KR-102964040-B1 - 1,4-Naphthoquinone Derivatives and Methods of Preparation Thereof

Abstract

The present invention relates to novel 1,4-naphthoquinone derivatives, methods for preparing the same, and uses thereof. When using the compounds of the present invention, effects such as enhanced NQO1 activity, increased NAD + , increased ATP, and improved mitochondrial function can be achieved, as well as preventive or therapeutic effects against related diseases.

Inventors

• 윤주석
• 서강식
• 권민정
• 박훈규
• 김보정
• 신혜영
• 문성제
• 윤수빈

Assignees

• 주식회사 큐롬바이오사이언스

Dates

Publication Date

20260513

Application Date

20240704

Claims (18)

1. Compounds represented by the following chemical formula 1, and their pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers, or diastereomers: [Chemical Formula 1] In the above formula, The above R1 and R2 are each independently hydrogen, a substituted or unsubstituted C1 to C6 alkyl, or a substituted or unsubstituted C5 to C8 cycloalkyl, and The above R3 is hydrogen, a substituted or unsubstituted C1 to C6 alkyl, or a substituted or unsubstituted C3 to C8 cycloalkyl, and The above R 4 is unsubstituted or a phenyl substituted with one or more substituents selected from the group consisting of unsubstituted C1 to C4 alkyl, unsubstituted C1 to C4 alkoxy, C1 to C4 alkyl substituted with one to three halogen elements, acetamido, and halogen elements; -COR' 1 ; -CO(O)R' 1 ; -COCH 2 -R' 1 ; -COCH 2 CH 2 -R' 1 or -CO(CH 2 ) n NR' 1 R' 2 (where n is an integer from 1 to 3, and the -(CH 2 ) n - portion may be substituted with a substituted or unsubstituted C1 to C4 alkyl group), and The above R'1 and R'2 are each independently hydrogen, hydroxyl, substituted or unsubstituted C1 to C6 alkoxy, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted C6 to C10 aryl, or substituted or unsubstituted C4 to C10 heteroaryl, or the above R'1 and R'2 can together constitute a C2 to C8 heterocycloalkyl, and Where R4 is a substituted or unsubstituted phenyl, R5 is a methoxy, ethoxy, C1 to C4 alkyl, thio C1 to C4 alkyl, -NO2 , -CN, or -NR'3R'4 , and Where R4 is -CO(O) R'1 , -COCH2 -R'1 , -COCH2CH2- R'1 or -CO( CH2 ) nNR'1R'2 (where n is an integer from 1 to 3, and the -( CH2 ) n- portion may be substituted with a substituted or unsubstituted C1 to C4 alkyl group), R5 is methoxy, ethoxy, C1 to C4 alkyl, thio C1 to C4 alkyl, -NO2 , or -CN, The above R'3 and R'4 are each independently hydrogen, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and If the above R 4 is -COR' 1 , R 5 is selected as hydrogen, and The functional group of the above substitution is substituted with one or more selected from the group consisting of a halogen element, a hydroxyl, a straight-chain or branched-chain C1-C6 alkyl, a straight-chain or branched-chain C1-C6 alkoxy, a C6-C10 aryl, and a C6-C10 heteroaryl.
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5. In paragraph 1, R1 and R2 are each independently hydrogen, or a substituted or unsubstituted C1 to C4 alkyl compound, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, or diastereomer thereof.
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11. In paragraph 1, A compound, wherein R4 is a C1 to C4 alkyl-substituted phenyl substituted with one to three halogen elements, and the halogen element is fluorine; a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, or diastereomer thereof.
12. Compounds selected from the group consisting of the following compounds 1 to 164, and their pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers, or diastereomers:
13. A pharmaceutical composition for the prevention or treatment of any one of the NAD+ reduction or mitochondrial dysfunction-related diseases selected from the group consisting of metabolic diseases, primary and secondary mitochondrial diseases, muscle diseases, neurodegenerative diseases, inflammatory diseases, fibrotic diseases, autoimmune diseases, or cancer, comprising a compound according to any one of claims 1, 5, 11, and 12.
14. A cosmetic composition comprising a compound according to any one of claims 1, 5, 11 and 12.
15. A food composition comprising a compound according to any one of claims 1, 5, 11 and 12.
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17. A pharmaceutical composition according to claim 13, wherein the metabolic disease is any one selected from the group consisting of obesity, diabetes, and metabolic disorder-related fatty liver disease.
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Description

