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CN-121990979-A - Compound and application thereof in preparation of anti-aging drugs

CN121990979ACN 121990979 ACN121990979 ACN 121990979ACN-121990979-A

Abstract

The present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, and its use in preventing, inhibiting, slowing or alleviating aging.

Inventors

  • OU JUANJUAN

Assignees

  • 渝粤病理科学研究中心

Dates

Publication Date
20260508
Application Date
20241105

Claims (10)

  1. 1. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing, inhibiting, slowing or alleviating aging, Wherein, the R 1 is unsubstituted or substituted by halogen, alkyl, or haloalkyl, aliphatic, aryl, aryloxy, heteroaryl, or heteroaryloxy; R 2 is unsubstituted or substituted by halogen, alkyl, or haloalkyl, aliphatic, aryl, aryloxy, heteroaryl, or heteroaryloxy; Q 1 is-L 1 or-C (=a 1 )–NH–L 1 ), wherein, -L 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, and heteroarylalkyl, and =A 1 is=o, =s, or=nh; Q 5 、Q 6 , and Q 7 are each independently selected from the group consisting of hydrogen, halogen, alkoxy, heteroaryl 、–C(＝O)–L 0 、–O–C(＝O)–L 0 、–NH–C(＝O)–L 0 、–S(＝O) 2 –L 0 、–NH–S(＝O) 2 –L 0 、–NH–C(＝O)–NH–L 0 、, and-NH-C (=S) -NH-L 0 , wherein-L 0 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, and heteroarylalkyl, and A 4 is carbon or nitrogen.
  2. 2. The use according to claim 1, wherein, The aging is aging of an organ selected from the group consisting of eyes, heart, liver, spleen, lung, kidney, pancreas, thyroid, thymus, brain, cerebellum, brown fat, white fat, beige fat, muscle, bone, joint, reproductive system, and neuron.
  3. 3. The use according to claim 1 or 2, wherein, The aging is selected from the group consisting of obesity, immune degeneration, reproductive degeneration, decreased expression of organ mitochondria, increased expression of organ senescence markers, decreased activity of brown fat, white brown fat, metabolic homeostasis, decreased metabolic rate or activity, decreased muscle strength or mass, increased muscle fibrosis, decreased insulin sensitivity, increased risk of hyperglycemia, increased risk of hyperlipidemia, increased risk of hypertension, increased risk of heart disease, increased risk of kidney disease, increased risk of diabetes, increased risk of osteoporosis, eye maculopathy, and increased risk of tumor.
  4. 4. The use according to claim 1 to 3, R 1 is a fatty, aliphatic oxy, aryl, aryloxy, heteroaryl, or heteroaryloxy group substituted with halogen or haloalkyl, still more particularly with fluorine or fluoroalkyl, particularly with fluorine or trifluoromethyl; Optionally, R 1 is aryl or heteroaryl, particularly phenyl, substituted by halogen or haloalkyl, still more particularly by fluorine or fluoroalkyl, particularly by fluorine or trifluoromethyl.
  5. 5. The use according to claim 1 to 4, R 1 is-Ph (-X) n , Wherein, the Each X is independently halogen or haloalkyl, especially halogen or trihalomethyl, especially fluorine or trifluoromethyl, and N is 1,2,3, 4, or 5, particularly 1,2, or 3; Optionally, R 1 comprises-X in the meta-position, optionally also at least one of the ortho-X and the para-X, with the bond-Ph (-X) n being in position 1.
  6. 6. The use according to claim 1 to 5, wherein, R 2 is a fatty, aliphatic oxy, aryl, aryloxy, heteroaryl, or heteroaryloxy group substituted with halogen or haloalkyl, still more particularly with fluorine or fluoroalkyl, particularly with fluorine or trifluoromethyl; Optionally, R 2 is aryl or heteroaryl, particularly phenyl, substituted by halogen or haloalkyl, still more particularly by fluorine or fluoroalkyl, particularly by fluorine or trifluoromethyl.
  7. 7. The use according to claim 1 to 6, wherein, R 2 is-Ph (-X) n , Wherein, the Each X is independently halogen or haloalkyl, especially halogen or trihalomethyl, especially fluorine or trifluoromethyl, and N is 1,2,3, 4, or 5, particularly 1,2, or 3; Optionally, R 2 comprises-X in the meta-position, optionally also at least one of the ortho-X and the para-X, with the bond-Ph (-X) n being in position 1.
  8. 8. The use according to any one of claims 1 to 7, wherein, Q 5 、Q 6 , and Q 7 are each independently selected from the group consisting of hydrogen 、–C(＝O)–L 0 、–O–C(＝O)–L 0 、–NH–C(＝O)–L 0 、–S(＝O) 2 –L 0 、–NH–S(＝O) 2 –L 0 、–NH–C(＝O)–NH–L 0 、 and-NH-C (=S) -NH-L 0 , wherein-L 0 is selected from the group consisting of hydrogen, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, aryl C 1-10 alkyl, and heteroaryl C 1-10 alkyl, and/or A 4 is C; Optionally, -L 0 is selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkenyl, C 1-3 alkynyl, aryl C 1-3 alkyl, and heteroaryl C 1-3 alkyl; Alternatively, Q 5 、Q 6 , and Q 7 are both hydrogen.
  9. 9. The use according to any one of claims 1 to 8, wherein, -L 1 is selected from the group consisting of hydrogen, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, azido C 1-10 alkyl, aryl C 1-10 alkyl, and heteroaryl C 1-10 alkyl; Optionally, -L 1 is selected from the group consisting of C 4-10 alkyl, C 4-10 alkenyl, C 4-10 alkynyl, azido C 4-10 alkyl, aryl C 4-10 alkyl, and heteroaryl C 4-10 alkyl; Alternatively, Q 1 is-L 1 and-L 1 is methyl.
  10. 10. The use according to any one of claims 1 to 9, wherein, R 1 is 3- (trifluoromethyl) phenyl; r 2 is 2,4, 5-trifluorophenyl; Q 1 is methyl; Q5, Q6, and Q7 are all hydrogen, and A4 is carbon.

