WO2015102370A1 - Dérivé de 1,2-naphtoquinone et son procédé de préparation - Google Patents

Dérivé de 1,2-naphtoquinone et son procédé de préparation Download PDF

Info

Publication number
WO2015102370A1
WO2015102370A1 PCT/KR2014/013039 KR2014013039W WO2015102370A1 WO 2015102370 A1 WO2015102370 A1 WO 2015102370A1 KR 2014013039 W KR2014013039 W KR 2014013039W WO 2015102370 A1 WO2015102370 A1 WO 2015102370A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
compound
pharmaceutically acceptable
aryl
Prior art date
Application number
PCT/KR2014/013039
Other languages
English (en)
Korean (ko)
Inventor
이휘성
이미정
김보정
노태철
이승훈
이규대
이유희
곽태환
Original Assignee
주식회사 케이티앤지생명과학
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 주식회사 케이티앤지생명과학 filed Critical 주식회사 케이티앤지생명과학
Publication of WO2015102370A1 publication Critical patent/WO2015102370A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/84—Naphthothiazoles
    • 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
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to 1,2 naphthoquinone derivatives, methods for their preparation and compositions having the therapeutic and prophylactic effect of metabolic diseases containing the same.
  • Metabolic disease refers to a syndrome in which risk factors such as hypertriglyceridemia, hypertension, abnormal glucose metabolism, abnormal blood glucose levels, and obesity are present.
  • Heart attacks, ischemic heart disease, type 2 diabetes, hypercholesterolemia It is one of the most threatening diseases in the modern world because it can be accompanied by diseases such as cancer, gallstones, arthritis, joint pain, respiratory diseases, sleep apnea, enlarged prostate, and menstrual irregularities.
  • NEP National Cholesterol Education Program
  • metabolic diseases are considered to be a major risk factor for chronic long-term high calorie intake. It is known that metabolic efficiency decreases during excessive energy intake, lack of exercise, life extension, and aging, and this causes the problem of excess energy, which leads to obesity, diabetes and metabolic diseases. As a treatment method, diet therapy, exercise therapy, behavioral therapy therapy, drug therapy, etc. are being performed. However, since the cause is not known precisely, the present effect is insignificant and only to relieve symptoms or slow the progression of the disease. Therapeutic targets for the development of therapeutics have also been proposed in various ways, but the technological therapeutic targets have not been reported.
  • the NAD + / NADH and NADP + / NADPH ratios are reduced in vivo or in vitro, and the NADH and NADPH remain in excess, they are not only used in the fat biosynthesis process, but also in excess.
  • ROS semi-ungseong oxygen species
  • fatty acidization by NAD + and NADP + if the environment can be created in vivo or in vitro so that the NAD + NADH and NADP + / NADPH ratios remain stable.
  • various energy metabolism can be activated.
  • it is possible to activate the mechanism of action to keep the concentration of NAD (P) H continuously low it is believed that it is possible to treat a variety of diseases including obesity by inducing excess energy to be consumed.
  • the method of increasing the concentration and ratio of NAD (P) + a signal transmitter known to perform such various functions, firstly, adjusts the salvage synthesis process of NAD (P) + biosynthesis process, and secondly, NAD (P) H.
  • NAD (P) + or its analogs, derivatives, precursors and prodrugs are supplied from outside. For example, a method of increasing the concentration of NAD (P) + may be considered.
  • N AD (P) H quinone oxidoreductase (EC1.6.99.2) is called DT-diaphorase, quinone reductase, menadione reductase, vitamin K reductase, or azo-dye reductase, and these NQOs have two isoforms, Present as NQ01 and NQ02 (ROM. J. INTERN. MED. 2000-2001, vol. 38-39, 33-50).
  • NQO is a flavoprotein and acts to catalyze two electron reduction and detoxification of quinones or quinone derivatives.
  • NQO uses both NADH and NADPH as electron donors.
  • NQO The activity of NQO prevents the formation of highly reactive quinone metabolites, detoxifies benzo (d) pyrene and quinone, and reduces the toxicity of crems.
  • the activity of NQO is present in all tissues, but the activity is tissue dependent. In general, NQO expression was found to be high in tissues such as cancer cell tissue, liver, stomach and kidney.
  • NQO gene expression is induced by xenobiotics, antioxidants, oxidants, heavy metals, ultraviolet radiation, and radiation.
  • NQO is part of numerous cell defense mechanisms induced by oxidative stress. The associated expression of genes involved in these defense mechanisms, including NQO, serves to protect cells against oxidative stress, free radicals and neoplasia.
