Lignan derivative, preparation method therefor and use thereof
Disclosed in the present invention are a lignan derivative, a preparation method therefor and the use thereof. The structure of the lignan derivative is as shown in a formula I, wherein in the formula, the definition of each substituent is as described in the description and claims. The lignan derivative of the present invention can be used as an inhibitor of mitochondrial respiratory chain complex I to inhibit mitochondrial oxidative phosphorylation and ATP generation, and can also be used for preventing and/or treating diseases associated with the elevated activity or expression of the mitochondrial respiratory chain complex I or enhanced mitochondrial oxidative phosphorylation.
1 . A compound represented by formula I, or an enantiomer, diastereomer, racemic mixture, deuterated compound or pharmaceutically acceptable salt thereof,
wherein,
R x is hydrogen;
R 0 is halogen, C 1 -C 6 alkyl, hydroxyl-substituted C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 1 is C 1 -C 6 alkoxy, or —O-L-G; wherein, L is a C 1-6 alkylene, a hydrogen atom of the alkylene is optionally substituted by hydroxyl in a manner and number allowed by the chemical bond; G is C 1 -C 6 haloalkyl or C 6-10 aryl; the aryl is unsubstituted or substituted by 1 or 2 groups selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
R 2 and R 3 are each independently C 1 -C 6 alkyl;
R 4 is hydrogen;
Ry is hydroxyl or
and
R 8 is hydrogen.
2 . The compound of claim 1 , or an enantiomer, diastereomer, racemic mixture, deuterated compound or pharmaceutically acceptable salt thereof, wherein the compound has the following formula (IIa):
wherein each substituent is defined as in claim 1 .
3 . The compound of claim 1 , or an enantiomer, diastereomer, racemic mixture, deuterated compound or pharmaceutically acceptable salt thereof, wherein the compound has the following formula (IIb):
wherein each substituent is defined as in claim 1 .
4 . The compound of claim 1 , or an enantiomer, diastereomer, racemic mixture, deuterated compound or pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 4 alkoxy or —O-L-G; wherein L is C 1-4 alkylene, and one hydrogen atom on the alkylene group is substituted by hydroxyl in a manner allowed by chemical bond; G is C 1 -C 4 haloalkyl or phenyl; the phenyl is unsubstituted or substituted by one C 1 -C 6 haloalkyl.
5 . The compound of claim 1 , or an enantiomer, diastereomer, racemic mixture, deuterated compound or pharmaceutically acceptable salt thereof, wherein R y is hydroxyl or —OP(O)(OH) 2 ;
R 0 is C 1 -C 6 alkyl;
R 2 and R 3 are each independently C 1 -C 4 alkyl;
R 1 is C 1 -C 4 alkoxy or —O-L-G; wherein L is a C 1-4 alkylene; and G is a phenyl or C 1 -C 4 haloalkyl.
6 . A compound, or an enantiomer, diastereomer, racemic mixture, deuterated compound or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
7 . A pharmaceutical composition, comprising the compound of claim 1 , or an enantiomer, diastereoisomer, racemic mixture, deuterated compound or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
8 . A method for treating a disease associated with increased activity or expression of mitochondrial respiratory chain complex I or a disease associated with enhanced mitochondrial oxidative phosphorylation comprising administering the compound of claim 1 , or an enantiomer, diastereoisomer, racemic mixture, deuterated compound or pharmaceutically acceptable salt thereof to a subject in need thereof.
9 . The method of claim 8 , wherein the disease is a tumor selected from the group consisting of acute myeloid leukemia, neuroglioma, lymphoma, pancreatic cancer, uterine cancer, breast cancer, non-small cell lung cancer, and hepatocellular carcinoma.
10 . The method of claim 8 , wherein the disease is related to cell senescence and selected from the group consisting of organ fibrosis disease, chronic lung disease, chronic kidney disease, chronic liver disease, osteoarthritis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, inflammatory bowel disease, atherosclerosis, glaucoma, cataracts, macular degeneration, diabetes, diabetic retinopathy, pigmentation, and sarcopenia.
11 . The method of claim 10 , wherein the organ fibrosis disease is pulmonary fibrosis, liver fibrosis or renal fibrosis;
the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
12 . The method of claim 11 , wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
13 . A method for inhibiting mitochondrial respiratory chain complex I comprising administering the compound of claim 1 , or an enantiomer, diastereoisomer, racemic mixture, deuterated compound or pharmaceutically acceptable salt thereof, to a subject in need thereof.
14 . A pharmaceutical composition, comprising the compound of claim 6 , or an enantiomer, diastereoisomer, racemic mixture, deuterated compound or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
15 . A method for treating a disease associated with increased activity or expression of mitochondrial respiratory chain complex I or a disease associated with enhanced mitochondrial oxidative phosphorylation comprising administering the compound of claim 6 , or an enantiomer, diastereoisomer, racemic mixture, deuterated compound or pharmaceutically acceptable salt thereof, to a subject in need thereof.
16 . The method of claim 15 , wherein the disease is a tumor selected from the group consisting of acute myeloid leukemia, neuroglioma, lymphoma, pancreatic cancer, uterine cancer, breast cancer, non-small cell lung cancer, and hepatocellular carcinoma.
17 . The method of claim 15 , wherein the disease is related to cell senescence and selected from the group consisting of organ fibrosis disease, chronic lung disease, chronic kidney disease, chronic liver disease, osteoarthritis, neurodegenerative disease, inflammatory bowel disease, atherosclerosis, glaucoma, cataracts, macular degeneration, diabetes, diabetic retinopathy, pigmentation, and sarcopenia.
18 . The method of claim 17 , wherein the organ fibrosis disease is pulmonary fibrosis, liver fibrosis or renal fibrosis;
the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or multiple sclerosis;
the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
19 . The method of claim 18 , wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
20 . A method for inhibiting mitochondrial respiratory chain complex I comprising administering the compound of claim 6 , or an enantiomer, diastereoisomer, racemic mixture, deuterated compound or pharmaceutically acceptable salt thereof, to a subject in need thereof.