WO2015102380A1 - Nouveau dérivé de 8-oxoprotoberbérine ou sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et composition pharmaceutique destinée à prévenir ou à traiter des maladies associées à l'activité du nfat5 le contenant à titre de principe actif - Google Patents

Nouveau dérivé de 8-oxoprotoberbérine ou sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et composition pharmaceutique destinée à prévenir ou à traiter des maladies associées à l'activité du nfat5 le contenant à titre de principe actif Download PDF

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WO2015102380A1
WO2015102380A1 PCT/KR2014/013059 KR2014013059W WO2015102380A1 WO 2015102380 A1 WO2015102380 A1 WO 2015102380A1 KR 2014013059 W KR2014013059 W KR 2014013059W WO 2015102380 A1 WO2015102380 A1 WO 2015102380A1
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WIPO (PCT)
Prior art keywords
derivative
nfat5
oxoprotoberberine
dioxolo
isoquinoline
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PCT/KR2014/013059
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English (en)
Korean (ko)
Inventor
조희영
임희종
이계형
박우규
김현영
정대영
김완욱
조철수
박수정
한은진
Original Assignee
한국화학연구원
가톨릭대학교 산학협력단
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Priority to US15/029,075 priority Critical patent/US9650389B2/en
Priority claimed from KR1020140193586A external-priority patent/KR101656394B1/ko
Publication of WO2015102380A1 publication Critical patent/WO2015102380A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems

Definitions

  • the present invention relates to a novel 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating NFAT5 and an activity-related disease containing the same as an active ingredient.
  • Autoimmunity refers to a condition in which the body recognizes its speculum or tissue as an externally derived antigen and causes an immune response.
  • the original immune response is a system made against external antigens such as pathogens.
  • autoimmunity attacks their own organs or tissues and causes various diseases.
  • Autoimmune diseases include rheumatoid arthritis, systemic scleroderma, thrush lupus, atopic dermatitis, Beche's disease, Sjogren's syndrome, multiple sclerosis, and Grave's hyperthyroidism.
  • Rheumatoid arthritis is an autoimmune disease that causes chronic remnant inflammation in many tissues and organs, but is mainly a symptomatic synovial attack, which causes pain and deformation and loss of function and mobility if not treated properly.
  • the joint swells with a large amount of synovial fluid, the fibrous tissue (pannus) develops in the synovial membrane, and the destruction of articular cartilage (ankylos is), the lungs, the pericardium, and the ribs. Inflammation spreads to the sclera of the eye, but the cause of autoimmunity that causes rheumatoid arthritis is not clear.
  • Non-Patent Document 1 Approximately 0.6% of American adults suffer from rheumatoid arthritis, with 2-3 times more women than men (Non-Patent Document 1).
  • the treatment of rheumatoid arthritis includes nonpharmacological physiotherapy, orthoses, occupational therapy, nutritional therapy, and pharmacological treatments such as analgesics and anti-inflammatory drugs.
  • the drugs used for pharmacological treatment are nonsteroidal anti-inflammatory drugs ( Non-steroidal anti-inflammatory drugs (NSAIDs) or anti-rheumatic drugs (disease-modified ant i -rheumatic drugs, DMARD) can be used.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • DMARD disease-modified ant i -rheumatic drugs
  • Anti-inflammatory drugs are mainly anti-inflammatory drugs that exhibit anti-inflammatory action by inhibiting the synthesis of prostaglandins by inhibiting cyclooxygenase (C0X) enzyme activity, an important mediator of inflammation, for example, diclofenac, piroxicam ), Indomethacin, meloloc 1 meloxicam, celecoxib, rofecoxib, and lumiracoxib, which can be used to stop the progression of joints. You can't.
  • Antirheumatic drugs that can slow or stop disease progression include methotrexate, lef hmomide,
  • NFAT nuclear factor of activated T cells
  • TonEBP tacrine binding protein
  • NFAT5 is composed of approximately 1,500 amino acids and is expressed in almost all tissues. In particular, NFAT5 is highly expressed in the kidneys, lungs, pituitary gland, placenta, testicles, thymus, etc., which are actively metabolized and proliferated (Non-Patent Document 4).
  • NFAT5 does not have a calcineurin domain, which is not directly affected by calcium concentration, and is activated by osmostress in hypertonic fluid with increased osmotic pressure to maintain homeostasis.
  • NFAT5 activated in T cells is known to bind to the promoter of CD24 to increase transcription of CD24, thereby enabling amplification of T cells.
  • Relevant factors at higher levels of NFAT5 include ROS reactive oxygen species and p38 MAPK, and it has been reported that R0S is related to NFAT5 activity induced by TLR (Toll-like receptor) (Non-Patent Document 5).
  • NO nitric oxide a type of R0S
  • iNOS lnducible nitric oxide synthase NO induced by iNOS is known to play an important role in various diseases, particularly inflammatory reactions, and the expression of iNOS has been reported to be related to various diseases.
