ⁇ -SMA proteins through Western blotting analysis
  • FIG. 9B shows the mRNA expression of ⁇ -SMA, COL1A1 and TGF ⁇ 1 through RT-PCR analysis.
  • 10a and 10b show the results of luciferase activity assay to confirm the effect of ODH-08 on SMAD transcriptional activity in hepatic stellate cell lines.
  • 11a and 11b show the effect of ODH-08 on inhibiting liver damage in an animal model of liver fibrosis induced by a Western-style diet.
  • 11a is a result of measuring liver weight
  • FIG. 11b is a result of measuring AST and ALT concentrations in blood.
  • FIG. 12a to 12d show the effect of ODH-08 on inhibiting fibrosis in an animal model of liver fibrosis induced by a Western diet.
  • Figure 12a shows the results of H&E staining
  • Figure 12b shows the results of Sirius red staining
  • Figure 12c shows the expression of Pro-COL1A1 and ⁇ -SMA proteins through Western blotting analysis
  • Figure 12d shows RT-PCR. This is the result of confirming the mRNA expression of ⁇ -SMA, COL1A1, COL1A2, COL3A1, MMP2, and TIMP1 through analysis.
  • the present inventors have found compounds with excellent ROR ⁇ activating effect compared to existing thiourea derivatives, and completed the present invention.
  • the present invention relates to a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
  • X is a C 1 -C 5 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group, or combined with Z to form a substituted or unsubstituted C forms a 3 -C 20 cycloalkyl ring, a substituted or unsubstituted C 3 -C 20 heterocycloalkyl ring, a substituted or unsubstituted C 6 -C 20 aryl ring, or a substituted or unsubstituted C 3 -C 20 heteroaryl ring;
  • Y is hydrogen, hydroxy group, halogen, OR 1 , CO 2 R 2 , NR 3 R 4 , substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, substituted or unsubstituted a C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group;
  • Z is N, O, or S
  • R 1 to R 4 are each independently hydrogen, a C 1 -C 5 alkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group,
  • C 1 -C 5 alkyl refers to a monovalent alkyl group having 1 to 5 carbon atoms or 2 to 5 carbon atoms. This term is exemplified by functional groups such as methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, tert -butyl and the like. Alkyl and substituents containing other alkyl moieties described in the present invention include both straight-chain and branched forms. Substituted alkyl means that one or more hydrogen atoms among hydrogen atoms are substituted with another substituent, and the substituent includes, but is not limited to, halogen, N, O, S, and the like.
  • halogen as used herein may include fluoro (F), chloro (Cl), and bromo (Br), iodine (I).
  • C 1 -C 3 alkoxy means a group —OR, where R means “C 1 -C 3 alkyl”.
  • Preferred alkoxy groups include, for example, methoxy, ethoxy, 2-methoxyethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy and the like.
  • C 6 -C 20 aryl refers to an unsaturated aromatic ring compound having 6 to 20 carbon atoms having a single ring (eg phenyl) or a plurality of condensed rings (eg naphthyl).
  • the aryl is a group consisting of phenyl, naphthyl, biphenyl, terphenyl, anthryl, indenyl, fluorenyl, phenanthryl, triphenylenyl, pyrenyl, perylenenyl, chrysenyl, naphthacenyl, and fluoranthenyl can be selected from.
  • C 3 -C 20 heteroaryl refers to an aryl group containing 1 to 3 heteroatoms selected from S, O and N, and includes dioxolyl, pyrimidyl, furanyl, furyl, and thiophenyl.
  • pyrrolyl pyranyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, furazanyl , monocyclic heteroaryl such as pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and benzofuranyl, benzothiophenyl, isobenzofuranyl, benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, benzooxazolyl, isoindolyl, indolyl, indazolyl, benzothiadia It may be selected from the group consisting of polycyclic heteroaryls such as zolyl, quinoly,
  • substitution means, unless otherwise specified, at least one substituent such as a halogen atom, nitro, hydroxy, cyano, amino, thiol, carboxyl, amide, nitrile, sulfide, disulfide, one or more than one of sulfenyl, formyl, formyloxy or formylamino.
  • substituent such as a halogen atom, nitro, hydroxy, cyano, amino, thiol, carboxyl, amide, nitrile, sulfide, disulfide, one or more than one of sulfenyl, formyl, formyloxy or formylamino.
  • the present invention Any group or structure described for the compound represented by Formula 1 may be substituted.
  • R 1 or R 2 is a substituted aryl group or a substituted heteroaryl group
  • an aromatic ring is a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a trifluoromethyl group, or It may be substituted with a t-butyl group, but is not limited thereto.
  • the R 3 and R 4 are bonded to each other to form a substituted or unsubstituted C 3 -C 20 cycloalkyl ring, a substituted or unsubstituted C 6 -C 20 heterocycloalkyl ring, or a substituted or unsubstituted C 6 -C It may form a 20 aryl ring or a substituted or unsubstituted C 3 -C 20 heteroaryl ring, but is not limited thereto.
  • Y is a substituted aryl group or a substituted heteroaryl group
  • the aromatic ring is substituted with a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a trifluoromethyl group, or a t-butyl group It may be, but is not limited thereto.
