KR101935794B1 - Inhibitor of function of cyclophilin and use of the same - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the treatment or prophylaxis of a cyclophilin-related disease or disorder, or a symptom of illness, comprising a stilbene derivative or a pharmaceutically acceptable salt thereof which inhibits the function of cyclophilin.

Description

Cyclophilin function inhibitors and methods of using the same

The present invention relates to a cyclophilin function inhibitor comprising a stilbene derivative or a pharmaceutically acceptable salt thereof and a use thereof, and is useful for the prevention or treatment of a cyclophilin-related disease or injury such as chronic viral infection, degenerative neurological disease and tumorigenesis ≪ / RTI >

Cyclophilin (CyP), a protein belonging to the immunophilin, is found in all cells of all organisms, both prokaryotes and eukaryotes, and is well structurally conserved through evolution. There are a total of 16 unique proteins in humans, including seven major CyPs: CyP A, CyP B, CyP C, CyP D, CyP E, CyP 40, and CyP NK.

Cyclophilins are found in most cells of the human body and CyP A and CyP 40 in mammals are cytoplasmic signal sequences whereas CyP B and CyP C have targeted amino-terminal signal sequences for the vesicular protein secretory pathway. CyP D has a signal sequence that directs to mitochondria, CyP E has an amino-terminal RNA binding domain, and CyP 40 has a TPR and is located in the cytoplasm. Human CyP NK is the largest CyP with a large hydrophilic and positively charged carboxyl end, located in the cytoplasm.

The cyclophilin is a multifunctional protein involved in cell processes, highly preserved through evolution, and has an essential function in cells.

Cyclopylline has been found to have enzymatic properties that catalyze cis-trans isomerization of peptidyl-prolyl conjugates. Thus, cyclophilin is referred to as peptidyl-prolyl cis-trans isomerase (PPIase), which can serve as an accelerating factor in proper folding of newly synthesized proteins , PPIase is also involved in repairing damaged proteins due to environmental stresses, including thermal stress, ultraviolet radiation, changes in the pH of the cellular environment, and oxidant treatment. This function is known as molecular chaperone activity. PPIase activity of cyclophilin was also found to be involved in intracellular protein trafficking, mitochondrial function and pre-mRNA processing.

Cyclosporine, one of the cyclophilin inhibitors, binds in the hydrophobic pocket of CyP A and inhibits PPIase activity. CyP A is a prototypical of the cyclophilin family and shows very high sequence homology with CyP B, CyP C, and CyP D in humans. The binding pockets of all cyclophilins are formed by approximately 109 amino acids, a highly conserved region, and the sequence identity between CyP A and CyP D is 100%. Therefore, CyP A binding affinity is the best predictor of CyP D binding affinity and vice versa.

This sequence homology between cyclophilins means that not only CyP D but also all cyclophilins are potential targets for functional inhibitors with binding affinity to CyP A. Suggesting that functional inhibitors of CyP A may be useful in the treatment of a number of disease manifestations involving cyclophilin.

Recently, there have been reports that cyclophilin is involved in various diseases. The diseases are largely divided into three categories: viral infection disease, diseases related to the inflammation process, and mitochondrial dysfunction (mitochondrial dysfunction) dysfunction).

Viral infection diseases include HAV viruses, HBV viruses, HCV viruses, HIV viruses, HDV viruses, HEV viruses, coronaviruses, influenza viruses and the like and are involved in the inflammation process The diseases are selected from the group consisting of cardiovascular diseases, rheumatoid arthritis, sepsis, periodontitis, acute lung inflammation, asthma, aging, alopecia, And alcoholic steatohepatitis (non-alcoholic steatohepatitis).

Diseases caused by mitochondrial dysfunction include neurodegenerative diseases, cancer, and acute injuries. In fact, cyclosporine or cyclosporine derivatives, which inhibit the function of cyclophilin, (Nigro P, et al., Cell Death Dis 2013, 4, e 888).

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 that it interacts with RAase NS5B, binds with HIV (Human Immunodeficiency Virus) capsid protein, and interacts with M1 protein (matrix protein 1) at the early stage of influenza virus replication.

Cardiovascular diseases resulting from the involvement of cyclophilin in the inflammation process include atherosclerosis, abdominal aortic aneurysms, ischaemic heart diseases, Cardiac hypertrophy, rheumatoid arthritis, sepsis, periodontal disease, collagen VI myopathies, post-cardiac arrest syndrome, heart failure, , Acute Lung Inflammation, Asthma, Aging, Alopecia, Non-Alcoholic Steatohepatitis, Obesity, Renal Fibrosis, Nephrotoxicity nephrotoxicity, obstructive nephropathy, cisplatin-induced renal disease, acute renal failure, chronic renal failure, renal globulin, end stage renal disease, bone disorder, osteoporosis, arthritis, osteoarthritis, Paget's disease, and the like are known.

In the case of rheumatoid arthritis (RA), which is caused by the involvement of cyclophilin in the inflammation process, it has been shown that CD147 interacts with MMP-9 and MMP-2 to increase secretion. Pseudomonas aeruginosa - induced septicemia has been shown to regulate cyclophilin expression in peripheral lymphocytes and alopecia to increase the growth phase of hair follicles during cyclophilin inhibition.

Neurodegenerative diseases resulting from mitochondrial dysfunction involving cyclophilin include Alzheimer ' s disease, Parkinson ' s disease, Huntington ' s disease, MS Multiple sclerosis, amyotrophic lateral sclerosis, muscular dystrophy, epilepsy, autism cerebral ischemia, multiple systems atrophy, cerebral ischemia, cerebral ischemia, The compounds of the present invention are useful in the treatment of cerebral palsy, diabetic neuropathy, bipolar disorder, excitotoxic injury, hepatic encephalopathy, hypoglycemia, manganese toxicity, Neuropathies, progressive muscular atrophy, peripheral neuropathy, trigeminal neuralgia, neuropathy, neuropathies, It is known, such as Tong (Glossopharyngeal neuralgia), facial nerve paralysis (Bell's palsy), myasthenia gravis (Myasthenia Gravis), neurological disorders (neurological disorder).

Cyclophilins are known to be involved in the growth of cancer tissues, including small and non-small cell lung cancers, bladder cancer, liver cancer, A cancer, a pancreatic cancer, a breast cancer, a squamous cell carcinoma, a melanoma, a prostate cancer, a colon cancer, a glioblastoma, endometrial cancer, thyroid cancer, lymphomas, ovarian cancer, and the like.

Acute injuries resulting from mitochondrial dysfunction involving cyclophilin include traumatic brain injuries, traumatic injuries of the spinal, peripheral, and central nerve cells. Ischemia Reperfusion Injury, Cardiac Reperfusion Injury in the Central Nervous Tissue, Ischemic Brain Injury, Kidney, Brain, Lung, Intestine, Heart, Injury, Stroke, Myocardial Infarction, Heart Failure, acute hepatotoxicity, cholestasis, storage / reperfusion injury of transplant organs, .

Korean Patent Registration No. 1309409

It is therefore an object of the present invention to provide an inhibitor which inhibits the function of cyclophilin which causes various diseases. It is also an object of the present invention to provide a method for preventing or treating a viral infection disease, a disease related to an inflammation process, a disease or damage related to mitochondrial dysfunction by inhibiting the function of cyclophilin . It is also an object of the present invention to provide a medicament for inhibiting the function of cyclophilin and for the treatment of viral infection diseases, cardiovascular diseases, rheumatoid arthritis, sepsis, periodontitis, Acute Lung Inflammatory diseases such as inflammation, inflammation, asthma, aging, alopecia, neurodegenerative diseases, cancer, acute injuries or the like, And to provide a pharmaceutical composition.

In order to solve the above problems, the present invention provides a cyclophilin 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 use in the prevention or treatment of a cyclophilin-related disease or injury comprising a stilbene derivative represented by the following formula (1), or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In this formula,

A is CR < a > 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, Cl, Br or I,

R a is hydrogen, halogen, NO ₂ , CN, OH, a C 1 -C 5 alkyl group, a C 2 -C 10 alkenyl group, a C 1 -C 6 alkoxy group, -COOR 1 wherein R 1 is hydrogen or a C 1 -C 5 alkyl group, C3-C10 cycloalkyl) or -OCOR2 (R2 is C1-C5 alkyl, C6-C12 aryl or C3-C10 cycloalkyl)

Rb is hydrogen, halogen, NO _2, CN, OH, C1-C20 alkyl group, an alkenyl group of C2-C10, an alkoxy group of the cycloalkyl, C1-C10 of C3-C10, aryl C6-C12, C5-C12 (Wherein R 1 is a hydrogen or a C 1 -C 5 alkyl, a C 6 -C 12 aryl or a C 3 -C 10 cycloalkyl) or -OCOR 2 (wherein R 2 is a C 1 -C 5 alkyl group, a C 6 -C 12 aryl or a C 3 -C 10 aryl group, C10 cycloalkyl) or -COR10 (R10 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or C5-C12 heterocyclic group)

Rc is selected from the group consisting of hydrogen, OH, halogen, CN, NO2, a C1-C20 alkyl group, a C2-C10 alkenyl group, a C3-C10 cycloalkyl group, a C1-C10 alkoxy group, R 3 is hydrogen, a C 1 -C 20 alkyl group or a C 6 -C 12 aryl group, R 4 is hydrogen, a C 1 -C 20 alkyl group or a C 6 -C 12 aryl group, and R 3 and R 4 may be combined to form a heterocycle (Wherein R5 is hydrogen, a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -OCOR6 (R6 is C1 (Wherein Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, R8 is a C1-C20 alkyl group, a C6-C12 aryl group, or a C3-C10 cycloalkyl group), -NR7CYR8 C3-C10 heterocyclic group of the cycloalkyl or C5-C12), -NHS (O ) 2 R9 (R9 is C1-C5 alkyl group, C6-C12 aryl or a heterocyclic group) or -COR10 of C5-C12 (R10 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or A heterocyclic group) of C5-C12,

