WO2018062954A1 - Inhibitor of function of cyclophilin and method for using same - Google Patents
Inhibitor of function of cyclophilin and method for using same Download PDFInfo
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- WO2018062954A1 WO2018062954A1 PCT/KR2017/010999 KR2017010999W WO2018062954A1 WO 2018062954 A1 WO2018062954 A1 WO 2018062954A1 KR 2017010999 W KR2017010999 W KR 2017010999W WO 2018062954 A1 WO2018062954 A1 WO 2018062954A1
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- Prior art keywords
- group
- aryl
- alkyl
- alkyl group
- hydrogen
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to inhibitors of cyclophylline function including stilbene derivatives or pharmaceutically acceptable salts thereof and uses thereof for the prevention or treatment of cyclophylline-related diseases or injuries such as chronic viral infection, neurodegenerative diseases and tumor formation. It relates to the composition of.
- Cyclophyllin is a protein belonging to the immunophyllin (immunopillin), which is found in all cells of all living things, ie prokaryotes and eukaryotes, and is well conserved through evolution. In humans there are a total of 16 unique proteins, including seven major CyPs: CyP A, CyP B, CyP C, CyP D, CyP E, CyP 40, and CyP NK.
- Cyclophylline is found in most cells of the human body and in mammals CyP A and CyP 40 are cytoplasmic signal sequences, whereas CyP B and CyP C have amino-terminal signal sequences that target the endoplasmic reticulum protein secretion pathway.
- CyP D has a signal sequence directed to the mitochondria
- CyP E has an amino-terminal RNA binding domain and is located in the nucleus
- CyP 40 has a TPR and is located in the cytoplasm.
- Human CyP NK is the largest CyP with huge hydrophilic and positively charged carboxyl ends, located in the cytoplasm.
- the cyclophylline is a multifunctional protein involved in cellular processes, is highly conserved through evolution, and has an essential function in the cell.
- Cyclophilin has been found to have enzymatic properties that catalyze the cis-trans isomerization of peptidyl-pryl bonds. Cyclophilin is therefore called peptidyl-prolyl cis-trans i somerase (PPIase), which is an accelerating factor in proper folding of newly synthesized proteins. PPIase is also involved in repairing proteins damaged by environmental stress, including thermal stress, UV irradiation, pH changes in the cell environment, and oxidant treatment. This function is known as molecular chaperone activity. In addition, PPIase activity of cyclophylline was found to be involved in intracellular protein trafficking, mitochondrial function and pre-mRNA processing.
- PPIase activity of cyclophylline was found to be involved in intracellular protein trafficking, mitochondrial function and pre-mRNA processing.
- Cyclosporin one of the cyclophylline inhibitors, binds to the hydrophobic pocket of CyP A to inhibit PPIase activity.
- CyP A is a prototype of the cyclophylline family and sequence homology with CyP B, CyP C, and CyP D in humans The last name is very high.
- the binding pocket of all cyclophilins is formed by approximately 109 amino acids, which are highly conserved regions, with 100% sequence identity between CyP A and CyP D. Therefore, CyP A binding affinity is the best predictor of CyP D binding affinity and vice versa.
- cyclophylline is involved in various diseases, which can be classified into three major categories: viral infection disease, diseases related to the inflammatory pathway, and mitochondrial dysfunction ( disease or injury related to the mitochondrial dysfunction.
- Viral infection diseases include HAV virus, HBV virus, HCV virus, HIV virus, HDV virus, HEV virus, coronavirus, influenza virus, etc., and are related to the inflammatory inflammation process.
- Diseases include cardiovascular diseases, rheumatoid arthritis, sepsis, periodontitis, acute Lung Inflammation, asthma, aging, alopecia, non Non-Alcohol ic Steatohepatitis.
- Cyclophyllin is involved in viral replication by interacting with small surface proteins (SHBs) of Hepatitis B Virus (HBV surface antigen, HBsAg), RNA polymer of HCV Hepatitis C Virus. It is known to interact with Laase NS5B, to bind with HIVGiuman Immunodeficiency Virus capsid protein, and to interact with the influenza virus replication early stage 1 Ml protein.
- SHBs small surface proteins of Hepatitis B Virus
- HBsAg Hepatitis B Virus
- RNA polymer of HCV Hepatitis C Virus RNA polymer of HCV Hepatitis C Virus. It is known to interact with Laase NS5B, to bind with HIVGiuman Immunodeficiency Virus capsid protein, and to interact with the influenza virus replication early stage 1 Ml protein.
- Cardiovascular diseases caused by cyclophylline in the inflammatory inflammation process include atherosclerosis, abdominal aortic aneurysms, ischemic heart diseases, and heart. Cardiac hypertrophy, rheumatism Rheumatoid arthritis, sepsis, periodontal disease, collagen VI myopathies, post-cardiac arrest syndrome, heart failure, acute pneumonia (Acute Lung Inflammation) ), Asthma, aging, alopecia, non-alcoholic steatohepatitis, obesity, renal fibrosis, nephrotoxicity, obstructive nephropathy (obstructive nephropathy), cisplatin-induced renal disease, acute renal failure, chronic renal failure, renal glomerulopathy, end stage renal disease, joints Bone disorders, osteoporosis, arthritis, osteoarthritis, and Paget's disease are known.
- RA rheumatoid arthritis
- Neurodeegenerative diseases caused by mitochondrial dysfunct involvement with cyclophylline include Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple Multiple Sclerosis (MS), amyotrophic lateral sclerosis (ALS), muscular dystrophy, epilepsy, Autism cerebral ischemia, multiple systems atrophy atrophy, cerebral palsy, diabetic neuropathy, bipolar disorder, excitotoxic injury, hepatic encephalopathy, hypoglycemia, manganese toxicity, neuropathies, progressive muscular atrophy, peripheral neuropathy, trigeminal neuropathy Trigeminal Neuralgia, Glossopharyngeal neuralgia, Bell's palsy, Myasthenia Gravis, and neurological disorders are known.
- MS multiple Multiple Sclerosis
- ALS amyotrophic lateral sclerosis
- muscular dystrophy epilepsy
- Autism cerebral ischemia multiple systems atrophy atrophy, cerebral palsy, diabetic neuropathy, bipolar disorder, excitotoxic injury, hepatic ence
- Cyclophilin is known to be involved in tumor tissue growth, and related tumors include small cell and non-small cell lung cancer, bladder cancer, and liver cancer.
- thyroid cancer thyroid cancer
- lymphomas lymphomas
- ovarian cancer ovarian cancer
- Acute injuries caused by mitochondrial dysfunction involving cyclophylline are traumatic brain injuries.
- the present invention to solve the above problems provides a cyclophylline function inhibitor comprising a stilbene derivative represented by the following formula (1), or a pharmaceutically acceptable salt thereof.
- the present invention also provides a composition for the prophylaxis or treatment of cyclophilin-related diseases or damages, including a stilbene derivative represented by Formula 1 below, or a pharmaceutically acceptable salt thereof.
- A is CRa or N
- B is CRb or N
- G is CRe or N
- J is CRf or N
- M is CRg or N
- D, E, and L are CRh or N
- x is H, CH 3) CN, NH 2) F, CI, Br or I,
- Ra is hydrogen, halogen, NO 2 , CN, OH, C 1 -C 5 alkyl group C 2 -C 10 alkenyl group, C 1 -C 6 alkoxy group, -COOR R 1 is hydrogen or C 1 -C 5 alkyl group C 6 -C 12 aryl or C 3 -C 10 Cycloalkyl) or -0C0R2 (R2 is a C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl),
- Rb is hydrogen halogen, N02, CN, OH, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 hetero ring -COORKRl is hydrogen or an alkyl group of CI— C5, aryl of C6-C12 or cycloalkyl of C3-C10) or _0C0R2 (R2 is an alkyl group of C1-C5, aryl of C6-C12 or cycloalkyl of C3-C10 ) Or -C0R10 (R10 is an alkyl group of C1-C20, an aryl of C6-C12, a cycloalkyl group of C3-C10 or a heterocyclic group of C5-C12)
- Rc is hydrogen, 0H, halogen, CN, N02, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 solution Ring, — NR3R4 (R3 is hydrogen, an alkyl group of C1-C20 or C6— C12 aryl, R4 is hydrogen, an alkyl group of C1-C20 or an aryl of C6-C12, and R3 and R4 combine to form a heterocycle And may further comprise one or more heteroatoms J, -C00R5 (R5 is hydrogen, C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group,
- Rd is 0H, halogen, N02, CN, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 heterocyclic group , -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R3 and R4 may combine to form a hetero ring, additionally 1 It may include more than one hetero atom.) -C00R5 (R5 is hydrogen, C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR
- Re is hydrogen, NH 2 , OH, halogen, CN, NCS, C1-C20 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy, C6-C12 aryloxy, C6-C12 aryl, C5- C12 heterocyclic group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 can combine to form a hetero ring And may further include one or more heteroatoms.), -C00R5 (R5 is C1-C5 alkyl, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1- C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is
- Rf is hydrogen, 3 ⁇ 4, OH, halogen, N02, N 2 +, C1-C4 alkyl group, alkenyl of C2-C10 alkenyl group, C1-C4 alkoxy group, a heterocyclic group of C6-C12 aryl, C5-C12 of , -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 can be joined to form a hetero ring, further It may contain one or more hetero atoms.), -C00R5 (R5 is C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 Alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CY
- Rg is hydrogen, NH 2 , OH, halogen, N02, C00H, CN, alkyl group of C1-C20, C2-C10 Alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6— C12 aryl, R4 is hydrogen, C1-C20 alkyl Or C6-C12 aryl, R3 and R4 may combine to form a hetero ring, and may further include one or more hetero atoms.), -C00R5 (R5 is an alkyl group of C1-C5, C6-C12 Aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -NR7CYR8
- Rh is hydrogen, H 2 , OH, C 1 -C 5 alkyl group or C 2 -C 10 alkenyl group, the hetero atom of the hetero ring group is at least one member selected from the group consisting of nitrogen, oxygen and sulfur,
- the alkyl group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5-C12 heterocyclic group and C3-C10 cycloalkyl group.
- the alkenyl group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, amine, C1-C5 alkoxy, C6-C12 aryl ⁇ C5-C12 heterocyclic group and C3-C10 cycloalkyl group.
- substituents selected from the group consisting of 0H, halogen, amine, C1-C5 alkoxy, C6-C12 aryl ⁇ C5-C12 heterocyclic group and C3-C10 cycloalkyl group.
- the alkoxy group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, C1-C5 alkoxy group, C6-C12 aryl, C3-C10 cycloalkyl group, carboxyl group, amine and aminocarbonyl group,
- the heterocyclic group may be substituted with one or more substituents selected from the group consisting of alkyl group, amine substituted alkyl group, amine, amide group and carboxyl group,
- the aryl may be substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, alkoxy, carboxyl, ester, nitro and amine groups,
- Rc and Rd may combine with neighboring groups to form a condensed ring.
- Cyclophylline inhibitors including stilbene derivatives according to the present invention has the effect of inhibiting the function of cyclophylline.
- the composition comprising a stilbene derivative according to the present invention is a viral infection (viral infect ion) disease, cardiovascul ar di seases, rheumatoid arthr itis, sepsis (sepsis), periodontitis (per iodont it is), acute pneumonia (Acute Lung Inf lammat ion), asthma, aging, alopecia, neurodegenerat ive diseases, tumor It is useful for the prevention of cyclophylline-related diseases or damages such as Acute Injuries, or for the treatment of signs of disease.
- Stilbene derivatives according to the present invention can increase the therapeutic effect by using in combination with existing therapeutic agents.
- 1 to 3 is a diagram showing the effect of using a stilbene derivative (Compound 225) of the present invention in combination with conventional HCV treatment.
- the present invention also provides a cyclophylline function inhibitor comprising a stilbene derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- the stilbene derivative of the present invention is advantageous as a cyclophylline inhibitor because it has a structure suitable for binding to an active pocket maintained in all proteins having a function of cyclophylline.
- the present invention provides a composition for the prevention or treatment of cyclophylline-related diseases comprising a stilbene derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- A is CRa or N
- B is CRb or N
- G is CRe or N
- J is CRf or N
- M is CRg or N
- D, E, and L are CRh or N
- Rx is H, CH 3 , CN, NH 2 , F, CI, Br or I
- Ra is hydrogen, halogen, ⁇ 2, CN, OH, C1-C5 alkyl group, C2-C10 alkenyl group, C1-C6 alkoxy group
- -COOR Rl is hydrogen or C1-C5 alkyl group, C6-C12 aryl or C3- C10 cycloalkyl) or -0C0R2 (R2 is a C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl),
- Rb is hydrogen, halogen, N0 2 , CN, OH, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 Heterocyclic group,
- C00RKR1 is hydrogen or alkyl group of C1-C5, aryl of C6-C12 or cycloalkyl of C3-C10) or -0C0R2 (R2 is alkyl group of C1-C5, aryl of C6-C12 or C3-C10 Cycloalkyl) or -C0R KR10 is an alkyl group of C1-C20, an aryl of C6-C12, a cycloalkyl group of C3-C10 or a heterocyclic group of C5-C12)
- Rc is hydrogen, 0H, halogen, CN, N0 2 , C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 Heterocyclic group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl group or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl group or C6-C12 aryl, R3 and R4 combine to form a hetero ring.
- -C00R5 (R5 is hydrogen, an alkyl group of C1-C20, an aryl of C6-C12 or a cycloalkyl group of C3-C10), -0C0R6 (R6 is C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6 — C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group), -NHS (0) 2 R9 (R9 is C1-C5 alkyl group, C6-C12 aryl or C5-C12 heterocyclic group) Or -C0R10 (R10 is an alkyl group of C1-C20. , C6-C12
- Rd is 0H, halogen, N02, CN, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 heterocyclic group , -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R3 and R4 may combine to form a hetero ring, additionally 1 It may include more than one hetero atom.), -C00R5 (R5 is hydrogen C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8
- Re is hydrogen, N3 ⁇ 4, OH, halogen, CN, NCS, C1-C20 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy, C6-C12 aryloxy, C6-C12 aryl, C5-C12 Heterocycle Group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R3 and R4 can combine to form a hetero ring, further It may contain one or more hetero atoms;), -C00R5 (R5 is C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), 0C0R6 (R6 is C1-C20 alkyl group, C6 -C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (
- Rf is hydrogen, NH 2, OH, halogen, N0 2, N 2 +, C1-C4 alkyl group, alkenyl of C2-C10 alkenyl group, C1-C4 alkoxy group, a C6-C12 aryl, heteroaryl, a C5-C12 Cyclic group, _NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 may combine to form a hetero ring, May contain one or more heteroatoms ⁇ ), -C00R5 (R5 is CI- C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 Alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, NR7CYR
- R g is hydrogen, N3 ⁇ 4, OH, halogen, N02, C00H, CN, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C5-C12 hetero ring
- R3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 may combine to form a hetero ring, further It may include one or more hetero atoms.), -C00R5 (R5 is C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is CI- C20 alkyl group, C6 -C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (
- Rh is hydrogen, N3 ⁇ 4, OH, an alkyl group of C1-C5 or an alkenyl group of C2-C10, and the hetero atom of the heterocyclic group is at least one selected from the group consisting of nitrogen, oxygen and sulfur,
- the alkyl group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5-C12 heterocyclic group and C3-C10 cycloalkyl group.
- the alkenyl group may be substituted with one or more substituents selected from the group consisting of OH, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5-C12 heterocyclic group and C3-C10 cycloalkyl group.
- the alkoxy group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, C1-C5 alkoxy group, C6-C12 aryl, C3-C10 cycloalkyl group, carboxyl amine and aminocarbonyl group,
- the heterocyclic group may be substituted with one or more substituents selected from the group consisting of an alkyl group, an amine substituted alkyl group, an amine, an amide group and a carboxyl group,
- the aryl may be substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, alkoxy, carboxyl, ester, nitro and amine groups,
- Rc and Rd may combine with adjacent groups to form a condensed ring.
- the stilbene derivative represented by Formula 1 of the present invention may be used as an inhibitor of cyclophylline function in combination with a pharmaceutically acceptable carrier, and may also be used as a prophylactic agent for the prevention of cyclophylline-related diseases or injuries or treatment of disease signs.
- the cyclophilin-related disease may be a viral infection disease, a disease related to an inflammatory inflammation process, or a disease related to mitochondrial dysfunct ion.
- the cyclophylline-related diseases may also include viral infections such as HBV, HCV, HIV, and influenza virus, cardiovascular diseases, rheumatoid arthritis, sepsis, and asthma. ), Periodontitis (periodontitis), aging (aging), hair loss (alopecia), neurodegenerative diseases (cancer), or tumor (cancer), but is not limited thereto.
- the cardiovascular disease is a disease caused by an inf ia ⁇ at ion process, specifically, atherosclerosis and abdominal aortic aneurysm. (abdominal aortic aneurysms), ischemic heart diseases, and cardi c hypertrophy.
- the cyclophylline related diseases include HAV virus, HBV virus, HCV virus, HDV virus, HEV virus, coronavirus, HIV virus, influenza virus infection, atherosclerosis , Abdominal aortic aneurysms, ischemic heart diseases, cardiac hypertrophy, rheumatoid ducts Rheumatoid arthritis, sepsis, per iodontal disease » collagen VI myopathies, post-cardiac arrest syndrome, heart failure, acute pneumonia Lung Inflammation, Asthma, Aging, Alopecia, Non-Alcoholic Steatohepatitis, Obesity, Renal fibrosis, Nephrotoxicity, Obstructive Nephropathy, ci splat in-induced renal disease, acute renal failure, chronic renal failure, renal glomerulopathy, end stage renal disease renal disease, bone disorders, osteoporosis, osteoarthritis, osteoarthritis, osteoarthritis, Paget's disease, Alzheimer's disease, Parkinson's disease
- the alkyl group, alkenyl group, alkoxy group may be linear or branched chain.
- the "halogen atom" may be fluorine, chlorine, bromine or iodine.
- the condensed ring when A, B, D, E, G, J, L, M, Rc, and Rd combine with adjacent groups to form a condensed ring, the condensed ring may preferably form a 6-membered or 5-membered ring. have.
- the condensed ring may include one or more hetero atoms of N, 0 or S.
- the condensed ring may be furan or thiophene.
- the pharmaceutically acceptable salt is preferably, but is not limited to, sodium salts, potassium salts, calcium salts and ammonium salts.
- A is CRa or N
- B is CRb
- G is CRe
- J is CRf
- M is CRg or N
- D E and L is preferably CH It is not limited to this.
- Rb is preferably hydrogen or an alkyl group of C1-C8, but is not limited thereto.
- Rc is preferably, but not limited to, an alkyl group of C1-C20, an alkoxy group of C1-C10, a phenylalkyl group, a nitro group, a cycloalkyl group of C3-C10, a heterocyclic group of C5-C12, or an alkyl ketone of C1-C10 .
- Rd is a C1-C20 alkyl group; C3-C10 ester group; C3-C10 cycloalkyl group; Methoxy in which a cycloalkyl group is substituted; Ethoxy in which an amine group is substituted; Carboxyl groups; A C1-C20 alkyl group substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, a carboxy group or a phenyl group unsubstituted or substituted; Amines; N—methylpiperazine; Piperidine; Morpholine (morphol ine); Or -C00R5 (R5 is preferably an alkyl group of C1-C5, an aryl of C6-C12 or a cycloalkyl group of C3-C10), but is not limited thereto.
- Re is preferably hydrogen, H 2 , OH, an alkyl group of C 1 -C 20 or an alkoxy group of C 1 -C 10, but is not limited thereto.
- Rg is hydrogen, NH 2 , OH, alkyl group of C1-C20; C3-C10 ester group; C3-C10 cycloalkyl group; Methoxy substituted with a cycloalkyl group; Ethoxy substituted with an amine group; A C2-C20 alkyl group substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, a carboxyl group or a substituted or unsubstituted phenyl group; Amines; N-methylpiperazine; Piperidine; Morpholine (morphol ine); Or a carboxy group, but is not limited thereto.
- Rh is preferably hydrogen, but is not limited thereto.
- the alkyl group used in the present invention may be substituted or unsubstituted alkyl, -CH 3 ( -CH2CH3, -CH 2 CH 2 CH 3) -CH 2 (CH 2 ) 2 CH 3 , -C3 ⁇ 4 (CH 2 ) 3 CH 3 , -CH (CH 3 ) CH 2 CH 3 , -CH 2 CH (CH 3 ) CH 2 C3 ⁇ 4, -CH 2 CH 2 CH (C3 ⁇ 4) 2 , -CH (C3 ⁇ 4) 2 , -C (CH 3 ) 3 , _CH 2 C (CH 3 ) 3 , -CH 2 CH (CH 3 ) 2 , -CH (CH 3 ) CH (CH 3 ) 2, -CH (CH 3 ) C (CH 3 ) 3 , -C (CH 3 ) 2 CH 2 C3 ⁇ 4,
- the alkoxy group may be a substituted or unsubstituted alkoxy group, wherein -0CH 3 , -OCF3, -OCH2CH3, -OCH2CH2CH3, -0CH 2 CH 2 CH 2 CH 3, -0CH (CH 3 ) CH 2 CH 3> -0CH 2 C0NH 2 ,
- Or may be, but is not limited to
- -C00R5 is C00CH 3 , -C00CH 2 CH 3) C00 (CH 2 ) 2 CH 3 , -C00 (CH2) 3 CH 3 ,
- the compounds of the present invention can be used to purchase or manufacture what is sold as a commodity, the preparation method is generally the case where Rx of Formula 1 is CN and the rest Can be different.
- the stilbene derivative represented by Chemical Formula 1 may be prepared by reacting a phenylacetonitrile (Phenylacetoni trile) derivative represented by Chemical Formula 2 with a benzaldehyde derivative represented by Chemical Formula 3 below.
