WO2014185561A1 - Nouveau composé ou son sel pharmaceutiquement acceptable et composition pharmaceutique pour la prévention ou le traitement de maladies associées à uch-l1, le contenant en tant que principe actif - Google Patents

Nouveau composé ou son sel pharmaceutiquement acceptable et composition pharmaceutique pour la prévention ou le traitement de maladies associées à uch-l1, le contenant en tant que principe actif Download PDF

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WO2014185561A1
WO2014185561A1 PCT/KR2013/004221 KR2013004221W WO2014185561A1 WO 2014185561 A1 WO2014185561 A1 WO 2014185561A1 KR 2013004221 W KR2013004221 W KR 2013004221W WO 2014185561 A1 WO2014185561 A1 WO 2014185561A1
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group
formula
straight
hydrogen
uch
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PCT/KR2013/004221
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Korean (ko)
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이공주
김유화
김현정
이희윤
정시원
정재은
서은경
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이화여자대학교 산학협력단
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Priority to PCT/KR2013/004221 priority Critical patent/WO2014185561A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/794—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to a novel compound or a pharmaceutically acceptable salt thereof and a pharmaceutical composition for the prevention or treatment of CKH-L1 related diseases containing the same as an active ingredient.
  • Ubiquitin is a small protein consisting of 76 amino acids that are involved in inducing degradation by selectively recognizing the protein of interest in the ubiquitin-proteasome pathway, which is known as the general pathway of proteolysis. As a molecule, the process of binding ubiquitin to a protein of interest is called "ubiquitination".
  • Ubiquitination plays an important role in the selective degradation and endocytosis of short-lived proteins in eukaryotic cells. Recently, ubiquitination, as well as apoptosis, growth and differentiation of programmed cells, It is known to play an important role in the disease, and is expected to have a very significant effect on the regulation of the physiological function of the cells is being actively researched.
  • cyclins that regulate the cell cycle transcription factors such as jun / Fos and NF ⁇ B that regulate gene expression, EGF (Epidermal Growth Factor) and platelet derived growth factor that regulate cell growth and differentiation Receptor, p53 (Wilkinson et al, 2000), known as a carcinogenic protein, is known to bind to ubiquitin and break down into proteasome complexes.
  • deubiquitination is a process of ubiquitin C-terminal hydrolase (UCH) or ubiquitin-specific prosessing protease, an enzyme that cleaves the C-terminus of ubiquitin. It is a process of decomposing ubiquitin of ubiquitinated protein by factors such as UBP).
  • the UCH-based hydrolase is a deubiquitination enzyme that hydrolyzes an ester bond between the amide of ubiquinine and the C-terminus of another ubiquitin, and its main role is to release polyubiquitin branches as a single ubiquitin to ubiquitination process. Enable the continuous functioning of
  • ubiquitin C-terminal hydrolase-L1, -L2, -L3 As the isoenzyme of UCH, ubiquitin C-terminal hydrolase-L1, -L2, -L3 (UCH-L1, UCH-L2, UCH-L3) and the like have been found.
  • UCH-L1 is a nerve.
  • UCH-L1 known as a neuron-specific ubiquitin recycling enzyme, is a protein that is specifically expressed in neural tissues throughout the neuronal cell differentiation process. It is known to be highly specific and also expressed in the majority of the brain, especially in the substantia nigra of the midbrain.
  • UCH-L1 is a target protein that is oxidized in connection with Alzheimer's disease and Parkinson's disease (J Biol Chem. 2004, Mar 26; 279 (13): 13256-64). Parkinson's disease caused by UCH-L1 mutation has been reported.
  • UCH-L1 is an enzyme that cleaves the link between ubiquitin and peptide. In vitro, ubiquitin aldehyde inhibits dopaminergic neuron killing and ⁇ -synun. Formation of cytoplasmic inclusion bodies stained with a crane ( ⁇ -synuclein) was confirmed (McNaught KS, et al., J Neurochem 2002; 81: 301-306).