  • Non-Patent Document 6 Recently, NFAT5 has been reported to be highly expressed in joint synovial fluid of rheumatoid patients with autoimmune diseases and to increase the secretion of inflammatory cytokines IL- ⁇ , TNF- ⁇ , and the like (Non-Patent Document 7).
  • Berberine is a quaternary ammonium salt of isoquinoline alkaloids contained in sulfur. It is well known as a herbal medicine and anti-cancer, anti-obesity and diabetes treatment effects have been reported. In addition, berberine is the main component of the commercial cold-form preparation Jeong, Ro-hwan, which has an inhibitory effect on intestinal bacteria, sedative nervous system, arteriosclerosis prevention, anti-inflammatory effect, biliary tract, and pancreatic fluid secretion.
  • a derivative having various substituents at the 13 position (protoberberine ring) of berberine, a protoberberine having a significantly improved NFAT5 inhibitory effect and a C0X enzyme inhibitory effect than berberine has been known to exhibit excellent inflammation inhibitory effect in arthritis animal models.
  • the protoberberine has a disadvantage in that it is difficult to develop as an oral administration agent because the solubility is not soaked upon oral administration. Accordingly, the present inventors recognize that arthritis or autoimmune disease is a disease that requires continuous treatment, and requires a new mechanism for the preparation of drug resistance and requires the development of an oral preparation rather than an injection, and shows the effect of an NFAT5 inhibitor.
  • the shangyu 8-oxoprotoberberine derivative according to the present invention has an excellent effect of inhibiting NFAT5, and has improved the physical properties and the oral absorption rate through pharmacokinetic studies, thereby treating oral administration of rheumatoid arthritis
  • the present invention has been completed by finding out that it can be useful.
  • Non-Patent Document 1 Handout on Health: Rheumatoid Arthr itis. Nat ional Inst i tute of Arthr itis and Musculoskeletal and Skin Di seases, Apr il 2013; [Non-Patent Document 2] Biochem. Pharm. 72 (2006) 1597-1604; [Non-Patent Document 3] Nuc lei c Acids Res. 33 (2005) 3845-3854; [Non-Patent Document 4] J. nmunol. 165 (2000) 4884-4894;
  • Non-Patent Document 6 Semin Cancer Biol. 15 (2005) 277-289.
  • Non-Patent Document 7 Arthr i t i s and Rheumat i sm. 63 (2011) 1843-1852.
  • An object of the present invention is to provide a novel 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a method for preparing the 8-oxoprotoberberine derivative.
  • Another object of the present invention is to provide a pharmaceutical composition containing the 8—oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating an activity-related disease of NFAT5 containing the 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention to provide an activity-related inhibitor of NFAT5 containing the 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a dietary supplement for the prevention or improvement of NFAT5 activity-related diseases containing the 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a method for preventing, ameliorating or treating NFTA5 related diseases, which comprises administering to a subject an effective amount of an 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof. It is another object of the present invention to provide the use of an 8-oxoprotobe.verberine derivative or a pharmaceutically acceptable salt thereof for use in the composition for preventing, ameliorating or treating NFTA5-related diseases.
  • the present invention provides an 8-oxoprotoberberine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • A is d- 6 alkylene, -C (O)-or -NHCO0)-;
  • R is hydroxy, amino, straight or branched d-6 alkoxy, C 6 - 12 aryl or a nitrogen (N), oxygen (O) and sulfur (S) be the same or different selected from the group consisting of an interrogating atoms 1 Heteroaryl of 5 to 8 membered single ring or 8 to 11 membered double ring containing at least one species, wherein the aryl or heteroaryl is unsubstituted or halogen and straight or branched Ci-6 alkyl or d- 6 alkoxy. It is substituted by 1 or more types from the group which consists of.
  • step 1 Reacting the compound represented by the formula (2) with the compound represented by the formula (3) to obtain a compound represented by the formula (4) (step 1);
  • step 2 Method of preparing the 8-oxoprotoberberine derivative of claim 1 represented by the formula (1) comprising the step (step 2) to obtain a compound represented by the formula (1) by reacting the compound represented by the formula (4) obtained in the step 1 under basic conditions
  • the present invention provides a pharmaceutical composition containing the 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition for preventing or treating an activity-related disease of NFAT5 containing the 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating an activity-related disease of NFAT5, which contains a novel 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides an inhibitor related to the activity of NFAT5 containing the 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a nutraceutical composition for preventing or ameliorating the activity-related diseases of NFAT5 containing a novel 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides an activity of NFAT5 comprising administering to a subject an effective amount of an 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof
  • an effective amount of an 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof Provides methods for preventing, ameliorating or treating related diseases.
  • the present invention provides the use of an 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof for use in the composition for preventing, ameliorating or treating NFTA5-related diseases.