- the phenylacetonitrile derivative represented by the formula (2) and the benzaldehyde derivative represented by the formula (3) may be purchased and used in the market, or may be prepared and used by methods known in the art.
- the reaction may be carried out under an organic solvent, or may be performed without a solvent.
- microwaves may be used to shorten the reaction time and increase the yield.
- the organic solvent is not limited, but preferably alcohols, more preferably butanol, methanol, ethanol, propanol and the like.
- A, B, D, E, G, J, L, M, Rc and Rd are the same as A, B, D, E, G, J, L, M, Rc and Rd of formula (1).
- the stilbene derivative represented by the formula (1) is an olefin derivative represented by the formula (4) and an organic represented by the formula (5) It can be prepared by reacting an organic halide derivative.
- the leupin derivatives represented by the formula (4) and the organic halide derivatives represented by the formula (5) may be purchased and used in the market, or may be prepared and used by methods known in the art.
- the reaction is preferably carried out using triethanolamine organic solvent as a catalyst and Palladium (II) acetate as a catalyst.
- Rx H, CH3, NH2
- Rx is hydrogen, CH 3 , NH 2> F, CI, Br or I,
- X is F, CI, Br or I
- A, B, D, E, G, J, L, M, Rc and Rd are the same as A, B, D, E, G, J, L, M, Rc and Rd of formula (1).
- the preparation method of the compound of the present invention may refer to Korean Patent Application 2017-0102983.
- pharmaceutically acceptable carrier used in the present invention is defined as a carrier or diluent which does not impair the biological activity and the properties of the active ingredient.
- the pharmaceutically acceptable carrier or additive one or more commonly used stabilizers, layering agents, extenders, wetting agents, disintegrating agents, lubricants, binders, and excipients such as surfactants can be used.
- agar, starch, alginic acid or its sodium salt, anhydrous calcium monohydrogen phosphate salt, etc. may be used, and as lubricant, silica, talc, stearic acid or its magnesium salt or calcium salt, polyethylene glycol, metasilicate Magnesium phosphate may be used, and as the binder, magnesium aluminum silicate.
- Starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyridine, low-substituted hydroxypropyl cellulose, and the like can be used.
- lactose dextrose, sucrose, manny, sorbbi, salose. Glycine, etc.
- commonly known boiling salts, absorbents, colorants, flavoring agents, and sweeteners may be used together.
- a stabilizer that does not contain sodium may be used as the stabilizer, for example magnesium aluminometasi 1 i cate, magnesium aluminate silicate (magnesium aluminosi 1 icate), magnesium aluminate (Magnesium aluminate), Dried aluminum hydroxide, Synthetic hydrotalcite, Synthetic aluminumsisi 1 icate, Magnesium carbonate, Precipitated calcium carbonate calcium carbonate, magnesium oxide, aluminum hydroxide, l-arginine, potassium phosphate, dipotassiumhydrogenphosphate, potassium dihydrogenphosphate , Ammonium chloride, aluminum chloride, etc., and one or two or more of the above-mentioned stabilizers may be used. can do.
- magnesium aluminometasi 1 i cate magnesium aluminate silicate (magnesium aluminosi 1 icate), magnesium aluminate (Magnesium aluminate), Dried aluminum hydroxide, Synthetic hydro
- compositions comprising a stilbene derivative of Formula 1 of the present invention may be administered in a variety of ways to facilitate administration of the compound into an organism.
- the pharmaceutical composition of the present invention is oral administration, rectal administration, vaginal administration, intranasal administration, intraocular administration, oral administration, sublingual administration, subcutaneous administration, intramuscular administration, intravenous administration, intrathecal administration, intradermal administration Administration, epidural administration, and the like.
- compositions of the present invention tablets, capsules, powders, drop pills
- Preferred tablets may be conventional tablets, coated tablets, dispersible tablets, effervescent tablets and the like, and may be multi-compressed tablets such as double tablets, nucleated tablets, multilayer tablets and the like.
- Preferred dosages of stilbene derivatives or pharmaceutically acceptable salts thereof contained in the pharmaceutical compositions provided herein vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route and duration of administration, Can be appropriately selected.
- the compound of formula 1 may be used in an amount of 1 to 100 mg / kg (weight), preferably 5 to 1, per day for mammals including humans
- It may be administered orally or via parenteral route once daily or divided into amounts of 50 mg / kg body weight.
- smaller dosages may be more suitable than the above-mentioned ranges, and higher dosages may be used without causing harmful side effects, and higher dosages may be administered in several smaller doses throughout the day. Can be dispensed.
- compositions useful in accordance with the present invention may comprise one or more compounds having Formula 1 above, together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients. Active ingredients essential for combination therapy may be combined in the pharmaceutical compositions of the present invention for simultaneous administration.
- formulations may be prepared in unit dosage form by any method well known in the pharmaceutical arts. Such methods include the step of bringing into association the active ingredient with the carrier consisting of one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then molding the product if necessary.
- a compound of Formula 1 was prepared by knoevenagel condensat ion reaction by reacting 1 equivalent of phenylacetonitrile derivative of Formula 2 and 1.3 equivalent of benzaldehyde derivative of Formula 3 with 0.2 equivalent of triphenylphosphine in a butanol solvent.
- a compound of Formula 1 was prepared using microwave using 1 equivalent of phenylacetonitrile derivative of Formula 2, 1.3 equivalents of Benzaldehyde of Chemical Formula 3 and 0.2 equivalents of triphenylphosphine. Using microwaves can reduce reaction time and improve yield.
- Rx CN Preparation Example 2. Preparation of a derivative of Rx hydrogen, CH 3 , NH 2 , F, CI, Br, I
- Example 1 Confirmation of cis-trans isomerase inhibitory activity of stilbene derivatives Chymotrypsin cleaves alanine-prine peptide bond in trans form. Mixing the Suc-AAPF-pNA (peptide substrate) with chymotrypsin results in the cleavage of the trans form peptide substrate and the cis form peptide substrate. The remaining cis-form peptide substrate is trans-formed by cis-trans isomerase and again cleaved by chymotrypsin. In other words, in the presence of cis-trans isomerase, chymotrypsin cleaves more of the trans form of the peptide substrate in a certain amount of time. This is used to determine the activity of cis-trans isomerase. The amount of peptide substrate in truncated trans form can be measured using absorbance at 390 nm.
- Cyclophylline has cis-trans isomerase activity and accelerates cleavage of the peptide form of the trans form by chymotrypsin.
- the stilbene derivatives of the present invention were treated with cyclophilin, the cleavage of the peptide substrate by chymotrypsin was not observed. It was confirmed that the stilbene derivatives of the present invention inhibit the activity of cyclophylline.
- CC 50 values of the compounds of the present invention were determined by MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] cytotoxicity test.
- the CC 50 value of the compounds of the present invention is at least 200 ⁇ .
- the CC 50 value for Compound 225 was 320 ⁇ , for Compound 226 284 ⁇ and for Compound 227 245 y M. Therefore, it can be seen that the compound of formula 1 of the present invention does not exhibit cytotoxicity.
- the antiviral activity of the stilbene derivatives against hepatitis C virus was measured.
- Replicon cells stably replicating the hepatitis C virus genome were attached to culture plates and incubated for 24 hours in a 37 C02 incubator.
- Replicon cells cultured for one day were washed with PBS (Phosphate-buffered sal ine) solution, and the compounds were treated and incubated for 72 hours.
- Ripleycone treated with stilbene derivative Wash the cells with cold PBS solution, add yL cytolysis solution and lyse the cells on ice for 20 minutes. After incorporating the lOiiL Renilla luciferase substrate, the amount of the expressed luminescence was measured to estimate the amount of the hepatitis C virus genome.
- Relative amounts of hepatitis C virus genome in replicon cells treated with stilbene derivatives of the present invention based on the amount of hepatitis C virus genome in replicon cells treated with dimethyl sulfoxide (DMS0) .
- antiviral activity (EC 50 ) values of compounds 1 to 315 of Tables 1-12 can be grouped as follows.
- Group D EC 50 is greater than 5 and less than 50 ⁇
- Group F EC 50 ⁇ 0.5 ⁇
- the compound of formula 1 of the present invention has an antiviral effect.
- Cyclophilin is a key protein that forms the permeability transition pore (FTP) of mitochondria.
- FTP permeability transition pore
- Cyclosporine known as an inhibitor of cyclophylline, is known to prevent the formation of permeable metastasis, preventing the expansion of mitochondria.
- the expansion experiment of mitochondria was carried out in the following manner. First, liver cells are disrupted using a dounce tissue grinder. The crushed cells are centrifuged at 700 X g for 10 minutes and the supernatant is transferred to a new tube. Mitochondria can be obtained by centrifugation of this supernatant at 12 mm 000 X g for 15 minutes.
- the mitochondrial expansion inhibition activity (IC 50 ) values of Compounds 1 to 315 of Tables 1-12 can be grouped as follows.
- Group G (G G ): IC 50> 50 ⁇ ⁇ 500 ⁇
- Example 5 Combination Formulation of Stilbene Derivatives with HCV Therapeutics To effectively treat HCV infection, a combination of HCV medications is used. Combining HCV treatments may increase the antiviral effect and reduce the incidence of drug resistance.
- Stilbene derivatives also have antiviral effects against viruses that are resistant to existing therapeutic agents (Table 13). According to Table 3 below, the stilbene derivative of the present invention (Compound 225) exhibits an antiviral effect in both viruses that exhibit drug resistance to Simeprevir or viruses that exhibit drug resistance to daclatasvir.
- Cyclophylline inhibitors including stilbene derivatives according to the present invention has the effect of inhibiting the function of cyclophylline.
- the composition comprising a stilbene derivative according to the present invention is a viral infection disease, cardiovascular diseases, rheumatoid arthritis, sepsis (sepsis), periodontitis (periodontitis), acute pneumonia ( Preventing or preventing cyclophilin-related diseases or injuries such as Acute Lung Inflammation, asthma, aging, alopecia, neurodegenerative diseases, tumors, and Acute Injuries Useful for the treatment of signs of disease.
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Abstract
The present invention relates to a pharmaceutical composition for use in preventing a disease or damage associated with a cyclophilin or in treating a symptom of the disease, the composition comprising a stilbene derivative, or a pharmaceutically acceptable salt thereof, for inhibiting a function of the cyclophilin.
Description
【명세서】 【Specification】
【발명의 명칭】 [Name of invention]
사이클로필린 기능 저해제 및 사용방법 Cyclophylline Inhibitors and Methods of Use
【기술분야】 Technical Field
본 발명은 스틸벤 유도체 또는 이의 약제학적으로 허용 가능한 염을 포함 하는 사이클로필린 기능 저해제 및 그 용도에 관한 것으로 만성 바이러스 감염， 퇴행성 신경질환 및 종양 형성 등의 사이클로필린 관련 질환 또는 손상의 예방 또는 치료용도의 조성물에 관한 것이다. The present invention relates to inhibitors of cyclophylline function including stilbene derivatives or pharmaceutically acceptable salts thereof and uses thereof for the prevention or treatment of cyclophylline-related diseases or injuries such as chronic viral infection, neurodegenerative diseases and tumor formation. It relates to the composition of.
【배경기술】 Background Art
사이클로필린 (cyclophi l in: CyP)은 임뮤노필린 ( immunophi l in)에 속하는 단백질로 모든 생물， 즉 원핵생물과 진핵생물의 모든 세포에서 발견되며 진화를 통해 구조적으로 잘 보존되어 있다. 인간에게는 7개의 주요 CyP, 즉 CyP A, CyP B, CyP C, CyP D, CyP E, CyP 40, 및 CyP NK를 포함하여 총 16개의 고유 단백질 이 존재한다. Cyclophyllin (CyP) is a protein belonging to the immunophyllin (immunopillin), which is found in all cells of all living things, ie prokaryotes and eukaryotes, and is well conserved through evolution. In humans there are a total of 16 unique proteins, including seven major CyPs: CyP A, CyP B, CyP C, CyP D, CyP E, CyP 40, and CyP NK.
사이클로필린은 인체 대부분의 세포내에서 발견되며 포유동물에서 CyP A 및 CyP 40은 세포질 신호 서열인데 반해， CyP B 및 CyP C는 소포체 단백질 분비 경로에 대한 표적으로 하는 아미노 -말단 신호 서열을 갖는다. CyP D는 미토콘드 리아로 향하게 하는 신호 서열을 가지며， CyP E는 아미노 -말단 RNA 결합 도메인 을 가지고 핵 내에 위치하며 , CyP 40은 TPR를 가지며 세포질 내에 위치한다. 인 간 CyP NK는 거대한 친수성 및 양전하를 띠는 카르복실 말단을 갖는 가장 큰 CyP 로서， 세포질 내에 위치한다. Cyclophylline is found in most cells of the human body and in mammals CyP A and CyP 40 are cytoplasmic signal sequences, whereas CyP B and CyP C have amino-terminal signal sequences that target the endoplasmic reticulum protein secretion pathway. CyP D has a signal sequence directed to the mitochondria, CyP E has an amino-terminal RNA binding domain and is located in the nucleus, CyP 40 has a TPR and is located in the cytoplasm. Human CyP NK is the largest CyP with huge hydrophilic and positively charged carboxyl ends, located in the cytoplasm.
상기 사이클로필린은 세포 과정에 관여하는 다기능 단백질이며， 진화를 거쳐 고도로 보존되었고 세포내 필수적인 기능을 하고 있다. The cyclophylline is a multifunctional protein involved in cellular processes, is highly conserved through evolution, and has an essential function in the cell.
사이클로필린은 펩티딜-프를릴 결합의 시스-트랜스 이성체화에 촉매작용 을 하는 효소 특성을 갖는 것으로 밝혀졌다. 따라서， 사이클로필린은 펩티딜-프 를릴一시스—트랜스 이소머라아제 (pept idyl prolyl ci s-trans i somerase, PPIase) 로 불리며, 이는 새롭게 합성된 단백질의 적절한 구조형성 ( folding)에 있어서 가 속화 인자로 작용할 수 있으며， PPIase는 또한 열적 스트레스， 자외선 조사, 세 포 환경의 pH의 변화 및 산화제 처리를 포함하는 환경적 스트레스로 인해 손상된 단백질을 복구하는데 관여한다. 이 기능은 분자 샤페론 활성으로 알려져 있다. 또한, 사이클로필린의 PPIase 활성은 세포내 단백질 수송 (traff icking)， 미토콘 드리아 기능 및 pre-mRNA 가공에도 관여하는 것으로 밝혀졌다. Cyclophilin has been found to have enzymatic properties that catalyze the cis-trans isomerization of peptidyl-pryl bonds. Cyclophilin is therefore called peptidyl-prolyl cis-trans i somerase (PPIase), which is an accelerating factor in proper folding of newly synthesized proteins. PPIase is also involved in repairing proteins damaged by environmental stress, including thermal stress, UV irradiation, pH changes in the cell environment, and oxidant treatment. This function is known as molecular chaperone activity. In addition, PPIase activity of cyclophylline was found to be involved in intracellular protein trafficking, mitochondrial function and pre-mRNA processing.
사이클로필린 저해물질 중의 하나인 사이클로스포린은 CyP A의 소수성 포 켓 (pocket ) 내에 결합하여 PPIase 활성을 저해한다. CyP A는 사이클로필린 패밀 리의 원형 (prototypical ) 으로 인간의 경우 CyP B, CyP C, 및 CyP D와 서열 상동
성이 매우 높음을 보여준다. 모든 사이클로필린의 결합 포켓은 고도로 보존된 영 역인 대략 109개의 아미노산에 의해 형성되며， CyP A 및 CyP D간의 서열 동일성 은 100%이다. 그러므로, CyP A결합친화도는 CyP D 결합친화도의 가장 좋은 예측 변수이며， 반대의 경우도 마찬가지이다. Cyclosporin, one of the cyclophylline inhibitors, binds to the hydrophobic pocket of CyP A to inhibit PPIase activity. CyP A is a prototype of the cyclophylline family and sequence homology with CyP B, CyP C, and CyP D in humans The last name is very high. The binding pocket of all cyclophilins is formed by approximately 109 amino acids, which are highly conserved regions, with 100% sequence identity between CyP A and CyP D. Therefore, CyP A binding affinity is the best predictor of CyP D binding affinity and vice versa.
이러한 사이클로필린 간의 서열 상동성은 CyP A와 결합친화도를 갖는 기 능 저해물질들에 대해 CyP D뿐만 아니라 모든 사이클로필린이 잠재적인 표적임을 의미한다. 즉 CyP A의 기능 저해물질이 사이클로필린이 관련된 다수의 질환 징후 의 치료에 유용할 수 있음을 시사한다. Sequence homology between these cyclophilins means that all cyclophilins as well as CyP D are potential targets for functional inhibitors having binding affinity with CyP A. This suggests that CyP A's inhibitor may be useful for the treatment of many disease manifestations involving cyclophylline.
최근 사이클로필린이 여러 질병에 관여한다는 연구 논문들이 보고되고 있 는데 그 질병을 크게 세가지로 나누어 보면， 바이러스 감염 (viral infection) 질환， 염증 반응경로 (inflammation process)에 관련된 질환, 및 미토콘드리아 기 능이상 (mitochondrial dysfunction)에 관련된 질환또는 손상이 있다. Recently, research papers have been reported that cyclophylline is involved in various diseases, which can be classified into three major categories: viral infection disease, diseases related to the inflammatory pathway, and mitochondrial dysfunction ( disease or injury related to the mitochondrial dysfunction.
바이러스 감염 (viral infection) 질환은 HAV 바이러스, HBV 바이러스, HCV 바이러스， HIV 바이러스， HDV 바이러스， HEV 바이러스， 코로나바이러스 (coronavirus), 인플루엔자 (influenza) 바이러스 등이 있고, 염증 반웅경로 (inflammation process)에 관련된 질환은 심혈관 질환 (cardiovascular diseases), 류마티스 관절염 (rheumatoid arthritis), 패혈증 (sepsis), 치주염 (periodontitis) , 급성 폐염 (Acute Lung Inflammation), 천식 (asthma), 노화 (aging), 탈모 (alopecia), 비알코올성 지방간염 (Non-Alcohol ic Steatohepatitis) 등이 있다. Viral infection diseases include HAV virus, HBV virus, HCV virus, HIV virus, HDV virus, HEV virus, coronavirus, influenza virus, etc., and are related to the inflammatory inflammation process. Diseases include cardiovascular diseases, rheumatoid arthritis, sepsis, periodontitis, acute Lung Inflammation, asthma, aging, alopecia, non Non-Alcohol ic Steatohepatitis.
미토콘드리아 기능이상 (mitochondrial dysfunct ion)으로 인한 질환은 퇴 행성 신경질환 (neurodegenerative diseases) , 종양 (cancer), 급성 손상 (Acute Injuries)등이 있으며， 실제로 사이클로필린의 기능을 저해하는 사이클로스포린 (cyclosporine) 또는 사이클로스포린 유도체들이 여러 질환에 대한 효과를 보인 다고 보고되고 있다 (Nigro P, et al, Cell Death Dis 2013, 4， e888). Diseases caused by mitochondrial dysfunct ions include neurodegenerative diseases, tumors, acute injuries, and cyclosporine or cyclosporine, which actually inhibits the function of cyclophilin. Derivatives have been reported to have effects on various diseases (Nigro P, et al, Cell Death Dis 2013, 4, e888).
사이클로필린이 바이러스 복제에 관여하는 방법은， HBV(Hepatitis B Virus) 표면항원 (HBV surface antigen, HBsAg)의 소표면단백질 (smal 1 surface proteins, SHBs)과 상호작용， HCV Hepatitis C Virus)의 RNA 폴리머라아제 NS5B 와 상호작용， HIVGiuman Immunodeficiency Virus) 캡시드 단백질과 결합， 인플루 엔자 바이러스 (influenza virus) 복제 초기단계어 1 Ml 단백질 (matrix protein 1) 과 상호작용 등에 의한 것으로 알려져 있다. Cyclophyllin is involved in viral replication by interacting with small surface proteins (SHBs) of Hepatitis B Virus (HBV surface antigen, HBsAg), RNA polymer of HCV Hepatitis C Virus. It is known to interact with Laase NS5B, to bind with HIVGiuman Immunodeficiency Virus capsid protein, and to interact with the influenza virus replication early stage 1 Ml protein.
사이클로필린이 염증 반웅경로 (inflammation process)에 관여하여 발생하 는 심혈관 질환 (cardiovascular diseases)으로는 죽상동맥경화증 (atherosclerosis) , 복부대동맥류 (abdominal aortic aneurysms) , 허혈성 심장질 환 (ischaemic heart diseases), 심장과비대 (cardiac hypertrophy) , 류마티스 관
절염 (rheumatoid arthritis) , 패혈증 (sepsis), 치주질환 (periodontal disease) , 콜라겐 VI 근병증 (collagen VI myopathies), 심정지후 증후군 (Post-cardiac arrest syndrome) , 심부전 (heart failure), 급성 폐렴 (Acute Lung Inflammation), 천식 (asthma), 노화 (aging), 탈모 (Alopecia)， 비알코올성 지방간 염 (Non-Alcohol ic Steatohepatitis) , 비만 (obesity), 신장섬유화 (renal fibrosis) , 신독성 (nephrotoxicity)， 폐쇄성 신병증 (obstructive nephropathy) , 시스플라틴 유래 신질환 (cisplatin-induced renal disease), 급성 신부전 (acute renal failure), 만성 신부전 (chronic renal failure), 신장 사구체병증 (renal glomerulopathy) , 말기 신질환 (end stage renal disease) , 관절형성이상 (bone disorder), 골다공증 (osteoporosis)， 관절염 (arthritis)， 골관절염 (osteoarthritis), 골파제트병 (Paget ' s disease) 등이 알려져 있다. Cardiovascular diseases caused by cyclophylline in the inflammatory inflammation process include atherosclerosis, abdominal aortic aneurysms, ischemic heart diseases, and heart. Cardiac hypertrophy, rheumatism Rheumatoid arthritis, sepsis, periodontal disease, collagen VI myopathies, post-cardiac arrest syndrome, heart failure, acute pneumonia (Acute Lung Inflammation) ), Asthma, aging, alopecia, non-alcoholic steatohepatitis, obesity, renal fibrosis, nephrotoxicity, obstructive nephropathy (obstructive nephropathy), cisplatin-induced renal disease, acute renal failure, chronic renal failure, renal glomerulopathy, end stage renal disease, joints Bone disorders, osteoporosis, arthritis, osteoarthritis, and Paget's disease are known.