Rd is OH, halogen, NO2, CN, a C1-C20 alkyl group, a C2-C10 alkenyl group, a C3-C10 cycloalkyl group, a C1-C10 alkoxy group, a C6-C12 aryl group, a C5-C12 heterocyclic group , -NR3R4 wherein R3 is hydrogen, C1-C20alkyl or C6-C12aryl, R4 is hydrogen, C1-C20alkyl or C6-C12aryl, R3 and R4 may combine to form a heterocycle, -COOR5 (R5 is hydrogen, a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, (Wherein Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, R8 is a C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group), -NR7CYR8 alkyl group or a C5-C12 heterocyclic _{group), -NHS (O) 2 R9} (R9 is a C6-C12 heterocyclic group of the aryl or C5-C12), or COR10 (R10 is an alkyl group of C1-C20, of C6-C12 Aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group)

Re is hydrogen, NH _2, OH, halogen, CN, NCS, C1-C20 alkyl, C2-C10 alkenyl group, C1-C10 alkoxy, C6-C12 aryl-oxy, aryl of C6-C12, C5-C12 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 heterocycle, (Wherein R5 is C1-C5 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), -OCOR6 (R6 is C1-C20 alkyl, (Wherein Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, R8 is a C1-C20 alkyl group, C6-C12 aryl, C3-C10 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -NR7CYR8 the cycloalkyl group or the heterocyclic group of C5-C12), -NHS (O ) 2 R9 (R9 is a C6-C12 heterocyclic group of the aryl or C5-C12), or -SR11 (R11 is C1-C5 alkyl group), and ,

Rf is hydrogen, NH _2, OH, halogen, NO _2, N ₂ ^+, C1-C4 alkyl group, an alkoxy group of C2-C10 alkenyl group, C1-C4, a C6-C12 aryl, heterocyclic ring of C5-C12 And R 3 and R 4 may be combined to form a heterocyclic ring, and further, R 3 and R 4 may be the same or different and each represents a hydrogen atom, a C 1 -C 20 alkyl group or a C 6 -C 12 aryl group, (Wherein R5 is a C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, C6 (Wherein Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, R8 is a C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group), -NR7CYR8 Or a C10-C12 heterocyclic group) or COR10 (wherein R10 is a C1-C20 alkyl group, a C6-C12 aryl group, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group)

Rg is hydrogen, NH _2, OH, halogen, NO2, COOH, CN, C1-C20 alkyl group, an alkenyl group of C2-C10, an alkoxy group, a heterocyclic group of C5-C12 cycloalkyl group, C1-C10 of the C3-C10 And R 3 and R 4 may be combined to form a heterocyclic ring, and further, R 3 and R 4 may be the same or different and each represents a hydrogen atom, a C 1 -C 20 alkyl group or a C 6 -C 12 aryl group, (Wherein R5 is a C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, C6 (Wherein Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, R8 is a C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group), -NR7CYR8 or a C5-C12 heterocyclic _{group), -NHS (O) 2 R9} (R9 is a C6-C12 heterocyclic group of the aryl or C5-C12), or COR10 (R10 is the aryl group, the C6-C12 C1-C20 , A C3-C10 cycloalkyl group or a C5-C12 heterocyclic group)

Rh is an alkenyl group of hydrogen, NH _2, OH, C1-C5 alkyl group or a C2-C10,

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 at least one substituent 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 alkenyl group may be substituted with at least one substituent selected from the group consisting of OH, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5- C12 heterocyclic group, and C3- However,

The alkoxy group may be substituted with at least one substituent selected from the group consisting of OH, 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 at least one substituent 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 at least one substituent selected from the group consisting of a halogen, an alkyl group, a hydroxy group, an alkoxy group, a carboxyl group, an ester group, a nitro group and an amine group,

A, B, D, E, G, J, L, and M. Rc and Rd may combine with each other to form a condensed ring.

The cyclophilin function inhibitor comprising the stilbene derivative according to the present invention has an effect of inhibiting the function of cyclophilin. As a result, the composition comprising a stilbene derivative according to the present invention can be used for the treatment of viral infection diseases, cardiovascular diseases, rheumatoid arthritis, sepsis, periodontitis, acute pneumonia Acute Lung Inflammation, asthma, aging, alopecia, neurodegenerative diseases, cancer, acute injuries, or the like, It is useful for symptomatic symptomatic treatment.

The stilbene derivatives according to the present invention can be used in combination with existing therapeutic agents to enhance the therapeutic effect.

FIGS. 1 to 3 show effects when the stilbene derivative (compound 225) of the present invention is used in combination with existing HCV therapeutic agents.

Hereinafter, the present invention will be described in detail.

The present invention also provides a cyclophilin 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 cyclophilin inhibitor since it has a structure suitable for binding to an active pocket held in all proteins having the function of cyclophilin.

The present invention provides a composition for preventing or treating a cyclophilin-related disease comprising a stilbene derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In this formula,

A is CR < a > 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, Cl, Br or I,

R a is hydrogen, halogen, NO ₂ , CN, OH, a C 1 -C 5 alkyl group, a C 2 -C 10 alkenyl group, a C 1 -C 6 alkoxy group, -COOR 1 wherein R 1 is hydrogen or a C 1 -C 5 alkyl group, C3-C10 cycloalkyl) or -OCOR2 (R2 is C1-C5 alkyl, C6-C12 aryl or C3-C10 cycloalkyl)

Rb is hydrogen, halogen, NO _2, CN, OH, C1-C20 alkyl group, an alkenyl group of C2-C10, an alkoxy group of the cycloalkyl, C1-C10 of C3-C10, aryl C6-C12, C5-C12 (Wherein R 1 is a hydrogen or a C 1 -C 5 alkyl, a C 6 -C 12 aryl or a C 3 -C 10 cycloalkyl) or -OCOR 2 (wherein R 2 is a C 1 -C 5 alkyl group, a C 6 -C 12 aryl or a C 3 -C 10 aryl group, C10 cycloalkyl) or -COR10 (R10 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or C5-C12 heterocyclic group)

Rc is hydrogen, OH, halogen, CN, NO _2, C1-C20 alkyl, C2-C10 alkenyl group, a cycloalkyl group of C3-C10, the alkoxy group of C1-C10, aryl C6-C12, C5-C12 A heterocyclic group, -NR3R4 wherein R3 is hydrogen, a C1-C20 alkyl group or C6-C12 aryl, R4 is hydrogen, a C1-C20 alkyl group or C6-C12 aryl, R3 and R4 are combined to form a heterocycle -COOR5 (R5 is hydrogen, a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -OCOR6 (R6 is a hydrogen atom, (Wherein Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, R8 is a C1-C20 alkyl group, a C6-C12 aryl group or a C6-C12 aryl group), -NR7CYR8 , A C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), -NHS (O) ₂ R9 wherein R9 is a C1-C5 alkyl group, a C6-C12 aryl or a C5-C12 heterocyclic group, COR10 wherein R10 is C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group Is a heterocyclic group) of C5-C12,

Rd is OH, halogen, NO _2, CN, C1-C20 alkyl, C2-C10 alkenyl group, an alkoxy group, a C6-C12 aryl, heterocyclic ring of C5-C12 cycloalkyl group, C1-C10 of the C3-C10 And R 3 and R 4 may be combined to form a heterocyclic ring, and further, R 3 and R 4 may be the same or different and each represents a hydrogen atom, a C 1 -C 20 alkyl group or a C 6 -C 12 aryl group, (Wherein R5 is hydrogen, a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group , Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, R8 is a C1-C20 alkyl group, C6-C12 aryl, C3-C10 aryl or C3-C10 cycloalkyl group), -NR7CYR8 cycloalkyl group or a C5-C12 heterocyclic _{group), -NHS (O) 2 R9} (R9 is a C6-C12 heterocyclic group of the aryl or C5-C12) or -COR10 (R10 represents an alkyl group of C1-C20, C6- An aryl of C12, a cycloalkyl group of C3-C10 or a heterocyclic group of C5-C12)

Re is hydrogen, NH _2, OH, halogen, CN, NCS, C1-C20 alkyl, C2-C10 alkenyl group, C1-C10 alkoxy, C6-C12 aryl-oxy, aryl of C6-C12, C5-C12 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 heterocycle, (Wherein R5 is C1-C5 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), -OCOR6 (R6 is C1-C20 alkyl, (Wherein Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, R8 is a C1-C20 alkyl group, C6-C12 aryl, C3-C10 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -NR7CYR8 the cycloalkyl group or the heterocyclic group of C5-C12), -NHS (O ) 2 R9 (R9 is a C6-C12 heterocyclic group of the aryl or C5-C12), or -SR11 (R11 is C1-C5 alkyl group), and ,

Rf is hydrogen, NH _2, OH, halogen, NO _2, N ₂ ^+, C1-C4 alkyl group, an alkoxy group of C2-C10 alkenyl group, C1-C4, a C6-C12 aryl, heterocyclic ring of C5-C12 And R 3 and R 4 may be combined to form a heterocyclic ring, and further, R 3 and R 4 may be the same or different and each represents a hydrogen atom, a C 1 -C 20 alkyl group or a C 6 -C 12 aryl group, (Wherein R5 is a C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, C6 (Wherein Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, R8 is a C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group), -NR7CYR8 Or a C10-C12 heterocyclic group) or COR10 (wherein R10 is a C1-C20 alkyl group, a C6-C12 aryl group, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group)

Rg is hydrogen, NH _2, OH, halogen, NO2, COOH, CN, C1-C20 alkyl group, an alkenyl group of C2-C10, an alkoxy group, a heterocyclic group of C5-C12 cycloalkyl group, C1-C10 of the C3-C10 And R 3 and R 4 may be combined to form a heterocyclic ring, and further, R 3 and R 4 may be the same or different and each represents a hydrogen atom, a C 1 -C 20 alkyl group or a C 6 -C 12 aryl group, (Wherein R5 is a C1-C5 alkyl group, C6-C12 aryl or C3-C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, C6 (Wherein Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, R8 is a C1-C20 alkyl group, C6-C12 aryl, C3-C10 cycloalkyl group), -NR7CYR8 or a C5-C12 heterocyclic _{group), -NHS (O) 2 R9} (R9 is a C6-C12 heterocyclic group of the aryl or C5-C12), or COR10 (R10 is the aryl group, the C6-C12 C1-C20 , A C3-C10 cycloalkyl group or a C5-C12 heterocyclic group)

Rh is an alkenyl group of hydrogen, NH _2, OH, C1-C5 alkyl group or a C2-C10,

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 at least one substituent 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 alkenyl group may be substituted with at least one substituent selected from the group consisting of OH, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5- C12 heterocyclic group, and C3- However,

The alkoxy group may be substituted with at least one substituent selected from the group consisting of OH, 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 at least one substituent 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 at least one substituent selected from the group consisting of a halogen, an alkyl group, a hydroxy group, an alkoxy group, a carboxyl group, an ester group, a nitro group and an amine group,

A, B, D, E, G, J, L, and M. Rc and Rd may combine with each other to form a condensed ring.