  • UCH-L1 is downregulated in idiopathic Parkinson's and Alzheimer's disease, and a direct link between oxidative damage and neuronal ubiquitination / deubiquitination mechanisms and sporadic Alzheimer's and Parkinson's disease has been suggested (Choi, J. et al., J Biol Chem 279, 13256-13264 (2004)), UCH-L1 is a constituent of lewy body, a pathological marker of Parkinson's disease, and dopaminergic neurons when inhibiting the activity of UCH-L1. It has been confirmed that cell death proceeds.
  • UCH-L1 is acute lymphocytic leukemia (Mohammad et al., 1996), non-small cell lung cancer (Hibi et al., 1999; Sasaki et al., 2001), neuroblastoma (Yanagisawa et al., 1998), pancreatic cancer (Tezel et al., 2000), prostate cancer (Leibling et al., 2007), medullary carcinoma (Takano et al., 2004), esophageal cancer (Takase et al., 2003), colon cancer (Yamazaki et al., 2002), which is known to be overexpressed in renal cancer (Fang et al .; Seliger et al., 2007), and that UCH-L1 is overexpressed in Burkitt's lymphoma, thereby improving infiltration ability by regulating
  • UCH-L1 has been suggested as a major regulator of tumor invasiveness and metastasis in the upstream activity of Akt (Kim et al., 2009), and the increase in UCH-L1 is associated with early tumor recurrence of invasive breast cancer. (Miyoshi et al., 2006), and high levels of UCH-L1 are known as biological indicators of renal cell carcinoma and colon cancer with metastatic phenotypes (Mizukami et al., 2008; Seliger et al., 2007).
  • Hybrigenic which is focusing on the research of new mechanisms for anticancer drugs that inhibit the interaction between proteins, ubiquitin carboxyl-terminal hydrolase, a cysteine protease 7;
  • Compounds that can act as inhibitors of USP7 can be used to treat cancer, neurodegenerative diseases such as Alzheimer's and Parkinson's disease, immune diseases, bone and joint diseases, osteoporosis, arthritis, inflammation, cardiovascular diseases, and infections
  • USP7 binds to the tumor suppressor protein p53, which stops cell proliferation and triggers a self-killing program.
  • Hybridgenics reported in the Molecular Cancer Therapy Journal in 2009 that small molecules that inhibit USP7 stabilize ubiquitin proteases and activate p53 as a new drug target for anticancer drugs (Mol Cancer Ther 2009; 8 (8). )).
  • Takeshi Mitsui discloses that the compound of the above formula can be used for the treatment of Alzheimer's disease and cancer because it has the effect of inhibiting UCH-L1 hydrolase activity (Takeshi Mitsui, et. Al., Neurochemistry International 56 (2010) 679-686).
  • UCH-L1 inhibitors include LDN 57444 of the above formula manufactured by Merck.
  • the LDN 57444 is a UCH-L1 inhibitor used for research, and it has been known that it has an effect of inhibiting UCH-L1 activity by directly binding at the active site of UCH-L1 (Yichin Liu, et. Al., Chemistry & Biology , 10, (2003), 837-846).
  • the present inventors while studying to develop a compound exhibiting an inhibitory effect of the activity of UCH-L1, the compounds of the present invention by inhibiting the activity of the UCH-L1 enzyme of the cancer or degenerative neurological disease of UCH-L1-related diseases It has been confirmed that there is potential for development as a prophylactic or therapeutic agent, and the present invention has been completed.
  • An object of the present invention is to provide a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are as defined herein).
  • Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of UCH-L1 related diseases containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Still another object of the present invention is to provide a method for treating UCH-L1 related diseases using the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention to provide a UCH-L1 activity inhibitor containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Still another object of the present invention is to provide a method of inhibiting the activity of UCH-L1 using the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are as defined herein).
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of UCH-L1 related diseases containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for treating a UCH-L1-related disease comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof. do.
  • the present invention also provides a UCH-L1 activity inhibitor containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method of inhibiting the activity of UCH-L1 comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof. to provide.
