Chiral CB1 (cannabinoid) receptor inhibitor, and preparation method and medical application thereof

A receptor inhibitor, C1-C16 technology, used in organic chemistry, pharmaceutical formulations, organic active ingredients, etc., can solve problems such as no further reports, and achieve the effect of overcoming toxicity and side effects, low toxicity, and reduced toxicity

Active Publication Date: 2012-07-25
范如霖 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mainland China has also invented a compound magic nabant (MJ-15) with the

Method used

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  • Chiral CB1 (cannabinoid) receptor inhibitor, and preparation method and medical application thereof
  • Chiral CB1 (cannabinoid) receptor inhibitor, and preparation method and medical application thereof
  • Chiral CB1 (cannabinoid) receptor inhibitor, and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1: (R / S)-1-nitroso-3-hydroxy-piperidine (II)

[0081] 3-hydroxypiperidine hydrochloride 40.03g (0.291mol), NaNO 2 , 40.2g (0.583mol) were dissolved in 200ml and 100ml of water, mixed, cooled to 0 ℃. Slowly add HOAc26.2g (0.437mol) dropwise therein at 0 to 5°C, and complete the addition within 60 minutes; then stir at 0°C for 4 hours and the reaction is complete. TLC: 0.80 (product nitroso); 0.28 (raw material) (ethanol:ammonia=10:1). Take Na 2 CO 3 30 g to neutralize residual acetic acid; use CH 2 Cl 2 Extract 6 times, 150ml each time; combine the organic phase; use Na 2 SO 4 Drying; Filtration; Concentration, 36.7g of yellow liquid was obtained; Yield 96.9%. directly used in the next reduction reaction. 1 H-NMR (CDCl 3 ): δ, 1.67-2.00 (m, 4H); 3.40-4.30 (m, 6H, containing OH).

Embodiment 2

[0082] Example 2: (R / S)-1-amino-3-hydroxy-piperidine (III)

[0083] Add 16.16g (0.426mol) of lithium aluminum hydride to 450ml of anhydrous THF that has been dried and distilled over sodium metal, and stir at about 40°C for 15 minutes; add dropwise 18.44g (0.142mol, 1 eq) in 100 ml dry THF. During the dropwise addition, the temperature was controlled at 40-45° C., and the dropwise addition took 45 minutes. Heat to reflux for 8 hours; cool to room temperature, add a mixture of 60ml of undried THF and 60ml of water (1:1); stir at room temperature at 30°C for 0.5 hours. Filter; wash the filter cake with THF (2×50ml); put the filter cake into 150ml THF and heat to reflux for 10 minutes, then filter again; repeat this operation twice. Combine all filtrates; use anhydrous Na 2 SO 4 After drying and evaporation, 14.7 g of light yellow liquid was obtained (the color is lighter than that of the raw material nitro compound); the yield of crude product is 89.1%. After drying in vacu...

Embodiment 3

[0085] Example 3: (R)-1-amino-3-hydroxypiperidine (IV)

[0086] A) Resolution of (R / S)-1-amino-3-hydroxy-piperidine:

[0087] Take 13 g (0.112 mol) of the above-mentioned racemic 1-amino-3-hydroxy-piperidine, dissolve it in 120 ml of isopropanol; add 17.0 g (0.112 mol) of S-mandelic acid to it in 150 ml of isopropanol at room temperature The solution. Crystals precipitated after about 1 hour; filtered after being placed in a refrigerator at 0°C for 4 hours; the filter cake was washed 4 times with cold ethyl acetate, 50ml each time; vacuum-dried to obtain 16.3g of white crystals; [α] D : +65.23° (C, 20.05; H 2 0, 25°C).

[0088] Dissolve the crude product in a mixture of 200ml of isopropanol, 30ml of methanol and 2ml of water; heat to reflux for 6 hours; cool to room temperature; place in a refrigerator at 0°C and filter after 6 hours; the filter cake is washed with cold ethyl acetate 4 times, 50ml each time; vacuum dried to obtain 11.28g of white crystals; [α] D : +65.84°...

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Abstract

The invention relates to a chiral CB1 (cannabinoid) receptor inhibitor which is showed as a general formula A1 and a general formula A2 and has optical asymetery performance, and slat or solvate which is physiologically acceptable, in particular relates to a diaryl-replaced pyrazole ramification CB1 receptor inhibitor which is showed as the general formula A and the general formula B, has optical asymetery performance and is hypotoxic, and the method also discloses a preparation method and an application used for preparing medicaments for detoxification, weight losing, diabetes mellitus treatment or cardiovascular disease preventing, and all application on medical science related with the CB1 receptor inhibitor.

Description

technical field [0001] The present invention relates to a CB1 receptor inhibitor, in particular to a CB1 receptor inhibitor with optically asymmetric activity, a preparation method and its medical use, in particular to the optically asymmetrically active, low-toxic diaryl-substituted CB1 receptor inhibitors of pyrazole derivatives, preparation methods and their application in the preparation of drugs for detoxification, weight loss, diabetes treatment, or prevention of cardiovascular system diseases, and all medical aspects related to CB1 receptor inhibitors use. Background technique [0002] As early as 1968, Roger had already begun to study the mechanism of the toxic effects of cannabis. In the 1990s, the concept of cannabinoid receptors was proposed, and it was found that there are at least two subtypes of cannabinoid receptors, CB1 and CB2, in the human body. The former is distributed throughout the body and produces a variety of physiological effects after being activ...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D403/12A61K31/454A61K31/4155A61K31/55A61P25/30A61P3/04A61P3/10A61P9/00
CPCC07D401/12A61K31/454C07D403/12C07D231/14A61K31/4155A61K31/55A61P3/04A61P3/10A61P9/00A61P25/30
Inventor 范如霖周晓红姚虎王华冯建科殷文陶
Owner 范如霖
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