The stilbene derivative represented by the formula (1) of the present invention can be used as a cyclophilin function inhibitor together with a pharmaceutically acceptable carrier, and can also be used as a therapeutic agent for the prevention of cyclophilin-related diseases or damage or a symptom of a disease.

The cyclophilin-related disease may be a viral infection disease, a disease associated with an inflammation process, or a disease associated with mitochondrial dysfunction.

The above-mentioned cyclophilin-related diseases may be viral infection diseases such as HBV, HCV, HIV, influenza virus, cardiovascular diseases, rheumatoid arthritis, sepsis, asthma But are not limited to, periodontitis, aging, alopecia, neurodegenerative diseases, or cancer.

The cardiovascular disease is a disease caused by an inflammation process and specifically includes atherosclerosis, abdominal aortic aneurysms, ischaemic heart diseases, cardiac hypertrophy ).

The above-mentioned cyclophilin-related diseases include HAV virus, HBV virus, HCV virus, HDV virus, HEV virus, coronavirus, HIV virus, influenza virus infection disease, atherosclerosis, Aortic aneurysms, ischaemic heart diseases, cardiac hypertrophy, rheumatoid arthritis, sepsis, periodontal disease, collagen < RTI ID = 0.0 > collagen VI myopathies, post-cardiac arrest syndrome, heart failure, acute lung inflammation, asthma, aging, Alopecia, nonalcoholic fatty liver disease Non-alcoholic steatohepatitis, obesity, renal fibrosis, nephrotoxicity, obstructive nephropathy, cisplatin-induced renal dise ase, acute renal failure, chronic renal failure, renal glomerulopathy, end stage renal disease, bone disorder, osteoporosis, arthritis Alzheimer ' s disease, Parkinson ' s disease, cerebral ischemia, multiple systems atrophy, cerebral palsy, cerebral ischemia, 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 Neuralgia, Glossopharyngeal neuralgia, Bell's palsy, Myasthenia Gravis, Neurological disorder, small and non-small cell lung cancer, bladder cancer, hepatocellular cancer, pancreatic cancer, breast cancer, squamous cell, Cancer, lymphoma, lymphoma, squamous cell carcinoma, melanoma, prostate cancer, colon cancer, glioblastoma, endometrial cancer, thyroid cancer, lymphoma ), Ovarian cancer, traumatic brain injury, traumatic injury of spinal, peripheral, or central nervous tissue, ischemic brain injury, Kidney, brain, lung, intestine, heart Ischemia Reperfusion Injury, Stroke, Myocardial Infarction, Heart Failure, Acute Hepatotoxicity, Biliary Secretion (kidney, brain, lung, intestine, heart) cholestasis, or storage / reperfusion injury of transplant organs.

Also, the stilbene derivative represented by the above formula (1) can be used as a reference material for comparing the therapeutic effect of a cyclophilin-related disease.

In the present invention, the alkyl group, the alkenyl group and the alkoxy group may be linear or branched.

The " halogen atom " used in the present invention may be fluorine, chlorine, bromine or iodine.

In the present invention, when A, B, D, E, G, J, L, M, Rc and Rd are bonded to each other to form a condensed ring, the condensed ring preferably forms a 6-membered ring or a 5-membered ring have. The condensed rings may contain one or more heteroatoms of N, O or S. The condensed rings may be furan or thiophene.

In one embodiment of the present invention, the pharmaceutically acceptable salt is preferably, but not limited to, a sodium salt, a potassium salt, a calcium salt, and an ammonium salt.

In one embodiment of the invention,

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.

In another embodiment of the present invention,

Rb is preferably hydrogen or a C1-C8 alkyl group, but is not limited thereto.

Rc is preferably a C1-C20 alkyl group, a C1-C10 alkoxy group, a phenylalkyl group, a nitro group, a C3-C10 cycloalkyl group, a C5-C12 heterocyclic group or a C1-C10 alkyl ketone.

Rd is a C1-C20 alkyl group; An ester group of C3-C10; A C3-C10 cycloalkyl group; Methoxy substituted with a cycloalkyl group; Ethoxy substituted by an amine group; A carboxy group; A C1-C20 alkyl group substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, a carboxyl group or an amine group substituted or unsubstituted phenyl group; Amine; N-methylpiperazine; Piperidine; Morpholine; Or -COOR5 (R5 is C1-C5 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), but is not limited thereto.

Re is hydrogen, NH _2, preferably OH, alkoxy group of C1-C20 alkyl group or a C1-C10, but not always limited thereto.

Rg is hydrogen, NH _2, OH, alkyl C1-C20; An ester group of C3-C10; A C3-C10 cycloalkyl group; Methoxy substituted with a cycloalkyl group; Ethoxy substituted by an amine group; A C2-C20 alkyl group substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, a carboxyl group or an amine group substituted or unsubstituted phenyl group; Amine; N-methylpiperazine; Piperidine; Morpholine; Or a carboxyl group, but is not limited thereto.

Rh is preferably hydrogen, but is not limited thereto.

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일 수 있으나 이에 한정되지 않는다.The alkyl group used in the present invention may be substituted or unsubstituted alkyl, and may be substituted or unsubstituted, such as -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ (CH ₂ ) ₂ CH ₃ , -CH _{2 CH 2) 3 CH 3, -CH} (CH 3) CH 2 CH 3, -CH 2 CH (CH 3) CH 2 CH 3, -CH 2 CH 2 CH (CH 3) 2, -CH (CH 3) 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 CH 3, -C (CH 3) 2 CH (CH 3) 2, -C (CH 3) 2 C (CH 3) 3, -CH 2 CH 2 _{C (CH 3) 3, -CH} 2 CH (CH 3) CH (CH 3) 2, -CH 2 CH 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,

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일 수 있으나 이에 한정되지 않는다.In the present invention, there alkoxy group is a substituted or unsubstituted alkoxy date _{-OCH 3, -OCF 3, -OCH 2} CH 3, -OCH 2 CH 2 CH 3, -OCH 2 CH 2 CH 2 CH 3, -OCH (CH ₃ ) CH ₂ CH ₃ , -OCH ₂ CONH ₂ , -OCH ₂ CH ₂ N (CH ₃ ) ₂ ,

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But is not limited thereto.

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일 수 있으나 이에 한정되지 않는다.In the present invention, the heterocyclic group

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일 수 있으나 이에 한정되지 않는다.-NR3R4 is _{-NH 2, -NHCH 3, -N (} CH 3) in the present invention _{2, N (CH 2 CH 3} ) 2,

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일 수 있으나 이에 한정되지 않는다.In the present invention, -COOR5 is _{COOCH 3, -COOCH 2 CH 3,} COO (CH 2) 2 CH 3, -COO (CH 2) 3 CH 3, COO (CH 2) 4 CH 3, COOCH (CH 3) 2,

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일 수 있으나 이에 한정되지 않는다.In the present invention, -OCOR6 is

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일 수 있으나 이에 한정되지 않는다.In the present invention, -NR7CYR8 is

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But is not limited thereto.

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일 수 있으나 이에 한정되지 않는다.In the present invention, -NHS (O) ₂ R < 9 >

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But is not limited thereto.

The compound of the present invention can be used by purchasing or selling a product sold in the form of a product. Generally, the preparation method may differ from the case of Rx in the general formula (1) and the remainder.

When Rx is CN, the stilbene derivative represented by the formula (1) can be prepared by reacting a phenylacetonitrile derivative represented by the following formula (2) with a benzaldehyde derivative represented by the following formula (3).

The phenylacetonitrile derivative represented by the general formula (2) and the benzaldehyde derivative represented by the general formula (3) may be commercially available or may be prepared by a method known in the art.

The reaction may be carried out in an organic solvent or without a solvent. In this case, microwave may be used to shorten the reaction time and increase the yield.

Examples of the organic solvent include, but are not limited to, alcohols, more preferably butanol, methanol, ethanol, propanol, and the like. The reaction can also be carried out by adding triphenylphosphine, piperidine or the like as a catalyst.

[Chemical Formula 1]

Rx = CN

(2)

(3)

In the general formulas (2) and (3)

A, B, D, E, G, J, L, M, Rc And Rd (A), B, D, E, G, J, L, M, Rc and Rd .

When Rx is a _{H, CH 3, NH 2,} F, Cl, Br, I, to the stilbene derivative represented by the following general formula (1) and olefins (olefin) derivative represented by the general formula [4] The organic halide represented by the formula (5) ( organic halide) derivatives.

The olefin derivative represented by the general formula (4) and the organic halide derivative represented by the general formula (5) may be commercially available or may be prepared by a method known in the art.

The reaction is preferably carried out using palladium (II) acetate [Palladium (II) acetate] as a catalyst, using a triethanolamine organic solvent.

[Chemical Formula 1]

Rx = H, CH3, NH2, F, Cl, Br, I

[Chemical Formula 4]

Rx = H, CH3, NH2, F, Cl, Br, I

Rx = H, CH3, NH2, F, Cl, Br, I

[Chemical Formula 5]

X = F, Cl, Br, I

X = F, Cl, Br, I

In the above formulas (4) and (5)

Rx is _{hydrogen, CH 3, NH 2, F} , Cl, Br or I,

X is F, Cl, Br or I

A, B, D, E, G, J, L, M, Rc And Rd (A), B, D, E, G, J, L, M, Rc and Rd .

The preparation method of the compound of the present invention can be referred to Korean Patent Application No. 2017-0102983.

The term " pharmaceutically acceptable carrier " as used herein is defined as a carrier or diluent that does not impair the biological activity and properties of the active ingredient.

As the pharmaceutically acceptable carrier or additive, one or more diluents or excipients such as stabilizers, fillers, extenders, wetting agents, disintegrators, lubricants, binders, surfactants and the like which are commonly used may be used.