  • X is a C 2 -C 4 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted C 3 -C 10 heteroaryl group, or combined with Z form a substituted or unsubstituted C 3 -C 10 heteroaryl ring;
  • Y is hydrogen, OR 1 , CO 2 R 2 , NR 3 R 4 , a substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 is a heteroaryl group;
  • Z is N or S
  • R 1 is hydrogen
  • R 2 is hydrogen or a t-butyl group
  • the R 3 and R 4 may each independently be hydrogen or a C 1 -C 5 alkyl group, but are not limited thereto.
  • the compound represented by Formula 1 may be selected from the group consisting of compounds having the following structural formula, but is not limited thereto.
  • the compound represented by Formula 1 may be an activator of ROR ⁇ protein, but is not limited thereto.
  • activator activating ROR ⁇ refers to (a) activation of ROR ⁇ gene expression; and/or (b) enhancing the transcriptional activity of the expressed ROR ⁇ protein.
  • the compounds may be compounds 1 to 21 shown in FIG. 1, but are not limited thereto.
  • the compound represented by Formula 1 may have a non-aromatic double bond and one or more asymmetric centers. Thus, they can occur as racemates and racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures and cis- or trans-isomers. All these isomeric forms are contemplated.
  • the present invention may include a derivative compound such as a hydrate of the compound represented by Formula 1 or a glycoside in which a compound such as glucose is bonded to each side chain.
  • the compound according to the present invention can be prepared by the chemical synthesis methods of Reaction Schemes 1 to 3, isolation from nature, or chemical synthesis methods of compounds known in the art.
  • the compounds of the present invention may be isolated and purified from natural plants. That is, it can be obtained from plants or plant parts using conventional methods for extracting and separating substances.
  • the stem, root or leaf is appropriately dried and macerated to obtain the desired extract, or only dried and extracted with an appropriate organic solvent, and the desired extract is obtained using a purification method known to those skilled in the art to which the present invention pertains. can be purified.
  • the present invention may include a pharmaceutically acceptable salt of the compound represented by Formula 1 as an active ingredient.
  • pharmaceutically acceptable salt includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.
  • acids examples include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like.
  • Acid addition salts can be prepared by conventional methods, for example, by dissolving a compound in an aqueous solution of excess acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can also be prepared by heating equimolar amounts of the compound and an acid or alcohol in water and then evaporating the mixture to dryness, or suction filtering the precipitated salt.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium.
  • An alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable for pharmaceutical purposes to prepare a sodium, potassium or calcium salt, and the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • a suitable silver salt eg, silver nitrate
  • the present inventors confirmed that the novel thiourea-based compounds markedly enhance the transcriptional activity of ROR ⁇ compared to the existing thiourea-based compound JC1-40, and that this effect appeared selectively for ROR ⁇ (see Experimental Examples 1 to 5),
  • ODH-08 decreased the expression of fibrotic proteins Pro-COL1A1 and ⁇ -SMA and the expression of genes ⁇ -SMA, COL1A1 and TGF ⁇ 1 transcripts in a concentration-dependent manner in hepatic stellate cells (see Experimental Example 8),
  • ODH-08 suppresses liver damage in a diet-induced liver fibrosis animal model by suppressing the increase in liver weight and significantly reducing blood AST and ALT concentrations (see Experimental Example 10),
  • ODH-08 inhibited the progress of liver tissue fibrosis, decreased collagen accumulation, and suppressed liver fibrosis-related proteins and genes in a diet-induced liver fibrosis animal model (see Experimental Example 11).
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention may be provided as a pharmaceutical composition for preventing or treating metabolic or inflammatory diseases or as an anti-inflammatory composition.
  • metabolic disease refers to a disease caused by excessive synthesis or accumulation of fat due to abnormal energy metabolism in the body due to various causes such as excessive energy intake or hormonal imbalance.
  • the metabolic disease may be insulin resistance syndrome, liver fibrosis, fatty liver, steatohepatitis, liver cirrhosis, type 2 diabetes, hyperlipidemia, cardiovascular disease, or arteriosclerosis.
  • fatty liver may mean a group of diseases covering all aspects of diseases from fatty liver to steatohepatitis and fatty liver-associated cirrhosis.
  • the "fatty liver” is caused by accumulation of fat in the liver due to excessive fat or alcohol intake, increased fat synthesis in the liver, reduced neutral fat emission and combustion, etc. Generally, it is defined as fatty liver when the proportion of fat accumulated in the liver is 5% or more . Most of the fat accumulated in fatty liver is triglycerides (triglycerides).
  • Fatty liver can be largely divided into alcoholic fat caused by excessive drinking and non-alcoholic fatty liver caused by liver and obesity, diabetes, hyperlipidemia or drugs.
  • Alcoholic fatty liver occurs when excessive intake of alcohol promotes fat synthesis in the liver and prevents normal energy metabolism.
  • non-alcoholic fatty liver occurs frequently in people suffering from obesity, insulin hypersensitivity, and diabetes. This phenomenon suggests that non-alcoholic fatty liver may be caused by an increase in the concentration of free fatty acids in the blood due to insulin resistance or excessive lipolysis.