  • NQO has a very broad substrate specificity. In addition to quinones, quinone-imines, nitro and azo compounds can be used as substrates.
  • NQ01 is mainly distributed in epithelial cells and endothelial cells. This means that it can act as a defense against compounds absorbed through air, esophagus or blood vessels.
  • gene expression of NQ01 was found to be significantly increased in adipose tissue of humans with metabolic disease, and especially in the fat cells with large fat cells, the expression level of NQ01 was significantly higher.
  • weight loss was induced by diet, NQ01 expression was proportionally decreased along with weight loss.
  • MRNA levels of NQ01 correlated proportionally with GOT and GPT, which are known as indicators of fatty liver.
  • NQ01 expression in adipose tissue is associated with adiposity, glucose tolerance, and liver function indices (The Journal of Clinical Endocrinology & Metabolism 92 (6): 2346. 2352).
  • an object of the present invention is to solve the problems of the prior art as described above and the technical problem that has been requested from the past.
  • the present invention provides a 1,2-naphthoquinone derivative having a novel structure.
  • Another object of the present invention is to provide a method for preparing such novel compounds.
  • Another object of the present invention is to provide a method for the treatment and prevention of metabolic diseases by using such a novel compound as an active ingredient.
  • the present invention provides a compound represented by the following formula (1), a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof. .
  • Ri and R 2 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4- C10 aryloxy, substituted or unsubstituted C2-C10 heteroaryl, -N0 2 , -NR ', R' 2 , -NR ' CO (0) R'i, -C (0) NR'iR ' 2 , -CN, -SO (0) R' ,, -SO (0) NR ' !
  • R ' 2 , -NR'i (SO (0) R' 2 ),-CSNR ', R' 2 or 3 ⁇ 4 and R 2 are substituted or unsubstituted by cyclic structure of cyclic structure of C4-C10 aryl, or substituted Or a cyclic structure of unsubstituted C2-C10 heteroaryl.
  • R '! And R ' 2 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or Unsubstituted C1-C8 heteroaryl, substituted or unsubstituted-(CR ⁇ R ' ⁇ m'-dCH) aryl, substituted S is unsubstituted-(CR ⁇ R' ⁇ m'-C ⁇ Cl O heteroaryl or substituted or Unsubstituted NR ⁇ R ⁇ where and R " 2 are each independently hydrogen, C1-C3 alkyl, or R" i and R " 2 are mutually bonded to form a substituted or unsubstituted cyclic structure of C4-C10 aryl.
  • R 3 is hydrogen, hydroxy, halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C20 alkene, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or Unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1-C10 heteroaryl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C 4 -C 10 aryl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C 4 -C 10 aryloxy, substituted or unsubstituted-(CR ' 5 R' 6 ) m -
  • R'5, and R'6 are each independently hydrogen or C1-C3 alkyl;
  • R '" 3 is C1-C6 alkyl;
  • substituent is hydroxy, halogenated nitro group, hydroxy, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, At least one selected from the group consisting of C3-C8 heterocycloalkyl, C4-C10 aryl, and C5-C10 heteroaryl;
  • X, X 2 , X 3 and 3 ⁇ 4 are each independently CH or N; m and m, each independently represent a natural number of 1 to 4; And
  • the hetero atom is at least one selected from ⁇ , ⁇ and S.
  • the compound of formula (1) as an active ingredient of a therapeutic agent includes a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or pharmaceutical agent thereof. All acceptable diastereomers are included, and they should all be construed as being included in the scope of the present invention. For convenience of description, it is also simply abbreviated herein as a compound of formula (1).
  • the compound of formula (1) according to the present invention has a novel structure known in the prior art, and as can be seen in the following experimental examples, excellent effect on the treatment and prevention of metabolic diseases through exercise mimicking effect in vivo Exert.
  • the compound of the formula (1) according to the present invention induces NAD (P) H: quinone oxidoreductase (NQ01) as a redox enzyme to increase the ratio of NAD + / NADH in vivo, thereby increasing the ratio of AMP / ATP.
  • NAD NAD
  • NQ01 quinone oxidoreductase
  • the increase in AMP in the cell activates AMPK, which acts as an energy gauge, promotes fat metabolism with PGCla expression that activates energy metabolism in the mitochondria, thereby compensating for insufficient ATP energy.