  • novel 8-oxoprotoberberine derivatives or pharmaceutically acceptable salts thereof according to the present invention have significantly improved oral absorption rate compared to conventional protoberberine due to the improvement of physical properties, and also inhibit the secretion of NFAT5 activity and inflammatory cytokines and rheumatoid arthritis.
  • NFAT5 activity-related diseases particularly rheumatoid arthritis or inflammatory diseases.
  • Figure 2 is a graph showing the effect of the derivative according to the invention on the transcriptional activity other than NFAT 3 ⁇ 4 ⁇ factor, specifically, A is NF- ⁇ , B is NFATc, C is C EB (CHO-Kl), D is CREBCHEK293 ), E is a graph showing the inhibition of transcriptional activity against ELK;
  • FIG. 3 is an image of a Western blot expressing p38 protein and active state p38 protein (phosphorylation) of the derivatives according to the invention
  • A is BGTl
  • B is A graph of the transcript of AR
  • A represents GM-CSF2
  • B represents MCP-1
  • C represents IL-6
  • Figure 7 is a graph showing the effect on the immune response of the mouse according to the derivative of the present invention, a control of the joint region of the mouse leg and a photograph after the injection of the derivative according to the present invention.
  • FIG. 8 is a diagram showing the inhibition of the expression of inflammatory cytokines (TNF- ⁇ , IL-6) induced by LPS in collagen-induced rheumatoid arthritis mice by the compound of Example 1.
  • FIG. 8 is a diagram showing the inhibition of the expression of inflammatory cytokines (TNF- ⁇ , IL-6) induced by LPS in collagen-induced rheumatoid arthritis mice by the compound of Example 1.
  • FIG. 9 is a diagram showing the inhibition of LPS-induced NFAT expression in collagen-induced rheumatoid arthritis mice by the compound of Example 1.
  • FIG. 9 is a diagram showing the inhibition of LPS-induced NFAT expression in collagen-induced rheumatoid arthritis mice by the compound of Example 1.
  • Figure 10a Figure 10b is a diagram showing metabolic stability and pharmacokinetics in hepatic microsomes by the compounds of Examples 1 and 3.
  • FIG. 11 is a diagram showing the inhibitory effect of inflammatory cytokine secretion by the compound of Example 1 in human mononuclear blood cells.
  • FIG. 12 is a diagram showing inhibition of differentiation into Thl7 cells by the compound of Example 1.
  • the present invention provides an 8-oxoprotoberberine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • R is one or more of the same or different hetero atoms selected from the group consisting of hydroxy, amino, straight or branched d- 6 alkoxy, C 6 — 12 aryl or nitrogen (N), oxygen (0) and sulfur (S)
  • R is preferably a hydroxy, amino, linear or Ci-4 alkoxy side chains, C 6 - 10 aryl or a nitrogen (N), oxygen (0) and the same sulfur is selected from the group consisting of (S) or different hetero A heteroaryl of 5 to 8 membered single ring or 8 to 11 membered dicyclic ring containing one subphase, wherein the aryl or heteroaryl consists of unsubstituted or halogen and linear or branched d- 6 alkyl or alkoxy.
  • One or more selected from the group more preferably one selected from the group consisting of hydroxy, amino, straight or branched d- 2 alkoxy, phenyl, pyridinyl, thiazolyl and benzoimidazolyl, wherein , with said phenyl, pyridinyl, thiazolyl or benzo-imidazolyl are unsubstituted or halogen, and straight chain or the group consisting of Cw alkyl or alkoxyalkyl side chain d- 4 Site is substituted with at least one member.
  • R is unsubstituted or halogen, methyl and Selected from the group consisting of phenyl, pyridinyl, thiazolyl and benzoimidazolyl substituted with one or more substituents selected from the group consisting of methoxy
  • the 8-oxoprotoberberine derivative represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, phosphoric acid, hydrobromic acid hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenylsubstituted alkanoates, hydroxy alkanoates and alkanedioates.
  • non-toxic organic acids such as aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-luluenesulfonic acid, tartaric acid, fumaric acid and the like.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, ' heptanoate, propiolate, oxalate, malonate, succinate, Suberates, Sebacates, Fumarates, Maleates, Butyne-1, 4-Diates, Nucleic Acids-1, 6 ⁇ dioates, Benzoates, Chlorobenzoates, Methylbenzoates, Dinitrobenzoates, Hydroxybenzoates , Methoxybenzoate, phthalate, terephthalate , Benzenesulfonate, toluenesulfon
  • Acid addition salts according to the present invention can be prepared by a conventional method, for example, the 8-oxoprotoberberine derivative represented by the formula (1), such as methane, ethanol, acetone, dichloromethane, acetonitrile, etc.
  • the precipitate produced by dissolving in an organic solvent and adding an organic acid or an inorganic acid may be prepared by filtration and drying, or the solvent and excess acid are distilled under reduced pressure and dried to crystallize under an organic solvent.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained by, for example, dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a natrim, potassium or calcium salt as the metal salt.