  • the fatty liver may be any one or more selected from the group consisting of alcoholic fatty liver, non-alcoholic fatty liver, nutritional fatty liver, starvation fatty liver, obese fatty liver, and diabetic fatty liver, preferably non-alcoholic fatty liver, obese fatty liver It may be fatty liver, diabetic fatty liver, and most preferably diabetic fatty liver, but is not limited thereto.
  • steatohepatitis refers to a case of inflammation or fibrotic lesions accompanied by liver cell damage (balloon degeneration) while showing fat deposition in the liver, showing fat deposition in the liver, but hepatocyte damage (balloon degeneration) and It is used to differentiate from “fatty liver” in which there is no evidence of fibrosis.
  • fatty liver-associated cirrhosis refers to liver cirrhosis accompanied by histological findings of fatty liver or steatohepatitis, or liver cirrhosis that has occurred in a patient with histologically proven fatty liver or steatohepatitis in the past.
  • liver fibrosis refers to a disease in which scars occur in liver tissue due to excessive accumulation of connective tissue such as collagen in the tissue due to repeated damage and regeneration of liver tissue in a chronic inflammatory state.
  • Liver fibrosis is reversible, consists of thin fibrils, and lacks nodule formation.
  • this liver fibrosis mechanism continues repeatedly, crosslinking between connective tissues increases, thick fibrils accumulate, and the normal structure of liver lobules is lost to form nodules. It progresses to irreversible cirrhosis.
  • hepatic stellate cells Activation of hepatic stellate cells is a major cause of liver fibrosis.
  • hepatic stellate cells maintain a non-proliferative, quiescent, and vitamin A storage phenotype, but when activated, they transform into proliferative, contractile, fibrotic, and chemotactic myofibroblasts.
  • the major mediators of hepatic stellate cell activation include a series of cytokines, reactive oxygen intermediates, and other paracrine and autocrine signals.
  • Proliferation of activated hepatic stellate cells primarily follows a pathway via transforming growth factor ⁇ (TGF ⁇ ), platelet-derived growth factor, vascular endothelial growth factor and connective tissue growth factor.
  • TGF ⁇ transforming growth factor ⁇
  • TGF ⁇ 1 is generally known as the most influential fibrogenic cytokine.
  • TGF ⁇ binding and phosphorylation of the type I receptor (TGFR1) induces phosphorylation of downstream SMAD proteins, primarily SMAD3.
  • TGFR1 type I receptor
  • SMAD3 phosphorylation of downstream SMAD proteins
  • hepatic stellate cells express ⁇ -SMA and extracellular matrix components including collagen type I and type II, fibronectin, and hyaluronan.
  • the activation of hepatic stellate cell fibrogenesis is an important target for the treatment of liver fibrosis.
  • an activator activating the ROR ⁇ gene can inhibit lipid accumulation in hepatocytes.
  • Kupffer cells which are macrophages present in the liver, are known to alleviate fatty liver disease when M2 polarization progresses.
  • the present inventors have demonstrated that when ROR ⁇ activator overexpresses ROR ⁇ in Kupffer cells, the expression of M2 polarity markers IL-10, Arg1, and CD163 is increased.
  • the metabolic disease may be a metabolic liver disease, but is not limited thereto.
  • the metabolic disease may be a lipid metabolism-related disease, but is not limited thereto.
  • the inflammatory disease is asthma, allergic and non-allergic rhinitis, gastritis, enteritis, ulcerative gastritis, nephritis, hepatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, irritable bowel syndrome, inflammatory pain, migraine, headache, Back pain, fibromyalgia, myofascial disease, viral infection (such as hepatitis C infection), bacterial infection, fungal infection, burns, surgical or dental wounds, gout, arthritis, rheumatoid arthritis, ankylosing spondylitis, Hodgkin's disease, pancreatitis, conjunctivitis, ulceris, scleritis, uveitis, dermatitis (including atopic dermatitis), eczema, and may be one or more selected from the group consisting of multiple sclerosis, but is not limited thereto.
  • anti-inflammatory means to include prevention, improvement, or treatment of inflammatory diseases
  • the inflammatory diseases include asthma, allergic and non-allergic rhinitis, gastritis, enteritis, ulcerative gastritis, nephritis, hepatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, irritable bowel syndrome, inflammatory pain, migraine, headache, back pain, fibromyalgia, myofascial disease, viral infection (eg hepatitis C infection), bacterial infection, fungal infection, burns, surgical or dental selected from the group consisting of surgical wounds, gout, arthritis, rheumatoid arthritis, ankylosing spondylitis, Hodgkin's disease, pancreatitis, conjunctivitis, ulceris, scleritis, uveitis, dermatitis (including atopic dermatitis), eczema, and multiple sclerosis It may be one or
  • the compound may inhibit or reduce inflammation by inhibiting the expression or secretion of pro-inflammatory cytokines or upregulating M2 macrophages, but is not limited thereto.
  • the content of the compound or a pharmaceutically acceptable salt thereof in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, etc., for example, 0.0001 to 99.9% by weight based on the total weight of the composition, Or it may be 0.001 to 50% by weight, but is not limited thereto.
  • the content ratio is a value based on the dry amount after removing the solvent.