Examples of the disintegrating agent include agar, starch, alginic acid or its sodium salt, anhydrous calcium monohydrogenphosphate, and the like. As the lubricant, silica, talc, stearic acid or its magnesium or calcium salt, polyethylene glycol, Magnesium and the like can be used, and as the binder, magnesium aluminum silicate. Starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, and low-substituted hydroxypropylcellulose. In addition, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose. Glycine, etc. may be used as a diluent. In some cases, generally known boiling salts, absorbents, coloring agents, flavors, sweeteners and the like may be used together.

Stabilizers that do not contain sodium stabilizer may be used. For example, magnesium stearate such as magnesium aluminometasilicate, magnesium aluminosilicate, magnesium aluminate, Aluminum hydroxide, dried aluminum hydroxide, synthetic hydrotalcite, synthetic aluminumsilicate, magnesium carbonate, precipitated calcium carbonate, magnesium oxide, aluminum hydroxide Aluminum hydroxide, L-arginine, potassium phosphate, dipotassium hydrogenphosphate, potassium dihydrogenphosphate, ammonium chloride, aluminum chloride, And one or more of the above-mentioned stabilizers may be used.

The pharmaceutical compositions comprising the stilbene derivatives of formula I of the present invention may be administered in a variety of ways that facilitate the administration of the compounds into the organism. The pharmaceutical composition of the present invention may be administered orally, rectally, intravaginally, intranasally, intradermally, intraoral, sublingually, subcutaneously, intramuscularly, intravenously, intracranially, intradermally , Epidural administration, and the like.

The pharmaceutical compositions of the present invention may be formulated in the form of tablets, capsules, powders, dropping pills, pulvis, boluses, tinctures, or poultices. Preferred tablets may be conventional tablets, coated tablets, dispersible tablets, foamable tablets, and the like, and may be multiple compressed tablets, such as double capsules, tablet presses, multi-layer tablets, and the like.

The preferred dosage of the stilbene derivative or pharmaceutically acceptable salt thereof contained in the pharmaceutical compositions provided herein varies depending on the condition and the weight of the patient, the degree of the disease, the type of the drug, the route of administration and the period of time, Can be appropriately selected.

Generally, the compound of the formula (I) as an active ingredient for an adult is administered to a mammal including a human in an amount of 1 to 100 mg / kg (body weight), preferably 5 to 50 mg / kg May be administered either orally or parenterally via an oral or parenteral route. In some cases, doses less than the above-mentioned ranges may be more suitable, and more doses may be used without causing harmful side effects, and more doses may be dispensed in several smaller doses per day .

Although it is possible to administer the compound of the present invention alone, it is preferable to administer it as a pharmaceutical composition. For both veterinary and human applications, pharmaceutical compositions useful in accordance with the present invention may comprise one or more compounds having Formula 1, together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients. Active ingredients necessary for combination therapy may be combined with the pharmaceutical compositions of the invention for simultaneous administration.

The formulations may be prepared in unit dosage form by any of the methods well known in the art of pharmacy. Such a method comprises the step of bringing the active ingredient into association with a carrier composed of one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with a liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product.

The present invention will now be described in more detail by way of non-limiting examples. However, the following examples are intended to further illustrate the present invention, 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.

Production Example 1. Preparation of CN < RTI ID = 0.0 >

1) How to use solvents

1 equivalent of the phenylacetonitrile derivative of Formula 2 and 1.3 equivalents of the benzaldehyde derivative of Formula 3 were refluxed in a butanol solvent to prepare a compound of Formula 1 by a knoevenagel condensation reaction.

2) How to use microwave

The compound of formula (1) was prepared using microwave, using 1 equivalent of phenylacetonitrile derivative of formula (2), 1.3 equivalents of benzaldehyde of formula (3) and 0.2 equivalents of triphenylphosphine. When using microwaves, the reaction time can be shortened and the yield can be improved.

[Reaction Scheme 1]

Rx = CN

 [Chemical Formula 2] < EMI ID =

Preparation Example 2. Preparation of Compound ₃ , NH ₂ , Preparation of F, Cl, Br, I derivatives

The compound of formula (1) was prepared by Heck Olefination reaction with 1 equivalent of the olefin derivative of formula (4) and 0.01 equivalent of palladium (II) acetate and 1 equivalent of organic halide derivative of formula (5) in a triethanolamine solvent.

[Reaction Scheme 2]

X = F, Cl, Br, I Rx = H, CH 3, NH 2, F, Cl, Br, I

 [Chemical Formula 4] < EMI ID =

Example 1. Confirmation of cis-trans isomerase inhibitory activity of stilbene derivatives

Chymotrypsin cleaves the alanine-proline peptide bond in the trans form. When Suc-AAPF-pNA (peptide substrate) and chymotrypsin are mixed, the trans-form peptide substrate is cleaved and the cis-form peptide substrate remains. The remaining cis-form peptide substrate is converted to a trans form by cis-trans isomerase and then cleaved by chymotrypsin. That is, in the presence of cis-trans isomerase, chymotrypsin cleaves more of the trans-form peptide substrate in a certain amount of time. This is used to determine the activity of the cis-trans isomerase. The amount of truncated trans-form peptide substrate can be measured using the absorbance at 390 nm.

Cyclophilin has cis-trans isomerase activity and accelerates cleavage of the trans-form peptide substrate by chymotrypsin. On the other hand, it was observed that when the stilbene derivatives of the present invention were treated with cyclophilin, the cleavage of the peptide substrate by chymotrypsin was not accelerated. As a result, it was confirmed that the stilbene derivatives of the present invention inhibited the activity of cyclophilin.

The following Compounds 1 to 315 (Table 1 to Table 12) can be grouped into cis-trans isomerase inhibitory activity (IC ₅₀ ) values as follows.

Group A (G _A ): IC _50> 200 to 2000 nM or less,

Group B (G _B ): IC ₅₀ 20 to 200 nM or less,

Group C (G _C ): IC ₅₀ less than 20 nM

compound A = CRa, B = CRb, G = CRe, J = CRf, D = E = L = M = CH Example R _x R _a R _b R _c R _d R _e R _f One 3 4 One CN H H CH ₂ CH ₃ Cl H H G _A G _D G _G 2 CN H H CH ₃ OCH ₃ H H G _A G _D G _G 3 CN H Cl H Cl H Cl G _A G _D G _G 4 CN H H CH ₃ H H OCH ₃ G _A G _D G _G 5 CN H H CH ₂ CH ₃ H H OCH ₃ G _A G _D G _G 6 CN H CF ₃ H Cl H Cl G _A G _D G _G 7 CN H H CH ₃ H H Cl G _A G _D G _G 8 CN H H NO ₂ F H H G _A G _D G _G 9 CN H H NO ₂ H H OCH ₃ G _A G _D G _G 10 CN H H NO ₂ H H

G _A G _D G _G 11 CN H H NO ₂ Cl H H G _A G _D G _G 12 CN H H NO ₂ H * -OCH ₂ O- * G _A G _D G _G 13 CN H H NO ₂ H Cl Cl G _A G _D G _G 14 CN H H NO ₂ H H NO ₂ G _A G _D G _G 15 CN H H OCH ₃ H H OCH ₃ G _A G _D G _G 16 CN H H NO ₂ H H NHCOCH ₃ G _A G _D G _G 17 CN H H NO ₂ OCH ₃ Br H G _A G _D G _G 18 CN H H OCH ₃ OCH ₃ H H G _A G _D G _G 19 CN H H H NO ₂ H H G _A G _D G _G 20 CN H H NO ₂ H OCH ₃ H G _A G _D G _G 21 CN H H NO ₂ H Br NO2 G _A G _D G _G 22 CN H H NO2 Cl H Cl G _A G _D G _G 23 CN H H NO ₂ CF ₃ H H G _A G _D G _G 24 CN H H NO ₂ COOCH ₃ H H G _A G _D G _G 25 CN H OCH ₂ CH ₃ OCH ₂ CH ₃ H H Cl G _B G _E G _H 26 CN H H NO ₂ OCH ₂ CONH ₂ Cl H G _A G _D G _G 27 CN H H NO ₂ OCH ₂ CH ₂ CH ₂ CH ₃ Cl H G _A G _D G _G 28 CN H H NO ₂ OCH ₂ CH ₃ Cl H G _A G _D G _G 29 CN H H Br NO ₂ OCH ₃ OCH ₃ G _A G _D G _G 30 CN H OCH ₂ CH ₃ OCH ₂ CH ₃ H OCH ₃ OCH ₃ G _A G _D G _G 31 CN H H NO ₂ H H OH G _A G _D G _G 32 CN NO ₂ OCH ₃ OCH ₃ H H Cl G _A G _D G _G 33 CN NO ₂ H H H H N (CH _{3) 2} G _A G _D G _G 34 CN NO ₂ H H H OCH ₂ Ph H G _A G _D G _G 35 CN CN H H H H N (CH _{3) 2} G _A G _D G _G 36 CN CN H H H H OCH ₃ G _A G _D G _G 37 CN OH H H H C (CH _{3) 2} OH H G _A G _D G _G 38 CN OCH ₃ H H H H i-Pr G _A G _D G _G 39 CN OCH ₃ H H H H t-Bu G _A G _D G _G 40 CN COOH H H H H CH ₃ G _A G _D G _G 41 CN H CH ₃ CH ₃ H H F G _A G _D G _G 42 CN H CH ₃ H H H COOH G _A G _D G _G 43 CN H CH ₃ H H OH OH G _A G _D G _G 44 CN H * -CH = CH-CH = CH- * CH ₃ H H G _A G _D G _G 45 CN H * -CH = CH-CH = CH- * Cl H H G _A G _D G _G 46 CN H NO ₂ H CH ₃ H H G _A G _D G _G 47 CN H NO ₂ H H H t-Bu G _A G _D G _G 48 CN H NO ₂ H H Ph Ph G _A G _D G _G 49 CN H NO ₂ H H H N (CH _{3) 2} G _A G _D G _G 50 CN H CN H H H N (CH _{3) 2} G _A G _D G _G 51 CN H CN H H Br CH ₃ G _A G _D G _G 52 CN H CN H H OCH ₂ CH ₃ H G _A G _D G _G 53 CN H CN H H H OCH ₂ Ph G _A G _D G _G 54 CN H CN H H H OCH ₂ COOH G _A G _D G _G 55 CN H CN H OCH ₂ Ph H H G _A G _D G _G 56 CN H OH OH H H CH ₂ CH ₃ G _A G _D G _G 57 CN H OCH ₃ H H OCH ₃ H G _A G _D G _G 58 CN H OCH ₂ CH ₃ OCH ₂ CH ₃ OCH ₃ H H G _C G _F G _I 59 CN H H Cl CH ₃ H H G _A G _D G _G 60 CN H H CH ₂ CH ₂ CH ₂ CH ₃ H CH ₃ H G _B G _E G _H 61 CN H H