사이클로필린이 염증 반웅경로 (infla隱 ation process)에 관여하여 발생하 는 류마티스 관절염 (rheumatoid arthritis, RA)의 경우 CD147 과 상호작용하여 MMP-9 과 MMP— 2 의 분비가 증가됨이 밝혀졌으며， 패혈증 (sepsis) 특히 녹농균 (Pseudomonas aeruginosa) 유래 패혈증의 경우 말초 림프구 (peripheral lymphocytes) 에서 사이클로필린이 발현조절되고, 탈모 (alopecia)의 경우 사이클 로필린 억제시 가는 머리털 환자의 모발성장주기 중 성장기를 증가시키는 효과를 확인하였다. In rheumatoid arthritis (RA), which is caused by the cyclophylline in the inflammation inflammatory process, it has been shown to increase the secretion of MMP-9 and MMP-2 by interacting with CD147. In particular, in the case of Pseudomonas aeruginosa-derived sepsis, cyclophilin is regulated in peripheral lymphocytes, and in the case of alopecia, cyclophilin suppresses the effect of increasing the growth phase in the hair growth cycle of thin hair patients. Confirmed.
사이클로필린이 관여된 미토콘드리아 기능이상 (mitochondrial dysfunct m)으로 발생하는 퇴행성 신경질환 (neurodegenerative diseases)으로는 알츠하이머 질환 (Alzheimer 's disease), 파킨슨 질환 (Parkinson's disease), 헌 팅튼 질환 (Huntington's disease), 다발성 경화증 (MS, Multiple Sclerosis), 근 위축성측색경화증 (ALS, amyotrophic lateral sclerosis), 근육위축증 (muscular dystrophy), 뇌전증 (Epi lepsy)， 자폐증 (Autism) 뇌허혈증 (cerebral ischemia) , 다계통 위축증 (multiple systems atrophy), 뇌성마비 (cerebral palsy), 당뇨병성 신경병증 (diabetic neuropathy) , 양극성 장애 (bipolar disorder), 흥분독성 손상 (excitotoxic injury) , 간성 뇌병증 (hepatic encephalopathy) , 저혈당증 (hypoglycemia) , 망간독성 (manganese toxicity), 신경병증 (neuropathies), 진행 성근육위축증 (progressive muscular atrophy), 말초신경병증 (peripheral neuropathy) , 삼차 신경병증 (Trigeminal Neuralgia), 설인신경통 (Glossopharyngeal neuralgia), 안면신경 마비 (Bell's palsy), 중증근무력증 (Myasthenia Gravis), 신경장애 (neurological disorder) 등이 알려져 있다. Neurodeegenerative diseases caused by mitochondrial dysfunct involvement with cyclophylline include Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple Multiple Sclerosis (MS), amyotrophic lateral sclerosis (ALS), muscular dystrophy, epilepsy, Autism cerebral ischemia, multiple systems atrophy atrophy, cerebral palsy, diabetic neuropathy, bipolar disorder, excitotoxic injury, hepatic encephalopathy, hypoglycemia, manganese toxicity, neuropathies, progressive muscular atrophy, peripheral neuropathy, trigeminal neuropathy Trigeminal Neuralgia, Glossopharyngeal neuralgia, Bell's palsy, Myasthenia Gravis, and neurological disorders are known.
사이클로필린은 종양 (cancer) 조직 성장에 관여하는 것으로 알려져 있는 데, 관련 종양으로는 소세포 및 비소세포 폐암 (Small Cell and Non-Small Cell Lung Cancer), 방광암 (Bladder Cancer), 간세포암 (Liver Cancer), 췌장암
(Pancreatic Cancer ) , 유방암 (Breast Cancer), 편평세포암 (squamQus cell carcinoma) , 폭색종 (melanoma)， 전립선암 (prostate cancer), 대장암 (colon cancer), 교모세포종 (glioblastoma)， 자궁내막암 (endometrial cancer), 갑상선암Cyclophilin is known to be involved in tumor tissue growth, and related tumors include small cell and non-small cell lung cancer, bladder cancer, and liver cancer. Pancreatic cancer Pancreatic Cancer, Breast Cancer, SquamQus cell carcinoma, Melanoma, Prostate cancer, Colon cancer, Glioblastoma, Endometrial cancer endometrial cancer
(thyroid cancer) , 림프종 ( lymphomas)， 난소암 (ovarian cancer) 등을 포함한다. 사이클로필린이 관여된 미토콘드리아 기능이상 (mitochondrial dysfunction)으로 기인하는 급성 손상 (Acute Injuries) 으로는 외상성 뇌손상(thyroid cancer), lymphomas, ovarian cancer, and the like. Acute injuries caused by mitochondrial dysfunction involving cyclophylline are traumatic brain injuries.
(Traumatic Brain Injury), 척추， 말초， 중앙 신경 세포의 외상성 손상Traumatic Brain Injury, Traumatic injury of the spine, peripheral and central nerve cells
(traumatic injury of spinal , peripheral or central nervous tissue), 허혈성 뇌손상 (Ischemic Brain Injury) , 신장， 뇌， 펴)， 장， 심장 (kidney, brain, lung, intestine, heart)의 허혈성 재관류손상 (Ischemia Reper fusion Injury) , 심장 재 관류손상 (Cardiac Reper fusion Injury) , 뇌졸중 (Stroke) , 심근경색증 (Myocardial(traumatic injury of spinal, peripheral or central nervous tissue), Ischemic Brain Injury, Ischemia Reperfusion injury of the kidney, brain, lung, intestine, heart fusion injury, cardiac reper fusion injury, stroke, myocardial infarction
Infarction), 심부전 (Heart Failure), 급성 간독성 (acute hepatotoxicity), 담즙 분비중지 (cholestasis), 이식장기 보관 /재관류 손상 (storage/reperfusion injury of trans lant organs) 등이 있다. Infarction, heart failure, acute hepatotoxicity, cholestasis, and storage / reperfusion injury of trans lant organs.
【발명와 상세한 설명】 [Invention and Detailed Description]
【기술적 과제】 [Technical problem]
따라서 본 발명의 목적은 다양한 질병의 원인이 되는 사이클로필린의 기 능을 억제하는 억제제를 제공하는 것이다. 또한 본 발명의 목적은 사이클로필린 의 기능을 억제하여 바이러스 감염 (viral infection) 질환， 염증 반웅경로 (infla議 ation process)에 관련된 질환， 미토콘드리아 기능이상 (mitochondrial dysfunction)에 관련된 질환 또는 손상을 예방 또는 치료하는 방법을 제공하는 것이다. 또한 본 발명의 목적은 사이클로필린의 기능을 억제하여 바이러스 감염 (viral infection) 질환， 심혈관 질환 (cardiovascular diseases) , 류마티스 관절 염 (rheumatoid arthritis), 패혈증 (sepsis), 치주염 (periodontitis)， 급성 폐염 (Acute Lung Inflammation) , 천식 (asthma), 노화 (aging), 탈모 (alopecia) , 퇴행 성 신경질환 (neurodegenerative diseases) , 종양 (cancer), 급성 손상 (Acute Injuries) 둥의 질환 또는 손상올 예방 또는 질환을 치료할 수 있는 약학 조성물 을 제공하고자 하는 것이다. It is therefore an object of the present invention to provide inhibitors that inhibit the function of cyclophylline to cause various diseases. It is also an object of the present invention to prevent or treat viral infection diseases, diseases related to the inflammatory inflamation process, diseases or damage related to mitochondrial dysfunction by inhibiting the function of cyclophilin To provide a way. It is also an object of the present invention to inhibit the function of cyclophylline, viral infection (cardial vascular disease), cardiovascular diseases (rheumatoid arthritis), sepsis (sepsis), periodontitis (periodontitis), acute pneumonia (Acute) Lung Inflammation, asthma, aging, alopecia, neurodegenerative diseases, tumors, acute injuries It is to provide a pharmaceutical composition that can be.
【기술적 해결방법】 Technical Solution
상기 과제를 해결하기 위하여 본 발명은 하기 화학식 1로 표시되는 스틸 벤 유도체， 또는 이의 약학적으로 허용 가능한 염을 포함하는 사이클로필린 기능 저해제를 제공한다. 본 발명은 또한 하기 화학식 1로 표시되는 스틸벤 유도체， 또는 이의 약학적으로 허용 가능한 염올 포함하는 사이클로필린 관련 질환 또는 손상의 예방 또는 치료용도의 조성물을 제공한다. The present invention to solve the above problems provides a cyclophylline function inhibitor comprising a stilbene derivative represented by the following formula (1), or a pharmaceutically acceptable salt thereof. The present invention also provides a composition for the prophylaxis or treatment of cyclophilin-related diseases or damages, including a stilbene derivative represented by Formula 1 below, or a pharmaceutically acceptable salt thereof.
[화학식 1]
상기 식에서， [Formula 1] In the above formula,
A는 CRa또는 N이고， A is CRa or N,
B는 CRb또는 N이고， B is CRb or N,
G은 CRe 또는 N이고 G is CRe or N
J은 CRf 또는 N이고， J is CRf or N,
M은 CRg또는 N이고， M is CRg or N,
D , E , 및 L은 CRh또는 N이고 D, E, and L are CRh or N
x는 H , CH3 ) CN , NH2 ) F , CI , Br또는 I이며， x is H, CH 3) CN, NH 2) F, CI, Br or I,
Ra는 수소， 할로겐， N02 , CN , OH , C1-C5 알킬기 C2-C10의 알케닐기， C1-C6 알콕시기， -COOR Rl은 수소 또는 C1-C5의 알킬기 C6-C12의 아릴 또는 C3-C10의 시클로알킬) 또는 -0C0R2(R2는 C1-C5의 알킬기, C6-C12의 아릴 또는 C3-C10의 시클로알킬) 이고， Ra is hydrogen, halogen, NO 2 , CN, OH, C 1 -C 5 alkyl group C 2 -C 10 alkenyl group, C 1 -C 6 alkoxy group, -COOR R 1 is hydrogen or C 1 -C 5 alkyl group C 6 -C 12 aryl or C 3 -C 10 Cycloalkyl) or -0C0R2 (R2 is a C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl),
Rb는 수소 할로겐, N02 , CN , OH , C1-C20의 알킬기， C2-C10의 알케닐기， C3-C10의 시클로알킬, C1-C10의 알콕시기， C6-C12의 아릴, C5-C12의 헤테로 고리 기， -COORKRl은 수소 또는 CI— C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클 로알킬) 또는 _0C0R2(R2는 C1-C5의 알킬기, C6-C12의 아릴 또는 C3-C10의 시클로 알킬) 또는 -C0R10(R10은 C1-C20의 알킬기, C6-C12의 아릴， C3-C10의 시클로알킬 기 또는 C5-C12의 헤테로 고리기)이고 Rb is hydrogen halogen, N02, CN, OH, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 hetero ring -COORKRl is hydrogen or an alkyl group of CI— C5, aryl of C6-C12 or cycloalkyl of C3-C10) or _0C0R2 (R2 is an alkyl group of C1-C5, aryl of C6-C12 or cycloalkyl of C3-C10 ) Or -C0R10 (R10 is an alkyl group of C1-C20, an aryl of C6-C12, a cycloalkyl group of C3-C10 or a heterocyclic group of C5-C12)
Rc는 수소， 0H , 할로겐， CN , N02 , C1-C20의 알킬기， C2-C10의 알케닐기， C3-C10의 시클로알킬기， C1-C10의 알콕시기, C6-C12의 아릴, C5-C12의 해테로 고 리기, — NR3R4(R3는 수소, C1-C20의 알킬기 또는 C6— C12 아릴， R4는 수소， C1-C20 의 알킬기 또는 C6-C12의 아릴이고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추가로 1종 이상의 헤테로 원자를 포함할 수 있다 J , -C00R5(R5은 수 소， C1-C20의 알킬기, C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -NR7CYR8(Y는 0 또는 S , R7은 수소 또는 C1-C5 알킬기， R8은 C1-C20의 알킬기， C6-C12 아릴, C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기)， -NHS(0)2R9(R9은 C1-C5의
알킬기, C6-C12의 아릴 또는 C5-C12의 헤테로 고리기)， 또는 -COR10(R10은 C1-C20의 알킬기， C6-C12의 아릴 C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고， Rc is hydrogen, 0H, halogen, CN, N02, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 solution Ring, — NR3R4 (R3 is hydrogen, an alkyl group of C1-C20 or C6— C12 aryl, R4 is hydrogen, an alkyl group of C1-C20 or an aryl of C6-C12, and R3 and R4 combine to form a heterocycle And may further comprise one or more heteroatoms J, -C00R5 (R5 is hydrogen, C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl , A cycloalkyl group of C3-C10 or a heterocyclic group of C5-C12), -NHS (0) 2 R9 (R9 is of C1-C5 Alkyl group, C6-C12 aryl or C5-C12 heterocyclic group), or -COR10 (R10 is C1-C20 alkyl group, C6-C12 aryl C3-C10 cycloalkyl group or C5-C12 heterocyclic group) ，
Rd는 0H , 할로겐， N02 , CN , C1-C20의 알킬기 , C2-C10의 알케닐기， C3-C10 의 시클로알킬기, C1-C10의 알콕시기， C6-C12의 아릴， C5-C12의 헤테로 고리기， -NR3R4(R3는 수소， C1-C20 알킬 또는 C6-C12 아릴, R4는 수소, C1-C20 알킬 또는 C6-C12 아릴이고, R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추가로 1종 이상의 헤테로 원자를 포함할 수 있다. ) -C00R5(R5은 수소， C1-C20의 알킬 기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -NR7CYR8(Y는 0 또는 S , R7은 수 소 또는 C1-C5 알킬기， R8은 C1-C20의 알킬기， C6-C12 아릴， C3-C10의 시클로알 킬기 또는 C5-C12의 헤테로 고리기)， -NHS(0)2R9(R9은 C6-C12의 아릴 또는 C5-C12의 헤테로 고리기) 또는 COR10(R10은 C1-C20의 알킬기, C6-C12의 아릴， C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고， Rd is 0H, halogen, N02, CN, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 heterocyclic group , -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R3 and R4 may combine to form a hetero ring, additionally 1 It may include more than one hetero atom.) -C00R5 (R5 is hydrogen, C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 Cycloalkyl group or C5-C12 heterocyclic group), -NHS (0) 2 R9 (R9 is C6-C12 aryl or C5-C12 heterocyclic group) or COR10 (R10 is C1-C20 alkyl, C6- C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group),
Re는 수소， NH2 , OH , 할로겐， CN , NCS , C1-C20의 알킬기, C2-C10의 알케닐 기， C1-C10의 알콕시, C6-C12의 아릴옥시, C6-C12의 아릴， C5-C12의 헤테로 고리 기， -NR3R4(R3는 수소， C1—C20 알킬 또는 C6-C12 아릴， R4는 수소， C1-C20 알킬 또는 C6-C12 아릴이고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추 가로 1종 이상의 해테로 원자를 포함할 수 있다. ) , -C00R5(R5은 C1-C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -0C0R6(R6는 C1-C20의 알킬기, C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -NR7CYR8(Y는 0 또는 S , R7은 수 소 또는 C1-C5 알킬기， R8은 C1-C20의 알킬기， C6-C12 아릴， C3-C10의 시클로알 킬기 또는 C5-C12의 헤테로 고리기)， -NHS(0)2R9(R9은 C6-C12의 아릴 또는 C5-C12의 헤테로 고리기) 또는 -SR1KR11는 C1-C5의 알킬기) 이고, Re is hydrogen, NH 2 , OH, halogen, CN, NCS, C1-C20 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy, C6-C12 aryloxy, C6-C12 aryl, C5- C12 heterocyclic group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 can combine to form a hetero ring And may further include one or more heteroatoms.), -C00R5 (R5 is C1-C5 alkyl, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1- C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group), -NHS (0) 2 R9 (R9 is C6-C12 aryl or C5-C12 heterocyclic group) or -SR1KR11 is C1-C5 alkyl group ) ego,
Rf는 수소， ¾ , OH , 할로겐， N02 , N2+, C1-C4의 알킬기， C2-C10의 알케닐 기, C1-C4의 알콕시기， C6-C12의 아릴， C5-C12의 헤테로 고리기， -NR3R4(R3는 수 소， C1-C20 알킬 또는 C6-C12 아릴， R4는 수소， C1—C20 알킬 또는 C6-C12 아릴이 고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며, 추가로 1종 이상의 헤 테로 원자를 포함할 수 있다. )， -C00R5(R5은 C1-C5의 알킬기， C6-C12의 아릴 또 는 C3-C10의 시클로알킬기) , -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -NR7CYR8(Y는 0 또는 S , R7은 수소 또는 C1-C5 알킬 기, R8은 C1-C20의 알킬기， C6-C12 아릴， C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 또는 C0R KR10은 C1-C20의 알킬기， C6-C12의 아릴， C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고, Rf is hydrogen, ¾, OH, halogen, N02, N 2 +, C1-C4 alkyl group, alkenyl of C2-C10 alkenyl group, C1-C4 alkoxy group, a heterocyclic group of C6-C12 aryl, C5-C12 of , -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 can be joined to form a hetero ring, further It may contain one or more hetero atoms.), -C00R5 (R5 is C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 Alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3- C10 cycloalkyl group or C5-C12 heterocyclic group) or C0R KR10 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group),
Rg는 수소, NH2 , OH , 할로겐， N02 , C00H , CN , C1-C20의 알킬기, C2-C10의
알케닐기， C3-C10의 시클로알킬기， C1-C10의 알콕시기， C5-C12의 헤테로 고리기, -NR3R4(R3는 수소， C1-C20 알킬 또는 C6— C12 아릴 , R4는 수소， C1-C20 알킬 또는 C6-C12 아릴이고, R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추가로 1종 이상의 헤테로 원자를 포함할 수 있다. )， -C00R5(R5은 C1-C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -NR7CYR8(Y는 0 또는 S, R7은 수 소 또는 C1-C5 알킬기， R8은 C1-C20의 알킬기， C6-C12 아릴, C3— C10의 시클로알 킬기 또는 C5-C12의 헤테로 고리기)， -NHS(0)2R9(R9은 C6-C12의 아릴 또는 C5-C12의 헤테로 고리기) 또는 C0R10 (R10은 C1—C20의 알킬기， C6-C12의 아릴, C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고， Rg is hydrogen, NH 2 , OH, halogen, N02, C00H, CN, alkyl group of C1-C20, C2-C10 Alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6— C12 aryl, R4 is hydrogen, C1-C20 alkyl Or C6-C12 aryl, R3 and R4 may combine to form a hetero ring, and may further include one or more hetero atoms.), -C00R5 (R5 is an alkyl group of C1-C5, C6-C12 Aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group, -NHS (0) 2 R9 (R9 is C6-C12 aryl Or C 5 -C 12 heterocyclic group) or C 0 R 10 (R 10 is a C 1 -C 20 alkyl group, C 6 -C 12 aryl, C 3 -C 10 cycloalkyl group or C 5 -C 12 heterocyclic group),
Rh는 수소, H2 , OH , C1-C5의 알킬기 또는 C2-C10의 알케닐기이고, 상기 헤테로 고리기의 헤테로 원자는 질소， 산소 및 황으로 이루어진 군 으로부터 선택된 1종 이상 이고, Rh is hydrogen, H 2 , OH, C 1 -C 5 alkyl group or C 2 -C 10 alkenyl group, the hetero atom of the hetero ring group is at least one member selected from the group consisting of nitrogen, oxygen and sulfur,
상기 알킬기는 0H, 할로겐， 아민， C1-C5의 알콕시， C6-C12의 아릴， C5-C12의 헤테로 고리기 및 C3-C10의 시클로알킬기로 구성된 군으로부터 선택되 는 1종 이상의 치환기로 치환될 수 있고, The alkyl group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5-C12 heterocyclic group and C3-C10 cycloalkyl group. There is,
상기 알케닐기는 0H , 할로겐， 아민， C1-C5의 알콕시, C6-C12의 아릴ᅳ C5-C12의 헤테로 고리기 및 C3-C10의 시클로알킬기로 구성된 군으로부터 선택되 는 1종 이상의 치환기로 치환될 수 있고, The alkenyl group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, amine, C1-C5 alkoxy, C6-C12 aryl ᅳ C5-C12 heterocyclic group and C3-C10 cycloalkyl group. Can,
상기 알콕시기는 0H, 할로겐， C1-C5의 알콕시기, C6-C12의 아릴， C3-C10 의 시클로알킬기, 카르복시기， 아민 및 아미노카르보닐기로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있고， The alkoxy group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, C1-C5 alkoxy group, C6-C12 aryl, C3-C10 cycloalkyl group, carboxyl group, amine and aminocarbonyl group,
상기 헤테로고리기는 알킬기, 아민 치환된 알킬기, 아민， 아마이드기 및 카르복실기로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있 고, The heterocyclic group may be substituted with one or more substituents selected from the group consisting of alkyl group, amine substituted alkyl group, amine, amide group and carboxyl group,
상기 아릴은 할로겐， 알킬기， 히드록시기, 알콕시기， 카르복실기， 에스터 기， 니트로기 및 아민기로 이루어진 군으로부터 선택되는 1총 이상의 치환기로 치환될 수 있고， The aryl may be substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, alkoxy, carboxyl, ester, nitro and amine groups,
A, B, D, E, G, J , L , M. Rc 및 Rd는 서로 이웃한 기와 결합하여 축합환 을 형성할 수 있다. A, B, D, E, G, J, L, M. Rc and Rd may combine with neighboring groups to form a condensed ring.