  • the pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
  • the excipient may be, for example, one or more selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, an adsorbent, a moisturizer, a film-coating material, and a controlled release additive.
  • compositions according to the present invention are powders, granules, sustained-release granules, enteric granules, solutions, eye drops, elsilic agents, emulsions, suspensions, spirits, troches, perfumes, and limonadese, respectively, according to conventional methods.
  • tablets, sustained-release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, perfusate It can be formulated and used in the form of external preparations such as warning agents, lotions, pasta agents, sprays, inhalants, patches, sterile injection solutions, or aerosols, and the external agents are creams, gels, patches, sprays, ointments, and warning agents.
  • lotion, liniment, pasta, or cataplasma may have formulations such as the like.
  • Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • Additives for the liquid formulation according to the present invention include water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, sucrose monostearate, polyoxyethylene sorbitol fatty acid esters (tween esters), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, and the like may be used.
  • a solution of white sugar, other sugars, or a sweetener may be used, and aromatics, coloring agents, preservatives, stabilizers, suspending agents, emulsifiers, thickeners, etc. may be used as necessary.
  • Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.
  • tragacantha methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose, HPMC 1828, HPMC 2906, HPMC 2910, etc. and, if necessary, surfactants, preservatives, stabilizers, colorants, and fragrances may be used.
  • Injections according to the present invention include distilled water for injection, 0.9% sodium chloride injection, IV injection, dextrose injection, dextrose + sodium chloride injection, PEG (PEG), lactated IV injection, ethanol, propylene glycol, non-volatile oil-sesame oil , solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; solubilizing agents such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, twins, nijuntinamide, hexamine, and dimethylacetamide; buffers such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumins, peptones, and gums; tonicity
  • the suppository according to the present invention includes cacao butter, lanolin, witapsol, polyethylene glycol, glycerogelatin, methyl cellulose, carboxymethyl cellulose, a mixture of stearic acid and oleic acid, subanal, cottonseed oil, peanut oil, palm oil, cacao butter + Cholesterol, Lecithin, Lannet Wax, Glycerol Monostearate, Tween or Span, Imhausen, Monolen (Propylene Glycol Monostearate), Glycerin, Adeps Solidus, Buytyrum Tego-G -G), Cebes Pharma 16, Hexalide Base 95, Cotomar, Hydroxycote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Hyde Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Masupol, Masupol-15,
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, for example, starch, calcium carbonate, sucrose, etc. ) or by mixing lactose and gelatin.
  • excipients for example, starch, calcium carbonate, sucrose, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc.
  • various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • composition according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, activity of the drug, It may be determined according to factors including sensitivity to the drug, administration time, route of administration and excretion rate, duration of treatment, drugs used concurrently, and other factors well known in the medical field.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by a person skilled in the art to which the present invention belongs.
  • the pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be envisaged, eg oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intrathecal) injection, sublingual administration, buccal administration, intrarectal insertion, vaginal It can be administered by intraoral insertion, ocular administration, otic administration, nasal administration, inhalation, spraying through the mouth or nose, dermal administration, transdermal administration, and the like.
  • the pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient together with various related factors such as the disease to be treated, the route of administration, the age, sex, weight and severity of the disease of the patient.
  • “individual” means a subject in need of treatment of a disease, and more specifically, a human or non-human primate, mouse, rat, dog, cat, horse, cow, etc. It may be a mammal of, but is not limited thereto.
  • administration means providing a given composition of the present invention to a subject by any suitable method.
  • prevention refers to any action that suppresses or delays the onset of a desired disease
  • treatment means that the desired disease and its resulting metabolic abnormality are improved or improved by administration of the pharmaceutical composition according to the present invention. All actions that are advantageously altered are meant, and “improvement” means any action that reduces a parameter related to a target disease, for example, the severity of a symptom, by administration of the composition according to the present invention.
  • the compound represented by Formula 1 may be chemically synthesized by the method shown in the following reaction schemes, but is not limited thereto.
  • Reaction Scheme 1 shows compounds within the scope of Formula 1 by coupling a substrate in the form of a substituted amine with 1-(benzyloxy)-4-(isothiocyanatomethyl)-benzene in the presence of diethyl ether or methylene chloride solvent. Synthesizes the compound of the thiourea parent nucleus.
  • triethylamine (TEA) is added dropwise, and methanol or DMF (dimethylformamide) can also be used if the starting material is not soluble.
  • R in Scheme 1 means “-X-Y” in Formula 1.
  • X is a C 1 -C 5 alkyl group, a benzyl group, a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group;
  • Y is hydrogen, hydroxy group, halogen, OR 1 , CO 2 R 2 , NR 3 R 4 , substituted or unsubstituted C 3 -C 20 cycloalkyl group, substituted or unsubstituted C 3 -C 20 heterocycloalkyl group, substituted or unsubstituted A C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 20 heteroaryl group.
  • Scheme 2 shows that (benzyloxy-phenyl)-methanamine is converted to 1-(benzyloxy)-4-(isocyanatomethyl)-benzene intermediate in a dimethylformamide (DMF) solvent through carboxyldiimidazole and triethylamine (TEA). synthesize Then, the compound within the scope of formula 1 is 1-(benzyloxy)-4-(iso Coupling with cyanatomethyl)-benzene synthesizes the desired urea parent compound. In the case of salt, triethylamine (TEA) is added dropwise.