  • Compound represented by the formula (1) according to the present invention is excellent in the inhibitory effect of the activity of UCH-L1, in particular, low cytotoxicity and excellent cell invasion inhibitory effect, such as cancer or Alzheimer's, Parkinson's disease associated with UCH-L1 It can be usefully used as a pharmaceutical composition for the prevention or treatment of degenerative neurological diseases.
  • 1 is a diagram showing the results of cytotoxicity after treatment of the compound according to the present invention with lung cancer cell line NCI-H157 at a concentration of 2 ⁇ M.
  • Figure 2 is a diagram showing the results of cytotoxicity after treatment of the example compound according to the present invention to the lung cancer cell line NCI-H157 at a concentration of 5 ⁇ M.
  • Figure 3 is a diagram showing the results of cytotoxicity after treatment of the compound according to the present invention to lung cancer cell line NCI-H157 at a concentration of 10 ⁇ M.
  • Figure 4 is a diagram showing the results of cytotoxicity after treatment of the compound according to the present invention in lung cancer cell line NCI-H157 at a concentration of 50 ⁇ M.
  • Figure 5 is a diagram showing the results of cell infiltration test after treatment of the compound according to the present invention with lung cancer cell line NCI-H157 by concentration.
  • the present invention provides a novel compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are each independently hydrogen; Hydroxyl group (-OH); C 1 -C 4 straight or branched alkyl group; C 1 -C 4 straight or branched alkoxy group; Carboxy group (-COOH); Aldehyde group (-CHO); Azide group (-N 3 ); Nitro group (-NO 2 ); Sodium sulfonate group (-SO 3 Na); Sulfonic acid group (-SO 3 H); Or an amino group unsubstituted or substituted with a C 1 -C 4 straight or branched alkylsulfonyl group, a C 1 -C 4 straight or branched haloalkylsulfonyl group, or a C 1 -C 4 straight or branched haloalkylcarbonyl group;
  • R 3 is hydrogen or a hydroxy group
  • R 4 is hydrogen, oxo ( ⁇ O), a C 1 -C 4 straight or branched alkylidedenyl group, or an azide group;
  • R 5 and R 6 are hydrogen, a C 1 -C 4 straight or branched alkyl group or a C 2 -C 4 straight or branched alkenyl group;
  • R 7 is a C 1 -C 4 straight or branched alkyl group, or a C 2 -C 4 straight or branched alkylideneyl group;
  • n is an integer from 0 to 20;
  • R 1 is hydrogen; Hydroxyl group; C 1 -C 4 straight or branched alkoxy group; Carboxyl groups; Aldehyde group; Sodium sulfonate group; Sulfonic acid groups; Or an amino group substituted with a C 1 -C 4 straight or branched alkylsulfonyl group, a C 1 -C 4 straight or branched haloalkylsulfonyl group, or a C 1 -C 4 straight or branched haloalkylcarbonyl group;
  • R 2 is hydrogen; Hydroxyl group; C 1 -C 4 straight or branched alkyl group; Azide groups; Nitro group; Or an amino group;
  • R 3 is hydrogen or a hydroxy group
  • R 4 is hydrogen, oxo, a C 1 -C 4 straight or branched alkylidedenyl group, or an azide group;
  • R 5 is hydrogen or a C 1 -C 4 straight or branched alkyl group
  • R 6 is hydrogen, a C 1 -C 4 straight or branched alkyl group or a C 2 -C 4 straight or branched alkenyl group;
  • R 7 is a C 1 -C 4 straight or branched alkyl group, or a C 2 -C 4 straight or branched alkylideneyl group;
  • n is an integer from 0 to 20;
  • R 1 is hydrogen; Hydroxyl group; C 1 -C 2 alkoxy group; Carboxyl groups; Aldehyde group; Sodium sulfonate group; Sulfonic acid groups; Or an amino group substituted with a C 1 -C 2 alkylsulfonyl group, a C 1 -C 2 haloalkylsulfonyl group, or a C 1 -C 2 haloalkylcarbonyl group;
  • R 2 is hydrogen; Hydroxyl group; C 1 -C 2 alkyl group; Azide groups; Nitro group; Or an amino group;
  • R 3 is hydrogen or a hydroxy group
  • R 4 is hydrogen, oxo, a C 1 -C 2 alkylidedenyl group, or an azide group
  • R 5 is hydrogen or a C 1 -C 2 alkyl group
  • R 6 is hydrogen, a C 1 -C 2 alkyl group or a C 2 -C 3 alkenyl group
  • R 7 is a C 1 -C 4 straight or branched alkyl group, or a C 3 -C 4 straight or branched alkylideneyl group;
  • n is an integer from 0 to 15;
  • R 1 is hydrogen; Hydroxyl group; Methoxy; Carboxyl groups; Aldehyde group; Sodium sulfonate group; Sulfonic acid groups; Trifluoromethylsulfonylamino group; Or a trifluoromethylcarbonylamino group;
  • R 2 is hydrogen; Hydroxyl group; methyl; Azide groups; Nitro group; Or an amino group;
  • R 3 is hydrogen or a hydroxy group
  • R 4 is hydrogen, oxo, methylidedenyl group, or azide group
  • R 5 is hydrogen or methyl
  • R 6 is hydrogen, ethyl, or ethenyl
  • R 7 is methyl, isopropyl, or isopropylidedenyl
  • n is an integer from 0 to 11;
  • the compound represented by Chemical 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, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanediodes.