  • the salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (for example, silver nitrate).
  • the present invention includes not only the 8-oxoprotoberberine derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, but also all solvates and hydrates prepared therefrom.
  • the novel 8-oxoprotoberberine derivatives according to the present invention are excellent in inhibiting the activity of NFAT5, and in particular, it can be seen that the derivatives of Examples 1, 3, 6 and 10 are excellent in inhibiting the activity of NFAT5. (See Experimental Examples 2 and 3).
  • Experimental Examples 2 and 3 See Experimental Examples 2 and 3.
  • the symptoms were alleviated, and histological staining also showed that the symptoms of arthritis recovered significantly (see Experimental Example 10).
  • the derivative according to the present invention can be usefully used as a pharmaceutical composition for the prevention or treatment of NFAT5 activity-related diseases.
  • the present invention as shown in the following reaction formula 1,
  • step 1 Reacting the compound represented by the formula (2) with the compound represented by the formula (3) to obtain a compound represented by the formula (4) (step 1);
  • step 2 Chemical formula comprising the step (step 2) to obtain a compound represented by formula 1 by reacting the compound represented by formula 4 obtained in step 1 under basic conditions
  • step 1 is a step of obtaining a compound represented by the formula (4) by reacting the compound represented by the formula (2) and the compound represented by the formula (3).
  • the compound represented by the formula (3) is preferably used in 1.2 to 2 equivalents of the compound represented by the formula (2).
  • a catalyst such as sodium iodide, potassium iodide, sodium chloride or potassium chloride may be used, and it is more preferable to use sodium iodide. desirable.
  • the solvent usable in step 1 is acetonitrile, chloroform, dimethylformamide, dimethylsulfoxide, methane, ethanol, propanol, butane, tetrahydrofuran, dioxane, methylene chloride, 1,2-dimethoxyethane and the like. It could be used alone or in combination, it is preferable to use acetonitrile or the like.
  • step 2 is a step of obtaining a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 4 obtained in Step 1 under basic conditions.
  • the base can be used without limitation as long as it is inexpensive, it is preferable to use a base such as potassium hydroxide, sodium hydroxide, calcium hydroxide, strontium hydroxide, more preferably using potassium hydroxide or sodium hydroxide as an aqueous solution desirable.
  • a base such as potassium hydroxide, sodium hydroxide, calcium hydroxide, strontium hydroxide, more preferably using potassium hydroxide or sodium hydroxide as an aqueous solution desirable.
  • step 2 is as shown in the following reaction formula 2,
  • Said step A by the formula (5) compound represented by the all-banung oxide obtained in step (step B) to obtain a compound represented by Formula 1; may be a step that includes:,
  • step A is a step of obtaining a compound represented by the formula (5) by reducing the compound represented by the formula (4).
  • the reducing agent that can be used may be sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, pyridine borohydride, zinc borohydride and the like, sodium cyanoborohydride, sodium borohydride It is preferable to use a lide, sodium triacetoxyborohydride and the like.
  • a base may be used as a catalyst, and any base can be used without limitation, but it is preferable to use a base such as potassium hydroxide, sodium hydroxide, calcium hydroxide, strontium hydroxide, and an aqueous solution of potassium hydroxide or sodium hydroxide. It is more preferable to use.
  • step B is a step of obtaining a compound represented by the formula (1) by oxidizing the compound represented by the formula (5) obtained in the step A.
  • manganese dioxide hydrogen peroxide, potassium dichromate, or the like may be used, and manganese dioxide is preferably used.
  • usable solvents include ether solvents such as methylene chloride, 1,2-dimethicethane, dimethylformamide, dimethyl sulfoxide and the like.
  • the present invention provides a pharmaceutical composition for preventing or treating an activity-related disease of NFAT5, which contains a novel 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof as an effective phase.
  • the activity-related diseases of NFAT5 may be arthritis, autoimmune diseases, and the like.
  • the arthritis disease is characterized in that rheumatoid arthritis.
  • the autoimmune disease is at least one selected from systemic scleroderma, lupus erythematosus, atopic dermatitis, Beche's disease, Sjogren's syndrome, multiple sclerosis and Graves' hyperthyroidism.
  • the novel 8-oxoprotoberberine derivatives are excellent in inhibiting the activity of NFAT5, and in particular, it can be seen that the derivatives of Examples 1, 3, 6 and 10 are excellent in inhibiting the activity of NFAT5 (experimental) See examples 2 and 3).
  • the symptoms of arthritis were alleviated when the joints of the mouse legs were visually observed in animal experiments, and the arthritis symptoms were recovered significantly through histological staining (see Experimental Example 11).
  • the compounds of the present invention inhibited the increase of LPS-induced iNOS gene expression (see Table 2), inhibited NFAT5 transcriptional activity (see Table 3, and FIG. 1) —another transcription factors, NF-kB, NFATc, It was also confirmed that the transcriptional activity of CREB and ELK was also inhibited (see FIG. 2).