  • TAA triethylamine
  • R is as mentioned above.
  • Scheme 3 synthesizes thiourea parent compound with various substituents by reacting Thiourea with diaminobenzene structure.
  • 1-(benzyloxy)-4-(isothiocyanatomethyl)-benzene is prepared using N,N-dimethylbenzene-1,2,4-triamine in a dichloromethane solvent to form an intermediate, in which mercury oxide , sulfur, and ethanol are added and heated to synthesize the desired material, benzimidazole.
  • a white solid (184mg, 0.59mmol) was obtained using propylamine in the same manner as in Example 2 (yield: 99%).
  • N,N -dimethyl-4-nitrobenzene-1,3-diamine (100mg, 0.55mmol), the material obtained from the above reaction, was substituted with argon in ethyl acetate and methanol solvent to Pd/C (Palladium on carbon). , 5.87mg, 0.055mmol) and sodium borohydride (52mg, 1.38mmol) were added and stirred. After confirming that the substrate was gone on TLC, the solvent was blown off and filtered with Celite, and the organic layer was used as a reactant for the next reaction without a separate filtration process.
  • N,N -dimethylbenzene-1,2,4-triamine (167mg, 1.10mmol), a material filtered through Celite, was mixed with 1-(benzyloxy)-4-(isothiocyanatomethyl) in dichloromethane solvent. )-Benzene (141mg, 0.55mmol) was added and stirred. After confirming the disappearance of the substrate on TLC (Thin layer chromatography), extraction was performed with dichloromethane and water, and the organic layer was washed with brine and filtered with magnesium sulfate. The filtered organic layer was solidified using a hexane solvent and filtered to obtain a white solid (203mg, 0.50mmol) (yield: 90%).
  • Chang liver cells (CCL-13) were purchased from American Type Culture Collection (ATCC). Chang liver cells (2.5 x 10 4 cells/well) were seeded in a 24-well culture plate and cultured overnight in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal bovine serum (FBS). Chang liver cells were maintained at 37°C in a humidified thermostat with 5% CO 2 and 95% air. After culturing, the cells were transformed with the RORE-tk-Luc reporter plasmid (50 ng) and the ROR ⁇ expression vector (10 ng) using PolyFect (QIAGEN). 24 hours after transformation, thiourea-based novel compounds (20 ⁇ M) or JC1-40 control were treated.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • luciferase activity was measured using an Analytical luminescence luminometer. To confirm the transformation efficiency, luciferase activity was normalized using the activity of 200 ng of ⁇ -galactosidase ( ⁇ -gal) expression vector. The results for this are shown in Table 1, and Table 1 is schematized and shown in FIG. 2.
  • Chang liver cells (1.25 x 10 4 cells/well) were seeded in a 24-well culture plate and cultured overnight in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal bovine serum (FBS).
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • Chang liver cells were maintained at 37°C in a humidified thermostat with 5% CO 2 and 95% air.
  • the RORE-Luc reporter (50 ng) and the ROR ⁇ expression vector (10 ng) were transfected into Chang liver cells using PolyFect (QIAGEN).
  • Chang liver cells were dissolved in dimethyl sulfoxide (DMSO) with Compound 8 (ODH-08), which had the highest effect on ROR ⁇ transcriptional activity observed in Experimental Example 1, and at a specific concentration (0.5 ⁇ M, 2 ⁇ M, 10 ⁇ M, 20 ⁇ M and 30 ⁇ M) or the same amount of solvent (control) for 18 hours.
  • Cell lysates were then obtained, and luciferase activity was analyzed and determined using an Analytical luminescence luminometer. Luciferase activity was normalized for transformation efficiency with ⁇ -gal activity, and the results are shown in FIG. 3 .
  • ODH-08 was docked to RORa through a stabilized non-covalent interaction.
  • the benzyloxybenzyl group of ODH-08 and the lipophilic pocket composed of Cys323, Ile327, Leu361, Phe 365, Val379, Tyr380, Phe381, Phe391, and Leu394 have hydrophobic interactions, and in particular, Phe391 has a benzyloxy group of ODH-08 ( benzyloxy group) and ⁇ - ⁇ stacking.
  • the tertiary dimethylamine group of ODH-08 has an H-bond with Gln289, which means that ODH-010 or ODH-011 has lower activity than ODH-08 as the length between the thiourea and amine groups increases.
  • the ethylamine (ODH-012) and piperidine (ODH-013) groups are less preferred than the dimethylamine group (ODH-08) because they are close to Tyr290, Glu329, and GLn289, which cause steric collisions.
  • pET21a + -GST-RORa-His plasmid was transformed into B21 cells and cultured in LB medium (Luria-Bertani broth) at 37°C. Thereafter, the cells were treated with 0.5 mM isopropyl ⁇ -D-1-thiogalactopyranoside and incubated at 30° C. for 6 hours. After the cells were lysed, the supernatant was collected by centrifugation. Proteins were separated and purified from the obtained supernatant by His-tag affinity chromatography.