  • non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
  • Acid addition salt according to the present invention is a conventional method, for example, a precipitate formed by dissolving a compound represented by the formula (1) in an organic solvent, for example methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, and adding an organic or inorganic acid
  • an organic solvent for example methanol, ethanol, acetone, methylene chloride, acetonitrile and the like
  • the solvent may be prepared by filtration, drying, or by distillation under reduced pressure of a solvent and an excess of acid, followed by drying or crystallization under an organic solvent.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts were obtained by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, for example, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • Corresponding silver salts were also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (e.g., silver nitrate).
  • the present invention includes not only the compound represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, and the like that can be prepared therefrom.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of UCH-L1-related diseases containing a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are as defined in Formula 1).
  • the compound of formula 1 according to the present invention is excellent in inhibiting cancer cell invasion and cancer cell metastasis.
  • UCH-L1 is a neuron-specific ubiquitin recycling enzyme, and UCH-L1 is known as a protein that is specifically expressed in neural tissues throughout the neuronal cell differentiation process. It is expressed very specifically in cells and these tumors. Therefore, in order to verify the UCH-L1 inhibitory activity of the compound represented by Formula 1 according to the present invention, after treating the compounds according to the present invention to UCH-L1 and measuring the inhibitory activity, IC 50 values were as low as 9.4 Up to 196.15 ⁇ M.
  • the IC 50 value was determined to be 9.4 to 36.00 ⁇ M, which resulted in better inhibitory activity than LDN 57444 (58.6 ⁇ M) (positive control), which is used as a conventional UCH-L1 inhibitor. It can be seen that. From this, the compounds of the present invention can be usefully used as a composition for preventing or treating UCH-L1 related diseases by inhibiting the activity of UCH-L1.
  • the compound of Formula 1 according to the present invention has the effect of inhibiting cancer cell invasion, low cytotoxicity, and inhibit metastasis of cancer cells.
  • the compounds of formula 1 according to the present invention can be used to prevent or treat cancer as UCH-L1 related diseases.
  • the cancer is, for example, acute lymphocytic leukemia, non-small cell lung cancer, neuroblastoma, pancreatic cancer, prostate cancer, myeloma, esophageal cancer, colon cancer, kidney cancer, breast cancer and the like.
  • the UCH-L1-related disease is a degenerative neurological disease.
  • the degenerative cranial nerve disease is Alzheimer's, Parkinson's disease and the like.
  • the present invention provides a method for treating a UCH-L1 related disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: do:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are as defined in Formula 1).
  • the UCH-L1-related disease according to the present invention is a cancer, more specifically, for example, acute lymphocytic leukemia, non-small cell lung cancer, neuroblastoma, pancreatic cancer, prostate cancer, medullary carcinoma, esophageal cancer, colon cancer, kidney cancer And breast cancer.
  • the UCH-L1 related diseases according to the present invention may include degenerative neurological diseases, and more specifically, for example, Alzheimer's and Parkinson's disease.