  • the compounds of the present invention showed no inhibitory effect on R0S induction, p38 activity, and C0X1 and C0X2 (see FIGS. 3 and 6, Tables 4 and 5), and showed little toxicity to cells, and inflammatory It was confirmed that the secretion of cytokines was inhibited (see Table 6 and FIG. 6).
  • Compounds of the present invention in collagen-induced rheumatoid arthritis mice recovered arthritis symptoms (Fig. 7 acupuncture), and were found to reduce the expression of inflammatory cytokines (TNF- ⁇ , IL-6) (see Fig. 8). .
  • the compounds of the present invention showed increased oral absorption (see Table 7), and inflammatory cytokines in human mononuclear blood cells. Secretion was inhibited (see FIG. 11), and it was confirmed to inhibit differentiation from T cells to Thl7 cells (see FIG. I 2 ).
  • novel 8-oxoprotoberberine derivatives of the present invention or pharmaceutically acceptable salts thereof have significantly improved oral absorption rate than the conventional protoberberine due to the improvement of physical properties and do not pass through p38, which is an upstream stage of NFAT5.
  • p38 which is an upstream stage of NFAT5.
  • directly inhibiting the transcription of NFAT5 inhibiting NFAT5 activity and inflammatory cytokine secretion and reducing the expression of NFAT5 in rheumatoid arthritis mice, thereby preventing or preventing activity-related diseases of NFAT5, particularly rheumatoid arthritis or inflammatory diseases. It can be usefully used as a therapeutic pharmaceutical composition.
  • the 8'oxoprotoberberine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in a variety of oral and parenteral formulations for clinical administration.
  • it may be prepared using conventional diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, and the like, wherein the solid preparations are at least one 8 ⁇ oxoprotoberberine derivative represented by Formula 1 of the present invention, or a pharmaceutical thereof.
  • It may be formulated by mixing at least one excipient, for example starch, calcium carbonate, sucrose or lactose or gelatin, etc. with a generally acceptable salt.
  • excipients for example starch, calcium carbonate, sucrose or lactose or gelatin, etc.
  • lubricants such as stearic acid magnesium talc and the like may also be used.
  • Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be used. Can be.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvents and suspensions propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used.
  • wi tepsol, macrogol, tvveen 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used. See also .
  • the dosage of the 8-oxoprotoberberine derivative represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, Based on an adult patient weighing 70 Kg, typically 0.1-1000 mg / day, preferably 1-500 mg / day, and also 1 day at regular time intervals as determined by the physician or pharmacist 1 time. It may be administered in several divided doses.
  • the pharmaceutical composition of the present invention may be used alone or in combination with methods using surgery, hormone therapy, chemotherapy and biological response modifiers for the prevention or treatment of arthritis or autoimmune diseases.
  • the present invention also provides a nutraceutical composition for preventing or ameliorating the activity-related diseases of NFAT5 containing a novel 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the derivative according to the present invention has an excellent effect of inhibiting the activity of NFAT5 can be usefully used as a health functional food composition for the prevention or improvement of NFAT5 activity-related diseases.
  • the disease associated with activity of NFAT5 may be arthritis or autoimmune disease.
  • the arthritis is characterized in that rheumatoid arthritis.
  • the autoimmune disease is at least one selected from systemic scleroderma, lupus erythematosus, atopic dermatitis, Beche's disease, Sjogren's syndrome, multiple sclerosis, and Graves' hyperthyroidism.
  • the novel 8-oxoprotoberberine derivatives of the present invention or pharmaceutically acceptable salts thereof have significantly improved oral absorption rate than the conventional protoberberine due to the improvement of physical properties and do not pass through p38, which is an upstream stage of NFAT5.
  • NFAT5 By directly inhibiting the transcription of NFAT5, inhibiting NFAT5 activity and inflammatory cytokine secretion and reducing the expression of NFAT5 in rheumatoid arthritis mice, thereby preventing or preventing activity-related diseases of NFAT5, particularly rheumatoid arthritis or inflammatory diseases. It can be usefully used as a dietary supplement for improvement. .
  • Examples of the food to which the substance may be added include drink, meat, sausage, bread, biscuit, rice cake, chocolate, candy, snacks, confectionary, pizza, ramen, other noodles, and 3 ⁇ 4.
  • Dairy products including ice cream, various soups, beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, and includes all the health functional foods in the ordinary sense.
  • 8 ⁇ oxoprotoberberine derivatives represented by the formula (1) according to the present invention can be used as it is or added to other foods or food ingredients as it is, and may be appropriately used according to conventional methods.
  • the combined amount of the active ingredient can be suitably determined depending on the purpose of use (prevention or improvement).
  • the amount of the compound in the health food can be added from 0.1 to 90 parts by weight of the total food weight.
  • the amount may be below the above range, and the active ingredient is in the above range because there is no problem in terms of safety.