  • the supernatant was passed through a column composed of Ni + -NTA resin (Qiagen) and passed through a solution composed of 50 mM Tris-HCl, 100 mM sodium chloride, and 50 mM imidazole to remove proteins that did not adhere to the column. Removed.
  • the target protein was eluted while increasing the concentration of imidazole in the mobile phase from 250 mM to 500 mM. After concentration and dilution, the solvent was replaced with a PBS-T solution composed of 137 mM sodium chloride, 2.7 mM potassium chloride, 8.1 mM disodium phosphate, 1.8 mM potassium dihydrogen phosphate, and 0.1% polysorbate 20 (Sigma Aldrich).
  • ODH-08 showed binding to RORa protein in the concentration range of 1-100 ⁇ M. In addition, it was confirmed that the binding strength with ROR ⁇ also increased in a concentration-dependent manner.
  • Chang liver cells (1.25 x 10 4 cells/well) were seeded in a 24-well culture plate and cultured overnight in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal bovine serum (FBS).
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • Chang liver cells were maintained at 37°C in a humidified thermostat with 5% CO 2 and 95% air.
  • the Gal4- tk -Luc reporter 50 ng
  • ROR ⁇ , ROR ⁇ and ROR ⁇ expression vectors (10 ng) were transfected into Chang liver cells using PolyFect (QIAGEN). 24 hours after transformation, treatment was performed with 20 ⁇ M ODH-08 or the same amount of solvent (control) for 18 hours.
  • Luciferase activity was analyzed and determined using an Analytical luminescence luminomete. Luciferase activity was normalized for transformation efficiency by ⁇ -gal activity, and the results are shown in FIG. 6A.
  • ODH-08 selectively increased only ROR ⁇ transcriptional activity without increasing the transcriptional activity of ROR ⁇ and ROR ⁇ .
  • Chang liver cells (1.25 x 10 4 cells/well) were seeded in a 24-well culture plate and cultured overnight in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal bovine serum (FBS).
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • Chang liver cells were maintained at 37°C in a humidified thermostat with 5% CO 2 and 95% air.
  • the Gal4- tk -Luc reporter 50 ng
  • PPAR ⁇ , PPAR ⁇ , PPAR ⁇ , and LXR ⁇ expression vectors (10 ng) were transfected into Chang liver cells using PolyFect (QIAGEN).
  • ODH-08 did not show a significant increase effect on PAR ⁇ , PPAR ⁇ , PPAR ⁇ and LXR ⁇ transcriptional activities.
  • HepG2 cells (2.5 x 10 5 cells/well) were seeded into 6-well dishes and cultured overnight in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal bovine serum (FBS). HepG2 cells were maintained at 37° C. in a humidified thermostat with 5% CO 2 and 95% air.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • ODH-08 treatment on the polarity regulation of Kupffer cells, which are liver resident macrophages, was confirmed.
  • ODH-08 or JC1-40 was treated with peritoneal macrophages isolated from mice to confirm changes in the expression of polar markers. Specifically, after the mice were anesthetized and laparotomy, 3 ml of osmotic phosphate buffered saline per mouse was put into the abdominal cavity. After shaking the intraperitoneal phosphate-buffered saline for 2 minutes, the phosphate-buffered saline was reacquired using a syringe to obtain peritoneal macrophages.
  • the separated cells were dispensed (5 x 10 4 cells/well) in a 24-well culture dish. 20 ⁇ M of ODH-08 dissolved in dimethyl sulfoxide and 20 ⁇ M of JC1-40 or the same amount of solvent (control group) were treated, and 5 ng/ml of lipopolysaccharide (LPS) or 20 ng/ml of interleukin-4 (IL-4) was added. Each treatment was incubated for 24 hours. Cells not treated with lipopolysaccharide (LPS) and interleukin-4 (IL-4) were treated with the same amount of tertiary sterile distilled water. During cultivation, it was maintained at 37°C in a humidified thermostat with 5% CO 2 and 95% air.
  • mRNA was extracted using the RNeasy Micro Kit (QIAGEN).
  • cDNA was synthesized from the extracted mRNA using reverse transcription polymerase chain reaction (RT-PCR). Then, using real-time polymerase chain reaction (qRT-PCR), M1 markers interleukin 1b (IL-1b), interleukin 6 (IL-6), and CD80, M2 markers interleukin 10 (IL-10), AR
  • qRT-PCR real-time polymerase chain reaction
  • M1 markers interleukin 1b (IL-1b), interleukin 6 (IL-6), and CD80 M2 markers interleukin 10 (IL-10), AR
  • Genase1 (Arg1) and CD206 were amplified and measured. More specifically, an mRNA-M-MLV mixture was prepared using M-MLV reverse transcriptase (Invitrogen) and a reverse transcription polymerase chain reaction was developed using a thermal cycler. Then, real-time polymerase chain reaction was performed using an ABI StepOnePlus Real-Time PCR
  • LPS lipopolysaccharide
  • treatment with interleukin 4 increased the expression of macrophage M2 markers, and treatment with ODH-08 further increased their expression.
