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Brain-targeting eslicarbazepine ester prodrug and application thereof

An ester prodrug and prodrug technology, applied in the field of medicine, can solve problems such as adverse reactions and intolerance of patients, achieve high blood-brain barrier penetration, improve brain intake, and high brain targeting Effect

Active Publication Date: 2017-04-26
北京现代药物代谢研究院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Carbamazepine (CBZ), which was launched in the 1960s, is the first generation of dibenzoazepine antiepileptic drugs (Antiepileptic drugs, AEDs). Indeed, but there are still 30-40% of patients who cannot tolerate it, and 33%-50% of patients need to suffer unnecessary adverse reactions (Epilepsia, 1996, 37(s2): S1-S3.)

Method used

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  • Brain-targeting eslicarbazepine ester prodrug and application thereof
  • Brain-targeting eslicarbazepine ester prodrug and application thereof
  • Brain-targeting eslicarbazepine ester prodrug and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Synthesis of the compound of formula (I)

[0094] The synthetic route is as follows Figure 4 shown.

[0095] Taking the synthesis of compounds I-01 to I-16 as an example, the synthesis method will be further described.

[0096] At room temperature, add (100.0g, 0.4mol) oxcarbazepine, 400mL methanol and 200mL water into a 1L round-bottomed flask, add (15.0g, 0.4mol) sodium borohydride in batches, stir at room temperature for 30min and place at 45°C Continue to react for 1h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to 200-300 mL, filtered, and washed with water three times to obtain 99.0 g of light yellow solid powder, which was compound 1, with a yield of 97.3%. m.p.188-192°C.

[0097]At room temperature, (9.2mmol) carboxylic acid, (18.4mmol) thionyl chloride and 1 drop of pyridine were added to 5mL of dichloromethane, and the reaction was refluxed for 3h. After the reaction was completed, the solvent and resid...

Embodiment 2

[0145] Preliminary Screening of Brain Uptake of Compounds of Formula (I) in Rats

[0146] Nine healthy Wistar rats weighed a certain amount of racemic licarbazepine, racemic licarbazepine acetate, I-03, I-04, I-07, I-11, I-13, I- 14. I-16, add 0.5% CMC-Na physiological saline (containing 0.9% NaCl) solution, and administer by intragastric administration at a dose of 0.13 mmol / kg. At 1, 5, 15, 30, 45, 60, and 180 minutes after administration, take 0.25 mL of whole blood from the venous plexus behind the eyes, put it in a heparinized EP tube containing the esterase inhibitor DDV, centrifuge at 3,500 rpm for 5 minutes at 4°C, and separate the plasma , take 0.1mL plasma, and store it at -80°C for testing.

[0147]27 healthy Wistar rats. Weigh a certain amount of racemic licarbazepine, racemic licarbazepine acetate, I-03, I-04, I-07, I-11, I-13, I-14, I-16, add 0.5% CMC-Na physiological saline (containing 0.9% NaCl) solution, administered by intragastric administration at a dose...

Embodiment 3

[0152] Further Verification of Brain Uptake of Compound of Formula (I) in Rats

[0153] In order to further verify that the compound of formula (I) has good brain uptake properties, 5 compounds of formula (I) with higher brain concentration were selected from Table 1 for chiral resolution to prepare the corresponding S-optical isomer The compound of formula (I) was evaluated for pharmacokinetics according to the method in Example 2, and compared with eslicarbazepine and eslicarbazepine acetate. The results show that, as shown in Table 2, compared with eslicarbazepine and eslicarbazepine acetate, the designed S-optical isomer formula (I) compound also has higher brain uptake, Especially compound I-26, namely (S)-10-(3-thiophene) acyloxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide, which enters After the brain is rapidly converted to eslicarbazepine, the brain content is as high as 501ng / g, which is 3.1 times that of eslicarbazepine alone and 2.2 times that of eslicarbaz...

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PUM

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Abstract

The invention relates to an eslicarbazepine ester prodrug and an application thereof, wherein the prodrug is a compound represented by the formula (I) or optical isomers or physiologically acceptable salts of the compound represented by the formula (I), wherein R represents a lipophilic substituent. The compound represented by the formula (I) is the eslicarbazepine ester prodrug containing the lipophilic substituent, is converted into eslicarbazepine through metabolism in vivo to play pharmacological effects, and can be applied in preparation of drugs for treatment, prevention or adjuvant treatment of central nervous system diseases, such as epilepsy and the like.

Description

technical field [0001] The invention relates to the field of medicine, in particular to an eslicarbazepine ester prodrug and its application. This type of compound has better distribution in the brain and is used in the field of treatment or auxiliary treatment of central nervous system diseases such as epilepsy. Background technique [0002] Carbamazepine (CBZ), which was launched in the 1960s, is the first generation of dibenzoazepine antiepileptic drugs (Antiepileptic drugs, AEDs). Indeed, 30-40% of patients still cannot tolerate it, and 33%-50% of patients need to suffer unnecessary adverse reactions (Epilepsia, 1996, 37(s2): S1-S3.). Oxcarbazepine (OXC) is a 10-keto derivative of CBZ, which belongs to the second-generation dibenzoazepine AEDs. Its clinical use is similar to that of CBZ, but its adverse reactions are milder than that of CBZ, and it is well tolerated by patients. The difference between OXC and CBZ in terms of adverse reactions and toxicity can be compare...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/22C07D409/12C07D405/12A61K31/55A61P25/08A61P25/12A61P25/22A61P25/18A61P25/04A61P25/14
Inventor 顾景凯张扬杨志超尹磊
Owner 北京现代药物代谢研究院
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