  • NAD + is used as a cofactor for glucose and fat metabolism-related enzymes in the body to promote metabolism
  • cADPR produced by the breakdown of NAD + , releases Ca 2+ from the endoplasmic reticulum (ER) to mitochondrial metabolism. Synergistic activation acts to mimic the effects of exercise in vivo.
  • pharmaceutically acceptable salts does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound.
  • the pharmaceutical salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbon acids such as citric acid, acetic acid, trichloroacetic acid, trichloroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, P-luluenesulfonic acid, etc.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid
  • Organic carbon acids such as citric acid, acetic acid, trichloroacetic acid, trich
  • carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, amino acid salts such as lysine, arginine, guanidine, dicyclonucleoamine, N Organic salts such as ⁇ methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine, and the like.
  • the compounds of formula (1) according to the invention can also be converted to their salts by conventional methods.
  • hydrate is a compound of the present invention comprising a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force.
  • salts thereof refers to a compound of the present invention or a salt thereof comprising a stoichiometric or non stoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • Preferred solvents therein are volatile, non-toxic, and / or solvents suitable for administration to humans.
  • prodrug is used to modify the parent drug in vivo.
  • Mean material Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions than the parent drug.
  • prodrugs are esters that facilitate the passage of cell membranes, which are hydrolyzed to carboxylic acids, which are active by metabolism, once the water solubility is detrimental to mobility, but once the water solubility is beneficial.
  • Drug ") Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group which is converted by metabolism to reveal the active site.
  • tautomer is a type of structural isomer that has the same chemical formula or molecular formula but differs in the way in which its members are linked, such as, for example, a keto-eno structure, reciprocating between both isomers Means change.
  • enantiomer or pharmaceutically acceptable diastereomer is an isomer which has the same chemical formula or molecular formula but is caused by a change in the spatial arrangement of atoms in a molecule
  • enantiomer is an enantiomer, such as the relationship between right and left hand.
  • isomers that do not overlap with each other, and “diastereomers” are stereoisomers that are not enantiomeric such as trans and cis forms, and are limited to pharmaceutically acceptable diastereomers in the present invention. All of these isomers and combinations thereof are also within the scope of the present invention.
  • alkyl refers to an aliphatic hydrocarbon group.
  • Alkyl in the present invention includes “saturated alkyl” meaning that it does not contain any alkenes or alkyne moieties, and at least one alkene or alkyne moiety.
  • unsaturated alkyl is used to include all of the term “unsaturated alkyl”, and in detail, may be “saturated alkyl” meaning that it does not contain any alkene or alkyne moiety.
  • the alkyl may include branched, straight chain or cyclic, and also includes structural isomers, for example, in the case of C3 alkyl, may mean propyl, isopropyl.
  • heterocycloalky is a substituent in which the ring carbon is substituted with oxygen, nitrogen, sulfur or the like.
  • aryl refers to an aromatic substituent having at least one ring having a covalent pi-electron field.
  • monocyclic or fused ring polycyclic ie, rings that divide adjacent pairs of carbon atoms).
  • the substituents may be appropriately bonded at ortho (0), meta (m), para (p) positions.
  • heteroaryl refers to an aromatic group containing at least one heterocyclic ring.
  • aryl or heteroaryl examples include, but are not limited to, phenyl, furan, pyran, pyridyl, pyrimidyl, triazyl, and the like.
  • halogen refers to elements belonging to group 17 of the periodic table, specifically fluorine, chlorine, bromine and iodine.
  • aryloxy means a group bonded to any one carbon and oxygen constituting an aromatic substituent, for example, when oxygen is bonded to a phenyl group-0-C 6 3 ⁇ 4, -C 6 H 4- Can be marked 0-.
  • X 2 are each independently CH, CO or N (R 3 ′); Where " Hydrogen or C 1 -C 3 alkyl; And X 3 and X 4 may each be CH.
  • X 2 are each independently CH, CO or N (R 3 ′); Where " Hydrogen or C 1 -C 3 alkyl; And X 3 and X 4 may each be CH.