  • the above amounts may also be used.
  • the health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. have.
  • natural carbohydrates examples include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And sugars such as polysaccharides, for example, conventional sugars such as textine, cyclotextine and the like, and xylyl, sorbitol, and erytri Colour
  • natural flavoring agents tactin, stevia extract (e.g. rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.
  • 8-oxoprotoberberine derivatives include flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, coloring and neutralizing agents (cheese, chocolate), pectic acid and salts thereof, alginic acid and its Salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.
  • the 8-oxoprotoberberine derivatives of the present invention may contain pulp for the production of natural fruit juices and fruit juice beverages and vegetable beverages.
  • the present invention also provides a method for preventing, ameliorating or treating an activity-related disease of NFAT5 comprising administering to a subject an effective amount of an 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof.
  • the 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof for use as a prophylactic or therapeutic agent for a disease related to activity of NFAT5 is provided.
  • the 8-oxoprotoberberine derivatives or pharmaceutically acceptable salts thereof for use as a dietary supplement for the prevention or improvement of NFAT5 activity-related diseases is provided.
  • the derivative according to the present invention can be usefully used as a preventive or therapeutic agent for the activity-related diseases of NFAT5, and a dietary supplement for improvement.
  • the present invention will be described in detail by Examples and Experimental Examples.
  • Berberine hydrochloride (5 g, 13.45 ⁇ ol) was added to a 5N aqueous sodium hydroxide solution (23 mL) by a known method, and after stirring to 0 o C, acetone (5 mL, 67.23 ⁇ ol) was slowly added dropwise. After stirring for 1 hour at real silver, the resulting solid was filtered, washed twice with 40 mL of 80% methane, and dried to obtain the target compound (4.65g, 89%).
  • Example 1 Step 1 and Example 1 except that 2-methylbenzyl bromide was used instead of 2-fluorobenzyl bromide in Step 1 of Example 1 In the same manner, the target compound (28%) was prepared.
  • the target compound (89%) was prepared by the same method as Step 1 of Example 1, except that 2-methoxybenzyl bromide was used instead of 2-fluorobenzyl bromide in Step 1 of Example 1.
  • the target compound (59 «) was prepared in the same manner as in Example 1, Step 1 except that 2-chloromethylbenzoamidazole was used instead of 2-poloroben 3/4 bromide in Step 1 of Example 1.
  • Example 4 9-10-dimethoxy— 13- (2-methylbenzyl) -5, 6-dihydro- [1,3] dioxolo [4,5-g] isoquinolino [3,2-a] isoquinoline- 13- (1H-benzo [d] imidazol-2-yl) methyl) -9, 10-dimethoxy-5, 6-dihydro- [1,3] diox obtained in step 1 instead of 7-umbromide
  • the target compound (8%) was obtained by the same method as Step 2 of Example 4, except that Solo [4 ′ 5-g] isoquinolino [3,2-a] isoquinoline-7-iumbromide was used. .
  • the target compound (51%) was prepared in the same manner as in Step 1 of Example 1, except that 2 ⁇ chloro-5-chloromethylthiazole was used instead of 2-fluorobenzyl bromide in Step 1 of Example 1. Prepared.
  • Step 2 13-((2-chlorothiazol-5-yl) meryl) -9,10-dimethoxy-5,6-dihydro-VII, 3] dioxolo [4, 5-g] isoquinolino [3 Al 2-alisoquinoline-8 (6H) -silver
  • the target compound (55%) was prepared in the same manner as in Step 1 of Example 1, except that ethyl chloroformate was used instead of 2-fluorobenzyl bromide in Step 1 of Example 1.
  • the compound according to the present invention has an effect of inhibiting iNOS inducing activity.
  • the derivatives according to the present invention can be usefully used as a pharmaceutical composition for the prevention or treatment of iNOS-induced activity-related diseases.
  • NFAT5 reporter search was performed. Remove the CMV promoter sequence from the backbone of pEGFP-Nl and bind the sequence of NFAT5 (TGGAAAATTACCG) partial transduced plasmid vector
  • Raw264.7 macrophages were cultured in 10% FBS-RPMr medium (containing 500 g / ml of G418). The cells were dispensed in a 96-well plate at a density of 3 X 10 3 cells / well and further incubated for 2 hours. After treatment with LPS at a concentration of 1 yg / ml for 48 hours, the cells were fixed and the expression of GFP was measured by HCS fluorescence. Measured by image (Thermo,
  • FIG. 1 is a graph showing the NFAT5 transcriptional activity inhibitory effect of the derivative according to the present invention.
  • the derivatives according to the present invention is excellent in the effect of inhibiting the activity of NFAT5, especially in Example 1, 3, 6 and 10 It can be seen that the derivative is excellent in the effect of inhibiting the activity of NFAT5. Therefore, the derivatives according to the present invention can be usefully used as a pharmaceutical composition for the prevention or treatment of NFAT5 activity-related diseases.