【발명의 효과】 【Effects of the Invention】
본 발명에 따른 스틸벤 유도체를 포함하는 사이클로필린 기능 저해제는 사이클로필린의 기능을 저해하는 효과가 있다. 그 결과， 본 발명에 따른 스틸벤 유도체를 포함하는 조성물은 바이러스 감염 (vi ral infect ion) 질환， 심혈관 질환 (cardiovascul ar di seases) , 류마티스 관절염 (rheumatoid arthr i t i s) , 패혈증
(sepsis) , 치주염 (per iodont it is)， 급성 폐염 (Acute Lung Inf lammat ion) , 천식 (asthma) , 노화 (aging) , 탈모 (alopecia) , 퇴행성 신경질환 (neurodegenerat ive diseases) , 종양 (cancer) , 급성 손상 (Acute Injuries) 등의 사이클로필린 관련 질환또는 손상의 예방 또는 질환의 징후 치료에 유용하다. Cyclophylline inhibitors, including stilbene derivatives according to the present invention has the effect of inhibiting the function of cyclophylline. As a result, the composition comprising a stilbene derivative according to the present invention is a viral infection (viral infect ion) disease, cardiovascul ar di seases, rheumatoid arthr itis, sepsis (sepsis), periodontitis (per iodont it is), acute pneumonia (Acute Lung Inf lammat ion), asthma, aging, alopecia, neurodegenerat ive diseases, tumor It is useful for the prevention of cyclophylline-related diseases or damages such as Acute Injuries, or for the treatment of signs of disease.
본 발명에 따른 스틸벤 유도체들은 기존의 치료제들과 복합 처방하여 사 용함으로써 치료효과를 높일 수 있다. Stilbene derivatives according to the present invention can increase the therapeutic effect by using in combination with existing therapeutic agents.
【도면의 간단한 설명】 [Brief Description of Drawings]
도 1 내지 도 3은 본 발명의 스틸벤 유도체 (화합물 225)를 기존의 HCV 치 료제들과 병용하였을 때 효과를 보여주는 도이다. 1 to 3 is a diagram showing the effect of using a stilbene derivative (Compound 225) of the present invention in combination with conventional HCV treatment.
【발명의 실시를 위한 최선의 형태】 [Best form for implementation of the invention]
이하 본 발명을 상세하게 설명한다. Hereinafter, the present invention will be described in detail.
본 발명은 또한 하기 화학식 1로 표시되는 스틸벤 유도체 또는 이의 약제 학적으로 허용 가능한 염을 포함하는사이클로필린 기능 저해제를 제공한다. 본 발명의 스틸벤 유도체는 사이클로필린의 기능을 가지는 모든 단백질에 서 유지되는 활성위치 (act ive pocket )에 결합하기 적당한 구조를 가지고 있어서 사이클로필린 저해제로 유리하다. The present invention also provides a cyclophylline function inhibitor comprising a stilbene derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof. The stilbene derivative of the present invention is advantageous as a cyclophylline inhibitor because it has a structure suitable for binding to an active pocket maintained in all proteins having a function of cyclophylline.
본 발명은 하기 화학식 1로 표시되는 스틸벤 유도체 또는 이의 약제학적 으로 허용 가능한 염올 포함하는 사이클로필린 관련 질환의 예방 또는 치료용도 의 조성물을 제공한다. The present invention provides a composition for the prevention or treatment of cyclophylline-related diseases comprising a stilbene derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1] [Formula 1]
A는 CRa 또는 N이고， A is CRa or N,
B는 CRb또는 N이고， B is CRb or N,
G은 CRe 또는 N이고 G is CRe or N
J은 CRf 또는 N이고, J is CRf or N,
M은 CRg또는 N이고, M is CRg or N,
D, E, 및 L은 CRh또는 N이고 D, E, and L are CRh or N
Rx는 H, CH3, CN, NH2, F, CI , Br또는 I이며，
Ra는 수소， 할로겐， Νθ2 , CN , OH , C1-C5 알킬기, C2-C10의 알케닐기， C1-C6 알콕시기, -COOR Rl은 수소 또는 C1-C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬) 또는 -0C0R2(R2는 C1-C5의 알킬기, C6-C12의 아릴 또는 C3-C10의 시클로알킬) 이고， Rx is H, CH 3 , CN, NH 2 , F, CI, Br or I, Ra is hydrogen, halogen, Νθ2, CN, OH, C1-C5 alkyl group, C2-C10 alkenyl group, C1-C6 alkoxy group, -COOR Rl is hydrogen or C1-C5 alkyl group, C6-C12 aryl or C3- C10 cycloalkyl) or -0C0R2 (R2 is a C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl),
Rb는 수소， 할로겐, N02 , CN , OH , C1-C20의 알킬기， C2-C10의 알케닐기， C3-C10의 시클로알킬， C1-C10의 알콕시기， C6-C12의 아릴， C5-C12의 헤테로 고리 기， C00RKR1은 수소 또는 C1-C5의 알킬기, C6-C12의 아릴 또는 C3-C10의 시클 로알킬) 또는 -0C0R2(R2는 C1-C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로 알킬) 또는 -C0R KR10은 C1-C20의 알킬기， C6-C12의 아릴， C3-C10의 시클로알킬 기 또는 C5— C12의 헤테로 고리기)이고 Rb is hydrogen, halogen, N0 2 , CN, OH, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 Heterocyclic group, C00RKR1 is hydrogen or alkyl group of C1-C5, aryl of C6-C12 or cycloalkyl of C3-C10) or -0C0R2 (R2 is alkyl group of C1-C5, aryl of C6-C12 or C3-C10 Cycloalkyl) or -C0R KR10 is an alkyl group of C1-C20, an aryl of C6-C12, a cycloalkyl group of C3-C10 or a heterocyclic group of C5-C12)
Rc는 수소, 0H , 할로겐, CN, N02 , C1-C20의 알킬기， C2-C10의 알케닐기， C3-C10의 시클로알킬기， C1-C10의 알콕시기, C6-C12의 아릴， C5-C12의 헤테로 고 리기， -NR3R4(R3는 수소， C1-C20의 알킬기 또는 C6-C12 아릴, R4는 수소, C1-C20 의 알킬기 또는 C6-C12의 아릴이고, R3와 R4는 결합하여 해테로 고리를 형성할 수 있으며， 추가로 1종 이상의 헤테로 원자를 포함할 수 있다.；)， -C00R5(R5은 수 소， C1-C20의 알킬기， C6-C12의 아릴 또는 C3— C10의 시클로알킬기)， -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -NR7CYR8(Y는 0 또는 S , R7은 수소 또는 C1-C5 알킬기， R8은 C1-C20의 알킬기， C6— C12 아릴， C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) , -NHS(0)2R9(R9은 C1-C5의 알킬기， C6-C12의 아릴 또는 C5-C12의 헤테로 고리기)， 또는 -C0R10(R10은 C1-C20의 알킬기， C6-C12의 아릴， C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고, Rc is hydrogen, 0H, halogen, CN, N0 2 , C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 Heterocyclic group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl group or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl group or C6-C12 aryl, R3 and R4 combine to form a hetero ring. And may further comprise one or more heteroatoms.), -C00R5 (R5 is hydrogen, an alkyl group of C1-C20, an aryl of C6-C12 or a cycloalkyl group of C3-C10), -0C0R6 (R6 is C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6 — C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group), -NHS (0) 2 R9 (R9 is C1-C5 alkyl group, C6-C12 aryl or C5-C12 heterocyclic group) Or -C0R10 (R10 is an alkyl group of C1-C20. , C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group),
Rd는 0H , 할로겐， N02 , CN , C1-C20의 알킬기， C2-C10의 알케닐기， C3-C10 의 시클로알킬기， C1-C10의 알콕시기， C6-C12의 아릴， C5— C12의 헤테로 고리기， -NR3R4(R3는 수소， C1-C20 알킬 또는 C6-C12 아릴， R4는 수소， C1-C20 알킬 또는 C6-C12 아릴이고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며, 추가로 1종 이상의 헤테로 원자를 포함할 수 있다. )， -C00R5(R5은 수소 C1-C20의 알킬 기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -NR7CYR8(Y는 0 또는 S , R7은 수 소 또는 C1-C5 알킬기, R8은 C1-C20의 알킬기, C6-C12 아릴， C3-C10의 시클로알 킬기 또는 C5— C12의 헤테로 고리기)， -NHS(0)2R9(R9은 C6-C12의 아릴 또는 C5-C12의 헤테로 고리기) 또는 -C0RKKR10은 C1-C20의 알킬기， C6-C12의 아릴， C3-C10의 시클로알킬기 또는 C5-C12의 해테로 고리기) 이고, Rd is 0H, halogen, N02, CN, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 heterocyclic group , -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R3 and R4 may combine to form a hetero ring, additionally 1 It may include more than one hetero atom.), -C00R5 (R5 is hydrogen C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 Cycloalkyl group or C5—heterocyclic group of C12), —NHS (0) 2 R9 (R9 is C6-C12 aryl or C5-C12 heterocyclic group) or —C0RKKR10 is C1-C20 alkyl group, C6-C12 Of aryl ， C3-C10 cycloalkyl Group or a heterocyclic group of C5-C12),
Re는 수소， N¾ , OH , 할로겐, CN , NCS , C1-C20의 알킬기， C2-C10의 알케닐 기， C1-C10의 알콕시, C6-C12의 아릴옥시， C6-C12의 아릴, C5-C12의 헤테로 고리
기， -NR3R4(R3는 수소， C1-C20 알킬 또는 C6-C12 아릴， R4는 수소， C1-C20 알킬 또는 C6-C12 아릴이고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추 가로 1종 이상의 헤테로 원자를 포함할 수 있다.；)， -C00R5(R5은 C1-C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， 0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -NR7CYR8(Y는 0 또는 S , R7은 수 소 또는 C1-C5 알킬기 , R8은 C1-C20의 알킬기， C6-C12 아릴， C3-C10의 시클로알 킬기 또는 C5-C12의 헤테로 고리기) , -NHS(0)2R9(R9은 C6-C12의 아릴 또는 C5-C12의 헤테로 고리기) 또는 -SR1KR11는 C1-C5의 알킬기) 이고, Re is hydrogen, N¾, OH, halogen, CN, NCS, C1-C20 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy, C6-C12 aryloxy, C6-C12 aryl, C5-C12 Heterocycle Group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R3 and R4 can combine to form a hetero ring, further It may contain one or more hetero atoms;), -C00R5 (R5 is C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), 0C0R6 (R6 is C1-C20 alkyl group, C6 -C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cyclo An alkyl group or a heterocyclic group of C5-C12), -NHS (0) 2 R9 (R9 is a aryl of C6-C12 or a heterocyclic group of C5-C12), or -SR1KR11 is an alkyl group of C1-C5),
Rf는 수소， NH2 , OH , 할로겐, N02 , N2+, C1-C4의 알킬기， C2-C10의 알케닐 기， C1-C4의 알콕시기， C6-C12의 아릴， C5-C12의 헤테로 고리기， _NR3R4(R3는 수 소, C1-C20 알킬 또는 C6-C12 아릴， R4는 수소, C1-C20 알킬 또는 C6-C12 아릴이 고, R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추가로 1종 이상의 헤 테로 원자를 포함할 수 있다ᅳ)， -C00R5(R5은 CI— C5의 알킬기， C6-C12의 아릴 또 는 C3-C10의 시클로알킬기)， -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , NR7CYR8(Y는 0 또는 S , R7은 수소 또는 C1-C5 알킬 기， R8은 C1-C20의 알킬기， C6-C12 아릴, C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 또는 C0RKKR10은 C1-C20의 알킬기， C6-C12의 아릴, C3— C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고， Rf is hydrogen, NH 2, OH, halogen, N0 2, N 2 +, C1-C4 alkyl group, alkenyl of C2-C10 alkenyl group, C1-C4 alkoxy group, a C6-C12 aryl, heteroaryl, a C5-C12 Cyclic group, _NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 may combine to form a hetero ring, May contain one or more heteroatoms ᅳ), -C00R5 (R5 is CI- C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 Alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3- C10 cycloalkyl group or C5-C12 heterocyclic group) or C0RKKR10 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group),
Rg는 수소, N¾ , OH , 할로겐， N02 , C00H , CN , C1-C20의 알킬기， C2-C10의 알케닐기， C3-C10의 시클로알킬기， C1-C10의 알콕시기， C5-C12의 헤테로 고리기, - R3R4(R3는 수소， C1-C20 알킬 또는 C6-C12 아릴， R4는 수소， C1-C20 알킬 또는 C6-C12 아릴이고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추가로 1종 이상의 헤테로 원자를 포함할 수 있다. )， -C00R5(R5은 C1-C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -0C0R6(R6는 CI— C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -NR7CYR8(Y는 0 또는 S , R7은 수 소 또는 C1-C5 알킬기， R8은 C1-C20의 알킬기， C6-C12 아릴， C3-C10의 시클로알 킬기 또는 C5-C12의 헤테로 고리기)， -NHS(0)2R9(R9은 C6-C12의 아릴 또는 C5-C12의 헤테로 고리기) 또는 C0R10 (R10은 C1-C20의 알킬기, C6-C12의 아릴, C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고， R g is hydrogen, N¾, OH, halogen, N02, C00H, CN, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C5-C12 hetero ring R3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 may combine to form a hetero ring, further It may include one or more hetero atoms.), -C00R5 (R5 is C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is CI- C20 alkyl group, C6 -C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cyclo Alkyl or C5-C12 heterocyclic group), -NHS (0) 2 R9 (R9 is C6-C12 aryl or C5-C12 heterocyclic group) or C0R10 (R10 is C1-C20 alkyl, C6-C12 Aryl, C3-C10 cycloalkyl group A heterocyclic group) of C5-C12,
Rh는 수소， N¾ , OH , C1-C5의 알킬기 또는 C2-C10의 알케닐기이고, 상기 헤테로 고리기의 헤테로 원자는 질소， 산소 및 황으로 이루어진 군 으로부터 선택된 1종 이상 이고， Rh is hydrogen, N¾, OH, an alkyl group of C1-C5 or an alkenyl group of C2-C10, and the hetero atom of the heterocyclic group is at least one selected from the group consisting of nitrogen, oxygen and sulfur,
상기 알킬기는 0H , 할로겐， 아민， C1-C5의 알콕시， C6-C12의 아릴， C5-C12의 헤테로 고리기 및 C3-C10의 시클로알킬기로 구성된 군으로부터 선택되 는 1종 이상의 치환기로 치환될 수 있고，
상기 알케닐기는 OH, 할로겐, 아민, C1-C5의 알콕시, C6-C12의 아릴， C5-C12의 헤테로 고리기 및 C3-C10의 시클로알킬기로 구성된 군으로부터 선택되 는 1종 이상의 치환기로 치환될 수 있고， The alkyl group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5-C12 heterocyclic group and C3-C10 cycloalkyl group. And The alkenyl group may be substituted with one or more substituents selected from the group consisting of OH, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5-C12 heterocyclic group and C3-C10 cycloalkyl group. Can
상기 알콕시기는 0H, 할로겐， C1-C5의 알콕시기, C6-C12의 아릴， C3-C10 의 시클로알킬기， 카르복시기 아민 및 아미노카르보닐기로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있고， The alkoxy group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, C1-C5 alkoxy group, C6-C12 aryl, C3-C10 cycloalkyl group, carboxyl amine and aminocarbonyl group,
상기 헤테로고리기는 알킬기， 아민 치환된 알킬기, 아민， 아마이드기 및 카르복실기로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있 고， The heterocyclic group may be substituted with one or more substituents selected from the group consisting of an alkyl group, an amine substituted alkyl group, an amine, an amide group and a carboxyl group,
상기 아릴은 할로겐， 알킬기， 히드록시기， 알콕시기, 카르복실기, 에스터 기, 니트로기 및 아민기로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있고, The aryl may be substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, alkoxy, carboxyl, ester, nitro and amine groups,
A, B, D, E, G, J, L, M. Rc 및 Rd는 서로 이웃한 기와 결합하여 축합환 을 형성할 수 있다. A, B, D, E, G, J, L, M. Rc and Rd may combine with adjacent groups to form a condensed ring.
본 발명의 상기 화학식 1로 표시되는 스틸벤 유도체는 약제학적으로 허용 되는 담체와 함께 사이클로필린 기능 저해제로 사용될 수 있고 또한 사이클로필 린 관련 질환 또는 손상의 예방 또는 질환 징후의 치료제로 사용될 수 있다. 상기 사이클로필린 관련 질환은 바이러스 감염 (viral infection) 질환， 염증 반웅경로 (inflammation process)에 관련된 질환， 미토콘드리아 기능이상 (mitochondrial dysfunct ion)에 관련된 질환일 수 있다. The stilbene derivative represented by Formula 1 of the present invention may be used as an inhibitor of cyclophylline function in combination with a pharmaceutically acceptable carrier, and may also be used as a prophylactic agent for the prevention of cyclophylline-related diseases or injuries or treatment of disease signs. The cyclophilin-related disease may be a viral infection disease, a disease related to an inflammatory inflammation process, or a disease related to mitochondrial dysfunct ion.
또한 상기 사이클로필린 관련 질환은 HBV, HCV, HIV, 인플루엔자 (influenza) 바이러스 등의 바이러스 감염 (viral infection) 질환， 심혈관 질환 (cardiovascular diseases) , 류마티스 관절염 (rheumatoid arthritis), 패혈증 (sepsis) , 천식 (asthma), 치주염 (periodontitis), 노화 (aging), 탈모 (alopecia)， 퇴행성 신경질환 (neurodegenerative diseases), 또는 종양 (cancer)일 수 있으나 이에 한정되지는 않는다. The cyclophylline-related diseases may also include viral infections such as HBV, HCV, HIV, and influenza virus, cardiovascular diseases, rheumatoid arthritis, sepsis, and asthma. ), Periodontitis (periodontitis), aging (aging), hair loss (alopecia), neurodegenerative diseases (cancer), or tumor (cancer), but is not limited thereto.
상기 심혈관 질환은 염증 반웅경로 (inf ia瞧 at ion process)에 기인된 질환 으로， 구체적으로 죽상동맥경화증 (atherosclerosis), 복부대동맥류. (abdominal aortic aneurysms) , 허혈성 심장질환 (ischaemic heart diseases) , 심장과비대 (cardi c hypertrophy) 등이 있다. The cardiovascular disease is a disease caused by an inf ia 瞧 at ion process, specifically, atherosclerosis and abdominal aortic aneurysm. (abdominal aortic aneurysms), ischemic heart diseases, and cardi c hypertrophy.
상기 사이클로필린 관련 질환은 HAV 바이러스， HBV 바이러스， HCV 바이러 스， HDV 바이러스， HEV 바이러스， 코로나바이러스 (coronavirus), HIV 바이러스, 인플루엔자 (influenza) 바이러스 감염 (viral infection) 질환， 죽상동맥경화증 (atherosclerosis) , 복부대동맥류 (abdominal aortic aneurysms) , 허혈성 심장질 환 (ischaemic heart diseases) , 심장과비대 (cardiac hypertrophy) , 류마티스 관
절염 (rheumatoid arthritis) , 패혈증 (sepsis), 치주질환 (per iodontal disease)», 콜라겐 VI 근병증 (collagen VI myopathies), 심정지후 증후군 (Post-cardiac arrest syndrome) , 심부전 (heart failure), 급성 폐염 (Acute Lung Inflammation), 천식 (asthma), 노화 (aging), 탈모 (Alopecia)， 비알코을성 지방간염 (Non-Alcoholic Steatohepatitis) , 비만 (obesity), 신장섬유화 (renal fibrosis), 신독성 (nephrotoxicity)， 폐쇄성 신병증 (obstruct ive nephropathy) , 시스플라틴 유래 신질환 (ci splat in-induced renal disease), 급성 신부전 (acute renal failure), 만성 신부전 (chronic renal failure), 신장 사구체병증 (renal glomerulopathy) , 말기 신질환 (end stage renal disease) , 관절형성이상 (bone disorder), 골다공증 (osteoporosis)， 관절염 (arthritis)， 골관절염 (osteoarthritis), 골파제트병 (Paget ' s disease), 알츠하이머 질환 (Alzheimer ' s disease) , 파킨슨 질환 (Parkinson' s disease) , 뇌허혈증 (cerebral ischemia) , 다 계통 위축증 (multiple systems atrophy), 뇌성마비 (cerebral palsy), 당뇨병성 신경병증 (diabetic neuropathy) , 헌팅튼 질환 (Huntington's disease), 다발성 경 화증 (MS, Multiple Sclerosis), 근위축성측색경화증 (ALS, amyotrophic lateral sclerosis) , 근육위축증 (muscular dystrophy), 뇌전증 (Epi lepsy) , 자폐증 (Autism) , 양극성 장애 (bipolar disorder) , 흥분독성 손상 (excitotoxic injury) , 간성 뇌병증 (hepatic encephalopathy), 저혈당증 (hypoglycemia) , 망간독성 (manganese toxicity) , 신경병증 (neuropathies) , 진행성근육취축증 (progressive muscular atrophy) , 말초신경병증 (peripheral neuropathy) , 삼차 신경병증 (Trigeminal Neuralgia) , 설인신경통 (Glossopharyngeal neuralgia) , 안면신경 마 비 (Bell's palsy), 중증근무력증 (Myasthenia Gravis), 신경장애 (neurological disorder),소세포 및 비소세포 폐암 (Small and Non-Small Cell Lung Cancer), 방 광암 (Bladder Cancer), 간세포암 (Hepatocel hilar Cancer), 췌장암 (Pancreatic Cancer), 유방암 (Breast Cancer ) , 편평세포암 (squamous cell carcinoma) , 혹색종 (melanoma) , 전립선암 (prostate cancer) , 대장암 (colon cancer) , 교모세포종 (glioblastoma), 자궁내막암 (endometrial cancer) , 갑상선암 (thyroid cancer) , 림프종 (1卿 homas)， 난소암 (ovarian cancer), 외상성 뇌손상 (Traumatic Brain Injury), 척추， 말초, 중앙 신경 세포의 외상성 손상 (traumatic injury of spinal , peripheral or central nervous tissue) , 허혈성 뇌손상 (Ischemic Brain Injury) , 신장， 뇌， 폐, 장， 심장 (kidney, brain, lung, intestine, heart)의 허 혈성 재관류손상 (Ischemia Reper fusion Injury), 뇌졸중 (Stroke), 심근경색증 (Myocardial Infarction) , 심부전 (Heart Failure), 급성 간독성 (acute hepatotoxicity), 담즙분비중지 (cholestasis)， 이식장기 보관 /재관류 손상 (storage/ r eper f us i on injury of trans lant organs)일 수 있다.