  • the 3 ⁇ 4 and R 2 are each independently hydrogen, a halogen atom, -OCH 3, -OCH 2 CH 3 , - 0 (CH 2) 2 CH 3, -CH 3, -N0 2, -CN, -NR 'iR' 2 , or -OH (wherein R ', and R' 2 are each independently hydrogen, C1-C3 alkyl, substituted or unsubstituted -C3 ⁇ 4-C4-C10 aryl, substituted or unsubstituted -C 2 H 4 -C4- C10 aryl, or substituted or unsubstituted C2-C10 heteroaryl, and the substituent is a halogen element.
  • R, and R 2 are each independently hydrogen, CI, —N0 2 , —NH 2 or — ⁇ ⁇ , (wherein, and R ′ 2 are each independently hydrogen, substituted or unsubstituted —CH 2 -C 4- C6 aryl and the substituent is a halogen element.
  • 3 ⁇ 4 is hydrogen, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, substituted or unsubstituted C4-C8 aryl, substituted or unsubstituted C4-C8 aryl Oxy, substituted or unsubstituted C 1 -C8 heteroaryl, substituted or unsubstituted-(CR'5R'6) m-C4-C K) aryl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4 -C 10 aryloxy, substituted or unsubstituted-(CR ' 5 R' 6 ) m -Cl -C 10 heteroaryl, substituted or unsubstituted-(CR ' 5 R' 6 ) m -C4-C10 heterocycl
  • R'5, and R '6 each independently is hydrogen or C 1 -C3 alkyl
  • the substituent is halogen, hydroxy, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C3-C8 At least one selected from the group consisting of heterocycloalkyl, C 4 -C 10 aryl, and C 5 -C 10 heteroaryl; Hetero atom is N, 0 or S; m may be a natural number of 1 to 4.
  • R 3 is hydrogen, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, substituted or unsubstituted C4-C8 aryl, substituted or unsubstituted C4-C8 Aryloxy, substituted or unsubstituted-(CH 2 ) m -C 4 -C 10 heterocycloalkyl, or substituted or unsubstituted-(CH 2 ) m -NR ' 5 R' 6 ;
  • R ' 5 , and R' 6 are each independently hydrogen or C1-C3 alkyl
  • R 3 may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, neopentyl, phenyl, phenyl substituted with halogen element,
  • 3 ⁇ 4 may be methyl, isopropyl, t-butyl, phenyl, or neopentyl.
  • the compound of Formula (1) may be exemplified as one of the compounds represented below, but the following compounds do not limit the present invention.
  • the present invention also provides a process for preparing the compound of formula (1).
  • the compound may be prepared by various methods, and all of these methods should be interpreted to include the scope of the present invention. That is, within the scope of the present invention, it is possible to prepare the compounds of the formula (1) by arbitrarily combining various synthesis methods described herein or disclosed in the prior art. Therefore, the scope of the present invention is not limited only to this doll.
  • step C) cyclization of the compound produced in step B) and optionally reaction with acid followed by oxidation reaction; It may be prepared through a process comprising a.
  • X, to X 4 and Ri to R 3 are as defined in formula (1) and 3 ⁇ 4 is hydrogen, C 1 -C 4 alkyl, phenyl, benzyl.
  • step A) may be a step A ′) of reacting R 3 C0C1 or (R 3 CO) 2 0 after halogenating the compound of Formula (2).
  • Lawesson's regaent is a reagent for introducing sulfur into a compound in the art
  • the cyclization reaction may include reacting with MX (wherein M is Al, B, Cu, Fe, or CN, and X is a halogen element).
  • the present invention provides a method further comprising the step D) for introducing a -N0 2 to the compound produced in step C) by banung and the compounds produced in the above step C) HN0 3.
  • the present invention provides a preparation method further comprising the step E) of introducing -NH 2 to the compound produced in step D) through the hydrogenation reaction of the compound produced in step D).
  • the present invention reacts the compound produced in step E) with M'X '(wherein M is Al, B, Cu, Fe or CN, and X is a halogen element).
  • M is Al, B, Cu, Fe or CN
  • X is a halogen element
  • the present invention further comprises the step G) of reacting the compound produced in step E) with R 5 CHO (wherein R 5 is substituted or unsubstituted C4-C6 aryl and the substituent is a halogen element) It provides a manufacturing method comprising the.
  • the invention also provides (a) a pharmacologically effective amount of a compound of formula (1) according to claim 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer and / or pharmaceutically acceptable salt thereof Possible diastereomers; And (b) a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof; provides a pharmaceutical composition for treating and preventing metabolic diseases.
  • the term "pharmaceutical composition” means a mixture of a compound of the invention with other chemical components, such as a diluent or carrier.