H H H G _C G _F G _I 62 CN H H CH ₂ CH ₂ CH ₂ CH ₃ Cl H H G _B G _E G _H 63 CN H H CN OCH2CH3 H H G _A G _D G _G 64 CN H H CN OCH2Ph H H G _A G _D G _G 65 CN H H CN H _{* -CH = C (OCH 3)} -CH = CH- * G _A G _D G _G 66 CN H H CN H -OCH ₂ O- G _A G _D G _G 67 CN H H CN H H t-Bu G _A G _D G _G 68 CN H H OCH ₂ CH ₂ CH ₂ CH ₃ H H OH G _C G _F G _I 69 CN H H OCH ₂ Ph H H H G _C G _F G _I 70 CN H H OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ OCH ₃ H H G _C G _F G _I 71 CN H H COOH H CH ₃ H G _A G _D G _G 72 CN H H COOH H OCH ₃ H G _A G _D G _G 73 CN H H COOH H Cl H G _A G _D G _G 74 CN H H COOH H SCH ₃ H G _A G _D G _G 75 CN H H COOH Cl H H G _A G _D G _G 76 CN H H COOH H H Ph G _A G _D G _G 77 CN H H COOH H H O-i-Pr G _A G _D G _G 78 CN H H COOH H H N (CH _{3) 2} G _A G _D G _G 79 CN H H COOH OCH ₂ CH ₃ H H G _A G _D G _G 80 CN H H COOCH ₂ CH ₃ H H Cl G _C G _F G _I 81 CN H H OCH ₂ OCH ₃ H OCH ₃ H G _B G _E G _H 82 CN H H OCH ₂ OCH ₃ H H COOH G _A G _D G _G 83 CN H OCH ₂ OCH ₃ OCH ₂ OCH ₃ H H H G _C G _F G _I 84 CN H H NH ₂ NH ₂ H H G _A G _D G _G 85 CN H H N (CH _{3) 2} H H H G _C G _F G _I 86 CN H H N (CH ₂ CH ₃ ) ₂ H H N ₂ ⁺ G _C G _F G _I 87 CN H H NHCOCH ₃ H H OCH ₃ G _B G _E G _H 88 CN H H NHCOPh H H NH ₂ G _C G _F G _I 89 CN H H NHSO ₂ CH ₃ OCH ₃ t-Bu H G _B G _E G _H 90 CN H H H

H H G _C G _F G _I 91 CN H H H t-Bu H H G _C G _F G _I 92 CN H H CH ₃ NO ₂ H H G _A G _D G _G 93 CN H H Ph NO ₂ H H G _C G _F G _I 94 CN H * -CH = CH-CH = CH- * NO ₂ H H G _A G _D G _G 95 CN H * - (CH ₂ ) ₄ - * NO ₂ H H G _A G _D G _G 96 CN H H CH ₃ NO ₂ * -OCH ₂ O- * G _A G _D G _G 97 CN H * -CH = CH-CH = CH- * NO ₂ * -OCH ₂ O- * G _A G _D G _G 98 CN H H NH ₂ CN H NH ₂ G _A G _D G _G 99 CN H H Cl OH H H G _A G _D G _G 100 CN H H CH ₃ OCH ₃ H H G _A G _D G _G

compound A = CRa, B = CRb, G = CRe, J = CRf, D = E = L = M = CH Example R _x R _a R _b R _c R _d R _e R _f One 3 4 101 CN H H H O-i-Pr H H G _A G _D G _G 102 CN H H H OCH ₂ CH ₂ CH ₃ H H G _A G _D G _G 103 CN H CN H OCH ₃ H H G _A G _D G _G 104 CN H H Cl O-i-Pr H H G _A G _D G _G 105 CN H H CH ₃ COOH H H G _A G _D G _G 106 CN H H

COOH H H G _C G _F G _I 107 CN H OCH ₃ OCH ₃ COOCH ₃ H H G _A G _D G _G 108 CN H H OCH ₃ NH ₂ H H G _A G _D G _G 109 CN H COCH ₃ H NH ₂ H H G _A G _D G _G 110 CN H H NO ₂ N (CH _{3) 2} H N (CH _{3) 2} G _A G _D G _G 111 CN H H OCH ₃ N (CH _{3) 2} NCS H G _A G _D G _G 112 CN H H CH ₃

NO ₂ H G _A G _D G _G 113 CN H H H NHCOCH ₃ H NHCOCH ₃ G _A G _D G _G 114 CN H H H OCH ₃ CH ₂ Ph H G _A G _D G _G 115 CN H H i-Pr H NO ₂ H G _A G _D G _G 116 CN H * -CH = CH-CH = CH- * H NO ₂ H G _A G _D G _G 117 CN H * - (CH ₂ ) ₄ - * H NO ₂ H G _A G _D G _G 118 CN H H CH ₃ H NO ₂ OCH ₂ Ph G _A G _D G _G 119 CN H H OCH ₃ H CN H G _A G _D G _G 120 CN H H H H OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ H G _A G _D G _G 121 CN H H Cl H OCH ₂ CH ₃ H G _A G _D G _G 122 CN H H H H OCH ₂ Ph H G _A G _D G _G 123 CN H H Cl H O-i-Pr H G _A G _D G _G 124 CN H H H H O-Ph H G _A G _D G _G 125 CN H H H H OCH ₂ CH ₂ Ph H G _A G _D G _G 126 CN H H Br H OCH ₂ CH ₂ = CH ₂ H G _A G _D G _G 127 CN H H CH ₃ H COOH OCH ₃ G _A G _D G _G 128 CN H H OCH ₃ H COOCH ₃ H G _A G _D G _G 129 CN H H OCH ₃ H OCOCH ₃ H G _A G _D G _G 130 CN H H OCH ₃ H OCOCH ₂ CH ₃ H G _A G _D G _G 131 CN H H H H OCOCH ₂ Ph H G _A G _D G _G 132 CN H H OCH ₃ H OCOCH ₂ Ph H G _A G _D G _G 133 CN H H OCH ₃ H NH ₂ H G _A G _D G _G 134 CN H H NO ₂ H N (CH _{3) 2} H G _A G _D G _G 135 CN H H NO ₂ H N (CH ₂ CH ₃ ) ₂ H G _A G _D G _G 136 CN H OCH ₃ OCH ₃ H NHCOCH ₃ H G _A G _D G _G 137 CN H H H H NHCOPh H G _A G _D G _G 138 CN H H OH H NHCOCH ₂ CH ₂
cyclohexane H G _A G _D G _G 139 CN H H H H NHSO ₂ Ph H G _A G _D G _G 140 CN H H OCH ₃ H H CH ₃ G _A G _D G _G 141 CN H H OCH ₃ H H t-Bu G _A G _D G _G 142 CN H H i-Pr H H NO ₂ G _A G _D G _G 143 CN H H Cl H H NO ₂ G _A G _D G _G 144 CN H H N (CH _{3) 2} H H NO ₂ G _A G _D G _G 145 CN OCH ₃ H H H H NO ₂ G _A G _D G _G 146 CN H H COPh H H NO ₂ G _C G _F G _I 147 CN H OCH ₃

H H NO ₂ G _B G _E G _H 148 CN H H CH ₂ CH ₂ CH ₂ CH ₃ H H CN G _B G _E G _H 149 CN Cl H H H H CN G _A G _D G _G 150 CN H H OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ H H CN G _C G _F G _I 151 CN H H OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ H H CN G _C G _F G _I 152 CN H H CH ₃ H H OH G _A G _D G _G 153 CN H H CH ₃ H H OCH ₃ G _A G _D G _G 154 CN H H Cl H H O-i-Pr G _A G _D G _G 155 CN H H COOH H H O-i-Pr G _A G _D G _G 156 CN H H CH ₃ H H COOH G _A G _D G _G 157 CN H CH ₃ H H H COOH G _A G _D G _G 158 CN H H OCH ₂ CH ₂ CH ₂ OH H H COOH G _B G _E G _H 159 CN H H OCH ₃ H H COOCH ₃ G _A G _D G _G 160 CN H H Cl H H OCOCH ₃ G _A G _D G _G 161 CN H H Cl H H NH ₂ G _A G _D G _G 162 CN H H CN H H N (CH _{3) 2} G _A G _D G _G 163 CN H H CH ₃ N (CH _{3) 2} H H G _A G _D G _G 164 CN H H CH ₂ CH ₃ COOH H H G _A G _D G _G 165 CN H H CH ₂ CH ₃ N (CH _{3) 2} H H G _A G _D G _G 166 CN H H i-Pr Cl H H G _A G _D G _G 167 CN H H i-Pr COOH H H G _A G _D G _G 168 CN H H i-Pr OCH ₃ H H G _A G _D G _G 169 CN H H NO ₂ N (CH _{3) 2} H H G _A G _D G _G 170 CN H H CH ₂ CH ₂ CH ₂ CH ₃ COOH H H G _B G _E G _H 171 CN H H _{CH (CH 3) CH 2 CH} 3 COOH H H G _B G _E G _H 172 CN H H t-Bu COOH H H G _B G _E G _H 173 CN H H t-Bu OCH ₃ H H G _A G _D G _G 174 CN H CH ₃ CH ₃ OCH ₃ H H G _A G _D G _G 175 CN H CH ₃ CH ₃ COOH H H G _A G _D G _G 176 CN H H COC (CH _{3) 3} OCH ₃ H H G _B G _E G _H 177 CN H H COC (CH _{3) 3} COOH H H G _A G _D G _G 178 CN H H OCH ₂ CH ₃ OCH ₃ H H G _A G _D G _G 179 CN H H OCH ₂ CH ₃ COOH H H G _A G _D G _G 180 CN H H OCH ₂ CH ₂ CH ₂ CH ₃ OCH ₃ H H G _B G _E G _H 181 CN H H OCH ₂ CH ₂ CH ₂ CH ₃ COOH H H G _B G _E G _H 182 CN H H CH ₂ Ph OCH ₃ H H G _C G _F G _I 183 CN H H CH ₂ Ph COOH H H G _C G _F G _I 184 CN H H NO ₂ CH ₂ CH ₃ H H G _A G _D G _G 185 CN H H NO ₂ i-Pro H H G _A G _D G _G 186 CN H H NO ₂ NH ₂ H H G _A G _D G _G 187 CN H H NO ₂