  • NF- ⁇ transcriptional activity was measured by culturing THPl-Lucia NF- ⁇ reporter cells in 10% FBS-RPMI medium (containing 100 ug / ml Zeocin). Cells were incubated in a 96-well plate at a density of 2 ⁇ 10 4 cells / well and incubated for 24 hours with the addition of 1 g / ml LPS and the compound. Luminescence was measured by adding 50 ⁇ 13 ⁇ 4 of a fluorescence assay reagent to 10 ⁇ of the supernatant.
  • NFAT transcription activity evaluation was measured by incubating THPl-XBhie-MD2-CD14 cells in 10% FBS-RPMI medium (containing 200 g / ml Zeocin, 25 Mg ml ⁇ ] G418). First, the cells were incubated in a 96-well plate at a density of 2 X 10 4 cells / well, incubated for 24 hours with LPS 1 (Jg / ml and the compound added), and secreted embryonic alkaline phosphatase (SEAP) detect ion medium in 20 ⁇ of supernatant. Add 180 ⁇ and incubate for 2 hours
  • CREB and EL 1 transcriptional activity was evaluated using CHO / CREB-luc, HEK293 / CREB-luc, and HL / ELK1 cells.
  • Cells were cultured in 10% FBS-F12 (containing 100 pg / ml hygromycin), 10% FBS-DMEM (containing 100 g / ml hygromycin), and 10% FBS-DMEM (containing 200 ug / ml G418).
  • FIG. 2 is a graph showing the effect of the derivative according to the invention on the transcriptional activity other than NFAT transcription factor, specifically, A is NF- ⁇ , B is NFATc, C is
  • CREB CHO-Kl
  • D CREB (HEK293)
  • E is a graph showing the inhibition of transcriptional activity against ELK.
  • the protoberberine derivatives according to the present invention showed a slight effect on other transcription factors, unlike inhibition of NFAT5 at 1 ⁇ M or more than 803 ⁇ 4>. It can be seen that the derivatives of Examples 1 and 3 according to the present invention slightly inhibit NF- ⁇ and NFAT promoter activity at 10 ⁇ M.
  • the protoberberine derivatives according to the present invention show selective inhibition of the transcription factor activity of NFAT5.
  • FIG. 1 is an image of the Western blot expressing the p38 protein and active state p38 protein (phosphorylation) of the derivative according to the present invention. As shown in Figure 3, the group treated with the derivative according to the present invention and There was no difference in the degree of p38 protein (phosphorylation) expression in the untreated controls.
  • R 264.7 (10% FBS-RPMI 1640 medium) was incubated at a density of 1.5 x 10 5 cells / well in a 12 well plate and stabilized for one day.
  • the compound of Example 1 according to the present invention was pretreated at a concentration of ⁇ for one hour, cells were stimulated with LPS for 12 hours.
  • mRNA was isolated from cells to synthesize cDNA, and mRNA expression of NFAT5 was measured by real-time polymerase reaction.
  • NFAT5 a transcriptional regulator
  • Figure 4 is a graph showing the effect of the derivative according to the invention on the transcriptional step and nuclear migration.
  • the expression of NFAT5 was increased in the protein isolated from the nucleus than in the protein isolated from the cytoplasm due to the treatment of LPS, and the LPS treatment when the compound of Example 1 according to the present invention was pretreated. Decreased protein levels due to
  • Example 1 specifically inhibits NFAT5, which is increased by LPS, from the transcript stage, thereby inducing the inhibition of NFAT5 protein expression.
  • Raw264.7 cells (1OT FBS-RPMI 1640 medium) were incubated at a density of 1.5 ⁇ 10 5 cells / well in 6-well plates to stabilize. After treating the compound of Example 1 ( ⁇ ) an hour ago, NaCK45 mM) was stimulated for 3 hours, cDNA was synthesized from the extracted mRNA, and the NFAT5 transcript was confirmed by real-time polymerase reaction. Indicated.
  • BGT1 is a graph showing the effect of the derivative according to the present invention on the transcript expression of NFAT5 increased by sodium chloride, specifically A is BGT1, B is a graph of the transcript of AR.
  • BGT1 and AR which are transcripts of NFAT5
  • FIG. 5 the expression of BGT1 and AR, which are transcripts of NFAT5 was increased when NaCl was treated, and the increased transcripts were different even when treated with the compound of Example 1 according to the present invention. Did not look.
  • Inhibition of C0X enzyme is a representative anti-inflammatory mechanism.
  • the inhibition degree of Example 1 was compared with berberine according to the present invention.
  • Example 1 according to the present invention can be seen that the C0X1 and C0X2 enzyme inhibitory effect is insignificant.
  • the derivative according to the present invention had a minimal toxicity to cells at 10 ⁇ or less.
  • GM-CSF2, MCP-1 and IL-6 are target genes of NFAT5.