  • the pharmaceutical composition facilitates administration of the compound into the organism.
  • There are a variety of techniques for administering compounds including but not limited to oral, injection, aerosol, parenteral, and topical administration.
  • the pharmaceutical composition may be obtained by reacting acid compounds such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, P-luenesulfonic acid, salicylic acid and the like.
  • terapéuticaally effective amount refers to the amount of the compound administered reduces or reduces to some extent one or more symptoms of the disorder being treated, or delays the onset of a clinical marker or symptom of a disease that requires prevention. It means the amount of active ingredient effective to.
  • the pharmacologically effective amount is (1) the effect of reversing the rate of progression of the disease, (2) more The amount has the effect of inhibiting progression to some extent and / or (3) alleviating (preferably eliminating) one or more symptoms associated with the disease.
  • a pharmacologically effective amount can be determined empirically by experimenting with compounds in known in vivo and in vitro model systems for diseases in need of treatment.
  • carrier is defined as a compound that facilitates the addition of a compound into a cell or tissue.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the incorporation of many organic compounds into a cell or tissue of an organism.
  • diot is defined as a compound that is not only to stabilize the biologically active form of a compound of interest, but also to be soluble in water that will dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Buffer salts rarely modify the compound's biological activity because buffer salts can take the pH of the solution at low concentrations.
  • the compounds used herein may be administered to a human patient as such or in combination with other active ingredients as in combination therapy or as a pharmaceutical composition combined with a suitable carrier or excipient.
  • Formulations and Administration of Compounds in this Application may be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990.
  • compositions of the present invention may be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, sugar-making, powdering, emulsifying, encapsulating, trapping or lyophilizing processes. .
  • compositions for use according to the invention can be used pharmaceutically It may also be prepared by conventional methods using one or more pharmaceutically acceptable carriers which comprise excipients or auxiliaries which facilitate the treatment of the active compounds in the formulations which can be employed. Proper formulation is dependent upon the route of administration chosen. Any of the known techniques, carriers and excipients can be used as precisely and as understood in the art, for example in Remingston's Pharmaceutical Sciences described above.
  • the compound of formula (1) may be formulated as an injection preparation, oral preparation, and the like as desired.
  • the components of the invention may be formulated in liquid solutions, preferably in pharmacologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline solution.
  • pharmacologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline solution.
  • noninvasive agents suitable for the barrier to pass through are used in the formulation. Such non-invasive agents are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmacologically acceptable carriers known in the art.
  • Such carriers allow the compounds of the present invention to be formulated into tablets, pills, powders, granules, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like.
  • the tablets, tablets, pills, powders and granules are possible, and especially the tablets and tablets are useful.
  • Tablets and pills are preferably prepared with enteric agents.
  • Pharmaceutical preparations for oral use include mixing one or more compounds of the invention with one or more excipients, optionally grinding such mixtures and, if necessary, the mixture of granules after permeation of appropriate adjuvants.
  • Treatment can yield a tablet or sugar core.
  • suitable excipients include fillers such as lactose, sucrose, manny, or sorbide; Corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragakens, methyl celrose, Hydroxypropylmethyl-celrose, sodium carboxymethyl celrose, and / or cellulose based materials such as polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • a disintergrinding agent such as cross-linked polyvinyl pyridone, butadiene, or a salt thereof such as alginic acid or sodium alginate and a lubricant such as magnesium stearate, a carrier such as a binder, or the like may be added.