1,4-Naphthoquinone Derivatives and Methods of Preparation Thereof The present invention relates to novel 1,4-naphthoquinone derivatives, methods for producing the same, and uses thereof. This study was conducted with funding from the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare, and with support from the National Drug Development Project of the National Drug Development Agency (RS-2024-00259507). This research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (RS-2024-00259507, Republic of Korea). NAD (Nicotinamide adenine dinucleotide) is a coenzyme involved in various biochemical reactions within the body and is divided into oxidized (NAD + ) and reduced (NADH) forms. NAD + is required for processes such as glycolysis, where cells break down sugars to produce energy, and fatty acid oxidation, which produces energy from fats; NADH is essential for cellular metabolic processes, serving as a substrate used in the electron transport chain when mitochondria synthesize ATP. It is well known that the amount of NAD + in cells decreases rapidly with aging or the progression of certain diseases, and this is closely related to increased activity of poly(ADP-ribose) polymerase (PARP), which uses NAD + as a substrate to repair DNA damage, or decreased activity of enzymes involved in NAD + production. Therefore, research is continuing to find treatments for various diseases by increasing or at least maintaining the amount of NAD + in cells, and this is being studied in various aspects, including methods to regulate the salvage pathway, which is the NAD + biosynthetic process, methods to supply NAD + synthesis precursors, and methods to increase intracellular NAD + concentration by activating enzymes that use NADH. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a protein that functions to maintain cellular homeostasis by removing external substances or oxidative stress. It is expressed in all tissues of the human body and exists at relatively low levels under normal conditions. However, it is known that the activity and expression of NQO1 are significantly increased in various diseases, such as obesity, metabolic disorders-related fatty liver disease, muscle diseases, neurodegenerative diseases, cancer, and diseases caused by mitochondrial dysfunction. Meanwhile, NQO1 can convert NADH to NAD + through enzymatic activity, and the increased NAD + can induce effects such as improved cellular energy metabolism and mitochondrial function through sirtuins and AMP-activated protein kinase (AMPK). Furthermore, diseases can be treated by effectively increasing intracellular NAD + by utilizing the phenomenon of increased NQO1 activity and expression in disease states. As a specific example, substrate compounds of NQO1 including β-Lapachone exhibit therapeutic effects on various disease groups such as metabolic diseases, neurodegenerative diseases, aging-related diseases, micochondria, inflammatory diseases, and fibrotic diseases through an increase in NAD + , including obesity, muscular dystrophy, Parkinson's disease, Huntington's disease, cancer, kidney disease, hypertension, hearing loss, heart disease, pulmonary fibrosis, MELAS syndrome, and primary sclerosing cholangitis. Mitochondria are organelles found in most eukaryotic cells, such as those of animals, plants, and fungi. They possess a double-membrane structure and generate intracellular energy (adenosine triphosphate, ATP) through aerobic respiration. In addition, mitochondria play a significant role in maintaining intracellular homeostasis, including cell signaling, differentiation, apoptosis, the cell cycle, and growth control. Furthermore, it is well known that mitochondrial dysfunction is closely associated with various diseases, including metabolic disorders, muscle diseases, cancer, neurodegenerative diseases, and mitochondrial disorders. Among these, over 300 types of mitochondrial diseases are currently identified, caused by direct problems in the expression and function of proteins constituting the mitochondrial complex due to nDNA or mtDNA mutations, with impaired ATP synthesis being the primary cause. With the exception of Leber hereditary optic neuropathy (LHON), there are currently no approved treatments for any of these mitochondrial diseases, and patients receive symptomatic treatment using antioxidants, vitamin cocktails, and the like. LHON, which is caused by a deficiency of mitochondrial complex I, is treated by idebenone, known as a substrate of NQO1, which is approved in Europe under the product name Raxone. Idebenone is known to treat the disease by inducing ATP synthesis through a method that bypasses the dysfunction of mitochondrial complex I by transferring electrons obtained from reduction by NQO1 to mitochondrial complex III. Based on the characteristics of increased NQO1 act