또한 상기 화학식 1로 표시되는 스틸벤 유도체는 사이클로필린 관련 질병 의 치료제 효능비교용 기준물질로 사용될 수 있다. The cyclophylline related diseases include HAV virus, HBV virus, HCV virus, HDV virus, HEV virus, coronavirus, HIV virus, influenza virus infection, atherosclerosis , Abdominal aortic aneurysms, ischemic heart diseases, cardiac hypertrophy, rheumatoid ducts Rheumatoid arthritis, sepsis, per iodontal disease », collagen VI myopathies, post-cardiac arrest syndrome, heart failure, acute pneumonia Lung Inflammation, Asthma, Aging, Alopecia, Non-Alcoholic Steatohepatitis, Obesity, Renal fibrosis, Nephrotoxicity, Obstructive Nephropathy, ci splat in-induced renal disease, acute renal failure, chronic renal failure, renal glomerulopathy, end stage renal disease renal disease, bone disorders, osteoporosis, osteoarthritis, osteoarthritis, osteoarthritis, Paget's disease, Alzheimer's disease, Parkinson's disease s dis ease, cerebral ischemia, multiple systems atrophy, cerebral palsy, diabetic neuropathy, Huntington's disease, Multiple Sclerosis ), Amyotrophic lateral sclerosis (ALS), muscular dystrophy, epilepsy, autism, bipolar disorder, excitotoxic injury, hepatic encephalopathy (hepatic encephalopathy), hypoglycemia, manganese toxicity, neuropathies, progressive muscular atrophy, peripheral neuropathy, trigeminal neuralgia, Yeti Neuralgia (Glossopharyngeal neuralgia), Bell's palsy, Myasthenia Gravis, Neurological disorders, Small and non-small cell lung cancer Lung Cancer, Bladder Cancer, Hepatocel hilar Cancer, Pancreatic Cancer, Breast Cancer, Breast Cancer, Squamous Cell Carcinoma, Melanoma, Prostate Cancer cancer, colon cancer, glioblastoma, endometrial cancer, thyroid cancer, lymphoma (1 homas), ovarian cancer, traumatic brain injury Injury, traumatic injury of spinal, peripheral or central nervous tissue, Ischemic Brain Injury, kidney, brain, lung, intestine, heart Ischemia Reper fusion Injury, Stroke, Myocardial Infarction, Heart Failure, Acute Hepatotoxicity, Cholestasis, Transplantation, Intestine, Heart Long-term storage / reperfusion damage (storage / r eper f us i on injury of trans lant organs). In addition, the stilbene derivative represented by Formula 1 may be used as a reference for comparing the efficacy of a therapeutic agent in a cyclophilin-related disease.
본 발명에서 알킬기， 알케닐기， 알콕시기는 직쇄 또는 분지쇄일 수 있다. 본 발명에서 사용된 "할로겐 원자' '는 불소, 염소， 브름 또는 요오드일 수 있다. In the present invention, the alkyl group, alkenyl group, alkoxy group may be linear or branched chain. As used herein, the "halogen atom" 'may be fluorine, chlorine, bromine or iodine.
본 발명에서 A , B, D , E , G, J , L , M, Rc 및 Rd가 서로 이웃한 기와 결합 하여 축합환을 형성할 경우， 축합환은 바람직하게는 6원환 또는 5원환을 형성할 수 있다. 또한 상기 축합환은 N , 0 또는 S의 헤테로 원자를 1개 이상 포함할 수 있다. 상기 축합환은 퓨란 (furan) , 티오펜 (thiophene) 일 수 있다. In the present invention, when A, B, D, E, G, J, L, M, Rc, and Rd combine with adjacent groups to form a condensed ring, the condensed ring may preferably form a 6-membered or 5-membered ring. have. In addition, the condensed ring may include one or more hetero atoms of N, 0 or S. The condensed ring may be furan or thiophene.
본 발명의 일 구현예에 있어서， 상기 약학적으로 허용 가능한 염은 나트 륨염， 칼륨염， 칼슘염 및 암모늄염인 것이 바람직하나 이에 한정되지 않는다. 본 발명의 일 구현예에 있어서, A는 CRa 또는 N이고, B는 CRb 이고， G은 CRe 이고， J은 CRf 이고, M은 CRg 또는 N 이고， D, E 및 L은 CH인 것이 바람직하 나 이에 한정되지 않는다. In one embodiment of the present invention, the pharmaceutically acceptable salt is preferably, but is not limited to, sodium salts, potassium salts, calcium salts and ammonium salts. In one embodiment of the present invention, A is CRa or N, B is CRb, G is CRe, J is CRf, M is CRg or N, D, E and L is preferably CH It is not limited to this.
본 발명의 다론 일 구현예에 있어서， In one embodiment of the present invention,
Rb는 수소 또는 C1-C8의 알킬기인 것이 바람직하나 이에 한정되지 않는 다. Rb is preferably hydrogen or an alkyl group of C1-C8, but is not limited thereto.
Rc는 C1-C20의 알킬기， C1-C10의 알콕시기， 페닐알킬기， 니트로기, C3-C10의 시클로알킬기, C5-C12의 헤테로 고리기 또는 C1-C10의 알킬케톤이 바람 직하나 이에 한정되지 않는다. Rc is preferably, but not limited to, an alkyl group of C1-C20, an alkoxy group of C1-C10, a phenylalkyl group, a nitro group, a cycloalkyl group of C3-C10, a heterocyclic group of C5-C12, or an alkyl ketone of C1-C10 .
Rd는 C1-C20의 알킬기; C3-C10의 에스터기; C3-C10의 시클로알킬기; 시클 로알킬기가 치환된 메톡시 ; 아민기가 치환된 에록시 ; 카르복시기; C1-C5의 알킬 기， C1-C5의 알콕시기， 카르복시기 또는 아민기로 치환 또는 비치환된 페닐기가 치환된 C1-C20의 알킬기; 아민; N—메틸피페라진; 피페리딘; 모르폴린 (morphol ine) ; 또는 -C00R5(R5은 C1-C5의 알킬기， C6-C12의 아릴 또는 C3—C10의 시클로알킬기)인 것이 바람직하나 이에 한정되지 않는다. Rd is a C1-C20 alkyl group; C3-C10 ester group; C3-C10 cycloalkyl group; Methoxy in which a cycloalkyl group is substituted; Ethoxy in which an amine group is substituted; Carboxyl groups; A C1-C20 alkyl group substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, a carboxy group or a phenyl group unsubstituted or substituted; Amines; N—methylpiperazine; Piperidine; Morpholine (morphol ine); Or -C00R5 (R5 is preferably an alkyl group of C1-C5, an aryl of C6-C12 or a cycloalkyl group of C3-C10), but is not limited thereto.
Re는 수소， H2 , OH, C1-C20의 알킬기 또는 C1-C10의 알콕시기인 것이 바 람직하나 이에 한정되지 않는다. Re is preferably hydrogen, H 2 , OH, an alkyl group of C 1 -C 20 or an alkoxy group of C 1 -C 10, but is not limited thereto.
Rg는 수소， NH2 , OH, C1-C20의 알킬기; C3-C10의 에스터기; C3-C10의 시클 로알킬기; 시클로알킬기가 치환된 메톡시; 아민기가 치환된 에톡시; C1-C5의 알 킬기， C1-C5의 알콕시기， 카르복시기 또는 아민기로 치환 또는 비치환된페닐기가 치환된 C2-C20의 알킬기; 아민; N-메틸피페라진; 피페리딘; 모르폴린 (morphol ine) ; 또는 카르복시기인 것이 바람직하나 이에 한정되지 않는다. Rg is hydrogen, NH 2 , OH, alkyl group of C1-C20; C3-C10 ester group; C3-C10 cycloalkyl group; Methoxy substituted with a cycloalkyl group; Ethoxy substituted with an amine group; A C2-C20 alkyl group substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, a carboxyl group or a substituted or unsubstituted phenyl group; Amines; N-methylpiperazine; Piperidine; Morpholine (morphol ine); Or a carboxy group, but is not limited thereto.
Rh는 수소인 것이 바람직하나 이에 한정되지 않는다. Rh is preferably hydrogen, but is not limited thereto.
본 발명에서 사용된 알킬기는 치환 또는 비치환된 알킬일 수 있으며 ,
-CH3( -CH2CH3, -CH2CH2CH3) -CH2(CH2)2CH3, -C¾(CH2)3CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH2C¾, -CH2CH2CH(C¾)2, -CH(C¾)2, -C(CH3)3, _CH2C(CH3)3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)C(CH3)3, -C(CH3)2CH2C¾,The alkyl group used in the present invention may be substituted or unsubstituted alkyl, -CH 3 ( -CH2CH3, -CH 2 CH 2 CH 3) -CH 2 (CH 2 ) 2 CH 3 , -C¾ (CH 2 ) 3 CH 3 , -CH (CH 3 ) CH 2 CH 3 , -CH 2 CH (CH 3 ) CH 2 C¾, -CH 2 CH 2 CH (C¾) 2 , -CH (C¾) 2 , -C (CH 3 ) 3 , _CH 2 C (CH 3 ) 3 , -CH 2 CH (CH 3 ) 2 , -CH (CH 3 ) CH (CH 3 ) 2, -CH (CH 3 ) C (CH 3 ) 3 , -C (CH 3 ) 2 CH 2 C¾,
-C(C¾)2CH(CH3)2, -C(C¾)2C(CH3)3. -CH2CH2C(CH3)3, -CH2CH(CH3)CH(CH3)2) -CH2CH2C(CH3)2CH2CH3, -CH2CH2CH(CH3)CH2C(CH3)3, -CH2Ph, CH2CH2Ph, -C (C¾) 2 CH (CH 3 ) 2 , -C (C¾) 2 C (CH 3 ) 3 . -CH 2 CH 2 C (CH 3 ) 3 , -CH 2 CH (CH 3 ) CH (CH 3 ) 2) -CH2CH 2 C (CH 3 ) 2 CH 2 CH 3 , -CH 2 CH 2 CH (CH 3 ) CH 2 C (CH 3 ) 3 , -CH 2 Ph, CH 2 CH 2 Ph,
되지 않는다. It doesn't work.
본 발명에서 알콕시기는 치환 또는 비치환된 알콕시기일 수 있는데 -0CH3, -OCF3, -OCH2CH3, -OCH2CH2CH3, -0CH2CH2CH2CH3, -0CH(CH3)CH2CH3> -0CH2C0NH2, In the present invention, the alkoxy group may be a substituted or unsubstituted alkoxy group, wherein -0CH 3 , -OCF3, -OCH2CH3, -OCH2CH2CH3, -0CH 2 CH 2 CH 2 CH 3, -0CH (CH 3 ) CH 2 CH 3> -0CH 2 C0NH 2 ,
발명에서 -C00R5는 C00CH3, -C00CH2CH3) C00(CH2)2CH3, -C00(CH2)3CH3,In the present invention, -C00R5 is C00CH 3 , -C00CH 2 CH 3) C00 (CH 2 ) 2 CH 3 , -C00 (CH2) 3 CH 3 ,
C00(CH2)4CH3, C00CH(CH3)2,
1 C00 (CH 2 ) 4 CH 3 , C00CH (CH 3 ) 2 , One
일 수 있으나 이에 한정되지 않는다. It may be, but is not limited thereto.
발명에서 — NHS(0)2R9는
In the invention — NHS (0) 2 R9
일 수 있으나 이에 한정
되지 않는다. May be limited to It doesn't work.
본 발명의 화합물은 상품으로 판매하는 것을 구입하거나 제조하여 사용될 수 있는데, 제조방법은 일반적으로 화학식 1의 Rx가 CN인 경우와 나머지의 경우
상이할 수 있다.The compounds of the present invention can be used to purchase or manufacture what is sold as a commodity, the preparation method is generally the case where Rx of Formula 1 is CN and the rest Can be different.
x가 CN인 경우, 화학식 1로 표시되는 스틸벤 유도체는 하기 화학식 2로 표시되는 페닐아세토니트릴 (Phenylacetoni tri le) 유도체와 하기 화학식 3으로 표 시되는 벤즈알데히드 (Benzaldehyde) 유도체를 반응시켜 제조할수 있다. When x is CN, the stilbene derivative represented by Chemical Formula 1 may be prepared by reacting a phenylacetonitrile (Phenylacetoni trile) derivative represented by Chemical Formula 2 with a benzaldehyde derivative represented by Chemical Formula 3 below.
화학식 2로 표시되는 페닐아세토니트릴 유도체 및 화학식 3으로 표시되는 벤즈알데히드 유도체는 시판 중인 것을 구매하여 사용할 수 있고， 당업계에 공지 된 방법으로 제조하여 사용할 수도 있다. The phenylacetonitrile derivative represented by the formula (2) and the benzaldehyde derivative represented by the formula (3) may be purchased and used in the market, or may be prepared and used by methods known in the art.
상기 반응은 유기용매하에서 이루어질 수도 있고， 용매없이 진행될 수도 있으며, 이 경우 마이크로웨이브를 사용하여 반응시간을 단축하고 수득율을 높일 수도 있다. The reaction may be carried out under an organic solvent, or may be performed without a solvent. In this case, microwaves may be used to shorten the reaction time and increase the yield.
상기 유기용매는 한정되지 않으나 바람직하게는 알코을류, 보다 바람직하 게는 뷰탄올， 메탄올， 에탄올， 프로판올 등을 들 수 있다. 또한 촉매로 트리페닐 포스핀, 피페리딘 등을 추가하여 반웅시킬 수 있다. The organic solvent is not limited, but preferably alcohols, more preferably butanol, methanol, ethanol, propanol and the like. In addition, it is possible to react by adding triphenyl phosphine, piperidine and the like as a catalyst.
[화학식 1] [Formula 1]
Rx = CN Rx = CN
[화학식 2] [Formula 2]
[화학식 3]
[Formula 3]
A, B, D, E, G, J, L, M, Rc 및 Rd 는 화학식 1의 A, B, D, E, G, J, L, M, Rc 및 Rd와 동일하다. A, B, D, E, G, J, L, M, Rc and Rd are the same as A, B, D, E, G, J, L, M, Rc and Rd of formula (1).
R가 H, CH3, NH2, F, CI, Br, I인 경우, 화학식 1로 표시되는 스틸벤 유도 체는 하기 화학식 4로 표시되는 올레핀 (olefin)유도체와 하기 화학식 5로 표시되 는 유기할라이드 (organic halide) 유도체를 반웅시켜 제조할 수 있다. When R is H, CH 3 , NH 2 , F, CI, Br, I, the stilbene derivative represented by the formula (1) is an olefin derivative represented by the formula (4) and an organic represented by the formula (5) It can be prepared by reacting an organic halide derivative.
화학식 4로 표시되는 을레핀유도체 및 화학식 5로 표시되는 유기할라이드 유도체는 시판 중인 것을 구매하여 사용할 수 있고， 당업계에 공지된 방법으로 제조하여 사용할 수도 있다. The leupin derivatives represented by the formula (4) and the organic halide derivatives represented by the formula (5) may be purchased and used in the market, or may be prepared and used by methods known in the art.
상기 반웅은 바람직하게는 트리에탄을아민 (triethanolamine) 유기용매를 사용하고 팔라디움 (II) 아세테이트 [Palladium(II) acetate]를 촉매로 하여 수행 된다. The reaction is preferably carried out using triethanolamine organic solvent as a catalyst and Palladium (II) acetate as a catalyst.
[화학식 1] [Formula 1]
Rx = H, CH3, NH2 Rx = H, CH3, NH2
[화학식 4]
[Formula 4]
H, C: 2， F, CI, BrH, C: 2, F, CI, Br
[화학식 5] [Formula 5]
Rx 는 수소， CH3, NH2> F, CI, Br또는 I이고， Rx is hydrogen, CH 3 , NH 2> F, CI, Br or I,
X는 F, CI, Br또는 I이고 X is F, CI, Br or I
A, B, D, E, G, J, L, M, Rc 및 Rd 는 화학식 1의 A, B, D, E, G, J, L, M, Rc 및 Rd 와동일하다. A, B, D, E, G, J, L, M, Rc and Rd are the same as A, B, D, E, G, J, L, M, Rc and Rd of formula (1).
본 발명의 화합물의 제조방법은 대한민국 특허출원 2017-0102983을 참조 할 수 있다. The preparation method of the compound of the present invention may refer to Korean Patent Application 2017-0102983.
본 발명에서 사용된 용어 "약제학적으로 허용 가능한 담체"은 유효성분의 생물학적 활성과 물성들을 손상시키지 않는 담체 또는 회석제로 정의된다. The term "pharmaceutically acceptable carrier" used in the present invention is defined as a carrier or diluent which does not impair the biological activity and the properties of the active ingredient.
약제학적으로 허용 가능한 담체 또는 첨가제로는 통상적으로 사용되는 안 정화제， 층진제， 증량제， 습윤제， 붕해제, 활택제， 결합제， 계면활성제 등의 회 석제 또는 부형제를 1종 이상사용할 수 있다. As the pharmaceutically acceptable carrier or additive, one or more commonly used stabilizers, layering agents, extenders, wetting agents, disintegrating agents, lubricants, binders, and excipients such as surfactants can be used.
붕해제로는 한천， 전분， 알긴산 또는 이의 나트륨염， 무수인산일수소칼슘 염 등이 사용될 수 있고， 활택제로는 실리카， 탈크, 스테아르산 또는 이의 마그 네슘염 또는 칼슘염， 폴리에틸렌 글리콜, 메타규산알루민산마그네슘 등이 사용될 수 있으며， 결합제로는 마그네슴 알루미늄 실리케이트. 전분 페이스트， 젤라틴, 트라가칸스， 메틸셀를로오스， 나트륨카복시메틸셀를로오스， 폴리비닐피를리딘， 저치환도하이드록시프로필셀를로오스 등이 사용될 수 있다. 이외에도 락토즈, 덱 스트로오스， 수크로오스， 만니를， 소르비를， 샐를로오스. 글리신 등을 회석제로
사용할 수 있으며 , 경우에 따라서는 일반적으로 알려진 비등염， 흡수제 착색제ᅳ 향미제， 감미제 등을 함께 사용할 수 있다. As a disintegrant, agar, starch, alginic acid or its sodium salt, anhydrous calcium monohydrogen phosphate salt, etc. may be used, and as lubricant, silica, talc, stearic acid or its magnesium salt or calcium salt, polyethylene glycol, metasilicate Magnesium phosphate may be used, and as the binder, magnesium aluminum silicate. Starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyridine, low-substituted hydroxypropyl cellulose, and the like can be used. In addition to lactose, dextrose, sucrose, manny, sorbbi, salose. Glycine, etc. In some cases, commonly known boiling salts, absorbents, colorants, flavoring agents, and sweeteners may be used together.
또한， 안정화제로 나트륨 (Na)이 포함되지 않은 안정화제를 사용할 수 있 으며， 예를 들어 메타규산알루민산마그네슘 (Magnesium aluminometasi 1 i cate) , 규산알루민산마그네슘 (Magnesium aluminosi 1 icate) , 알루민산마그네슘 (Magnesium aluminate) , 건조 수산화알루미늄 (Dried aluminum hydroxide) , 합성 히드로탈시트 (Synthet ic hydrotalcite) , 합성 규산알루미늄 (Synthet ic aluminumsi 1 icate) , 탄산마그네슴 (Magnesium carbonate) , 침전탄산칼슘 (Preci i tated calcium carbonate) , 산화마그네슘 (Magnesium oxide) , 수산화알 루미늄 (Aluminum hydroxide) , ᄂ一아르기닌 (L-arginine) , 인산칼륨 (Potassium phosphate) , 제이인산칼륨 (Dipotassiumhydrogenphosphate) , 인산이수소칼롬 (Potassium dihydrogenphosphate) , 염화암모늄 (Ammonium chloride) , 염화알루미 늄 (Aluminum chloride) 등이 있으며， 상술한 안정화제 중 1종 또는 2종 이상을 사용할 수 있다. In addition, a stabilizer that does not contain sodium (Na) may be used as the stabilizer, for example magnesium aluminometasi 1 i cate, magnesium aluminate silicate (magnesium aluminosi 1 icate), magnesium aluminate (Magnesium aluminate), Dried aluminum hydroxide, Synthetic hydrotalcite, Synthetic aluminumsisi 1 icate, Magnesium carbonate, Precipitated calcium carbonate calcium carbonate, magnesium oxide, aluminum hydroxide, l-arginine, potassium phosphate, dipotassiumhydrogenphosphate, potassium dihydrogenphosphate , Ammonium chloride, aluminum chloride, etc., and one or two or more of the above-mentioned stabilizers may be used. can do.