  • Hepatic stellate cells Lx-2 (3 x 10 5 cells/well) were dispensed into a 60-cm 2 dish and cultured overnight in DMEM (Dulbecco's modified Eagle's medium) medium containing 2% fetal bovine serum (FBS). Lx-2 cells were maintained at 37° C. in a humidified thermostat with 5% CO 2 and 95% air. After culturing, Lx-2 cells were treated with 5ng/ml of TGF ⁇ 1 and ODH-08 compound at specific concentrations (5 ⁇ M, 10 ⁇ M, 20 ⁇ M and 30 ⁇ M) or the same amount of solvent (control) for 18 hours.
  • DMEM Dynamic fibroblast growth factor
  • FBS fetal bovine serum
  • Cells not treated with TGF ⁇ 1 were treated with the same amount of phosphate-buffered saline (PBS) containing 0.5% BSA. After treatment, protein expression was analyzed by Western blotting analysis. That is, after treatment with the test substance, Lx-2 cells were disrupted for 30 minutes on ice using a lysis buffer containing 50 mM NaCl, 50 mM Tris (pH 7.4), 5 mM EDTA, 1% NP-40 and protease inhibitors, and centrifuged. Separated to obtain whole cell lysate.
  • PBS phosphate-buffered saline
  • HRP horseradish peroxidase
  • BCA bicinchoninic acid
  • RNA was dissolved with EASY BLUE (Intron, Korea) for extraction, and isopropanol fractionation and ethanol precipitation were used.
  • cRNA was synthesized with each RNA sample, an oligomer amplifying the cDNA of a specific gene was used, and the expression of 18s rRNA was monitored as a control. More specifically, an mRNA-M-MLV mixture was prepared using M-MLV reverse transcriptase (Invitrogen) and a reverse transcription polymerase chain reaction was developed using a thermal cycler. Then, real-time polymerase chain reaction was performed using an ABI StepOnePlus Real-Time PCR system (Applied Biosystems).
  • ODH-08 suppresses the expression of fibrosis genes in hepatic stellate cells, and thus has an effect on metabolic liver diseases such as liver fibrosis.
  • TGF- ⁇ is the most potent fibrosis-promoting cytokine of hepatic stellate cells, and hepatic stellate cells themselves are the main producer of TGF- ⁇ , promoting the production of extracellular matrix including type I, III, and IV collagen.
  • TGF- ⁇ binds to the type II receptor and phosphorylates the type I receptor, which then contacts and phosphorylates Smad2 and Smad3. Then, the complex of Smad2 and Smad3 binds to Smad4 and moves into the nucleus to regulate transcription of the target gene.
  • the transcription of collagen ⁇ 1 and ⁇ 2 is promoted through such TGF- ⁇ and Smad signaling, the production of collagen is increased. Therefore, regulation of the Smad signaling network is regarded as a representative drug action point that can treat hepatic fibrotic disease through the activation control of hepatic stellate cells.
  • Lx-2 Hepatic stellate cells Lx-2 (2.5 x 10 4 cells/well) were seeded into a 24-well culture plate and cultured overnight in Dulbecco's modified Eagle's medium (DMEM) medium containing 2% fetal bovine serum (FBS). Lx-2 cells were maintained at 37° C. in a humidified thermostat with 5% CO 2 and 95% air. After culturing, Lx-2 cells were transfected with the SMAD cignal reporter (20 ng) alone or together with the ROR ⁇ expression vector (10 ng) using X-tremeGENE HP DNA transfection reagent (Roche, Mannheim, Germany).
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • Lx-2 cells were treated with 5 ng/ml of TGF ⁇ 1 and specific concentrations (10 ⁇ M, 20 ⁇ M) of ODH-08 or Obeticholic acid (OCA, positive control) or the same amount of solvent (control) for 18 hours.
  • Cells not treated with TGF ⁇ 1 were treated with the same amount of PBS containing 0.5% BSA.
  • Cell lysates were then obtained, and luciferase activity was analyzed and determined using an Analytical luminescence luminometer. Luciferase activity was normalized for transformation efficiency with ⁇ -gal activity,
  • the SMAD signal reporter transcriptional activity which was increased by TGF ⁇ 1, decreased in a concentration-dependent manner of ODH-08.
  • ODH-08 showed better SMAD inhibitory activity compared to OCA of FIG. 10a.
  • ODH-08 was orally administered at a concentration of 10 mg/kg once a day for 5 weeks.
  • a drug was prepared by weighing and adding an amount of ODH-08 corresponding to the final concentration to sterile water containing 0.5% carboxymethylcellulose (CMC) and then evenly suspending the mixture using a mortar and pestle.
  • CMC carboxymethylcellulose
  • Doses for individual mouse subjects were calculated and administered orally using a sonde.
  • Sterile water containing 0.5% carboxymethylcellulose was administered to the control group in the same manner.
  • mice were anesthetized openly and blood was collected from the inferior vena cava of the liver, and then the liver was removed, weighed, and some were fixed using a 4% paraformaldehyde solution, and the rest were stored at -70 ° C. frozen.
  • the collected blood was subjected to coagulation at room temperature (15-25 ° C) for 2 hours, and then centrifuged at 13000 rpm for 10 minutes at the same temperature to obtain the supernatant.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • the weight of the liver of mice (WD) fed only Western-style diet was significantly increased compared to that of the control group (CD), but the liver weight of mice experimental group (WD + ODH-08) administered with ODH-08 to Western-style diet The weight was significantly decreased compared to the experimental group (WD) of mice fed only Western diet.