  • compositions that can be used orally may include soft sealing capsules made of gelatin and plasticizers such as glycols or sorbates, as well as pushable capsules made of gelatin.
  • the push-fix capsule may contain the active ingredients as a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate.
  • the active compounds may be dissolved or dispersed in fatty acids, liquid paraffin, or a suitable solution ground with liquid polyethylene glycol.
  • stabilizers may be included. All preparations for oral administration should be in amounts suitable for such administration.
  • the compounds may be formulated for parenteral administration by injection, for example by large pill injection or continuous infusion.
  • injectable formulations may also be presented in unit dose form, eg, as a 3/4 or multi-dos container with preservatives added.
  • the compositions may take the form of suspensions, solutions, emulsions on oily or liquid vehicles, and may include formulation components such as suspending, stabilizing and / or dispersing agents.
  • the active ingredient may also be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.
  • a suitable vehicle such as sterile pyrogen-free water
  • compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount of a compound effective to prolong the survival of the subject to be treated or to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.
  • the compound of formula (1) as the active ingredient is preferably contained in a unit dose of about 0.1 to 1,000 mg.
  • the dosage of the compound of formula (1) depends on the doctor's prescription depending on factors such as the patient's weight, age and the particular nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 1 to 1000 mg per day, depending on the frequency and intensity of administration. Intramuscular or intravenous administration to adults will be divided into single doses, usually at a total dosage of about 1 to 500 mg per day, but for some patients a higher daily dose may be desirable.
  • the target disease may be obesity, fatty liver, arteriosclerosis, stroke, myocardial infarction, cardiovascular disease, ischemic disease, diabetes mellitus, hyperlipidemia, hypertension, retinopathy or kidney failure, Huntington's disease or inflammation, specifically fatty liver, diabetes Or Huntington's disease, but is not limited to that.
  • the invention also provides a pharmacologically effective amount of a compound of formula (1) according to claim 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof Using in an effective amount, a method of treating or preventing metabolic diseases is provided.
  • “Therapeutic” means stopping or delaying the progression of the disease when used in a subject exhibiting symptoms of the disease, and “preventing” means stopping or manifesting the disease when used in a subject who does not exhibit symptoms but has a high risk of developing the disease. Delayed Means that.
  • Example 1 is a graph showing the weight gain rate, weight change, and intake of obese rats (ob / ob) for the compound according to Example 2 of Experimental Example 3 and the control group;
  • Figure 2 is a rat obese to the compound and the control according to Example 7 of Experimental Example 3-1
  • FIG. 3 shows obese rats for the compound and the control group according to Example 9 of Experimental Example 3-2
  • Dissolve compound 6 (3.14g, 10.39mmol) in methanol (100ml) and MC (50ml), add 5% Pd / C (2.2g, i.039mmol) and connect the hydrogen balloon. Stir at room temperature for 1 hour. After filtering the semi-aqueous solution through Celite, the filtrate was purified by recrystallization concentrated under reduced pressure to obtain 7-amino- 2 -isopropylnaphtho [l, 2 -d] thiazole-4,5-dione.
  • Enzyme reactions included 25 mM Tris / HCl (pH 7.4), 0.14% bovine serum albumin, 200 uM NADH, 77 uM Cytochrome C and 5 ng of NQOl protein. Enzyme reactions are initiated by addition of NADH and are performed at 37 degrees. In this case, the reaction rate is increased by absorbing Cytochrome C for 10 minutes at 550 nm. Observed, NQ01 activity is represented by the amount of reduced cytochrome C [nmol cytochrome C reduced I min Iug protein].
  • the compound according to Example 2 synthesized in the present invention was administered once every day for 1 week at a dose of 150 mg / kg for each of three C57BL / 6J Lep ob / ob mice, using a disposable syringe with oral administration sonde for 10 days. A ml / kg dose was forced orally in the stomach. As a control group, 0.1% SLS was administered to three C57BL / 6J Lep ob / ob mice using the same method at a dose of 150 mg / kg. Body weight gain with time of administration was measured and shown in Figure 1 below.