본 발명의 화학식 1의 스틸벤 유도체를 포함하는 약학 조성물은 생물체 내로 화합물의 투여를 용이하게 하는 다양한 방법으로 투여될 수 있다. 본 발명 의 약학 조성물은 경구 투여， 직장 내 투여， 질 내 투여, 비강 내 투여， 안구 내 투여， 구강 내 투여， 설하 투여， 피하 내 투여， 근육 내 투여， 정맥 내 투여， 척 수강 내 투여， 피내 투여 , 경막 외 투여 등으로 투여될 수 있다. Pharmaceutical compositions comprising a stilbene derivative of Formula 1 of the present invention may be administered in a variety of ways to facilitate administration of the compound into an organism. The pharmaceutical composition of the present invention is oral administration, rectal administration, vaginal administration, intranasal administration, intraocular administration, oral administration, sublingual administration, subcutaneous administration, intramuscular administration, intravenous administration, intrathecal administration, intradermal administration Administration, epidural administration, and the like.
본 발명의 약학 조성물은， 정제, 캡슐， 분말 (powder) , 드롭 알약 Pharmaceutical compositions of the present invention, tablets, capsules, powders, drop pills
(dropping pi l l ) , 산제 (pulvis) , 볼루스, 틴크제， 또는 습포제의 형태로 제형화 될수 있다. 바람직한 정제는 통상적인 정제， 코팅정， 분산성 정제， 발포성 정제 등일 수 있고， 이중정， 유핵정, 다층정 등의 다중압축정일 수 있다. It can be formulated in the form of (dropping pi), powder (pulvis), bolus, tincture, or poultice. Preferred tablets may be conventional tablets, coated tablets, dispersible tablets, effervescent tablets and the like, and may be multi-compressed tablets such as double tablets, nucleated tablets, multilayer tablets and the like.
본 명세서에서 제공되는 약학 조성물에 포함된 스틸벤 유도체 또는 이의 약학적으로 허용 가능한 염의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도， 약물의 형태， 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하 게 선택될 수 있다. Preferred dosages of stilbene derivatives or pharmaceutically acceptable salts thereof contained in the pharmaceutical compositions provided herein vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route and duration of administration, Can be appropriately selected.
일반적으로는， 성인에게 유효성분으로서 화학식 1의 화합물은 사람을 포 함하는 포유동물에 대해 하루 1 내지 100 mg/kg (체중)， 바람직하게는 5 내지 In general, as an active ingredient in adults, the compound of formula 1 may be used in an amount of 1 to 100 mg / kg (weight), preferably 5 to 1, per day for mammals including humans
50mg/kg (체중)의 양으로 1일 1회 또는 분할하여 경구 또는 비경구적경로를 통하 여 투여될 수 있다. 일부의 경우에 있어서, 상기 언급된 범위보다 적은 투여량이 보다 적합할 수 있고, 해로운 부작용을 일으키지 않으면서도 보다 많은 양이 사 용될수도 있으며， 보다 많은 투여량의 경우는 하루에 걸쳐 수회의 적은 분량으로 분배될 수 있다. It may be administered orally or via parenteral route once daily or divided into amounts of 50 mg / kg body weight. In some cases, smaller dosages may be more suitable than the above-mentioned ranges, and higher dosages may be used without causing harmful side effects, and higher dosages may be administered in several smaller doses throughout the day. Can be dispensed.
본 발명의 화합물을 단독으로 투여하는 것이 가능하지만, 약학 조성물로
서 투여하는 것이 바람직하다. 수의과 및 인간 용도 모두를 위해， 본 발명에 따 라 유용한 약학 조성물은 상기 화학식 1을 갖는 하나 이상의 화합물을， 하나 이 상의 약학적으로 허용가능한 담체 및 임의로 기타 치료 성분과 함께 포함될 수 있다. 조합 요법에 필수적인 유효 성분이 동시 투여를 위해 본 발명의 약학 조성 물에 조합될 수 있다. It is possible to administer the compounds of the invention alone, but as pharmaceutical compositions Administration is preferred. For both veterinary and human use, pharmaceutical compositions useful in accordance with the present invention may comprise one or more compounds having Formula 1 above, together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients. Active ingredients essential for combination therapy may be combined in the pharmaceutical compositions of the present invention for simultaneous administration.
제형은 약학계에 잘 알려진 임의의 방법에 의해 단위 투여량 형태로 제조 될 수 있다. 이러한 방법은 유효 성분을 하나 이상의 부속 성분으로 구성된 담체 와 결부시키는 단계를 포함한다. 일반적으로 제형은 유효 성분을 액체 담체 또는 미분된 고체 담체 또는 두가지 모두와 균일하고 긴밀하게 결부시킨 다음， 필요하 다면 생성물을 성형함으로써 제조된다. The formulations may be prepared in unit dosage form by any method well known in the pharmaceutical arts. Such methods include the step of bringing into association the active ingredient with the carrier consisting of one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then molding the product if necessary.
【발명의 실시를 위한 형태】 [Form for implementation of invention]
이하 비한정적인 실시예를 통하여 본 발명을 더욱 상세하게 설명한다. 그 러나 하기 실시예는 본 발명을 더욱 구체적으로 설명하기 위한 것으로서， 본 발 명의 범위가 하기의 실시예에 의하여 한정되는 것은 아니다. 하기의 실시예는 본 발명의 범위 내에서 당업자에 의해 적절히 수정, 변경될 수 있다. Hereinafter, the present invention will be described in more detail with reference to non-limiting examples. However, the following examples are intended to illustrate the present invention in more detail, and the scope of the present invention is not limited by the following examples. The following examples can be appropriately modified and changed by those skilled in the art within the scope of the present invention.
제조예 1. Rx가 CN인스틸벤 유도체의 제조 Preparation Example 1 Preparation of Rx is CN Instilbene Derivative
1) 용매 사용방법 1) How to use solvent
화학식 2의 페닐아세토니트릴 유도체 1당량과 화학식 3의 벤즈알데히드 유도체 1.3당량을 트리페닐포스핀 0.2당량을 부탄올 용매에서 환류시켜 knoevenagel condensat ion 반응으로 화학식 1의 화합물을 제조하였다. A compound of Formula 1 was prepared by knoevenagel condensat ion reaction by reacting 1 equivalent of phenylacetonitrile derivative of Formula 2 and 1.3 equivalent of benzaldehyde derivative of Formula 3 with 0.2 equivalent of triphenylphosphine in a butanol solvent.
2) 마이크로웨이브 사용 방법 2) How to use microwave
화학식 2의 페닐아세토니트릴 유도체 1당량， 화학삭 3의 벤즈알데히드 1.3당량 및 트리페닐포스핀 0.2당량을 사용하고 마이크로웨이브 (microwave)를 이용하여 화학식 1의 화합물을 제조하였다. 마이크로웨이브를 이용하는 경우 반 웅시간을 줄일 수 있고 수득률을 향상시킬 수 있다. A compound of Formula 1 was prepared using microwave using 1 equivalent of phenylacetonitrile derivative of Formula 2, 1.3 equivalents of Benzaldehyde of Chemical Formula 3 and 0.2 equivalents of triphenylphosphine. Using microwaves can reduce reaction time and improve yield.
[반웅식 1] [Banungsik 1]
Rx=CN
[화학식 2] [화학식 3] [화학식 1] 제조예 2. Rx가수소， CH3, NH2, F, CI , Br , I인 유도체의 제조 Rx = CN Preparation Example 2. Preparation of a derivative of Rx hydrogen, CH 3 , NH 2 , F, CI, Br, I
화학식 4의 올레핀유도체 1당량과 화학식 5의 오가닉할라이드유도체 1당 량을 팔라듐 ( I I ) 아세테이트 0.이당량 및 트리에탄올아민 용매에서 환류시켜 Heck Olef inat ion 반응으로 화학식 1의 화합물을 제조하였다. One equivalent of the olefin derivative of Formula 4 and one equivalent of the organic halide derivative of Formula 5 were refluxed in 0. di equivalent of palladium (I) acetate and triethanolamine solvent to prepare a compound of Formula 1 by Heck Olef inat ion reaction.
[반응식 2] Scheme 2
X = F, CI , Br , I ， C¾, NH2, X = F, CI, Br, I, C¾, NH 2 ,
I I
[화학식 4] [화학식 5] [화학식 1] 실시예 1. 스틸벤 유도체의 시스-트랜스 이소머라제 저해 활성 확인 키모트립신 (chymotrypsin)은 트랜스 형태의 알라닌-프를린 펩타이드 결 합을 절단한다. Suc-AAPF-pNA (펩타이드 기질)과 키모트립신을 섞어 주면 트랜스 형태의 펩타이드 기질은 절단되고 시스 형태의 펩타이드 기질은 남게 된다. 남은 시스 형태의 펩타이드 기질은 시스-트랜스 이소머라제에 의해서 트랜스 형태로 바뀌며 또다시 키모트립신에 의해서 절단된다. 즉, 시스-트랜스 이소머라제가 존 재하는 경우에 키모트립신은 일정 시간 안에 더 많은 양의 트랜스 형태의 펩타이 드 기질을 절단하게 된다. 이를 이용하여 시스-트랜스 이소머라제의 활성을 결정 한다. 절단된 트랜스 형태의 펩타이드 기질의 양은 390nm에서의 흡광도를 이용하 여 측정할 수 있다. Example 1. Confirmation of cis-trans isomerase inhibitory activity of stilbene derivatives Chymotrypsin cleaves alanine-prine peptide bond in trans form. Mixing the Suc-AAPF-pNA (peptide substrate) with chymotrypsin results in the cleavage of the trans form peptide substrate and the cis form peptide substrate. The remaining cis-form peptide substrate is trans-formed by cis-trans isomerase and again cleaved by chymotrypsin. In other words, in the presence of cis-trans isomerase, chymotrypsin cleaves more of the trans form of the peptide substrate in a certain amount of time. This is used to determine the activity of cis-trans isomerase. The amount of peptide substrate in truncated trans form can be measured using absorbance at 390 nm.
사이클로필린은 시스-트랜스 이소머라제 활성을 가지며 키모트립신에 의 한 트랜스 형태의 펩타이드 기질의 절단을 가속화한다. 반면， 본 발명의 스틸벤 유도체들을 사이클로필린과 함께 처리하였을 경우에는 키모트립신에 의한 펩타이 드 기질의 절단이 가속화되지 않음올 관찰하였다. 이를 통하여 본 발명의 스틸벤 유도체들이 사이클로필린의 활성을 저해한다는 것을 확인할 수 있었다. Cyclophylline has cis-trans isomerase activity and accelerates cleavage of the peptide form of the trans form by chymotrypsin. On the other hand, when the stilbene derivatives of the present invention were treated with cyclophilin, the cleavage of the peptide substrate by chymotrypsin was not observed. It was confirmed that the stilbene derivatives of the present invention inhibit the activity of cyclophylline.
하기 화합물 1 내지 화합물 315 (표 1 내지 표 12)은 시스-트란스 이소머라 제 저해 활성 ( IC50) 값으로 아래와 같이 그룹화될 수 있다.
Group A (GA) IC50이 200초과 2000 nM 이하 Group B (GB) IC50이 20초과 200 nM이하, Group C (Gc) IC50이 20 nM이하 The following compounds 1 to 315 (Tables 1 to 12) can be grouped as follows with cis-trans isomerase inhibitory activity (IC 50 ) values. Group A (GA) IC 50> 200 nM Group B (GB) IC 50> 20 nM and Group C (Gc) IC 50 ~ 20 nM
【표 1】 Table 1
【표 5】
【표 6】
Table 5 Table 6
【표 7]
[Table 7]
【표 8]
[Table 8]
【표 9]
【표 11】 [Table 9] Table 11
【표 12】 Table 12
스틸벤 유도체들의 세포'독성을 측정하였다. C형 간염 바이러스 게놈을 안정적으로 복제하는 리플리콘 세포를 96-wel l 플레이트에 부착시키고 37°C의 C02 배양기에서 24시간 동안 배양하였다. 하루 동안 배양된 리플리콘 세포를 PBS(phosphate buf fered sal ine) 용액으로 씻어 주고， 본 발명의 화합물들로 처 리한 후 72시간 동안 배양했다. 이 후에The cell ' toxicity of stilbene derivatives was measured. Replicon cells stably replicating the hepatitis C virus genome were attached to 96-wel l plates and incubated for 24 hours in a C0 2 incubator at 37 ° C. Ripicon cells cultured for one day were washed with PBS (phosphate buf fered saline) solution, and treated with the compounds of the present invention, and then cultured for 72 hours. Since the
MTT[3-(4, 5-dimethylthiazol-2-yl )-2, 5-diphenyltetrazol ium bromide] 세포독성 실험을 통해 본 발명 화합물들의 CC50값을 측정하였다. 본 발명 화합물들의 CC50 값은 200 μ Μ 이상이다. 화합물 225의 CC50값은 320 μ Μ이며， 화합물 226의 경우에 는 284 μ Μ, 화합물 227의 경우에는 245 y M 이였다. 따라서 본 발명의 화학식 1 의 화합물은 세포독성을 나타내지 않음을 알 수 있다. CC 50 values of the compounds of the present invention were determined by MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] cytotoxicity test. The CC 50 value of the compounds of the present invention is at least 200 μΜ. The CC 50 value for Compound 225 was 320 μΜ, for Compound 226 284 μΜ and for Compound 227 245 y M. Therefore, it can be seen that the compound of formula 1 of the present invention does not exhibit cytotoxicity.
실시예 3. 스틸벤 유도체의 항바이러스 활성 확인 Example 3. Confirmation of antiviral activity of stilbene derivatives
스틸벤 유도체들의 C형 간염 바이러스에 대한 항바이러스 활성을 측정하 였다. C형 간염 바이러스 게놈을 안정적으로 복제하는 리플리콘 세포를 배양 플 레이트에 부착시키고 37의 C02 배양기에서 24시간 동안 배양하였다. 하루 동안 배양된 리플리콘 세포를 PBS(Phosphate-buffered sal ine) 용액으로 씻어 주고 화 합물들을 처리한 후 72시간 동안 배양했다. 스틸벤 유도체로 처리된 리플리콘 세
포를 차가운 PBS 용액으로 씻어 주고 yL의 세포용해 용액을 넣고 20분간 얼음 에서 세포를 용해시킨다. lOOiiL의 레닐라루시퍼라아제 기질을 넣어 준 후, 발현 되는 루미네센스를 측정하여 C형 간염 바이러스 게놈의 양을 추정하였다. 디메틸 설폭사이드 (DMS0)를 처리한 리플리콘 세포에서의 C형 간염 바이러스 게놈의 양을 기준으로 본 발명의 스틸벤 유도체로 처리된 리플리콘 세포에서의 C형 간염 바이 러스 게놈의 양을 상대적으로 나타낸다. The antiviral activity of the stilbene derivatives against hepatitis C virus was measured. Replicon cells stably replicating the hepatitis C virus genome were attached to culture plates and incubated for 24 hours in a 37 C02 incubator. Replicon cells cultured for one day were washed with PBS (Phosphate-buffered sal ine) solution, and the compounds were treated and incubated for 72 hours. Ripleycone treated with stilbene derivative Wash the cells with cold PBS solution, add yL cytolysis solution and lyse the cells on ice for 20 minutes. After incorporating the lOiiL Renilla luciferase substrate, the amount of the expressed luminescence was measured to estimate the amount of the hepatitis C virus genome. Relative amounts of hepatitis C virus genome in replicon cells treated with stilbene derivatives of the present invention based on the amount of hepatitis C virus genome in replicon cells treated with dimethyl sulfoxide (DMS0) .
표 1 내지 표 12의 화합물 1 내지 화합물 315의 항바이러스 활성 (EC50) 값 으로 아래와 같이 그룹화될 수 있다. The antiviral activity (EC 50 ) values of compounds 1 to 315 of Tables 1-12 can be grouped as follows.
Group D (GD): EC50이 5초과 50 μΜ 이하, Group D (GD): EC 50 is greater than 5 and less than 50 μΜ,
Group E (GE): EC50이 0.5초과 5 μΜ이하， Group E (G E ): EC 50 is greater than 0.5 and less than 5 μΜ,
Group F (GF): EC50이 0.5 μΜ이하 Group F (GF): EC 50 < 0.5 μΜ
따라서 본 발명의 화학식 1의 화합물은 항바이러스 효과가 있음을 알 수 있다. Therefore, it can be seen that the compound of formula 1 of the present invention has an antiviral effect.
실시예 4. 미토콘드리아의 팽창 저해 활성 실험 Example 4 Experiment of Expansion Inhibition Activity of Mitochondria
사이클로필린은 미토콘드리아의 투과성전이세공 (permeability transition pore: FTP)을 형성하는 핵심 단백질이다. 투과성전이세공이 생성되면 미토콘드리아는 팽창하고, 이로 인하여 와막이 파열되면서 세포사멸이 진행된다. 이와 같은 미토콘드리아 기능이상 (mitochondrial dysfunction)은 퇴행성 신경질 환 (neurodegenerative diseases), 종양 (cancer) 등을 비롯한 많은 질환의 원인이 된다. 사이클로필린의 저해제로 알려진 사이클로스포린은 투과성전이세공의 형성 을 막아 미토콘드리아의 팽창을 막는다고 알려져 있다. Cyclophilin is a key protein that forms the permeability transition pore (FTP) of mitochondria. When permeable metastasis is generated, the mitochondria expand, resulting in rupture of the vortex and cell death. Such mitochondrial dysfunction is the cause of many diseases, including neurodegenerative diseases, tumors, and the like. Cyclosporine, known as an inhibitor of cyclophylline, is known to prevent the formation of permeable metastasis, preventing the expansion of mitochondria.
미토콘드리아의 팽창 실험은 다음과 같은 방법으로 진행되었다. 먼저 간 세포를 세포분쇄기 (dounce tissue grinder)를 이용하여 파쇄한다. 파쇄된 세포 를 10분동안 700 X g 에서 원심분리하고 상층액을 새로운 튜브에 옮겨 담는다. 이 상층액을 15분동안 12ᅳ 000 X g 에서 원심분리하면 미토콘드리아를 얻을 수 있 다. The expansion experiment of mitochondria was carried out in the following manner. First, liver cells are disrupted using a dounce tissue grinder. The crushed cells are centrifuged at 700 X g for 10 minutes and the supernatant is transferred to a new tube. Mitochondria can be obtained by centrifugation of this supernatant at 12 mm 000 X g for 15 minutes.
추출된 미토콘드리아에 칼슘을 넣으면 팽창 (swelling) 되며， 이는 520nm 에서의 흡광도를 측정함으로써 확인할 수 있다. 반면， 상기 스틸벤 유도체들은 칼슘에 의한 미토콘드리아의 팽창을 저해하는 효과를 보인다. Incorporation of calcium into the extracted mitochondria causes swelling, which can be confirmed by measuring the absorbance at 520 nm. On the other hand, the stilbene derivatives have an effect of inhibiting the expansion of mitochondria by calcium.
표 1 내지 표 12의 화합물 1 내지 화합물 315의 미토콘드리아 팽창 저해 활 성 (IC50) 값은 아래와 같이 그룹화될 수 있다. The mitochondrial expansion inhibition activity (IC 50 ) values of Compounds 1 to 315 of Tables 1-12 can be grouped as follows.
Group G (GG): IC50이 50초과 500 μΜ이하， Group G (G G ): IC 50> 50 μΜ <500 μΜ
Group H (GH): ICM이 5초과 50 μΜ이하， Group H (GH): IC M greater than 5 and less than 50 μΜ,
Group I (Gi): IC50이 5 μΜ이하 Group I (Gi): IC 50 < 5 μΜ
실시예 5. 스틸벤 유도체와 HCV 치료제들과의 복합 처방
HCV 감염을 효과적으로 치료하기 위해서는 HCV 치료제들을 복합 처방하여 사용한다. HCV 치료제들을 복합 처방하면 항바이러스 효과를 높일 수 있으며 (synergy effect) 약물 내성의 발생도 줄일 수 있다. Example 5 Combination Formulation of Stilbene Derivatives with HCV Therapeutics To effectively treat HCV infection, a combination of HCV medications is used. Combining HCV treatments may increase the antiviral effect and reduce the incidence of drug resistance.
상기 스틸벤 유도체 (화합물 225)와 기존의 HCV 치료제들 (daclatasvir -'NS5A inhibitor , simeprevir :NS3 inhibitor , sofosbuvir .'NS5B inhibitor)과의 복합 처방하였을 때 보다 좋은 항바이러스 효과 (synergy effect)를 보인다 (도 1 내지 도 3). Said stilbene derivative (Compound 225) with the existing HCV treatment -: good anti than when complex prescription hayeoteul with (daclatasvir 'NS5A inhibitor, simeprevir. NS3 inhibitor, sofosbuvir' NS5B inhibitor) shows a virus effect (synergy effect) ( 1 to 3).
도 1 내지 도 3에서 두 개의 약물의 상호작용은 블리스 독립 모델 (Bliss- independence model)을 사용하여 구하였다. 가로축은 약물의 농도를 나타 내며 , 세로축은 두 개의 약물의 상호작용을 나타낸다. 도 1 내지 도 3에서 0%는 부가효과 (additive effect), 0% 초과는 상승효과 (synergy effect), 0% 미만은 길항효과 (antagonism)를 나타낸다. 1 to 3, the interaction of two drugs was obtained using the Bliss independence model. The horizontal axis represents the concentration of the drug and the vertical axis represents the interaction of the two drugs. 1 to 3, 0% represents an additive effect, more than 0% represents a synergy effect, and less than 0% represents an antagonism.