Description

Compound and application thereof in preparation of anti-aging drugs Technical Field The application relates to the field of biological medicine, in particular to a compound and application thereof in preparing anti-aging medicines. Background Aging or aging refers to a progressive, irreversible biological process that gradually leads to a decline in body structure and tissue cell function, physiological, biochemical, morphological changes, reduced adaptability and resistance, and ultimately to biological death with age. Aging is by far the most important risk factor for various diseases such as cancer, coronary artery disease, alzheimer's disease, parkinson's disease and chronic renal failure. Aging includes immune aging, which may cause dysfunction of the lymphatic system and cells, and increase the occurrence of infections, tumors (including cancers), and the like. Anti-aging can inhibit immune aging, enhance immunity, and inhibit tumor growth. Telomeres, mitochondria, and inflammation are markers of aging. With age, mitochondrial dynamics imbalance causes mitochondrial dysfunction, accelerates aging progression, and is closely related to the occurrence and development of aging-related diseases. The aging process is closely related to mitochondrial dysfunction. Brown adipose tissue is a part of a fat organ. The abundance of brown fat correlates with lower prevalence of heart metabolic disease and lower incidence of type II diabetes. However, with age, the metabolic activity of brown adipose tissue gradually decreases. The aging condition of brown adipose tissue of the presenility mice is evaluated by detecting the transcription and protein expression levels of the brown adipose tissue active molecular marker uncoupling proteinase 1 (UCP 1). In the last decades, the biomedical field has extensively explored the mechanisms of anti-aging to prevent diseases, and a variety of small molecule compounds and drugs have been discovered that potentially can extend the life of organisms. However, there is still a need in the art to explore the discovery of more anti-aging agents. Disclosure of Invention There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the use thereof in the manufacture of a medicament for the prevention, inhibition, alleviation or amelioration of ageing, or the prevention or treatment of a disease associated with ageing, Wherein, the R 1 may be unsubstituted or substituted with halogen, alkyl, or haloalkyl, aliphatic, aryl, aryloxy, heteroaryl, or heteroaryloxy; R 2 may be unsubstituted or substituted with halogen, alkyl, or haloalkyl, aliphatic, aryl, aryloxy, heteroaryl, or heteroaryloxy; Q 1 is-L 1 or-C (=a 1)–NH–L1), wherein, -L 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, and heteroarylalkyl, and =A 1 is=o, =s, or=nh; Q 5、Q6, and Q 7 are each independently selected from the group consisting of hydrogen, halogen, alkoxy, heteroaryl 、–C(＝O)–L0、–O–C(＝O)–L0、–NH–C(＝O)–L0、–S(＝O)2–L0、–NH–S(＝O)2–L0、–NH–C(＝O)–NH–L0、, and-NH-C (=S) -NH-L 0, wherein-L 0 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, and heteroarylalkyl, and A 4 is carbon or nitrogen. The compounds of some embodiments of the present application are effective in improving metabolic homeostasis, reducing muscle strength decline due to aging, improving insulin sensitivity, and enhancing anti-tumor immunity and improving organ aging (including but not limited to improving kidney aging, increasing the number of mitochondria in the lung, increasing brown fat browning trend, increasing brown fat metabolic activity, etc.). Drawings FIG. 1 shows that administration of the compound of the present application is effective in improving metabolic homeostasis in aged rats, as shown by (a) weekly weight measurements, (b) grip strength measurements, (c) insulin resistance test (ITT), and (d) intraperitoneal glucose tolerance test (IPGTT) in each group of mice of Experimental example 1. (a) The horizontal axis shows the time period (weeks) after the first administration, the vertical axis shows the body weight (g), the ∈ is the control group, the ∈ is the #43 compound group, (b) the horizontal axis shows the control group, the right is the #43 compound group, the vertical axis shows the grip strength (N), the (c, d) the horizontal axis shows the time period (minutes) after the injection, the vertical axis shows the blood glucose (mmol/L), the ∈ is the control group, and the ■ is the #43 compound group. FIG. 2 photographs of (a) whole, (b) spleen, (c) white fat and (d) brown fat, and (e) comparison of weights of heart, liver, spleen, lung, pancreas, thyroid, brain, cerebellum, brown adipose tissue, white adipose tissue, and beige adipose tissue after the mice of experimental example 2 were inoculated with the transplanted tumors and dissected. The left panel (a) is the control group and the right panel is the #43 compound group. (