WO2022206654A1 - 一种醌类化合物及其药学应用 - Google Patents
一种醌类化合物及其药学应用 Download PDFInfo
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- WO2022206654A1 WO2022206654A1 PCT/CN2022/083261 CN2022083261W WO2022206654A1 WO 2022206654 A1 WO2022206654 A1 WO 2022206654A1 CN 2022083261 W CN2022083261 W CN 2022083261W WO 2022206654 A1 WO2022206654 A1 WO 2022206654A1
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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Definitions
- PQQ converts oxidized glutathione (GSSG) to reduced glutathione (GSH) faster by accelerating the "NAD+ ⁇ NADH" reaction.
- PQQ scavenge reactive oxygen species
- mice can be prevented by pre-injecting a certain dose of PQQ and its derivatives into the abdominal cavity.
- PQQ can reduce the generation of ROS caused by hepatotoxic substances, significantly reduce the levels of serum bilirubin glutamic pyruvic transaminese (GPT) and lactate dehydrogenase, block liver cell necrosis, and not affect the routine biochemical indicators of rats (such as blood sugar, blood and urine nitrogen, etc.).
- GPT serum bilirubin glutamic pyruvic transaminese
- lactate dehydrogenase lactate dehydrogenase
- Nerve growth factor is the earliest neurotrophic factor discovered and the most thorough researched. It has the dual biological functions of neuron nutrition and neuroprotection. , regeneration and biological function-specific expression all play an important regulatory role.
- PQQ can stimulate L-M cells and Schwann cells to generate NGF in vitro [Urakami T, Tanaka A, Yamaguchi K, et al. Synthesis of esters of coenzyme PQQ and IPQ, and stimulation of nerve growth factor production. [J]. Biofactors, 1995, 5(3):139.].
- AMPK is also an important target for research on delaying aging and prolonging lifespan [Burkewitz K, Zhang Y, Mair WB. AMPKat the nexus of energetics andaging. Cell Metab. 2014 Jul 1;20(1):10-25.]. Cheng et al.
- R 5 is selected from H, C 1 -C 3 alkyl, OH, NH 2 , NHR, -COOH or SH;
- R 6 is selected from H, C 1 -C 3 alkyl, OH, NH 2 , NHR, -COOH or SH;
- R is a C 1 -C 6 alkyl group; in some specific embodiments, R is a C 1 -C 3 alkyl group.
- the present invention also provides the use of the compounds of the present invention or their pharmaceutically acceptable salts, esters, stereoisomers, solvates or prodrugs in the preparation of antitumor drugs.
- the present invention also provides the compounds of the present invention or their pharmaceutically acceptable salts, esters, stereoisomers, solvates or prodrugs in the preparation of chemotherapeutics, chemical substances or drugs for the prevention and treatment of cytotoxic tumors and chronic hepatitis
- chemotherapeutics chemical substances or drugs for the prevention and treatment of cytotoxic tumors and chronic hepatitis
- the present invention also provides the use of the compounds of the present invention or their pharmaceutically acceptable salts, esters, stereoisomers, solvates or prodrugs in the preparation of medicaments for preventing and treating peripheral neuropathy caused by chemotherapy. Pain from chemotherapy, for example.
- the substituents are preferably one or more, more preferably one, two or three, still more preferably one or two, independently selected from lower alkyl, trihaloalkyl, halogen, hydroxy , lower alkoxy, mercapto, (lower alkyl) thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, etc.
- Fig. 1 is a graph of the analgesic effect after a single oral administration of 20 mg/kg of SP3101 in rats;
- Figure 4 shows the long-acting analgesic effect of AMPK inhibitor compound c inhibiting SP3101
- Figure 6 shows that SP3101 inhibits cox-2 activity
- RAW264.7 was purchased from Peking Union Cell Center.
- Figure 3 is a graph showing the analgesic effect of oral administration of 20 mg/kg/day SP330 (ie PQQ) in rats for three consecutive days. There was no analgesic effect after oral administration for 1.5 hours on the first day, and there was obvious analgesic effect on 2/3/4/5/6/7 days.
- mice Seven days after the operation, Von Frey filaments were used to detect mechanical pain in mice.
- the mice were first placed in a transparent plexiglass plantar test platform to adapt for 20 minutes, and a series of Von Frey were used to vertically stimulate one side of the mouse model (that is, the right hind foot). Forefoot, first start stimulation with a lower level of intensity, if the intensity cannot cause a positive response, use a stronger level to start stimulation, and rapid foot withdrawal is a positive response, then use the adjacent lower level of intensity to stimulate again, Record the intensity interval of the first positive and negative reaction. The model was successfully established when the positive reaction was less than 0.4 g.
- OFT open field test
- DAY6-10 Administer SP3101 and water only by gavage.
- DAY16-21 Observe only, and detect mechanical pain domain on DAY21.
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Abstract
Description
编号 | 1HNMR | 13CNMR |
1 | 6.24d,1H,j=2.4 | 105.4 |
2 | 6.91d,1H,j=2.4 | 126.7 |
3 | / | 124.4 |
4 | / | 184.9 |
5 | / | 159.9 |
6 | / | 136.2 |
7 | / | 165.9 |
8 | 8.15,1H,s | 128.4 |
9 | / | 147.1 |
10 | / | 133.1 |
11 | / | 149.7 |
12 | / | 167.0 |
编号 | 1H NMR | 13C NMR |
1 | 2.28,3H,s | 20.3 |
2 | 5.0,1H,s | / |
3 | 6.40d,1H,j=7.5 | 104.4 |
4 | 6.95d,1H,j=7.5 | 118.3 |
5 | 7.82,1H,s | 112.9 |
6 | 11.0,1H,s | / |
7 | / | 122.7 |
8 | / | 125.2 |
9 | / | 126.4 |
10 | / | 137.2 |
11 | / | 144.8 |
12 | / | 156.4 |
13 | / | 167.7 |
14 | / | 172.6 |
15 | / | 173.5 |
16 | / | 176.7 |
编号 | 1H NMR | 13C NMR |
1 | 3.80,3H,s | 54.1 |
2 | 5.0,1H,s | / |
3 | 6.40d,1H,j=7.5 | 104.4 |
4 | 6.95d,1H,j=7.5 | 118.3 |
5 | 7.82,1H,s | 112.9 |
6 | 11.0,1H,s | / |
7 | / | 115.0 |
8 | / | 122.7 |
9 | / | 125.2 |
10 | / | 135.7 |
11 | / | 144.2 |
12 | / | 162.4 |
13 | / | 167.7 |
14 | / | 173.5 |
15 | / | 176.7 |
Claims (12)
- 一种药物组合物,其包括本发明所述化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药,以及药学上可接受的载体。
- 权利要求1-3任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、 溶剂化合物或前药作为AMPK激动剂的应用。
- 权利要求1-3任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药作为Cox-2酶的抑制剂的应用。
- 权利要求1-3任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备镇痛药物中的应用。
- 权利要求1-3任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备预防和治疗炎症疾病药物中的应用。
- 权利要求1-3任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备抗肿瘤药物中的应用;或者在制备预防和治疗细胞毒素进行肿瘤的化学治疗、化学物质或药物以及慢性肝炎引发的多种肝损伤、肝功能衰退以及预防和治疗心肌梗塞损伤、病毒性心肌炎药物中的应用;在制备预防和治疗神经退化、变化疾病及癫痫、偏头痛药物中的应用。
- 权利要求1-3任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备预防和治疗化疗导致的周围神经病变药物中的应用。
- 要求1-3任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备预防和治疗抗抑郁症、镇静或催眠药物中的应用。
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