또한 스틸벤 유도체는 기존 치료제에 내성을 보이는 바이러스에 대해서도 항바이러스 효과를 보인다 (표 13). 하기 표 3에 의하면 본 발명의 스틸벤 유도 체 (화합물 225)는 Simeprevir에 약물내성을 보이는 바이러스나 daclatasvir에 약물 내성을 보이는 바이러스 모두에서 항바이러스 효과를 보인다. Stilbene derivatives also have antiviral effects against viruses that are resistant to existing therapeutic agents (Table 13). According to Table 3 below, the stilbene derivative of the present invention (Compound 225) exhibits an antiviral effect in both viruses that exhibit drug resistance to Simeprevir or viruses that exhibit drug resistance to daclatasvir.
【표 13] Table 13
【산업상 이용가능성】 Industrial Applicability
본 발명에 따른 스틸벤 유도체를 포함하는 사이클로필린 기능 저해제는 사이클로필린의 기능을 저해하는 효과가 있다. 그 결과， 본 발명에 따른 스틸벤 유도체를 포함하는 조성물은 바이러스 감염 (viral infection) 질환， 심혈관 질환 (cardiovascular diseases) , 류마티스 관절염 (rheumatoid arthritis) , 패혈증 (sepsis) , 치주염 (periodontitis), 급성 폐염 (Acute Lung Inflammation), 천식 (asthma) , 노화 (aging), 탈모 (alopecia)， 퇴행성 신경질환 (neurodegenerative diseases), 종양 (cancer), 급성 손상 (Acute Injuries) 등의 사이클로필린 관련 질환또는 손상의 예방 또는 질환의 징후 치료에 유용하다.
Cyclophylline inhibitors, including stilbene derivatives according to the present invention has the effect of inhibiting the function of cyclophylline. As a result, the composition comprising a stilbene derivative according to the present invention is a viral infection disease, cardiovascular diseases, rheumatoid arthritis, sepsis (sepsis), periodontitis (periodontitis), acute pneumonia ( Preventing or preventing cyclophilin-related diseases or injuries such as Acute Lung Inflammation, asthma, aging, alopecia, neurodegenerative diseases, tumors, and Acute Injuries Useful for the treatment of signs of disease.
Claims
【청구의 범위】 [Range of request]
【청구항 11 [Claim 11
하기 화학식 1로 표시되는 스틸벤 유도체, 또는 하기 화학식 1로 To a stilbene derivative represented by Formula 1, or
표시되는 스틸벤 유도체와 이의 약학적으로 허용 가능한 염을 포함하는 Containing a stilbene derivative represented by the pharmaceutically acceptable salt thereof
사이클로필린 기능 저해제 Cyclophylline inhibitors
[화학식 1] [Formula 1]
A는 CRa 또는 N이고， A is CRa or N,
B는 CRb 또는 N이고， B is CRb or N,
G은 CRe 또는 N이고 G is CRe or N
J은 CRf 또는 N이고， J is CRf or N,
M은 CRg또는 N이고， M is CRg or N,
D, E, 및 L은 CRh또는 N이고 D, E, and L are CRh or N
Rx는 H, C¾, CN, NH2, F , CI , Br또는 I이며, Rx is H, C¾, CN, NH 2 , F, CI, Br or I,
Ra는 수소， 할로겐, N02, CN, OH, C1-C5 알킬기, C2-C10의 알케닐기, C1-C6 알콕시기， -C00RUR1은 수소 또는 C1-C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬) 또는 0C0R2(R2는 CI— C5의 알킬기, C6-C12의 아릴 또는 C3-C10의 시클로알킬) 이고， Ra is hydrogen, halogen, N0 2 , CN, OH, C1-C5 alkyl group, C2-C10 alkenyl group, C1-C6 alkoxy group, -C00RUR1 is hydrogen or C1-C5 alkyl group, C6-C12 aryl or C3- C10 cycloalkyl) or 0C0R2 (R2 is CI— an alkyl group of C5, C6-C12 aryl or C3-C10 cycloalkyl),
Rb는 수소， 할로겐， N02 , CN, OH , C1-C20의 알킬기, C2-C10의 알케닐기， C3-C10의 시클로알킬， CI— C10의 알복시기, C6-C12의 아릴， C5-C12의 헤테로 고리 기， -C00RKR1은 수소 또는 C1-C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클 로알킬) 또는 -0C0R2(R2는 CI— C5의 알킬기， C6-C12의 아릴 또는 C3— C10의 시클로 알킬) 또는 -C0RKKR10은 C1-C20의 알킬기， C6-C12의 아릴， C3-C10의 시클로알킬 기 또는 C5-C12의 헤테로 고리기)이고 Rb is hydrogen, halogen, N0 2 , CN, OH, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl, CI- C10 aryl group, C6-C12 aryl, C5-C12 Heterocyclic group, -C00RKR1 is hydrogen or C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl) or -0C0R2 (R2 is CI- C5 alkyl group, C6-C12 aryl or C3-C10 Cycloalkyl) or -C0RKKR10 is an alkyl group of C1-C20, an aryl of C6-C12, a cycloalkyl group of C3-C10 or a heterocyclic group of C5-C12)
Rc는 수소, 0H, 할로겐， CN, N02 , C1—C20의 알킬기， C2-C10의 알케닐기ᅳ C3-C10의 시클로알킬기, C1-C10의 알콕시기， C6-C12의 아릴, C5-C12의 헤테로 고 리기， -NR3R4(R3는 수소， C1-C20의 알킬기 또는 C6-C12 아릴， R4는 수소， C1-C20
의 알킬기 또는 C6-C12의 아릴이고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며, 추가로 1종 이상의 해테로 원자를 포함할 수 있다. )， -C00R5(R5은 수 소, C1-C20의 알킬기, C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， NR7CYR8(Y는 0 또는 S , R7은 수소 또는 C1-C5 알킬기, R8은 C1-C20의 알킬기， C6-C12 아릴, C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) , -NHS(0)2R9(R9은 C1-C5의 알킬기， C6-C12의 아릴 또는 C5-C12의 헤테로 고리기)， 또는 -C0R10(R10은 C1-C20의 알킬기， C6-C12의 아릴， C3— C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고， Rc is hydrogen, 0H, halogen, CN, N02, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 hetero Ring, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 It is an alkyl group of or C6-C12 aryl, R3 and R4 may combine to form a hetero ring, and may further include one or more heteroatoms. ), -C00R5 (R5 is hydrogen, C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 alkyl group, C6-C12 aryl or C3-C10 Cycloalkyl group), NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group) -NHS (0) 2 R9 (R9 is C1-C5 alkyl group, C6-C12 aryl or C5-C12 heterocyclic group), or -C0R10 (R10 is C1-C20 alkyl group, C6-C12 aryl, C3— C10 cycloalkyl group or C5-C12 heterocyclic group),
Rd는 0H , 할로겐， N02 , CN , C1-C20의 알킬기 , C2-C10의 알케닐기， C3-C10 의 시클로알킬기， C1-C10의 알콕시기， C6-C12의 아릴， C5-C12의 헤테로 고리기， -NR3R4(R3는 수소， C1-C20 알킬 또는 C6—C12 아릴， R4는 수소， C1-C20 알킬 또는 C6-C12 아릴이고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추가로 1종 이상의 헤테로 원자를 포함할 수 있다. )， -C00R5(R5은 수소, C1-C20의 알킬 기 , C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -0C0R6(R6는 CI— C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -NR7CYR8(Y는 0 또는 S, R7은 수 소 또는 C1-C5 알킬기， R8은 C1-C20의 알킬기， C6-C12 아릴, C3-C10의 시클로알 킬기 또는 C5-C12의 헤테로 고리기)， -NHS(0)2R9(R9은 C6-C12의 아릴 또는 C5-C12의 헤테로 고리기) 또는 -CORIOG O은 C1-C20의 알킬기, C6— C12의 아릴， C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고， Rd is 0H, halogen, N02, CN, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 heterocyclic group , -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6—C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R3 and R4 may combine to form a hetero ring, additionally 1 It may include more than one hetero atom), -C00R5 (R5 is hydrogen, C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is CI- C20 alkyl group , C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 Cycloalkyl group or C5-C12 heterocyclic group), -NHS (0) 2R9 (R9 is C6-C12 aryl or C5-C12 heterocyclic group) or -CORIOG O is C1-C20 alkyl, C6— C12 aryl, C3-C10 cycloalkyl Or a heterocyclic group) of C5-C12,
Re는 수소， N¾ , OH , 할로겐， CN , NCS , C1-C20의 알킬기， C2-C10의 알케닐 기 , C1-C10의 알콕시， C6-C12의 아릴옥시， C6-C12의 아릴， C5-C12의 헤테로 고리 기， -NR3R4(R3는 수소， C1-C20 알킬 또는 C6-C12 아릴, R4는 수소， C1-C20 알킬 또는 C6-C12 아릴이고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추 가로 1종 이상의 헤테로 원자를 포함할 수 있다.；)， -C00R5(R5은 C1-C5의 알킬기, C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -0C0R6 R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -NR7CYR8(Y는 0 또는 S , R7은 수 소 또는 C1-C5 알킬기, R8은 C1-C20의 알킬기， C6-C12 아릴， C3-C10의 시클로알 킬기 또는 C5-C12의 헤테로 고리기)， -NHS(0)2R9(R9은 C6-C12의 아릴 또는 C5-C12의 헤테로 고리기) 또는 -SR1UR11는 C1-C5의 알킬기) 이고, Re is hydrogen, N¾, OH, halogen, CN, NCS, C1-C20 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy, C6-C12 aryloxy, C6-C12 aryl, C5-C12 Heterocyclic group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R3 and R4 can be combined to form a hetero ring, It may further include one or more heteroatoms;), -C00R5 (R5 is C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 R6 is C1-C20 Alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3- C10 cycloalkyl group or C5-C12 heterocyclic group), -NHS (0) 2 R9 (R9 is C6-C12 aryl or C5-C12 heterocyclic group) or -SR1UR11 is C1-C5 alkyl group) ,
Rf는 수소, H2 , OH , 할로겐, N02 , N2+ , C1-C4의 알킬기， C2-C10의 알케닐 기， C1-C4의 알콕시기, C6-C12의 아릴, C5-C12의 헤테로 고리기， -NR3R4(R3는 수 소， C1-C20 알킬 또는 C6-C12 아릴， R4는 수소， C1-C20 알킬 또는 C6—C12 아릴이 고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며 추가로 1종 이상의 헤 테로 원자를 포함할 수 있다. )， -C00R5(R5은 C1-C5의 알킬기， C6-C12의 아릴 또
는 C3-C10의 시클로알킬기)， _0C0R6(R6는 C1-C20의 알킬기 , C6—C12의 아릴 또는 C3-C10의 시클로알킬기) , -NR7CYR8(Y는 0 또는 S , R7은 수소 또는 C1-C5 알킬 기 , R8은 C1-C20의 알킬기， C6-C12 아릴, C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 또는 C0R10(R10은 C1-C20의 알킬기, C6-C12의 아릴， C3— C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고， Rf is hydrogen, H 2 , OH, halogen, NO 2 , N 2 +, alkyl group of C1-C4, alkenyl group of C2-C10, alkoxy group of C1-C4, aryl of C6-C12, hetero of C5-C12 A ring group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6—C12 aryl, and R3 and R4 may combine to form a hetero ring. It may further comprise one or more hetero atoms.), -C00R5 (R5 is C1-C5 alkyl group, C6-C12 aryl or Is C3-C10 cycloalkyl group), _0C0R6 (R6 is C1-C20 alkyl group, C6—C12 aryl or C3-C10 cycloalkyl group), -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl , R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group) or C0R10 (R10 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 Cycloalkyl group or C5-C12 heterocyclic group),
Rg는 수소, NH2 , OH , 할로겐， N02 , C00H , CN , C1-C20의 알킬기， C2-C10의 알케닐기， C3-C10의 시클로알킬기， C1-C10의 알콕시기, C5-C12의 헤테로 고리기, - R3R4(R3는 수소， C1—C20 알킬 또는 C6-C12 아릴， R4는 수소， C1-C20 알킬 또는 C6-C12 아릴이고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며, 추가로 1종 이상의 헤테로 원자를 포함할 수 있다. )， -C00R5(R5은 C1-C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -0C0R6(R6는 C1—C20의 알킬기, C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -NR7CYR8(Y는 0 또는 S , R7은 수 소 또는 C1-C5 알킬기， R8은 C1-C20의 알킬기， C6-C12 아릴， C3-C10의 시클로알 킬기 또는 C5-C12의 헤테로 고리기) , -NHS(0)2R9(R9은 C6-C12의 아릴 또는 C5-C12의 헤테로 고리기) 또는 C0R10 (R10은 C1-C20의 알킬기， C6-C12의 아릴， C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고， Rg is hydrogen, NH 2 , OH, halogen, N02, C00H, CN, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C5-C12 hetero ring R3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 may combine to form a hetero ring, further It may include one or more hetero atoms.), -C00R5 (R5 is C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 alkyl group, C6 -C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cyclo Alkyl or C5-C12 heterocyclic group), -NHS (0) 2R9 (R9 is C6-C12 aryl or C5-C12 heterocyclic group) or C0R10 (R10 is C1-C20 alkyl group, C6-C12 Aryl, C3-C10 cycloalkyl group or C5 Heterocyclic group of -C12),
Rh는 수소， N¾ , OH , C1-C5의 알킬기 또는 C2-C10의 알케닐기이고, 상기 해테로 고리기의 해테로 원자는 질소, 산소 및 황으로 이루어진 군 으로부터 선택된 1종 이상 이고， Rh is hydrogen, N¾, OH, C1-C5 alkyl group or C2-C10 alkenyl group, the heteroatoms of the heterocyclic group are at least one selected from the group consisting of nitrogen, oxygen and sulfur,
상기 알킬기는 0H , 할로겐, 아민， C1-C5의 알콕시， C6-C12의 아릴， C5-C12의 헤테로 고리기 및 C3-C10의 시클로알킬기로 구성돤 군으로부터 선택되 는 1종 이상의 치환기로 치환될 수 있고， The alkyl group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5-C12 heterocyclic group and C3-C10 cycloalkyl group. Can
상기 알케닐기는 0H , 할로겐， 아민， C1-C5의 알콕시, C6— C12의 아릴, C5-C12의 헤테로 고리기 및 C3-C10의 시클로알킬기로 구성된 군으로부터 선택되 는 1종 이상의 치환기로 치환될 수 있고， The alkenyl group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5-C12 heterocyclic group and C3-C10 cycloalkyl group. Can
상기 알콕시기는 0H , 할로겐， C1ᅳ C5의 알콕시기， C6-C12의 아릴, C3-C10 의 시클로알킬기， 카르복시기, 아민 및 아미노카르보닐기로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있고， The alkoxy group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, C1 ᅳ C5 alkoxy group, C6-C12 aryl, C3-C10 cycloalkyl group, carboxyl group, amine and aminocarbonyl group,
상기 헤테로고리기는 알킬기， 아민 치환된 알킬기, 아민， 아마이드기 및 카르복실기로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있 고， The heterocyclic group may be substituted with one or more substituents selected from the group consisting of an alkyl group, an amine substituted alkyl group, an amine, an amide group and a carboxyl group,
상기 아릴은 할로겐， 알킬기, 히드록시기, 알콕시기， 카르복실기, 에스터 기, 니트로기 및 아민기로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있고, The aryl may be substituted with one or more substituents selected from the group consisting of halogen, alkyl group, hydroxy group, alkoxy group, carboxyl group, ester group, nitro group and amine group,
A, B, D , E , Gᅳ J , L , M . Rc 및 Rd는 서로 이웃한 기와 결합하여 축합환
을 형성할 수 있다. A, B, D, E, G ᅳ J, L, M. Rc and Rd are condensed with a group adjacent to each other Can be formed.
【청구항 21 [Claim 21]
청구항 1에 있어서， A는 CRa또는 N이고， B는 CRb 이고， G은 CRe 이고， J은 CRf 이고, M은 CRg또는 N 이고， D, E 및 L은 CH인 사이클로필린 기능 저해제 The cyclophylline inhibitors of claim 1 wherein A is CRa or N, B is CRb, G is CRe, J is CRf, M is CRg or N, and D, E and L are CH.