  • the body weight of the test animals was measured six times a week from the time of group separation (just before administration of the test substance) and from the start of the administration to the end of the test, and the total weight gain was calculated by subtracting the weight at the start of the experiment from the weight measured on the day before the end of the experiment.
  • the dietary intake was measured twice a week from the start of the administration of the test substance to the end of the test.
  • ORIENTBIO's genetic obesity C57BL / 6J Lep ob / ob mouse 6.5 weeks of age at 22-24 degrees, relative humidity 50-30%, illuminance 150-300 lux, contrast cycle 12 hours, exhaust 10-
  • polycarbonate breeding box 200 ⁇ ⁇ > ⁇ 2601 ⁇ 13011 (mm)
  • Three-shine maintained 15 times / hr of feeding environment, two animals per breeding box were fed and low fat diet (11.9 kcal%) by ORIENTBIO.
  • fat, 5053, Labdiet was purchased and fed into the feeder and freely ingested.
  • Drinking water was filtered and filtered using a filter and an oil sterilizer, and then freely ingested into a polycarbonate drinking bottle (250 mL).
  • the compound according to Example 7 synthesized in the present invention was administered using a disposable syringe attached to a sonde for oral administration once a day for a total of 1 week at a dose of 150 mg / kg for 3 mice each of C57BL / 6J Lep ob / ob mice.
  • a ml / kg dose was forced orally in the stomach.
  • 0.1% SLS was administered to three C57BL / 6J Lep ob / ob mice using the same method at a dose of 150 mg / kg.
  • the weight gain rate according to the administration time is shown in Figure 2 below.
  • the body weight of the test animals was measured six times a week from the time of group separation (just before administration of the test substance) and from the start of the administration to the end of the test, and the total weight increase was calculated by subtracting the weight at the start of the experiment from the weight measured on the day before the end of the experiment.
  • the dietary intake was measured twice a week from the start of the administration of the test substance to the end of the test.
  • the compound according to Example 9 synthesized in the present invention was administered once every day for 5 days at a dose of 150 mg / kg for 3 mice each of C57BL / 6J Lep ob / ob mice, using a disposable syringe attached with a sonde for oral administration for 5 days.
  • a ml / kg dose was forced orally in the stomach.
  • 0.1% SLS was administered to three C57BL / 6J Lep ob / ob mice using the same method at a dose of 150 mg / kg.
  • the weight gain rate with time of administration was measured and shown in FIG. 3.
  • the body weight of the test animals was measured at the time of group separation (just before administration of the test substance) and six times a week from the start date to the end date of the test, and the total weight gain was calculated by subtracting the weight at the start of the experiment from the weight measured on the day before the end of the test.
  • the dietary intake was measured twice a week from the start of the administration of the test substance to the end of the test.
  • the novel 1,2-naphthoquinone derivatives according to the present invention increase the ratio of NAD (P) + / NAD (P) H through NQ01 activity in vivo, thereby increasing the cellular energy environment.
  • Mitochondrial activity by inducing long-term calorie restriction and genetic changes during exercise, such as AMPK activation, an energy consumption mechanism, and PGCla expression that activates mitochondrial energy metabolism Improvements in the system, such as mitochondrial biosynthesis and changes in endurance motility muscle fibers due to ignition, have the effect of treating exercise mimics that increase the physical activity of the body. It can be useful for prevention.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne : un composé représenté par la formule chimique (1), un sel pharmaceutiquement acceptable correspondant, un hydrate, un solvate, un promédicament, un tautomère, un énantiomère ou un diastéréoisomère pharmaceutiquement acceptable, un procédé pour sa préparation et une composition pharmaceutique le contenant et présentant des effets de traitement ou de prévention de maladies métaboliques. Dans la formule chimique (1), R1 à R3 et X1 à X4 sont identiques à la définition dans la revendication 1.
PCT/KR2014/013039 2013-12-30 2014-12-30 Dérivé de 1,2-naphtoquinone et son procédé de préparation WO2015102370A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20130166729 2013-12-30
KR10-2013-0166729 2013-12-30

