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CN-121991337-A - Phenol polyethylene glycol derivative, preparation method thereof and application thereof in medicine

CN121991337ACN 121991337 ACN121991337 ACN 121991337ACN-121991337-A

Abstract

The invention relates to a phenol polyethylene glycol derivative, a preparation method thereof and application thereof in medicine. Specifically, the invention relates to a phenol polyethylene glycol derivative shown in a general formula (A-I), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, and application of the phenol polyethylene glycol derivative in medicines, wherein the structure of the compound shown in the general formula (A-I) is shown as the following, and the group definition of the compound is consistent with the definition of the instruction book.

Inventors

  • YANG XUAN
  • Lv Wenchuan
  • WANG WEI
  • SHENG SHOUYI
  • ZHANG LINQI
  • WANG SHUOWEN

Assignees

  • 上海灵创盛伟医药科技有限公司
  • 四川夏派森医药科技有限公司
  • 上海喀露蓝科技有限公司

Dates

Publication Date
20260508
Application Date
20251103
Priority Date
20241104

Claims (12)

  1. 1. A compound of the general formula (a-I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: Wherein: R 1 and R 2 are each independently selected from alkyl, wherein said alkyl is optionally further substituted with cycloalkyl; R 3 is selected from a hydrogen atom; Or R 2 and R 3 together with the attached carbon atom form a 4-5 membered ring, wherein said 4-5 membered ring is optionally further substituted with one or more alkyl groups; n is 1 to 16, preferably n is 2 to 16, more preferably n is 11 to 16; Provided that when R 1 and R 2 are isopropyl groups, n is 11 to 16.
  2. 2. A compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (I): Wherein: R 1 and R 2 are each independently selected from alkyl, wherein said alkyl is optionally further substituted with cycloalkyl; n is 1-16, preferably n is 2-16, more preferably n is 11-16; Provided that when R 1 and R 2 are isopropyl groups, n is 11 to 16.
  3. 3. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is isopropyl and R 2 is 1-cyclopropylethyl.
  4. 4. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are 1-cyclopropylethyl.
  5. 5. The compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are isopropyl, and n is 12 to 16.
  6. 6. The compound according to claim 1 or 2, which is a compound of the general formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, Wherein R 1 and n are as defined in formula (I).
  7. 7. The compound of claim 6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is isopropyl or 1-cyclopropylethyl.
  8. 8. The compound according to claim 1 or 2, which is a compound of the general formula (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, Wherein n is defined as in the general formula (I).
  9. 9. The compound according to claim 1, which is a compound of the formula (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, Wherein: R a and R b are each independently selected from a hydrogen atom or an alkyl group; m is 0 or 1; R 1 and n are as defined in the general formula (A-I).
  10. 10. The compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
  11. 11. a pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
  12. 12. Use of a compound according to claims 1-10 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a composition according to claim 11, for the preparation of a medicament for inducing and maintaining anesthesia in an animal or human, promoting sedative hypnotic activity in an animal or human, treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy.

Description

Phenol polyethylene glycol derivative, preparation method thereof and application thereof in medicine Technical Field The invention relates to a phenol polyethylene glycol derivative, a preparation method thereof and application thereof in medicine. In particular to a phenol polyethylene glycol derivative shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the same and application thereof in preparing medicines. Background Polyethylene glycol consists of repeated oxyethylene groups, has good water solubility, and can be dissolved in organic solvents such as dichloromethane, N-dimethylformamide, acetonitrile, ethanol and the like. Polyethylene glycol is a neutral, nontoxic and high molecular polymer with unique physicochemical properties and good biocompatibility, is also one of very few synthetic polymers approved by FDA and can be used as in vivo injection administration, and is widely applied to modification of medicines. Its components have less interaction with blood (low plasma protein binding rate) and high biocompatibility. When coupled with the drug molecules, the excellent properties of the modified drug molecules can be endowed, the solubility of the drug is changed, a space barrier is generated around the modified drug, the enzymolysis of the drug is reduced, the drug is prevented from being quickly eliminated in metabolism, and the toxicity of the drug can be reduced. Therefore, the polyethylene glycol prodrug effectively solves the problem of low solubility of the parent drug, reduces toxic and side effects of the drug, prolongs the half-life period of the drug in blood, can improve targeting and increase curative effect, and has unique advantages compared with other prodrug carriers. Cyclophenol is a novel intravenous anesthetic, a short acting GABAA receptor agonist, whose mechanism of action is to produce sedation or anesthesia by enhancing GABAA-mediated chloride influx. Is suitable for the sedation or anesthesia of various inspections, the general anesthesia of surgical operations, ICU sedation and the like. Currently approved indications include digestive endoscopy sedation and induction of general anesthesia in adult patients. Cyclopol has high selectivity for 2 competitive binding targets TBPS and TBOB of GABAA receptor chloride channel and has about 5 times the affinity to GABAA receptor. Clinical researches show that the higher the plasma drug concentration of the cycloparaffin is in the dosage range of 0.3-0.9 mg/kg, the deeper the sedation or anesthesia degree is, the improved vigilance/sedation score (MOAA/S) gradually decreases until consciousness disappears, the response to noxious stimuli is weakened, the BIS value decreases with the increase of the dosage and reaches below 60, the sedation or anesthesia time is shorter after the cycloparaffin is singly dosed, the MOAA/S score and the BIS value quickly recover with the drug distribution metabolism, the recovery time is dose-dependent, and the 0.4-0.6 mg/kg of the cycloparaffin is equivalent to the sedation or anesthesia effect generated by 1.5-2.5 mg/kg of the propofol and the recovery time is similar. The cycloparaffin is widely distributed after single intravenous administration, the plasma drug concentration of a human body is in direct proportion to the dosage, the plasma protein binding rate is about 95 percent, and the cycloparaffin is easy to penetrate the blood brain barrier. The common adverse reaction (incidence rate is more than or equal to 1%) related to the cycloparaffin is similar to that of the propofol. Adverse reactions in which significant attention is required include hypotension, bradycardia, apnea, respiratory depression, hypoxia, and injection pain. The incidence of cycloparaffin injection pain is significantly lower than that of propofol. Disclosure of Invention The invention combines the advantages of polyethylene glycol and phenol derivatives, and modifies the phenol derivatives with polyethylene glycol with different chain lengths, thereby providing a novel phenol polyethylene glycol derivative which can improve the water solubility, improve the absorption and metabolism distribution characteristics of the medicine in vivo, improve the oral bioavailability of the medicine, reduce the food influence, reduce the dosage and frequency of administration, improve the use compliance of patients, improve the safety and prolong the action time. Specifically, the present invention relates to a compound represented by the general formula (a-I): Wherein: R 1 and R 2 are each independently selected from alkyl, wherein said alkyl is optionally further substituted with cycloalkyl; R 3 is selected from a hydrogen atom; Or R 2 and R 3 together with the attached carbon atom form a 4-5 membered ring, wherein said 4-5 membered ring is optionally further substituted with one or more alkyl groups; n is 1 to 16, pre