  • Raw264.7 cells were incubated in a 10% FBS-RPMI medium at a density of 1.5 x 10 6 cells / well in a 12-well plate, and the LPS (lpg / ml) was added the following day after pretreatment of the compound of Example 1 with ⁇ . Treatment was for 6 hours. After 6 hours of treatment, the supernatants of the wells were determined by ELISA for GM-CSF, MCP-1, and IL-6, and are shown in FIG. 6. 6 is a graph showing the inflammatory cytokine inhibitory effect of the derivatives according to the present invention. Specifically, A represents GM-CSF2, B represents MCP-1, and C represents IL-6.
  • the symptoms of arthritis were alleviated when the joints of the mouse legs of the group treated with the compound of Example 1 of the present invention were visually observed as compared with the negative control group.
  • histological staining showed that the symptoms of arthritis recovered significantly.
  • the derivative according to the present invention for preventing or treating arthritis diseases It will be appreciated that it may be useful as a pharmaceutical composition.
  • arthritis-induced mice were used as collagen used in Experimental Example 10. After the cells were extracted from the spleen of the mouse, the cells were stabilized by culturing the spleen cells in a 12 well plate. After stimulating with LPS for 12 hours, expression of inflammatory cytokines (TNF- ⁇ IL-6) was measured by ELISA.
  • TNF- ⁇ IL-6 inflammatory cytokines
  • TNF-a inflammatory cytokines
  • IL-6 inflammatory cytokines
  • NFAT protein In order to measure the expression of NFAT protein in rheumatoid arthritis mice, the following experiment was performed. Specifically, after stimulating LPS from splenocytes of arthritis induced by collagen-induced mouse splenocytes in the same manner as in ⁇ Experimental Example 11>, the protein was extracted from the cells, and NFAT5 was confirmed.
  • Table 7 was obtained by measuring the amount of the compound remaining after each compound was incubated for 30 minutes with rat and human liver microsome fractions.
  • male pharmacokinetic profiles administered at 5 mg / kg by intravenous (i v ) and oral (po) rats were obtained as shown in FIGS. 10A and 10B.
  • PBMC monocytes
  • the capsule was prepared by filling in gelatin capsule according to a conventional method for preparing capsules.
  • the compound according to the invention was dissolved in an appropriate volume of sodium chloride BP for injection, the pH of the resulting solution was adjusted to 3.5 using dilute hydrochloric acid BP, and the volume was adjusted and sufficiently mixed with injection of sodium chloride BP.
  • the solution was filled into a 5 type I ampoule of clear glass, encapsulated under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120 0 C for at least 15 minutes to prepare an injection solution.
  • Vitamin B2 0. 15 nig
  • Vitamin B6 0.5 nig
  • composition ratio of the vitamin and mineral mixture mentioned above is relatively dry
  • the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health functional food manufacturing method, and then granules are prepared, It can be used to prepare possible product compositions.
  • Purified water is added to the total 900
  • the resulting solution is filtered and obtained in a sterilized container, sealed and sterilized and then stored in a steamed beverage Used to prepare the composition.
  • composition ratio is a composition that is relatively suitable for a preferred beverage in a preferred embodiment
  • the compounding ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.

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Abstract

La présente invention concerne un nouveau dérivé de 8-oxoprotoberbérine ou un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et une composition pharmaceutique destinée à prévenir ou à traiter des maladies associées à l'activité du NFAT5 le contenant à titre de principe actif. Le nouveau dérivé de 8-oxoprotoberbérine ou le sel pharmaceutiquement acceptable de celui-ci selon l'invention peut être utile dans une composition pharmaceutique destinée à prévenir ou à traiter des maladies associées à l'activité du NFAT5, et en particulier, la polyarthrite rhumatoïde ou les maladies inflammatoires puisqu'il a été vérifié que le dérivé ou un sel pharmaceutiquement acceptable de celui-ci a une absorption orale considérablement accrue comparativement à la protoberbérine connue en raison d'une amélioration de ses propriétés, et inhibe l'activité du NFAT5 et la sécrétion des cytokines inflammatoires et réduit l'expression du NFAT5 chez la souris atteinte de polyarthrite rhumatoïde par inhibition directe de la transcription du NFAT5.
PCT/KR2014/013059 2013-12-31 2014-12-30 Nouveau dérivé de 8-oxoprotoberbérine ou sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et composition pharmaceutique destinée à prévenir ou à traiter des maladies associées à l'activité du nfat5 le contenant à titre de principe actif WO2015102380A1 (fr)

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KR10-2013-0168600 2013-12-31
KR20130168600 2013-12-31
KR1020140193586A KR101656394B1 (ko) 2013-12-31 2014-12-30 신규한 8-옥소프로토베르베린 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 nfat5의 활성 관련 질환의 예방 또는 치료용 약학적 조성물
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CN105218537A (zh) * 2015-10-14 2016-01-06 西南大学 黄连素苯并咪唑类化合物或其可药用盐及其制备方法和应用

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