  • the present invention also provides a UCH-L1 activity inhibitor containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for inhibiting the activity of UCH-L1, comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. do.
  • the pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be used in various oral or parenteral dosage forms as described below. It may be formulated and administered, but is not limited thereto.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
  • compositions comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, which is an ampoule or vial unit dosage form. It can be prepared by.
  • the compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
  • the dosage of the pharmaceutical composition containing the compound of Formula 1 as an active ingredient to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and preferably 0.01 to 200 mg.
  • / Kg / day may be administered by oral or parenteral route by dividing a predetermined time interval several times a day, preferably once to three times a day, depending on the judgment of the doctor or pharmacist.
  • Preparation Example or Example is an example of a method for preparing the compound of Formula 1, the preparation method described by the following Preparation Example or Example can be obtained using synthetic conditions, appropriate reagents and the like well known in the field of organic synthesis. have.
  • a vinyl grignard reagent solution (1M in THF, 13.1 mL) was added to a mixture of cuprous nitrile (0.294 g, 13.1 mmol) and 33 mL of THF, followed by cooling to -40 ° C. After stirring at ⁇ 40 ° C. for 15 minutes, citral (1.13 mL) was dissolved in THF and added. After further stirring for 2 hours at -40 °C, the reaction was terminated by adding a saturated aqueous solution of ammonium chloride (30 mL), and then the organic layer was extracted three times with ethyl acetate. The extracted solution was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified by column chromatography to obtain 582 mg (49.4%, 6.47 mmol) of the target compound.
  • Step 2 Preparation of 1- (4- (tert-butyldimethylsilyloxy) phenyl) -3,7-dimethyl-3-vinylocta-6-en-1-ol
  • Dibromoethane (144 ⁇ l) was added to a mixture of 267 mg of magnesium and 7.4 mL of THF under argon atmosphere.
  • (4-bromophenoxy) (tert-butyl) dimethylsilane (1.6 g, 5.56 mmol) was dissolved in 3.7 mL of THF and the resulting mixture was refluxed for 30 minutes. After completion of reflux, the resulting mixture was transferred to a syringe, and the 3,7-dimethyl-3-vinylocta-6-ene (501 mg, 2.78 mmol) was dissolved in 9.2 mL of THF and cooled to 0 ° C. and added. The mixture was stirred at 0 ° C.
  • Step 3 Preparation of 4- (1-hydroxy-3,7-dimethyl-3-vinylocta-6-enyl) phenol
  • Step 1 Preparation of 1- (4- (tert-butyldimethylsilyloxy) phenyl) -3,7-dimethyl-3-vinylocta-6-en-1-one
  • Step 2 Preparation of 1- (4-hydroxyphenyl) -3,7-dimethyl-3-vinylocta-6-en-1-one
  • Step 1 Preparation of tert-butyl (4- (4,8-dimethyl-4-vinylnona-1,7-dien-2-yl) phenoxy) dimethylsilane
  • Step 2 Preparation of 4- (4,8-dimethyl-4-vinylnona-1,7-dien-2-yl) phenol
  • Step 1 Preparation of (E) -tert-butyl (4- (3,7-dimethyl-3-vinylocta-1,6-dienyl) phenoxy) dimethylsilane
  • Step 2 Preparation of tert-butyl (4- (3-ethyl-3,7-dimethyloctyl) phenoxy) dimethylsilane
  • Step 1 Preparation of 1- (4- (tert-butyldimethylsilyloxy) phenyl) -3-ethyl-3,7-dimethyloctan-1-ol
  • Step 2 Preparation of (E) -tert-butyl (4- (3-ethyl-3,7-dimethylocta-1-enyl) phenoxy) dimethylsilane
  • Step 3 Preparation of (E) -4- (3-ethyl-3,7-dimethylocta-1-enyl) phenol
  • step 2 (E) -tert-butyl (4- (3-ethyl-3,7-dimethylocta-1-enyl) phenoxy) dimethylsilane (10.3 mg, 0.028 mmol) obtained in step 2 was used. 1 mg (13.7%, 3.7 ⁇ mol) of the target compound were obtained by the same method as step 3 of 1.