H H G _A G _D G _G 188 CN H H NO _{2 OCH (CH 3) CH 2 CH} 3 H H G _A G _D G _G 189 CN H H NO ₂

H H G _B G _E G _H 190 CN H H NO _{2 OCH 2 CH 2 N (CH 3} ) 2 H H G _A G _D G _G 191 CN H H NO ₂

H H G _A G _D G _G 192 CN H H NO ₂

H H G _A G _D G _G 193 CN H H NO ₂

H H G _B G _E G _H 194 CN H H NO ₂ H OCH ₂ CH ₂ CH (CH ₃ ) ₂ H G _A G _D G _G 195 CN H H NO ₂ H OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ H G _A G _D G _G 196 CN H H NO ₂ CH ₂ CH (CH ₃ ) ₂ H H G _A G _D G _G 197 CN H H NO ₂ CH ₂ C (CH ₃ ) ₃ H H G _B G _E G _H 198 CN H H NO ₂ CH ₂ CH ₂ CH (CH ₃ ) ₂ H H G _B G _E G _H 199 CN H H NO ₂

H H G _B G _E G _H 200 CN H H NO ₂ CH ₂ CH ₂ Ph H H G _C G _F G _I

compound A = CRa, B = CRb, G = CRe, J = CRf, D = E = L = M = CH Example R _x R _a R _b R _c R _d R _e R _f One 3 4 201 CN H H NO ₂

H H G _C G _F G _I 202 CN H H NO ₂

H H G _C G _F G _I 203 CN H H NO ₂

H H G _C G _F G _I 204 CN H H NO ₂ CH ₂ CH ₂ CH ₂ Ph H H G _A G _D G _G 205 CN H H NO ₂ CH ₂ CH ₂ C (CH ₃ ) ₃ H H G _B G _E G _H 206 CN H H NO ₂

H H G _B G _E G _H 207 CN H H NO ₂

H 3 G _B G _E G _H 208 CN H H NO ₂

H H G _B G _E G _H 209 CN H H NO ₂

H H G _B G _E G _H 210 CN H H NO ₂

H H G _B G _E G _H 211 CN H H NO ₂

H H G _A G _D G _G 212 CN H H NO ₂

H H G _A G _D G _G 213 CN H H NO ₂

H H G _B G _E G _H 214 CN H H NO ₂

H H G _B G _E G _H 215 CN H H CH ₂ C (CH ₃ ) ₃ COOH H H G _C G _F G _I 216 CN H H _{CH (CH 3) CH (CH} 3) 2 COOH H H G _B G _E G _H 217 CN H H _{CH (CH 3) C (CH} 3) 3 COOH H H G _B G _E G _H 218 CN H H CH ₂ CH ₂ C (CH ₃ ) ₃ COOH H H G _C G _F G _I 219 CN H H CH ₂ CH (CH ₃ ) CH (CH ₃ ) ₂ COOH H H G _B G _E G _H 220 CN H H

COOH H H G _C G _F G _I 221 CN H H

COOH H H G _C G _F G _I 222 CN H H

COOH H H G _C G _F G _I 223 CN H H

COOH H H G _C G _F G _I 224 CN H H

COOH H H G _B G _E G _H 225 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _C G _F G _I 226 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ CH ₃ H G _B G _E G _H 227 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ CH ₂ CH ₃ H G _B G _E G _H 228 H CH ₃ H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 229 H CH ₂ CH ₃ H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 230 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H CH ₃ G _B G _E G _H 231 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ CH ₃ CH ₃ G _B G _E G _H 232 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₂ CH ₃ H H G _C G _F G _I 233 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₄ CH ₃ H H G _C G _F G _I 234 H H H CH ₂ C (CH ₃ ) ₃ COOCH (CH _{3) 2} H H G _C G _F G _I 235 H H H CH ₂ C (CH ₃ ) ₃

H H G _C G _F G _I 236 H H H CH ₂ C (CH ₃ ) ₃

H H G _B G _E G _H 237 H H H CH ₂ C (CH ₃ ) ₃ COOCH ₂ Ph H H G _C G _F G _I 238 H H H CH ₂ C (CH ₃ ) ₃

H H G _B G _E G _H 239 H H H CH ₂ CH (CH ₃ ) CH ₂ CH ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 240 H H H

COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 241 H H H

COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 242 H H H

COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 243
CH ₃ H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 244 CH ₃ H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ CH ₃ H G _B G _E G _H 245 CH ₃ CH ₃ H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 246 CH ₃ H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H CH ₃ G _B G _E G _H 247 CH ₃ H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ CH ₃ CH ₃ G _B G _E G _H 248 CH ₃ H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₂ CH ₃ H H G _B G _E G _H 249 CH ₃ H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 250 CH ₃ H H CH ₂ C (CH ₃ ) ₃ COOCH (CH _{3) 2} H H G _B G _E G _H 251 CH ₃ H H CH ₂ C (CH ₃ ) ₃

H H G _B G _E G _H 252 CH ₃ H H CH ₂ C (CH ₃ ) ₃

H H G _B G _E G _H 253 CH ₃ H H CH ₂ C (CH ₃ ) ₃ COOCH ₂ Ph H H G _B G _E G _H 254 CH ₃ H H CH ₂ C (CH ₃ ) ₃

H H G _B G _E G _H 255 CH ₃ H H CH ₂ CH (CH ₃ ) CH ₂ CH ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 256 CH ₃ H H

COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 257 CH ₃ H H

COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 258 CH ₃ H H COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 259 NH ₂ H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 260 NH ₂ H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ CH ₃ H G _B G _E G _H 261 NH ₂ CH ₃ H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 262 NH ₂ H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H CH ₃ G _B G _E G _H 263 NH ₂ H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ CH ₃ CH ₃ G _B G _E G _H 264 NH ₂ H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 265 NH ₂ H H CH ₂ C (CH ₃ ) ₃ COOCH (CH _{3) 2} H H G _B G _E G _H 266 NH ₂ H H CH ₂ C (CH ₃ ) ₃

H H G _B G _E G _H 267 NH ₂ H H CH ₂ C (CH ₃ ) ₃ COOCH ₂ Ph H H G _B G _E G _H 268 NH ₂ H H CH ₂ C (CH ₃ ) ₃

H H G _B G _E G _H 269 NH ₂ H H CH ₂ CH (CH ₃ ) CH ₂ CH ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 270 NH ₂ H H

COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 271 NH ₂ H H

COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 272 NH ₂ H H

COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 273 F H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _C G _F G _I 274 Cl H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ CH ₃ H G _C G _F G _I 275 Br CH ₃ H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _C G _F G _I 276 I H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H CH ₃ G _C G _F G _I 277 F H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ CH ₃ CH ₃ G _C G _F G _I 278 Cl H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _C G _F G _I 279 Br H H CH ₂ C (CH ₃ ) ₃ COOCH (CH _{3) 2} H H G _C G _F G _I 280 I H H CH ₂ C (CH ₃ ) ₃

H H G _C G _F G _I 281 F H H CH ₂ C (CH ₃ ) ₃ COOCH ₂ Ph H H G _C G _F G _I 282 Cl H H CH ₂ C (CH ₃ ) ₃

H H G _C G _F G _I 283 Br H H CH ₂ CH (CH ₃ ) CH ₂ CH ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H 284 H H H CH ₂ C (CH ₃ ) ₃ COOCH ₃ H H G _C G _F G _I 285 H H H CH ₂ CH (CH ₃ ) CH ₂ CH ₃ COOCH ₃ H H G _B G _E G _H 286 H H H

COOCH ₃ H H G _B G _E G _H 287 H H H

COOCH ₃ H H G _B G _E G _H 288 H H H

COOCH ₃ H H G _B G _E G _H 289 H H H CH ₂ CH (CH ₃ ) ₂ COOCH ₃ H H G _B G _E G _H 290 H H H CH ₂ (CH ₂ ) ₃ CH ₃ COOCH ₃ H H G _C G _F G _I 291 H H H CH ₂ CH (CH ₃ ) ₂ COO (CH ₂ ) ₃ CH ₃ H H G _C G _F G _I 292 H H H CH ₂ (CH ₂ ) ₃ CH ₃ COO (CH ₂ ) ₃ CH ₃ H H G _C G _F G _I 293 H H H CH ₂ C (CH ₃ ) ₃

H H G _B G _E G _H 294 H H H CH ₂ C (CH ₃ ) ₃ COOH H H G _C G _F G _I 295 H H H CH ₂ C (CH ₃ ) ₃ COOH OH H G _C G _F G _I 296 H H H CH ₂ C (CH ₃ ) ₃ COOH H OH G _C G _F G _I 297 H H H CH ₂ C (CH ₃ ) ₃ COOH NH ₂ H G _C G _F G _I 298 H H H CH ₂ C (CH ₃ ) ₃ COOH H NH ₂ G _C G _F G _I 299 H H H CH ₂ C (CH ₃ ) ₃ COOH CH ₃ H G _C G _F G _I 300 H H H CH ₂ C (CH ₃ ) ₃ COOH H CH ₃ G _C G _F G _I 301 H H H CH ₂ C (CH ₃ ) ₃ CONH ₂ H H G _C G _F G _I

compound A = CRa, B = CRb, G = CRe, D = E = M = CH R _x R _a R _b R _c R _d R _e J and L are condensed ring formation Example One 3 4 302 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H

