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Dual-functional oleanolic acid derivatives as well as preparation method and application thereof

An oleanolic acid and dual-function technology, which is applied in the field of oleanolic acid derivatives and their preparation, can solve the problems of excessive inhibition of bone turnover, the need for subcutaneous administration, and inaccurate long-term efficacy, and achieves inhibition of osteoclasts. Cell production and bone resorption activity, bone formation promotion activity, platelet aggregation inhibitory effect

Inactive Publication Date: 2014-07-23
南京惠特莱医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Female osteoporosis caused by the sharp decline of estrogen due to menopause and other reasons accounts for the majority of patients. Estrogen is the most suitable drug, but it has serious estrogen-like side effects, which is why many female patients refuse to use this type of drug Reason: Calcium preparations have no effect on fractures caused by osteoporosis; bisphosphonates are currently the first-line clinical drugs, but long-term use can excessively inhibit bone turnover and affect bone strength; calcitonin, fluoride, raloxifene etc., or the price is expensive, or the long-term curative effect is uncertain, which is not ideal
Unfortunately, the current clinical drug that can promote bone formation is only one parathyroid hormone (PTH1–34), but it must be administered subcutaneously, and it can only be used for 24 months, which will cause an increase in osteosarcoma. Patients with calcemia, hyperthyroidism and Paget's disease
In addition, there is no drug that can inhibit bone resorption and promote bone formation at the same time.
Although it has been reported that strontium ranelate (a bone resorption inhibitor) can promote bone formation, but animal experiments have confirmed that there is no such effect

Method used

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  • Dual-functional oleanolic acid derivatives as well as preparation method and application thereof
  • Dual-functional oleanolic acid derivatives as well as preparation method and application thereof
  • Dual-functional oleanolic acid derivatives as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] 1. The preparation of compound 1, the reaction formula is:

[0030]

[0031] Preparation of Compound A

[0032] Na 2 HPO 4 12H 2 O (1.7g, 4.8mmol) and NaH 2 PO 4 2H 2 O (0.75g, 4.8mmol) was fully dissolved in 95mL of water to prepare a phosphate buffer solution. Na 2 WO 4 2H 2 O (4g, 12mmol) dissolved in 35% aqH 2 o 2 (28mL) and added to phosphate buffered saline. Add OA (11g, 24mmol) and DMF (50mL) in a 500mL round bottom flask, and heat to 90°C, add the above Na 2 WO 4 -H 2 o 2 Phosphate buffered saline, and the reaction was stirred for 1 hour. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound A (9.8 g, 89%).

[0033] Preparation of Compound B

[0034] A 250 mL round bottom flask was charged with compound A (9.0 g, 20 mmol), toluene (100 mL). Sodium methoxide (2.8 g, 50 mm...

Embodiment 2

[0304] Example 2 Specific activity examples of oleanolic acid derivatives:

[0305] 1 Inhibition of osteoclasts generated in vitro

[0306] Osteoclast induction in vitro: 1) RAW264.7 cells were passaged 2-3 times with a disposable cell scraper after recovery, and the confluence was 60-70% (the differentiation potential of RAW264.7 cells was significantly reduced after being completely overgrown and subcultured), and the cells were in Scrape off with a cell scraper during logarithmic division, centrifuge at 1000g for 10min, resuspend in phenol red-free α-MEM containing 10% heat-inactivated FBS and 30ng / mL RANKL, count, and use 1X10 4 mL -1 The density was seeded in a 96-well cell culture plate with 100 μ cell solution per well. 2) Replace half of the phenol red-free α-MEM medium containing 10% heat-inactivated FBS and 30ng / mL RANKL every other day. 3) TRAP staining was performed on the second day of culture, and more than 90% of the cell populations were TRAP-positive mononu...

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Abstract

The invention discloses dual-functional oleanolic acid derivatives as well as a preparation method and application thereof. The oleanolic acid derivatives comprise pyrazole, isoxazoles oleanolic acid derivatives, quinoxalines oleanolic acid derivatives, oxazole, thiazoles oleanolic acid derivatives and pyrans oleanolic acid derivatives. The oleanolic acid derivatives disclosed by the invention have anti-inflammatory, anti-viral, anti-tumor and immune regulating effects and important biomedical activities such as inhibiting platelet aggregation and are widely used in the preparation of a medicament for the treatment of osteoporosis. According to the preparation method of the oleanolic acid derivatives disclosed by the invention, novel anti-osteoporosis oleanolic acid derivatives, which have dual characteristics of inhibiting osteoclast formation and bone resorption activity and promoting bone formation activity, are successfully prepared by introducing different heterocyclic ring systems such as quinoxaline, pyrazole, isoxazole, thiazole, pyran ring at oleanolic acid A ring and introducing different substituents at 28-position and have good practicability.

Description

technical field [0001] The invention belongs to the technical field of chemistry and medicine, and in particular relates to a class of oleanolic acid derivatives with dual functions and a preparation method and application thereof. Background technique [0002] Osteoporosis (Osteoporosis) is known as a silent epidemic. It is characterized by damage to the microstructure of bone tissue, a continuous reduction in the proportion of bone mineral components and bone matrix, bone thinning, and a decrease in the number of trabecular bones. A systemic disorder of bone metabolism with increased bone fragility and increased fracture risk. WHO statistics show that the total number of osteoporosis patients in the world exceeds 200 million, mainly due to primary osteoporosis related to menopause and old age. October 20 every year is "International Osteoporosis Day". Osteoporosis is recognized as the second largest health killer after cardiovascular disease, and long-term treatment is r...

Claims

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Application Information

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IPC IPC(8): C07J71/00C07J63/00A61K31/58A61K31/56A61P35/00A61P29/00A61P31/12A61P7/02A61P19/10A61P37/02
Inventor 李建新
Owner 南京惠特莱医药科技有限公司
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