Publications (1)

Publication Number Publication Date
WO2015102370A1 true WO2015102370A1 (fr) 2015-07-09

Family

ID=53493652

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2014/013039 WO2015102370A1 (fr) 2013-12-30 2014-12-30 Dérivé de 1,2-naphtoquinone et son procédé de préparation

Country Status (2)

Country Link
KR (1) KR101644778B1 (fr)
WO (1) WO2015102370A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110709079A (zh) * 2018-04-09 2020-01-17 煊有限责任公司 包含1，2-萘醌衍生物化合物的实体癌或血液癌的预防或治疗用药物组合物

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7447013B2 (ja) 2018-04-09 2024-03-11 ユンジン ファーム．カンパニー、リミテッド １，２－ナフトキノン誘導体化合物を含む固形癌または血液癌の予防または治療用薬学組成物
KR102247694B1 (ko) * 2019-05-31 2021-05-03 주식회사 엘마이토테라퓨틱스 나프토퀴논 또는 벤조인다졸 화합물을 유효성분으로 포함하는 염증성 질환 치료용 약학적 조성물
KR20220007554A (ko) 2020-07-10 2022-01-18 (주)나디안바이오 나프토퀴논계 화합물 및 면역관문 억제제를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120196852A1 (en) * 2009-08-05 2012-08-02 The Johns Hopkins University Inhibitors of methionine aminopeptidases and methods of treating disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120196852A1 (en) * 2009-08-05 2012-08-02 The Johns Hopkins University Inhibitors of methionine aminopeptidases and methods of treating disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JULIANO S. DE TOLEDO ET AL.: "Synthesis, Cytotoxicity and In Vitro Antileishmanial Activity of Naphthothiazoles.", CHEM BIOL DRUG DES., vol. 81, no. 6, June 2013 (2013-06-01), pages 749 - 756 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110709079A (zh) * 2018-04-09 2020-01-17 煊有限责任公司 包含1，2-萘醌衍生物化合物的实体癌或血液癌的预防或治疗用药物组合物
JP2020524133A (ja) * 2018-04-09 2020-08-13 ヒュエン カンパニー リミテッドＨｕｅｎ Ｃｏ．，Ｌｔｄ． １，２−ナフトキノン誘導体化合物を含む固形癌または血液癌の予防または治療用薬学組成物
JP7007746B2 (ja) 2018-04-09 2022-01-25 ヒュエン カンパニー リミテッド １，２－ナフトキノン誘導体化合物を含む固形癌または血液癌の予防または治療用薬学組成物
US11717511B2 (en) 2018-04-09 2023-08-08 Huen Co., Ltd. Pharmaceutical composition comprising derivative compound of 1,2-naphthoquinone for preventing or treating solid cancer or blood cancer
CN110709079B (zh) * 2018-04-09 2023-09-12 煊有限责任公司 包含1，2-萘醌衍生物化合物的实体癌或血液癌的预防或治疗用药物组合物

Also Published As

Publication number Publication date
KR101644778B1 (ko) 2016-08-16
KR20150080426A (ko) 2015-07-09

Similar Documents

Publication Publication Date Title
KR101864426B1 (ko) 1,2 나프토퀴논 유도체 및 이의 제조방법
US10766882B2 (en) 1,2-naphthoquinone based derivative and method of preparing the same
KR102342250B1 (ko) 1,2 나프토퀴논 유도체 및 이의 제조방법
JP2010510982A (ja) 再狭窄の治療および予防のための医薬組成物
WO2010043592A1 (fr) Inhibiteurs de la lipase destinés à être utilisés dans le traitement de l’obésité
JP6903266B2 (ja) １，２ナフトキノン誘導体及びその製造方法
WO2015102370A1 (fr) Dérivé de 1,2-naphtoquinone et son procédé de préparation
TW201002725A (en) Thiazolyl-and oxazolyl-isoquinolinones and methods for using them
KR100916160B1 (ko) 약제학적 항암 조성물
US20240092744A1 (en) Tricyclic compound, and preparation method therefor and medical use thereof
WO2008066297A1 (fr) Composition pharmaceutique pour le traitement et la prévention de la resténose
KR20160116214A (ko) 1,2 나프토퀴논 유도체 및 이의 제조방법
BR112016015290B1 (pt) Compostos derivados à base de 1,2-naftoquinona, métodos para preparação dos mesmos, composição farmacêutica e uso dos ditos compostos para tratar ou prevenir síndromes metabólicas

Legal Events

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

Ref document number: 14876553

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14876553

Country of ref document: EP

Kind code of ref document: A1