G _B G _E G _H

compound A = N, B = CRb, G = CRe, J = CRf, D = E = L = M = CH R _x R _b R _c R _d R _e R _f Example One 3 4 303 H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H

compound A = CRa, B = N, G = CRe, J = CRf, D = E = L = M = CH R _x R _a R _c R _d R _e R _f Example One 3 4 304 H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H

compound A = CRa, B = CRb, G = N, J = CRf, D = E = L = M = CH R _x R _a R _b R _c R _d R _f Example One 3 4 305 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H G _B G _E G _H

compound A = CRa, B = CRb, G = CRe, J = N, D = E = L = M = CH R _x R _a R _b R _c R _d R _e Example One 3 4 306 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H G _B G _E G _H

compound A = CRa, B = CRb, G = CRe, J = CRf, D = E = M = CH, L = N R _x R _a R _b R _c R _d R _e R _f Example One 3 4 307 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H

compound A = CRa, B = CRb, G = CRe, J = CRf, D = E = L = CH, M = N R _x R _a R _b R _c R _d R _e R _f Example One 3 4 308 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H G _B G _E G _H

compound A = CRa, B = CRb, G = CRe, J = CRf, M = CRg, D = E = L = CH Rx Ra Rb Rc Rd Re Rf Rg Example One 3 4 309 H H H CH ₂ C (CH ₃ ) ₃ COO (CH ₂ ) ₃ CH ₃ H H COO (CH ₂ ) ₃ CH ₃ G _B G _E G _H 310 H H H CH ₂ C (CH ₃ ) ₃ COOH H H OH G _C G _F G _I 311 H H H CH ₂ C (CH ₃ ) ₃ COOH H H NH ₂ G _C G _F G _I 312 H H H CH ₂ C (CH ₃ ) ₃ COOH H H CH ₃ G _C G _F G _I

compound A = CRa, B = CRb, G = CRe, J = CRf, L = CRh, D = E = M = CH Rx Ra Rb Rc Rd Re Rf Rh Example One 3 4 313 H H H CH ₂ C (CH ₃ ) ₃ COOH H H OH G _B G _E G _H 314 H H H CH ₂ C (CH ₃ ) ₃ COOH H H NH ₂ G _B G _E G _H 315 H H H CH ₂ C (CH ₃ ) ₃ COOH H H CH ₃ G _B G _E G _H

Example 2. Cytotoxicity of stilbene derivatives

The cytotoxicity of stilbene derivatives was measured. The replicon cells stably replicating the hepatitis C virus genome were attached to 96-well plates and cultured in a CO ₂ incubator at 37 ° C for 24 hours. The replicon cells cultured for one day were washed with PBS (phosphate buffered saline) solution, treated with the compounds of the present invention, and incubated for 72 hours. The CC ₅₀ values of the compounds of the present invention were measured 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 200 μM or more. The CC ₅₀ value of the compound 225 was 320 μM, 284 μM in the case of the compound 226, and 245 μM in the case of the compound 227. Therefore, it can be seen that the compound of Chemical Formula 1 of the present invention does not show cytotoxicity.

Example 3. Identification of antiviral activity of stilbene derivatives

The antiviral activity of stilbene derivatives against hepatitis C virus was measured. The replicon cells stably replicating the hepatitis C virus genome were attached to a culture plate and cultured in a 37 CO ₂ incubator for 24 hours. The replicon cells cultured for one day were washed with PBS (phosphate-buffered saline) solution, treated with the compounds and cultured for 72 hours. Cells treated with stilbene derivatives are washed with cold PBS and 20 μL of cell lysate is added and the cells are lysed on ice for 20 minutes. After adding 100 μL of Renilla luciferase substrate, the expression of the luminescence was measured to estimate the amount of the hepatitis C virus genome. Relative amount of hepatitis C virus genome in the replicon cells treated with the stilbene derivative of the present invention is shown on the basis of the amount of hepatitis C virus genome in replicon cells treated with dimethyl sulfoxide (DMSO).

The antiviral activity (EC ₅₀ ) values of the compounds 1 to 315 of Tables 1 to 12 can be grouped as follows.

Group D (G _D ): EC ₅₀ greater than 5 and less than 50 μM,

Group E (G _E ): EC ₅₀ greater than 0.5 and less than 5 μM,

Group F (G _F ): EC _{50 <} 0.5 μM

Therefore, the compound of Chemical Formula 1 of the present invention has an antiviral effect.

Example 4. Expansion inhibition activity of mitochondria

Cyclophilin is a key protein that forms the permeability transition pore (PTP) of mitochondria. When permeable metastatic pores are formed, the mitochondria expand and, as a result, the outer membrane ruptures and cell death progresses. Such mitochondrial dysfunction causes many diseases including neurodegenerative diseases, cancer, and the like. Cyclosporine, which is known as an inhibitor of cyclophilin, is known to block the formation of permeable metastatic pores and prevent the expansion of mitochondria.

Expansion experiments of mitochondria proceeded as follows. First, hepatocytes are disrupted using a dounce tissue grinder. The disrupted cells are centrifuged at 700 x g for 10 min and the supernatant is transferred to a new tube. The supernatant is centrifuged at 12,000 x g for 15 minutes to obtain mitochondria.

When calcium is added to the extracted mitochondria, it swells, 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.

The mitochondrial expansion inhibitory activity (IC ₅₀ ) values of the compounds 1 to 315 of Tables 1 to 12 can be grouped as follows.

Group G (G _G ): IC ₅₀ greater than 50 and less than 500 μM,

Group H (G _H ): IC ₅₀ 5 to 50 μM or less,

Group I (G _I ): IC ₅₀ less than 5 μM

Example 5: Combination of stilbene derivatives and HCV therapeutic agents

In order to effectively treat HCV infection, HCV therapeutic agents are used in combination. The combination of HCV therapies can increase the antiviral effect (synergy effect) and reduce the incidence of drug resistance.

A synergistic effect is shown when the combination of the stilbene derivative (compound 225) and the conventional anticancer drugs (daclatasvir: NS5A inhibitor, simeprevir: NS3 inhibitor, sofosbuvir: NS5B inhibitor) 3).

The interaction of the two drugs in Figures 1-3 was determined using a Bliss-independence model. The horizontal axis represents the drug concentration and the vertical axis represents the interaction of the two drugs. In FIGS. 1 to 3, 0% indicates an additive effect, 0% indicates a synergy effect, and 0% indicates an antagonism.

Stilbene derivatives also have an antiviral effect against viruses resistant to conventional drugs (Table 13). According to the following Table 3, the stilbene derivative (Compound 225) of the present invention shows an antiviral effect in both the drug showing resistance to Simeprevir and the drug showing resistance to daclatasvir.

Compound Fold resistance (EC ₅₀  for variant / EC ₅₀  for wild) Simeprevir-resistant variant Daclatasvir-resistant variant Compound 225 1.3 1.1 Simeprevir 45.4 1.5 Daclatasvir 1.6 333.0

Claims (14)

A stilbene derivative represented by the following formula (1), or a stilbene derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In this formula,
A is CRa,
B is CRb,
G is CRe,
J is CRf,
M is CRg,
D and E are CH,
L is CRh,
Rx is _{H, CH 3, CN, NH} 2, F, Cl, Br or I,

Ra is hydrogen, halogen, NO ₂ , CN, OH, a C 1 -C 5 alkyl group, a C 1 -C 6 alkoxy group, or -COOR 1 (R 1 is hydrogen or a C 1 -C 5 alkyl group)
R b is hydrogen, halogen, NO ₂ , CN, OH, a C 1 -C 20 alkyl group, a C 2 -C 10 alkenyl group, a C 1 -C 10 alkoxy group, or -COR 10 (R 10 is a C 1 -C 20 alkyl group)
Rc is hydrogen, OH, halogen, CN, NO2, C1-C20 alkyl, C2-C10 alkenyl, R3 is hydrogen or a C1-C20 alkyl group, R4 is hydrogen, a C1-C20 alkyl group or C6-C12 aryl, R3 and R4 may combine to form a heterocycle, and further include one or more heteroatoms (Wherein R5 is hydrogen or a C1-C20 alkyl group), -NR7CYR8 (Y is O or S, R7 is a hydrogen or a C1-C5 alkyl group, R8 is a C1-C20 alkyl group or C6- ), -NHS (O) ₂ R9 (R9 is a C1-C5 alkyl group), or -COR10 (R10 is C1-C20 alkyl or C6-C12 aryl)
Rd is OH, halogen, NO2, CN, a C1-C20 alkyl group, a C3-C10 cycloalkyl group, a C1-C10 alkoxy group, a C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen or C1- R 4 is hydrogen or C 1 -C 20 alkyl, R 3 and R 4 may combine to form a heterocyclic ring, and may further contain at least one heteroatom), -COOR 5 (R 5 is hydrogen, C 1 -C 20 (Wherein Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group), and R &lt; 7 &gt;
Re is hydrogen, NH _2, OH, halogen, CN, NCS, C1-C20 alkyl group, an alkenyl group of C2-C10, an alkoxy of C1-C10, aryloxy C6-C12, C6-C12 aryl, -NR3R4 ( (Wherein R5 is a C1-C5 alkyl group), -OCOR6 (wherein R6 is a C1-C20 alkyl group), - (C1-C20 alkyl) NR7CYR8 (Y is O or S, R7 is hydrogen or C1-C5 alkyl groups, R8 is an alkyl group of C1-C20, C6-C12 aryl, or a cycloalkyl group of C3-C10), -NHS (O ) 2 R9 (R9 is C6 -C12 aryl) or -SR11 (wherein R11 is a C1-C5 alkyl group)
Rf is hydrogen, NH _2, OH, halogen, NO _2, N ₂ ^+, C1-C4 alkyl, C1-C7 alkoxy group, a heterocyclic group of C6-C12 aryl, C5-C12, -NR3R4 (R3 is of the And R &lt; 3 &gt; and R &lt; 4 &gt; may combine to form a heterocyclic ring and may further include at least one heteroatom), -COOR5 R5 is hydrogen or a C1-C5 alkyl group), -OCOR6 (R6 is a C1-C20 alkyl group), or -NR7CYR8 (Y is O or S, ego,
Rg is hydrogen, NH _2, OH, C1-C20 alkyl group or a -COOR5 (R5 is hydrogen, C1-C5 alkyl group, C6-C12 aryl group or a cycloalkyl group of C3-C10 a) of,
Rh is an alkyl group of hydrogen, NH _2, OH, or C1-C5,
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 at least one substituent 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 alkenyl group may be substituted with at least one substituent selected from the group consisting of OH, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5- C12 heterocyclic group, and C3- However,
The alkoxy group may be substituted with at least one substituent selected from the group consisting of OH, 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 at least one substituent 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 at least one substituent selected from the group consisting of a halogen, an alkyl group, a hydroxy group, an alkoxy group, a carboxyl group, an ester group, a nitro group and an amine group,
A, B, G, J, L, and M. Rc and Rd may combine with each other to form a condensed ring,
The cyclophilin function inhibitor may be selected from the group consisting of HBV virus, HCV virus, coronavirus, HIV virus, influenza viral infection disease, atherosclerosis, abdominal aortic aneurysms, (Eg, ischaemic heart diseases, cardiac hypertrophy, rheumatoid arthritis, sepsis, periodontal disease, collagen VI myopathies, Post- cardiac arrest syndrome, heart failure, acute lung inflammation, asthma, aging, Alopecia, non-alcoholic steatohepatitis, obesity, Renal fibrosis, acute renal failure, chronic renal failure, osteoporosis, Alzheimer &apos; s disease, Parkinson &apos; s disease e.), cerebral ischemia, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, muscular dystrophy, bipolar disorder, ), Excitotoxic injury, neurological disorder, small and non-small cell lung cancer, bladder cancer, hepatocellular cancer, pancreatic cancer Cancer, breast cancer, squamous cell carcinoma, melanoma, prostate cancer, colon cancer, glioblastoma, endometrial cancer, Lymphoma, traumatic brain injury, spinal cord, peripheral, central nervous tissue, traumatic injury of the central nervous system, ischemic brain injury, , Lung, intestine, heart (kidney, brain, lu Ischemia Reperfusion Injury, Stroke, Myocardial Infarction, acute hepatotoxicity, cholestasis, or transplantation long term storage / reperfusion injury of ng, intestine, heart) / &lt; / RTI &gt; reperfusion injury of transplant organs)
delete The method according to claim 1,
Rb is hydrogen or a C1-C8 alkyl group,
Rc is a C1-C20 alkyl group, a C2-C10 alkoxy group, a phenylalkyl group, a nitro group, a C3-C10 cycloalkyl group, a C5-C12 heterocyclic group or a C1-
Rd is a C1-C20 alkyl group; An ester group of C3-C10; A C3-C10 cycloalkyl group; Methoxy substituted with a cycloalkyl group; Ethoxy substituted by an amine group; A carboxy group; A C1-C20 alkyl group substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, a carboxyl group or an amine group substituted or unsubstituted phenyl group; Amine; N-methylpiperazine; Piperidine; Morpholine; Or -COOR5 (R5 is C1-C5 alkyl, C6-C12 aryl or C3-C10 cycloalkyl)
Re is hydrogen, NH _2, OH, an alkoxy group of C1-C10 alkyl group or a C1-C20, and
Rg is hydrogen, NH _2, OH, an alkyl group or a carboxy group of C1-C20 cycloalkyl pilrin function inhibitors The method according to claim 1,
The alkyl group is _{-CH 3, -CH 2 CH 3,} -CH 2 CH 2 CH 3, -CH 2 (CH 2) 2 CH 3, -CH 2 (CH 2) 3 CH 3, -CH (CH 3) CH _{2 CH 3, -CH 2 CH (} CH 3) CH 2 CH 3, -CH 2 CH 2 CH (CH 3) 2, -CH (CH 3) 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 _{CH 3, -C (CH 3)} 2 CH (CH 3) 2, -C (CH 3) 2 C (CH 3) 3, -CH 2 CH 2 C (CH 3) 3, -CH 2 CH (CH 3 _{) CH (CH 3) 2,} -CH 2 CH 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,