  • Step 2 Preparation of 1- (3- (benzyloxy) phenyl) dodecane-1-ol
  • Step 2 Preparation of 1- (3,4-bis (benzyloxy) phenyl) dodecane-1-ol
  • step 2 1- (3,4-bis (benzyloxy) phenyl) dodecane-1-ol (197 mg, 0.41 mmol) obtained in step 2 was carried out in the same manner as in step 3 of Example 15, 47.4 mg (34%, 0.14 mmol) of compound were obtained.
  • the compound of the present invention in powder form was dissolved in DMSO at a concentration of 100 mM and used. Diluted in UCH-L1 reaction buffer (Tris-HCl, pH 7.6, 0.5 mM EDTA, 5 mM DTT, 0.05 mg / mL BSA) at 4 ° C. to initiate activity screening. LDN 57444 was used as a positive control.
  • the enzyme and substrate were diluted in UCH-L1 reaction buffer at 4 ° C. 50 ⁇ L of 0.2 mM compound according to the present invention, DMSO control (untreated group) and positive control, were each aliquoted into black microwell plates treated with nothing (final total concentration 50 ⁇ M).
  • the first and second screening confirmed the compounds of Examples 1-16 according to the invention to inhibit the enzymatic activity of UCH-L1 and were selected as potential UCH-L1 inhibitors.
  • the compounds have been found to be selective and have a concentration dependent UCH-L1 inhibitory effect.
  • the compound of the present invention in powder form was dissolved in DMSO at a concentration of 100 mM and used. Diluted in UCH-L1 reaction buffer (Tris-HCl, pH 7.6, 0.5 mM EDTA, 5 mM DTT, 0.05 mg / mL BSA) at 4 ° C. to initiate activity screening. LDN 57444 was used as a positive control. To determine the IC 50 value, the compounds according to the invention were dissolved in 100 mM DMSO, and then each compound was serially diluted (200 ⁇ M to 0.2 ⁇ M) in UCH-L1 buffer, respectively. 50 ⁇ l of different concentrations of compounds were taken and added to each well.
  • UCH-L1 reaction buffer Tris-HCl, pH 7.6, 0.5 mM EDTA, 5 mM DTT, 0.05 mg / mL BSA
  • the initial velocity Vo was determined by measuring the fluorescence for 3 minutes and the IC 50 value was determined using Table curve software (Jandel Scientific, Erkrath, Germany). The screening was performed four times for reproducibility.
  • the compound according to the present invention was confirmed that the IC 50 value of 9.4 to 196.15 ⁇ M has an effect of inhibiting UCH-L1 activity, in particular, in the case of the compounds of Examples 14-16 , IC 50 value was 9.4 to 36.00 ⁇ M, it was confirmed that the effect of inhibiting UCH-L1 activity was superior to the positive control LDN 57444 (58.6 ⁇ M).
  • the compounds according to the invention were determined to selectively inhibit UCH-L1 over the positive control. From this it can be seen that the compounds of the present invention inhibit the activity of UCH-L1.
  • the compound according to the present invention is excellent in the inhibitory effect of the activity of UCH-L1 and can be usefully used as a pharmaceutical composition for the prevention or treatment of degenerative cranial nerve diseases such as cancer or Alzheimer's and Parkinson's disease, which are UCH-L1 related diseases. have.
  • Lung cancer cell line NCI-H157 cells were applied to each well of E-plate 96 (ACEA, san Diego, Calif., USA) and then incubated at 37 ° C. for 24 hours. Thereafter, the compounds of Examples 14 and 15 were treated at various concentrations to measure NCI-H157 cell viability for 100 hours using a real time cell analyzer xCELLigence. It is shown in Figures 1 to 4 below.
  • the cytotoxicity was measured by treating the compounds of Examples 14 and 15 according to the present invention by concentration, it was confirmed that the cytotoxicity when treated at 50 ⁇ M concentration.
