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Synthesis of high-b-cyclic berberine and palmatine derivatives and their use as hypoglycemic agents

A derivative, berberine technology, applied in the field of compound drugs, can solve the problems of poor solubility of berberine, unsatisfactory, low oral bioavailability, etc., and achieve good medicinal potential, mild reaction conditions, and efficacy. clear effect

Active Publication Date: 2020-05-15
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, berberine has unfavorable factors such as poor solubility and low oral bioavailability. Although researchers have conducted some research based on these problems, they have not fundamentally made substantial progress and are still not satisfactory.

Method used

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  • Synthesis of high-b-cyclic berberine and palmatine derivatives and their use as hypoglycemic agents
  • Synthesis of high-b-cyclic berberine and palmatine derivatives and their use as hypoglycemic agents
  • Synthesis of high-b-cyclic berberine and palmatine derivatives and their use as hypoglycemic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1, the synthesis of methanesulfonic acid high B ring berberine (Ber-1)

[0038]

[0039] As shown in the above synthetic route: with 3,4-(methylenedioxy)benzaldehyde as the initial raw material, the carbon chain of the B ring is extended by construction, and then the C ring D ring isoquinoline mother ring is constructed, and finally the B ring is cyclized. ring to obtain the target compound methanesulfonic acid homo-B-ring berberine (Ber-1).

[0040] Synthesis of compound 2b:

[0041] In a 250ml round bottom flask, dissolve compound 1b (12g, 79.9mmol), malonic acid (16.6g, 159.9mmol) with 7.2ml piperidine and 140ml pyridine, then move the reaction solution to an oil bath at 115°C and heat to reflux for about 2 hours. The reaction process was monitored by TLC until the reaction of compound 1b was complete. After the reaction solution was cooled to room temperature, the reaction solution was slowly poured into 200 ml of hydrochloric acid solution (2 mol / L...

Embodiment 2

[0064] Embodiment 2, the synthesis of high B ring berberine hydrochloride (Ber-2)

[0065]

[0066] As shown in the above synthetic route: the high B-ring berberine hydrochloride (Ber-2) was obtained by alkalinizing and hydrochlorizing methanesulfonic acid high-B-ring berberine (Ber-1) as a starting material.

[0067] Synthesis of compound 12b:

[0068] Dissolve Ber-1 with 6 ml of methanol / water mixed solvent (V / V=5 / 1) at room temperature, and then slowly add calcium oxide solid therein to adjust the pH of the reaction system to 9-10. Move the reaction solution to a 60°C oil bath and heat it for 3 hours, then pour the reaction solution into 10ml of water, extract the water layer 4 times with dichloromethane, combine the dichloromethane layers, wash with saturated saline, and wash with anhydrous sodium sulfate Dry, filter and concentrate under reduced pressure to obtain the crude product 12b, which is directly reacted in the next step without further purification.

[0069]...

Embodiment 3

[0072] The synthesis of embodiment 3, Ber-3

[0073]

[0074]As shown in the above synthetic route: use compound 7b as the starting material to couple with 2-bromo-4,5-dimethoxybenzaldehyde (compound 8') through the Sonogashira reaction, and then through the ring closure of the isoquinoline ring and Ring closure of the high B ring yields compound Ber-3.

[0075] Synthesis of compound 9b':

[0076] Similar to the synthesis of compound 9b in Example 1.

[0077] Put compound 7b, 2-bromo-4,5-dimethoxybenzaldehyde 8', bistriphenylphosphine palladium dichloride and cuprous iodide in a 50ml double-necked bottle, and replace the gas with argon three times. Dissolve it with triethylamine and place it at 70°C for three hours. The reaction process was monitored by TLC until the reaction of compound 7b was complete. The reaction solvent was spun off under reduced pressure, and the residue was redissolved in ethyl acetate and washed with water. The aqueous layer was extracted twice...

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Abstract

The invention provides a new high B-ring berberine and palmatine derivative. The structural formula is shown in the description. The invention also provides a preparation technology and application ofthe high B-ring berberine and palmatine derivative. Pharmacodynamic tests prove that the compound provided by the invention has a relatively good effect of reducing blood glucose in vitro and is partially superior to a positive control of berberine hydrochloride. The high B-ring berberine and palmatine derivative provided by the invention has a remarkable drug effect and possibly provides a new clinical medication option.

Description

technical field [0001] The invention belongs to the field of compound medicines, in particular to a class of novel high-B-ring berberine and palmatine derivatives and their use for lowering blood sugar. Background technique [0002] Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia, usually caused by defects in insulin secretion or its biological action, or both. The long-term high blood sugar in diabetes leads to chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves. Therefore, diabetes seriously affects the quality of life and health of patients. At present, the commonly used hypoglycemic drugs in clinic can be roughly divided into oral hypoglycemic drugs and injection hypoglycemic drugs. Oral hypoglycemic drugs include insulin secretagogues, metformin, α-glucosidase inhibitors, thiazolidinedione derivatives, DDP-4 enzyme inhibitors, etc., while injection hypoglycemic drugs mainly...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D491/147A61P3/10A61P5/50
CPCC07D471/04C07D491/147
Inventor 吴勇海俐李伟剑管玫
Owner SICHUAN UNIV
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