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or

Cyclophilin function inhibitor The method according to claim 1,
The alkoxy groups are _{-OCH 3, -OCF 3, -OCH 2} CH 3, -OCH 2 CH 2 CH 3, -OCH 2 CH 2 CH 2 CH 3, -OCH (CH 3) CH 2 CH 3, -OCH 2 CONH ₂ , -OCH ₂ CH ₂ N (CH ₃ ) ₂ ,

_,

_,

_,

_,

_,

or

Cyclophilin function inhibitor The method according to claim 1,
The heterocyclic group is

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or

Cyclophilin function inhibitor The method according to claim 1,
-COOR5 is _{COOCH 3, -COOCH 2 CH 3,} COO (CH 2) 2 CH 3, -COO (CH 2) 3 CH 3, COO (CH 2) 4 CH 3, COOCH (CH 3) 2,

,

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or

Cyclophilin function inhibitor The method according to claim 1,
-OCOR6

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or

Cyclophilin function inhibitor The method according to claim 1,
-NR3R4 is _{-NH 2, -NHCH 3, -N (} CH 3) 2, N (CH 2 CH 3) 2,

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or

Cyclophilin function inhibitor The method according to claim 1,
-NR7CYR8 is

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or

Cyclophilin function inhibitor The method according to claim 1,
-NHS (O) ₂ R &lt; 9 &gt;

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or

Cyclophilin function inhibitor A pharmaceutical composition for preventing or treating cyclophilin-related diseases or disorders comprising a stilbene derivative represented by the following formula (1), or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In this formula,
A is CRa,
B is CRb,
G is CRe,
J is CRf,
M is CRg,
D and E are CH,
L is CRh,
Rx is _{H, CH 3, CN, NH} 2, F, Cl, Br or I,

Ra is hydrogen, halogen, NO ₂ , CN, OH, a C 1 -C 5 alkyl group, a C 1 -C 6 alkoxy group, or -COOR 1 (R 1 is hydrogen or a C 1 -C 5 alkyl group)
R b is hydrogen, halogen, NO ₂ , CN, OH, a C 1 -C 20 alkyl group, a C 2 -C 10 alkenyl group, a C 1 -C 10 alkoxy group, or -COR 10 (R 10 is a C 1 -C 20 alkyl group)
Rc is hydrogen, OH, halogen, CN, NO2, C1-C20 alkyl, C2-C10 alkenyl, R3 is hydrogen or a C1-C20 alkyl group, R4 is hydrogen, a C1-C20 alkyl group or C6-C12 aryl, R3 and R4 may combine to form a heterocycle, and further include one or more heteroatoms (Wherein R5 is hydrogen or a C1-C20 alkyl group), -NR7CYR8 (Y is O or S, R7 is a hydrogen or a C1-C5 alkyl group, R8 is a C1-C20 alkyl group or C6- ), -NHS (O) ₂ R9 (R9 is a C1-C5 alkyl group), or -COR10 (R10 is C1-C20 alkyl or C6-C12 aryl)
Rd is OH, halogen, NO2, CN, a C1-C20 alkyl group, a C3-C10 cycloalkyl group, a C1-C10 alkoxy group, a C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen or C1- R 4 is hydrogen or C 1 -C 20 alkyl, R 3 and R 4 may combine to form a heterocyclic ring, and may further contain at least one heteroatom), -COOR 5 (R 5 is hydrogen, C 1 -C 20 (Wherein Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group), and R &lt; 7 &gt;
Re is hydrogen, NH _2, OH, halogen, CN, NCS, C1-C20 alkyl group, an alkenyl group of C2-C10, an alkoxy of C1-C10, aryloxy C6-C12, C6-C12 aryl, -NR3R4 ( (Wherein R5 is a C1-C5 alkyl group), -OCOR6 (wherein R6 is a C1-C20 alkyl group), - (C1-C20 alkyl) NR7CYR8 (Y is O or S, R7 is hydrogen or C1-C5 alkyl groups, R8 is an alkyl group of C1-C20, C6-C12 aryl, or a cycloalkyl group of C3-C10), -NHS (O ) 2 R9 (R9 is C6 -C12 aryl) or -SR11 (wherein R11 is a C1-C5 alkyl group)
Rf is hydrogen, NH _2, OH, halogen, NO _2, N ₂ ^+, C1-C4 alkyl, C1-C7 alkoxy group, a heterocyclic group of C6-C12 aryl, C5-C12, -NR3R4 (R3 is of the And R &lt; 3 &gt; and R &lt; 4 &gt; may combine to form a heterocyclic ring and may further include at least one heteroatom), -COOR5 R5 is hydrogen or a C1-C5 alkyl group), -OCOR6 (R6 is a C1-C20 alkyl group), or -NR7CYR8 (Y is O or S, ego,
Rg is hydrogen, NH _2, OH, C1-C20 alkyl group or a -COOR5 (R5 is hydrogen, C1-C5 alkyl group, C6-C12 aryl group or a cycloalkyl group of C3-C10 a) of,
Rh is an alkyl group of hydrogen, NH _2, OH, or C1-C5,
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 at least one substituent 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 alkenyl group may be substituted with at least one substituent selected from the group consisting of OH, halogen, amine, C1-C5 alkoxy, C6-C12 aryl, C5- C12 heterocyclic group, and C3- However,
The alkoxy group may be substituted with at least one substituent selected from the group consisting of OH, 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 at least one substituent 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 at least one substituent selected from the group consisting of a halogen, an alkyl group, a hydroxy group, an alkoxy group, a carboxyl group, an ester group, a nitro group and an amine group,
A, B, G, J, L, and M. Rc and Rd may combine with each other to form a condensed ring,

The pharmaceutical composition may be used in combination with other therapeutic agents such as HBV virus, HCV virus, coronavirus, HIV virus, influenza viral infection disease, atherosclerosis, abdominal aortic aneurysms, ischaemic heart diseases, cardiac hypertrophy, rheumatoid arthritis, sepsis, periodontal disease, collagen VI myopathies, post-cardiac arrest syndrome, heart failure, acute lung inflammation, asthma, aging, Alopecia, non-alcoholic steatohepatitis, obesity, renal fibrosis renal fibrosis, acute renal failure, chronic renal failure, osteoporosis, Alzheimer's disease, Parkinson's disease, cerebral ischemia (cer Huntington's disease, MS, Multiple sclerosis, amyotrophic lateral sclerosis, muscular dystrophy, bipolar disorder, excitotoxic damage, neurological disorder, small cell and non-small cell lung cancer, bladder cancer, hepatocellular cancer, pancreatic cancer, breast cancer, Cancer, gastric cancer, squamous cell carcinoma, melanoma, prostate cancer, colon cancer, glioblastoma, endometrial cancer, lymphomas, Traumatic brain injury, spinal cord, peripheral, central nervous tissue, traumatic injury of spinal, peripheral or central nervous tissue, ischemic brain injury, kidney, brain, Heart (kidney, brain, lung, intestine, heart) Ischemia Reperfusion Injury, Stroke, Myocardial Infarction, Acute Hepatotoxicity, Cholestasis, or Storage / Reperfusion Injury of Transplant organs ) Or a pharmaceutical composition for the prevention or treatment of a disease
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