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Antipyretic and analgesic ibuprofen-beta-cyclodextrin secondary-side derivative and preparation method thereof

An antipyretic and analgesic, cyclodextrin technology, applied in the directions of antipyretics, drug combinations, pharmaceutical formulations, etc., can solve the problem of reducing the antipyretic and analgesic time of ibuprofen, the large fluctuation of blood drug concentration, and the aggravation of bleeding tendency. and other problems, to avoid the peaks and valleys of drug efficacy, reduce fluctuations in blood concentration, and avoid heartburn.

Pending Publication Date: 2019-09-27
NINGXIA MEDICAL UNIV
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Problems solved by technology

However, because ibuprofen is released too quickly in the human body, it reduces the antipyretic and analgesic time of ibuprofen in the human body, and because its half-life is longer, reaching 1.8-2 hours, it takes 2-3 times a day, causing The plasma concentration of ibuprofen in the human body fluctuates greatly, causing patients to often experience hemolysis after taking the drug, causing adverse reactions such as heartburn, stomach pain, nausea, and vomiting, and aggravating bleeding tendency, especially in hemophilia or other diseases. Ibuprofen should be used with caution in patients with bleeding disorders

Method used

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  • Antipyretic and analgesic ibuprofen-beta-cyclodextrin secondary-side derivative and preparation method thereof
  • Antipyretic and analgesic ibuprofen-beta-cyclodextrin secondary-side derivative and preparation method thereof
  • Antipyretic and analgesic ibuprofen-beta-cyclodextrin secondary-side derivative and preparation method thereof

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preparation example Construction

[0023] The present invention also proposes a preparation method for antipyretic and analgesic ibuprofen-β-cyclodextrin second derivatives, comprising the following steps:

[0024] Step a), the synthesis of ibuprofen imidazolate, ibuprofen is dissolved in dichloromethane, N, N'-carbonyldiimidazole (CDI) is dissolved in dichloromethane, and then the dichloromethane of ibuprofen The methane solution is added dropwise into the dichloromethane solution of CDI through the dropping funnel, stirred evenly until the reaction is completed, and dried after acid-base extraction and n-hexane precipitation to obtain imidazolate ibuprofen;

[0025] The synthetic route of ibuprofen imidazolate is:

[0026]

[0027] Step b), the synthesis of ibuprofen-β-cyclodextrin second side derivatives, the ibuprofen imidazolate prepared in step a) is dissolved in N,N-dimethylformamide (DMF), Add β-cyclodextrin to the DMF solution of ibuprofen imidazolate, stir evenly at room temperature, then add a ca...

Embodiment 1

[0041] The preparation of ibuprofen imidazolate: ibuprofen 0.01mol (2.06g) is dissolved in 30ml dichloromethane; CDI0.015mol (2.43g) is dissolved in 60ml dichloromethane; The dichloromethane solution of ibuprofen is passed through The dropping funnel was added dropwise into the dichloromethane solution of CDI, reacted for 12-24 hours, extracted with acid and alkali, precipitated with n-hexane and dried to obtain imidazolate ibuprofen (yield 80%).

[0042] The ibuprofen imidazolate that this embodiment makes, nuclear magnetic data is as follows:

[0043] 1 H NMR (400MHz, DMSO-d 6 ):8.49,7.71,7.32,7.30,7.13,7.11,7.01, 4.76,4.74,2.51,2.39,2.37,1.82-1.72,1.49,1.47,0.82,0.80; 13 C NMR (400MHz, DMSO-d 6 ): 171.8, 140.88, 137.63, 130.75, 130.07, 127.53, 117.24, 44.61, 44.36, 40.60-39.44, 29.99, 22.59, 19.59.

[0044] Preparation of ibuprofen β-cyclodextrin second side derivatives: Ibuprofen imidazolate 0.015mol (3.84g) was dissolved in 600mL N,N-dimethylformamide (DMF), and β-cyc...

Embodiment 2

[0047] The preparation of ibuprofen imidazolate: ibuprofen 0.01mol (2.06g) is dissolved in 30ml dichloromethane; CDI0.015mol (2.43g) is dissolved in 60ml dichloromethane; The dichloromethane solution of ibuprofen is passed through The dropping funnel was added dropwise into the dichloromethane solution of CDI, reacted for 5-10 hours, extracted with acid and alkali, precipitated with n-hexane and dried to obtain imidazolate ibuprofen (yield 68%).

[0048] Preparation of ibuprofen β-cyclodextrin second side derivatives: Ibuprofen imidazolate 0.015mol (3.84g) was dissolved in 600mL N, in N-dimethylformamide (DMF), added β-CD0. 0225mol (25.5g), while adding triethylamine (65ml). Continue to stir the reaction at room temperature for 12-24h, and evaporate the solvent under reduced pressure. The residue was chromatographed with excess acetone and filtered to obtain a crude product. The crude product was purified by a C18 reverse-phase column, and dried in vacuum to obtain a pure se...

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Abstract

The invention provides an antipyretic and analgesic ibuprofen-beta-cyclodextrin secondary-side derivative and a preparation method thereof. An intermediate product ibuprofen imidazolate is prepared from ibuprofen and CDI (1,1'-carbonyldiimidazole) as raw materials, and ibuprofen imidazolate is subjected to a reaction with beta-cyclodextrin, triethylamine is added to effectively activate secondary hydroxyl on the secondary side of beta-cyclodextrin, and the ibuprofen-beta-cyclodextrin secondary-side derivative is prepared. Hydroxyl on the secondary side of beta-cyclodextrin is modified with ibuprofen functional groups selectively, the release rate of ibuprofen functional groups in the human body is greatly reduced, antipyretic and analgesic time of ibuprofen in the human body is prolonged, and antipyretic and analgesic effects are improved; besides, the drug effect is released smoothly, hemolysis no longer occurs after patients take the ibuprofen-beta-cyclodextrin secondary-side derivative, and adverse reactions such as gastric burning sensation, stomachache, nausea and vomiting of the patients are avoided.

Description

technical field [0001] The invention relates to the technical field of medicinal chemical synthesis, in particular to an antipyretic and analgesic ibuprofen-β-cyclodextrin second derivative and a preparation method thereof. Background technique [0002] β-cyclodextrin and its derivatives, as a drug molecular carrier with selective inclusion ability, play a role in pharmacy that is difficult for common excipients. Its molecular structure is a ring-shaped, hollow cylinder. Compared with other macrocyclic molecules, β-cyclodextrin is special in that it has a rigid conical cavity structure with a hydrophobic inner cavity and a hydrophilic outer cavity. The hydroxyl groups on the surface of cyclodextrin are mainly divided into two types, among which the primary hydroxyl group (ie, the 6-position hydroxyl group) constitutes the main surface (ie, the first surface) of the cyclodextrin cone-shaped cavity structure, and the secondary hydroxyl group (ie, the 2-position Hydroxyl and 3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/61A61K31/192A61P29/00C08B37/16
CPCA61K47/61A61K31/192A61P29/00C08B37/0012
Inventor 王玉营黄青褚慧敏魏世杰王志忠
Owner NINGXIA MEDICAL UNIV
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