  • the AST and ALT blood concentrations of the mouse experimental group (WD) fed with the Western-style diet were significantly increased compared to the control group (CD), but the experimental group of mice fed with ODH-08 with the Western-style diet (WD +ODH-08) was confirmed to be significantly reduced compared to both WD.
  • liver damage induced by Western-style diet was significantly improved by ODH-08, and through this, the liver damage inhibitory effect of ODH-08 could be confirmed.
  • the paraffin sections were immersed in 1% hematoxylin solution for 30 seconds and stained, washed once with distilled water, reacted again in 0.25% hydrogen chloride (HCl) for 1 second, and washed once with distilled water. Then, 10% lithium carbonate, a mordant for hematoxylin, was reacted for 2-4 seconds, and then washed with distilled water. Thereafter, eosin was treated for 2 seconds to stain the cytoplasm, and then final dehydration and clearing steps were sequentially performed using 95% ethanol and 100% ethanol. The cleared section was mounted, observed under an optical microscope, and a photograph was obtained to observe the state of fat accumulation in the liver tissue. The results are shown in Figure 12a.
  • pro-COL1A1 and ⁇ -SMA which are fibrosis markers
  • the protein expression of pro-COL1A1 and ⁇ -SMA increased significantly in the experimental group (WD) fed with a Western-style diet, but in the experimental group administered with ODH-08 (WD + ODH-08 ), the amount was significantly reduced.
  • mRNA was isolated from mouse liver tissue. A portion of frozen liver tissue was placed in easy-BLUE (iNtRON biotechnology) and solubilized using TissueLyser II (QIAGEN). After treatment with 200 ⁇ l chloroform and centrifugation, the supernatant containing RNA was taken. After treatment with the same amount of 70% ethanol as the supernatant, RNA was extracted using RNeasy Mini Kit (QIAGEN). cDNA was synthesized from the extracted mRNA using reverse transcription polymerase chain reaction (RT-PCR), and amplified and measured using real-time polymerase chain reaction (qRT-PCR). Reverse transcription polymerase chain reaction and real-time polymerase chain reaction were performed in the same manner as in Experimental Example 7. The results are shown in Figure 12d.
  • RT-PCR reverse transcription polymerase chain reaction
  • qRT-PCR real-time polymerase chain reaction
  • liver fibrosis induced by a Western-style diet was significantly improved by ODH-08, and through this, the liver fibrosis inhibitory effect of ODH-08 could be confirmed.
  • the compound according to the present invention exhibits effects in the treatment and prevention of metabolic or inflammatory diseases through various in vivo mechanisms of ROR ⁇ .
  • excellent effects on suppression of fibrosis-related gene expression and activity of cytokines in hepatic stellate cells were confirmed, as well as the effect was reconfirmed in animal models, making it useful as a preventive and therapeutic agent for metabolic liver diseases including liver fibrosis. expected to be utilized.

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Abstract

La présente invention concerne un nouveau dérivé de thio-urée utilisé en tant qu'activateur de RORα et une composition pharmaceutique le comprenant. Un composé selon la présente invention est prévu pour être efficace dans le traitement et la prévention de maladies métaboliques et inflammatoires par diverses fonctions in vivo de RORα, et est particulièrement prévu pour être utile dans le traitement et la prévention de maladies métaboliques, notamment la fibrose hépatique par l'inhibition de l'activité cellulaire stellaire hépatique.
PCT/KR2022/017924 2021-11-15 2022-11-15 Nouveau dérivé de thio-urée utilisé en tant qu'activateur de rorα et composition pharmaceutique le comprenant WO2023085894A1 (fr)

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Citations (4)

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WO2000031067A1 (fr) * 1998-11-23 2000-06-02 Celltech Therapeutics Limited Derives d'acide propanoique utilises en tant qu'inhibiteurs des integrines
WO2001044194A2 (fr) * 1999-12-17 2001-06-21 Celltech R & D Limited Derives d'acide propanoique en tant qu'inhibiteurs d'integrine
KR20070007759A (ko) * 2003-07-10 2007-01-16 아칠리온 파르마세우티칼스 인코포레이티드 바이러스 복제 억제제로서 유용한 치환된 아릴티오우레아유도체
KR20160132534A (ko) * 2015-05-11 2016-11-21 경북대학교병원 ＲＯＲα 활성조절제를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물

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WO2000031067A1 (fr) * 1998-11-23 2000-06-02 Celltech Therapeutics Limited Derives d'acide propanoique utilises en tant qu'inhibiteurs des integrines
WO2001044194A2 (fr) * 1999-12-17 2001-06-21 Celltech R & D Limited Derives d'acide propanoique en tant qu'inhibiteurs d'integrine
KR20070007759A (ko) * 2003-07-10 2007-01-16 아칠리온 파르마세우티칼스 인코포레이티드 바이러스 복제 억제제로서 유용한 치환된 아릴티오우레아유도체
KR20160132534A (ko) * 2015-05-11 2016-11-21 경북대학교병원 ＲＯＲα 활성조절제를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물

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