【청구항 3] [Claim 3]
청구항 1에 있어서， Rb는 수소 또는 C1-C8의 알킬기이고， The method according to claim 1, Rb is hydrogen or an alkyl group of C1-C8,
Rc는 C1-C20의 알킬기， C2-C10의 알콕시기, 폐닐알킬기， 니트로기， C3-C10의 시클로알킬기, C5-C12의 헤테로 고리기 또는 C1-C10의 알킬케톤이고， Rc is an alkyl group of C1-C20, an alkoxy group of C2-C10, a pentylalkyl group, a nitro group, a cycloalkyl group of C3-C10, a heterocyclic group of C5-C12, or an alkyl ketone of C1-C10,
Rd는 C1-C20의 알킬기; C3-C10의 에스터기; C3-C10의 시클로알킬기; 시클 로알킬기가 치환된 메톡시 ; 아민기가' 치환된 에톡시 ; 카르복시기; C1-C5의 알킬 기， C1-C5의 알콕시기, 카르복시기 또는 아민기로 치환 또는 비치환된 페닐기가 치환된 CI— C20의 알킬기; 아민; N-메틸피페라진; 피페리딘; 모르폴린 (morpholine); 또는 -C00R5(R5은 C1-C5의 알킬기 , C6-C12의 아릴 또는 C3-C10의 시클로알킬기)이고， Rd is a C1-C20 alkyl group; C3-C10 ester group; C3-C10 cycloalkyl group; Methoxy in which a cycloalkyl group is substituted; Ethoxy in which an amine group is substituted; Carboxyl groups; CI—C20 alkyl group substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, a phenyl group substituted or unsubstituted with a carboxyl group or an amine group; Amines; N-methylpiperazine; Piperidine; Morpholine; Or -C00R5 (R5 is an alkyl group of C1-C5, an aryl of C6-C12 or a cycloalkyl group of C3-C10),
Re는 수소， N , OH, C1-C20의 알킬기 또는 C1-C10의 알콕시기이고 Re is hydrogen, N, OH, a C1-C20 alkyl group or a C1-C10 alkoxy group
Rg는 수소， NH2, OH, C1-C20의 알킬기; C3-C10의 에스터기; C3-C10의 시클 로알킬기; 시클로알킬기가 치환된 메톡시; 아민기가 치환된 에톡시; C1-C5의 알 킬기， C1-C5의 알콕시기， 카르복시기 또는 아민기로 치환 또는 비치환된페닐기가 치환된 C2-C20의 알킬기; 아민; N-메틸피페라진; 피페리딘; 모르폴린 (morpholine); 또는 카르복시기인 사이클로필린 기능 저해제 Rg is hydrogen, NH 2 , OH, alkyl group of C1-C20; C3-C10 ester group; C3-C10 cycloalkyl group; Methoxy substituted with a cycloalkyl group; Ethoxy substituted with an amine group; A C2-C20 alkyl group substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, a carboxyl group or a substituted or unsubstituted phenyl group; Amines; N-methylpiperazine; Piperidine; Morpholine; Or cyclophylline inhibitors that are carboxyl groups
【청구항 4】 [Claim 4]
청구항 1에 있어서， 상기 알킬기는 -CH3, -CH2CH3) — C¾CH2C¾, -C¾(CH2)2C¾, — CH2(C )3CH3, -CH(CH3)CH2CH3, — CH2CH ((¾)(¾(¾， -CH2CH2CH(CH3)2, -CH(CH3)2, -C(CH3)3, -CH2C(C¾)3, — CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)C(CH3)3, -C(CH3)2CH2C¾, -C(CH3)2CH(CH3)2, -C(CH3)2C(C¾)3, -C¾CH2C(CH3)3, -CH2CH(CH3)CH(CH3)2, -CH2CH2C(CH3)2CH2CH3, The method according to claim 1, wherein the alkyl group is -CH 3 , -CH 2 CH 3) — C¾CH 2 C¾, -C¾ (CH 2 ) 2 C¾, —CH 2 (C) 3 CH 3 , -CH (CH 3 ) CH 2 CH 3 , — CH 2 CH ((¾) (¾ (¾, -CH 2 CH 2 CH (CH 3 ) 2 , -CH (CH 3 ) 2 , -C (CH 3 ) 3 , -CH 2 C (C¾ ) 3 , — CH 2 CH (CH 3 ) 2 , -CH (CH 3 ) CH (CH 3 ) 2 , -CH (CH 3 ) C (CH 3 ) 3, -C (CH 3 ) 2 CH 2 C¾, -C (CH 3 ) 2 CH (CH 3 ) 2 , -C (CH 3 ) 2 C (C¾) 3 , -C¾CH2C (CH 3 ) 3 , -CH 2 CH (CH 3 ) CH (CH 3 ) 2, -CH 2 CH 2 C (CH 3 ) 2 CH 2 CH 3 ,
또는 、」 ^ 인 사이클로필린 기능 저해제 Or ^^ phosphorus cyclophilin function inhibitors
【청구항 5] [Claim 5]
청구항 1에 있어서, 상기 알콕시기는 _0(¾， -0CF3, -0C¾CH3, -OCH2CH2CH3,The method of claim 1, wherein the alkoxy group is _0 (¾, -0CF 3 , -0C¾CH 3 , -OCH2CH2CH3,
-OCH2CH2CH2CH3, -0CH(CH3)CH2CH3, -OCH2CONH2, -0CH2CH2N(CH3)2,
-OCH2CH2CH2CH3, -0CH (CH 3 ) CH 2 CH3, -OCH2CONH2, -0CH 2 CH2N (CH 3 ) 2,
【청구항 6】 [Claim 6]
청구항 1에 있어서， 헤테로 고리기는
The heterocyclic group according to claim 1, wherein the heterocyclic group
【청구항 8】 [Claim 8]
청구항 1에 있어서， -0C0R6는
The method according to claim 1, -0C0R6 is
저해제 Inhibitor
【청구항 9】 [Claim 9]
청구항 1에 있어서, -NR3R4는 -NH2, -NHCH3, -N(CH3)2, N(CH2CH3)2,
The method according to claim 1, -NR 3 R 4 is -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , N (CH 2 CH 3 ) 2 ,
기능 저해제 Function inhibitors
【청구항 10】 [Claim 10]
【청구항 12】 [Claim 12]
하기 화학식 1로 표시되는 스틸벤 유도체， 또는 이의 약제학적으로 허용 가능한 염을 포함하는 사이클로필린 관련 질환또는 손상의 예방또는 치료용도의 조성물
[화학식 1] A composition for preventing or treating cyclophylline-related diseases or injuries, including a stilbene derivative represented by Formula 1, or a pharmaceutically acceptable salt thereof [Formula 1]
A는 CRa또는 N이고， A is CRa or N,
B는 CRb 또는 N이고， B is CRb or N,
G은 CRe 또는 N이고 G is CRe or N
J은 CRf 또는 N이고， J is CRf or N,
M은 CRg또는 N이고， M is CRg or N,
D , E , 및 L은 CRh또는 N이고 D, E, and L are CRh or N
R 는 H , CH3 , CN , NH2 , F , CI , Br또는 I이며, R is H, CH 3 , CN, NH 2 , F, CI, Br or I,
Ra는 수소, 할로겐， N02 , CN , OH , C1-C5 알킬기， C2-C10의 알케닐기, C1-C6 알콕시기， -C00R R1은 수소 또는 C1-C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬) 또는 -0C0R2(R2는 CI— C5의 알킬기， C6— C12의 아릴 또는 C3-C10의 시클로알킬) 이고， Ra is hydrogen, halogen, N0 2 , CN, OH, C1-C5 alkyl group, C2-C10 alkenyl group, C1-C6 alkoxy group, -C00R R1 is hydrogen or C1-C5 alkyl group, C6-C12 aryl or C3 -C10 cycloalkyl) or -0C0R2 (R2 is CI-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl),
Rb는 수소， 할로겐, N02 , CN , OH , C1-C20의 알킬기， C2-C10의 알케닐기, C3-C10의 시클로알킬， C1-C10의 알콕시기, C6-C12의 아릴, C5-C12의 해테로 고리 기， -C00RUR1은 수소 또는 C1-C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클 로알킬) 또는 -0C0R2(R2는 C1-C5의 알킬기 , C6-C12의 아릴 또는 C3-C10의 시클로 알킬) 또는 -CORKKR10은 C1-C20의 알킬기, C6-C12의 아릴， C3-C10의 시클로알킬 기 또는 C5-C12의 헤테로 고리기)이고 Rb is hydrogen, halogen, N0 2 , CN, OH, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 Heterocyclic group, -C00RUR1 is hydrogen or C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl) or -0C0R2 (R2 is C1-C5 alkyl group, C6-C12 aryl or C3- C10 cycloalkyl) or -CORKKR10 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group)
Rc는 수소， 0H , 할로겐， CN , N02 , C1-C20의 알킬기， C2-C10의 알케닐기， C3-C10의 시클로알킬기， C1-C10의 알콕시기, C6-C12의 아릴， C5-C12의 헤테로 고 리기， NR3R4(R3는 수소, C1-C20의 알킬기 또는 C6-C12 아릴， R4는 수소, CI— C20 의 알킬기 또는 C6-C12의 아릴이고, R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추가로 1종 이상의 헤테로 원자를 포함할 수 있다. ) , -C00R5(R5은 수 소, C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -NR7CYR8(Y는 0 또는 Sᅳ R7은 수소 또는 CI— C5 알킬기， R8은 C1-C20의 알킬기， C6-C12 아릴,
C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기)， -NHS(0)2R9(R9은 C1-C5의 알킬기， C6-C12의 아릴 또는 C5-C12의 헤테로 고리기)， 또는 -COR10(R10은 C1-C20의 알킬기 C6-C12의 아릴, C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고, Rc is hydrogen, 0H, halogen, CN, N02, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 hetero Ring, NR3R4 (R3 is hydrogen, C1-C20 alkyl group or C6-C12 aryl, R4 is hydrogen, CI- C20 alkyl group or C6-C12 aryl, R3 and R4 can combine to form a hetero ring, , And may further include one or more hetero atoms.), -C00R5 (R5 is hydrogen, C1-C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1 -C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S ᅳ R7 is hydrogen or CI- C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group), -NHS (0) 2 R9 (R9 is C1-C5 alkyl group, C6-C12 aryl or C5-C12 heterocyclic group), or -COR10 (R10 is C1-C20 alkyl group C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group),
Rd는 0H, 할로겐， N02 , CN, C1-C20의 알킬기， C2-C10의 알케닐기 , C3-C10 의 시클로알킬기， C1-C10의 알콕시기， C6-C12의 아릴， C5-C12의 헤테로 고리기， - R3R4(R3는 수소， C1-C20 알킬 또는 C6-C12 아릴 , R4는 수소, C1-C20 알킬 또는 C6-C12 아릴이고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추가로 1종 이상의 헤테로 원자를 포함할 수 있다. )， -C00R5(R5은 수소, CI— C20의 알킬 기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -NR7CYR8(Y는 0 또는 S , R7은 수 소 또는 C1-C5 알킬기， R8은 C1-C20의 알킬기， C6-C12 아릴, C3-C10의 시클로알 킬기 또는 C5-C12의 헤테로 고리기)， -NHS(0)2R9(R9은 C6-C12의 아릴 또는 C5-C12의 헤테로 고리기) 또는 -COR10(R10은 C1-C20의 알킬기, C6-C12의 아릴， C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고， Rd is 0H, halogen, N02, CN, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C6-C12 aryl, C5-C12 heterocyclic group ,-R3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R3 and R4 can combine to form a hetero ring, additionally 1 It may contain more than one hetero atom), -C00R5 (R5 is hydrogen, CI- C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 alkyl group) , C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 Cycloalkyl group or C5-C12 heterocyclic group), -NHS (0) 2R9 (R9 is C6-C12 aryl or C5-C12 heterocyclic group) or -COR10 (R10 is C1-C20 alkyl, C6 -C12 aryl, C3-C10 cycloalkyl group Is a heterocyclic group) of C5-C12,
Re는 수소， NH2 , OH , 할로겐, CN , NCS , C1-C20의 알킬기， C2-C10의 알케닐 기, C1-C10의 알콕시， C6-C12의 아릴옥시， C6-C12의 아릴， C5-C12의 헤테로 고리 기 , -NR3R4(R3는 수소， C1-C20 알킬 또는 C6-C12 아릴 , R4는 수소， C1-C20 알킬 또는 C6-C12 아릴이고， R3와 R4는 결합하여 해테로 고리를 형성할 수 있으며， 추 가로 1종 이상의 헤테로 원자를 포함할 수 있다. ) , -C00R5(R5은 C1-C5의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -NR7CYR8(Y는 0 또는 S , R7은 수 소 또는 C1-C5 알킬기, R8은 CI— C20의 알킬기， C6-C12 아릴， C3-C10의 시클로알 킬기 또는 C5-C12의 헤테로 고리기)， -NHS(0)2R9(R9은 C6-C12의 아릴 또는 C5-C12의 헤테로 고리기) 또는 -SR1KR11는 C1-C5의 알킬기) 이고， Re is hydrogen, NH 2 , OH, halogen, CN, NCS, C1-C20 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy, C6-C12 aryloxy, C6-C12 aryl, C5- C12 heterocyclic group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 are joined to form a hetero ring. And may further include one or more heteroatoms.), -C00R5 (R5 is C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1- C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is CI- C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group), -NHS (0) 2 R9 (R9 is C6-C12 aryl or C5-C12 heterocyclic group) or -SR1KR11 is C1-C5 alkyl group ) ego,
Rf는 수소， H2 , OH, 할로겐, N02 , N2 +, C1-C4의 알킬기， C2-C10의 알케닐 기， C1-C4의 알콕시기， C6-C12의 아릴， C5-C12의 헤테로 고리기， -NR3R4(R3는 수 소， C1-C20 알킬 또는 C6-C12 아릴， R4는 수소, C1-C20 알킬 또는 C6-C12 아릴이 고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추가로 1종 이상의 헤 테로 원자를 포함할 수 있다. ) , -C00R5(R5은 C1-C5의 알킬기， C6-C12의 아릴 또 는 C3-C10의 시클로알킬기) , -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기) , -NR7CYR8(Y는 0 또는 S , R7은 수소 또는 C1-C5 알킬 기， R8은 C1-C20의 알킬기， C6-C12 아릴， C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 또는 C0RKKR10은 C1-C20의 알킬기， C6-C12의 아릴， C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고，
Rg는 수소， NH2 ) OH, 할로겐， N02 , C00H, CN, C1-C20의 알킬기, C2-C10의 알케닐기， C3-C10의 시클로알킬기, C1-C10의 알콕시기， C5-C12의 헤테로 고리기， -NR3R4(R3는 수소， C1-C20 알킬 또는 C6-C12 아릴， R4는 수소, C1-C20 알킬 또는 C6-C12 아릴이고， R3와 R4는 결합하여 헤테로 고리를 형성할 수 있으며， 추가로 1종 이상의 헤테로 원자를 포함할 수 있다. )， -C00R5(R5은 C1-C5의 알킬기, C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -0C0R6(R6는 C1-C20의 알킬기， C6-C12의 아릴 또는 C3-C10의 시클로알킬기)， -NR7CY 8(Y는 0 또는 S, R7은 수 소 또는 C1-C5 알킬기 , R8은 C1-C20의 알킬기 , C6-C12 아릴, C3— C10의 시클로알 킬기 또는 C5-C12의 헤테로 고리기) , -NHS(0)2R9(R9은 C6-C12의 아릴 또는 C5-C12의 헤테로 고리기) 또는 C0R10 (R10은 C1-C20의 알킬기， C6-C12의 아릴， C3-C10의 시클로알킬기 또는 C5-C12의 헤테로 고리기) 이고， Rf is hydrogen, H 2 , OH, halogen, NO 2 , N 2 + , alkyl group of C1-C4, alkenyl group of C2-C10, alkoxy group of C1-C4, aryl of C6-C12, hetero of C5-C12 A ring group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 may combine to form a hetero ring. And may further contain one or more hetero atoms.), -C00R5 (R5 is an alkyl group of C1-C5, an aryl of C6-C12 or a cycloalkyl group of C3-C10), -0C0R6 (R6 is C1- C20 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group, -NR7CYR8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group) or C0RKKR10 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group or C5-C12 heterocyclic group), Rg is hydrogen, NH 2) OH, halogen, N02, C00H, CN, C1-C20 alkyl group, C2-C10 alkenyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy group, C5-C12 hetero ring Group, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R3 and R4 may combine to form a hetero ring, further It may include one or more hetero atoms.), -C00R5 (R5 is C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -0C0R6 (R6 is C1-C20 alkyl group, C6 -C12 aryl or C3-C10 cycloalkyl group, -NR7CY 8 (Y is 0 or S, R7 is hydrogen or C1-C5 alkyl group, R8 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 Cycloalkyl or C5-C12 heterocyclic group), -NHS (0) 2 R9 (R9 is C6-C12 aryl or C5-C12 heterocyclic group) or C0R10 (R10 is C1-C20 alkyl group, C6- C12 aryl, C3-C10 cycloalkyl group or C5-C12 A heterocyclic group),
Rh는 수소， NH2 , OH, C1-C5의 알킬기 또는 C2-C10의 알케닐기이고, 상기 헤테로 고리기의 헤테로 원자는 질소， 산소 및 황으로 이루어진 군 으로부터 선택된 1종 이상 이고, Rh is hydrogen, NH 2 , OH, C 1 -C 5 alkyl group or C 2 -C 10 alkenyl group, and the hetero atom of the hetero ring group is at least one member selected from the group consisting of nitrogen, oxygen and sulfur,
상기 알킬기는 아 1， 할로겐， 아민， C1-C5의 알콕시， C6-C12의 아릴， C5-C12의 헤테로 고리기 및 C3-C10의 시클로알킬기로 구성된 군으로부터 선택되 는 1종 이상의 치환기로 치환될 수 있고， The alkyl group may be substituted with one or more substituents selected from the group consisting of a 1, halogen, amine, alkoxy of C1-C5, aryl of C6-C12, heterocyclic group of C5-C12 and cycloalkyl group of C3-C10. Can
상기 알케닐기는 0H, 할로겐， 아민， C1-C5의 알콕시， C6-C12의 아릴， C5-C12의 헤테로 고리기 및 C3-C10의 시클로알킬기로 구성된 군으로부터 선택되 는 1종 이상의 치환기로 치환될 수 있고， The alkenyl group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5-C12 heterocyclic group and C3-C10 cycloalkyl group. Can
상기 알콕시기는 0H, 할로겐， C1-C5의 알콕시기， C6-C12의 아릴， C3-C10 의 시클로알킬기, 카르복시기， 아민 및 아미노카르보닐기로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있고， The alkoxy group may be substituted with one or more substituents selected from the group consisting of 0H, halogen, C1-C5 alkoxy group, C6-C12 aryl, C3-C10 cycloalkyl group, carboxyl group, amine and aminocarbonyl group,
상기 헤테로고리기는 알킬기， 아민 치환된 알킬기， 아민， 아마이드기 및 카르복실기로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있 고， The heterocyclic group may be substituted with one or more substituents selected from the group consisting of alkyl group, amine substituted alkyl group, amine, amide group and carboxyl group,
상기 아릴은 할로겐， 알킬기， 히드톡시기， 알콕시기, 카르복실기， 에스터 기, 니트로기 및 아민기로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있고， The aryl may be substituted with one or more substituents selected from the group consisting of halogen, alkyl group, hydroxy group, alkoxy group, carboxyl group, ester group, nitro group and amine group,
A, B , D , E , G, J , L , M. Rc 및 Rd는 서로 이웃한 기와 결합하여 축합환 을 형성할 수 있다. A, B, D, E, G, J, L, M. Rc and Rd may combine with adjacent groups to form a condensed ring.
【청구항 13] [Claim 13]
청구항 12에 있어서， 상기 사이클로필린 관련 질환 또는 손상은 바이러스 감염 (vi ral infect ion) 질환, 염증 반웅경로 ( inf lammat ion process)에 관련된 질환, 또는 미토콘드리아 기능이상 (mi tochondr ial dysfunct ion)에 관련된 질환인
것을 특징으로 하는 사이클로필린 관련 질환또는 손상의 예방또는 치료용도의 조성물 The method of claim 12, wherein the cyclophilin-related disease or injury is a viral infection disease, a disease associated with an inf lammat ion process, or a disease associated with mitochondrial dysfunct ion. sign Composition for the prevention or treatment of cyclophylline-related diseases or damages, characterized in that
【청구항 14】 [Claim 14]
청구항 12에 있어서 상기 사이클로필린 관련 질환 또는 손상은 HAV 바이 러스， HBV 바이러스, HCV 바이러스, HDV 바이러스， HEV 바이러스， 코로나바이러 스(«)1"0113 1 3)， HIV 바이러스， 인플루엔자 (influenza) 바이러스 감염 (viral infection) 질환， 죽상동맥경화증 (atherosclerosis), 복부대동맥류 (abdominal aortic aneurysms) , 허혈성 심장질환 (ischaemic heart diseases) , 심장과비대 (cardiac hypertrophy) , 류마티스 관절염 (rheumatoid arthritis), 패혈증 (sepsis), 치주질환 (periodontal disease)», 콜라겐 VI 근병증 (collagen VI myopathies) , 심정지早 증후군 (Post—cardiac arrest syndrome) , 심부전 (heart failure), 급성 폐염 (Acute Lung Inflammation) , 천식 (asthma), 노화 (aging), 탈모 (Alopecia), 비알코올성 지방간염 (Non-Alcohol ic Steatohepatitis) , 비만 (obesity), 신장섬유화 (renal fibrosis), 신독성 (nephrotoxicity)， 폐쇄성 신병 증 (obstructive nephropathy) , 시스플라틴 유래 신질환 (cisplatirHnduced renal disease) , 급성 신부전 (acute renal failure), 만성 신부전 (chronic renal failure), 신장 사구체병증 (renal glomerulopathy), 말기 신질환 (end stage renal disease) , 관절형성이상 (bone disorder), 골다공증 (osteoporosis)， 관절염 (arthritis), 골관절염 (osteoarthritis) , 골파제트병 (Paget ' s disease), 알츠하 이머 질환 (Alzheimer 's disease), 파킨슨 질환 (Parkinson' s disease), 뇌허혈증 (cerebral ischemia) , 다계통 위죽증 (multiple systems atrophy) , 뇌성마비 (cerebral palsy), 당뇨병성 신경병증 (diabetic neuropathy) , 헌팅튼 질환 (Huntington's disease), 다발성 경화증 (MS, Multiple Sclerosis), 근위축성측색 경화증 (ALS, amyotrophic lateral sclerosis) , 근육위축증 (muscular dystrophy) , 뇌전증 (Epilepsy), 자폐증 (Autism)， 양극성 장애 (bipolar disorder), 흥분독성 손상 (excitotoxic injury) , 간성 뇌병증 (hepatic encephalopathy) , 저혈당증 (hypoglycemia) , 망간독성 (manganese toxicity) , 신경병증 (neuropathies)， 진행 성근육취축증 (progressive muscular atrophy), 말초신경병증 (peripheral neuropathy) , 삼차 신경병증 (Trigeminal Neuralgia), 설인신경통 (Glossopharyngeal neuralgia), 안면신경 마비 (Bell's palsy), 중증근무력증 (Myasthenia Gravis), 신경장애 (neurological disorder), 소세포 및 비소세포 폐 암 (Small and Non-Small Cell Lung Cancer), 방광암 (Bladder Cancer), 간세포암 (Hepatocellular Cancer), 췌장암 (Pancreatic Cancer) , 유방암 (Breast Cancer), 편평세포암 (squamous cell carcinoma) , 혹색종 (melanoma) , 전립선암 (.prostate cancer), 대장암 (colon cancer), 교모세포종 (gl ioblastoma)， 자궁내막암
(endometrial cancer) , 갑상선암 (thyroid cancer) , 림프종 ( lymphomas)， 난소암 (ovarian cancer), 외상성 뇌손상 (Traumatic Brain Injury), 척추， 말초, 중앙 신경 세포의 외상성 손상 (traumatic injury of spinal , peripheral or central nervous tissue) , 허혈성 뇌손상 (Ischemic Brain Injury) , 신장, 뇌， 폐， 장， 심 장 (kidney, brain, lung, intestine, heart)의 허혈성 재관류손상 (Ischemia Reper fusion Injury) , 뇌졸중 (Stroke)， 심근경색증 (Myocardial Infarction) , 심 부전 (Heart Failure), 급성 간독성 (acute hepatotoxicity) , 담즙분비중지 (cholestasis), 또는 이식장기 보관 /재관류 손상 (storage/reperfus ion injury of transplant organs)인 것을 특징으로 하는 사이클로필린 관련 질환 또는 손상의 예방 또는 치료용도의 조성물
The method according to claim 12, wherein the cyclophylline-related disease or injury is HAV virus, HBV virus, HCV virus, HDV virus, HEV virus, coronavirus («) 1 " 0113 1 3), HIV virus, influenza virus Viral infection diseases, atherosclerosis, abdominal aortic aneurysms, ischemic heart diseases, cardiac hypertrophy, rheumatoid arthritis, sepsis ), Periodontal disease », collagen VI myopathies, post-cardiac arrest syndrome, heart failure, Acute Lung Inflammation, asthma, aging (aging), alopecia, non-alcoholic steatohepatitis, obesity, renal fibrosis, nephrotoxicity, obstructive nephropathy (obstructive nephropathy), cisplatirHnduced renal disease, acute renal failure, chronic renal failure, renal glomerulopathy, end stage renal disease, arthropathy (bone disorder), osteoporosis, arthritis, osteoarthritis, osteoarthritis, Paget's disease, Alzheimer's disease, Parkinson's disease, Cerebral ischemia, multiple systems atrophy, cerebral palsy, diabetic neuropathy, Huntington's disease, Multiple Sclerosis, MS Amyotrophic lateral sclerosis (ALS), muscular dystrophy, epilepsy, autism, bipolar disorder, excitotoxic injury ), Hepatic encephalopathy, hypoglycemia, manganese toxicity, neuropathies, progressive muscular atrophy, peripheral neuropathy, trigeminal neuropathy Trigeminal Neuralgia, Glossopharyngeal neuralgia, Bell's palsy, Myyasthenia Gravis, Neurological disorders, Small and Non-Small Cell Lung Cancer, Bladder Cancer, Hepatocellular Cancer, Pancreatic Cancer, Breast Cancer, Breast Cancer, Squamous Cell Carcinoma, Melanoma, Prostate Cancer, Colon Cancer (colon cancer), glioblastoma, endometrial cancer (endometrial cancer), thyroid cancer, lymphomas, ovarian cancer, traumatic brain injury, traumatic injury of the spine, peripheral and central nerve cells (traumatic injury of spinal, peripheral or central nervous tissue, Ischemic Brain Injury, Ischemia Reper fusion Injury, Stroke, Kidney, Brain, Lung, Intestine, Heart ， Myocardial infarction, heart failure, acute hepatotoxicity, cholestasis, or storage / reperfus ion injury of transplant organs A composition for preventing or treating cyclophylline-related diseases or damages
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| KR1020170103064A KR20180036523A (en) | 2016-09-30 | 2017-08-14 | Inhibitor of function of cyclophilin and use of the same |
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