  • the inside of the upper chamber of the transwell was coated with 80 ⁇ g Matrigel (Matrigel TM basement membrane matrix, BD Bioscience, NJ, USA) at 37 ° C. for 1 hour.
  • the lower chamber was filled with RPMI medium containing 10% FBS.
  • NCI-H157 cells were cultured in an upper chamber (containing 0.5-1 ⁇ 10 4 cells in 150 ⁇ l) and then incubated at 37 ° C. for 24 hours.
  • the migrated cells after the culture were stained with crystal violet (0.5% w / v crystal violet, 25% methanol).
  • the non-mobile cells were removed from inside the upper chamber with a cotton filter.
  • the moving cell number was calculated at 100 times magnification using a microscope. The results are shown in Table 3 and FIG. 5.
  • the compound according to the present invention is excellent in the inhibitory effect of the activity of UCH-L1, in particular, low cytotoxicity to cancer cells, and excellent cell invasion inhibitory effect, cancer or Alzheimer's disease, Parkinson's disease associated with UCH-L1 It can be usefully used as a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases such as diseases.
  • the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention can be formulated in various forms according to the purpose.
  • the following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • the above ingredients are mixed and filled in an airtight cloth to prepare a powder.
  • tablets are prepared by tableting according to a conventional method for preparing tablets.
  • the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
  • the amount of the above ingredient is prepared per ampoule (2 ml).
  • each component is added to the purified water to dissolve, the lemon flavor is added appropriately, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by the addition of purified water, and then filled into a brown bottle.
  • the liquid is prepared by sterilization.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur une composition pharmaceutique pour la prévention ou le traitement de maladies associées à UCH-L1, contenant un composé inhibiteur d'UCH-L1 et un sel pharmaceutiquement acceptable de celui-ci en tant que principes actifs. Le composé selon la présente invention inhibe de façon remarquable l'activité d'UCH-L1 et, en particulier, inhibe la cicatrisation de plaie en ce qui concerne des cellules cancéreuses et a une faible cytotoxicité et un excellent effet d'inhibition de l'infiltration cellulaire et, ainsi, peut être utile sous forme d'une composition pharmaceutique pour la prévention ou le traitement de maladies neurodégénératives telles qu'un cancer, la maladie d'Alzheimer ou la maladie de Parkinson, qui sont des maladies associées à UCH-L1.
PCT/KR2013/004221 2013-05-13 2013-05-13 Nouveau composé ou son sel pharmaceutiquement acceptable et composition pharmaceutique pour la prévention ou le traitement de maladies associées à uch-l1, le contenant en tant que principe actif WO2014185561A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
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WO2015176153A1 (fr) * 2014-05-23 2015-11-26 The Governing Council Of The University Of Toronto Modulateurs de ppar
WO2016038379A1 (fr) * 2014-09-10 2016-03-17 Royal Holloway And Bedford New College Composé anticonvulsivant

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EP0942896B1 (fr) * 1996-11-20 2003-04-16 Aventis Pharmaceuticals Inc. Phenols et thiophenols substitues utilises comme agents antioxydant
KR100732298B1 (ko) * 2005-11-24 2007-06-25 이화여자대학교 산학협력단 유비키틴 ｃ-말단 가수분해제-ｌ1을 이용한 암전이 진단용조성물
KR20130112519A (ko) * 2012-04-04 2013-10-14 이화여자대학교 산학협력단 Ｕｃｈ－ｌ１ 저해 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 ｕｃｈ－ｌ１ 관련 질환의 예방 또는 치료용 약학적 조성물

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KR100732298B1 (ko) * 2005-11-24 2007-06-25 이화여자대학교 산학협력단 유비키틴 ｃ-말단 가수분해제-ｌ1을 이용한 암전이 진단용조성물
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015176153A1 (fr) * 2014-05-23 2015-11-26 The Governing Council Of The University Of Toronto Modulateurs de ppar
WO2016038379A1 (fr) * 2014-09-10 2016-03-17 Royal Holloway And Bedford New College Composé anticonvulsivant
US10301263B2 (en) 2014-09-10 2019-05-28 Royal Holloway And Bedford New College Anticonvulsant compound

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