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Pentazocine prodrug as well as preparation method and application thereof

A technology of pentazocine and prodrug, applied in the field of medicinal chemistry, can solve problems such as unsatisfactory, and achieve the effects of improving bioavailability, stable biological properties, and delaying drug action time

Pending Publication Date: 2020-06-30
ANHUI HEALSTAR PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, there remains a clear unmet need for improved drugs, such as prodrugs of existing drugs

Method used

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  • Pentazocine prodrug as well as preparation method and application thereof
  • Pentazocine prodrug as well as preparation method and application thereof
  • Pentazocine prodrug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The synthesis of embodiment 1 pentazocine prodrug (compound 1)

[0045]

[0046] 1, Synthesis of 2-acetyl-2-methyl-butyrolactone (intermediate 1)

[0047] N 2 For protection, a solution of 2-acetylbutyrolactone (51g, 0.4mol) in 400ml of anhydrous dichloromethane was added dropwise to [Me 2 Cl][Al(OTeF 5 ) 4 ] (0.8mol) solution, stirred at room temperature overnight, filtered, the solid was washed several times with an appropriate amount of dichloromethane, and concentrated under reduced pressure to obtain 51.7 g of light yellow oil, with a yield of 91.0%.

[0048] 2. Synthesis of 5-chloro-3-methylpentan-2-one (intermediate 2)

[0049] 2-acetyl-2-methyl-butyrolactone (51g, 0.359mol), concentrated hydrochloric acid (128ml, 32%, 1.07mol), 150ml of distilled water, heated carefully until the gas ceased, and the reaction compound was distilled to collect 140ml of distillate, The residue was added to 90ml of distilled water, and 80ml of distillate was collected by dis...

Embodiment 2

[0082] Synthesis of embodiment 2 deuterated pentazocine prodrug (compound 2)

[0083]

[0084] With embodiment 1, wherein the synthesis of intermediate 11, use [4,4'- 2 h 6 ]-1-bromo-3-methyl-2-butene [For the synthesis method, please refer to the invention patent applied by the applicant: 202010177342.6 Example 1] instead of 1-bromo-3-methyl-2-butene, it is convenient to prepare Obtained deuterated pentazocine prodrug (compound 2) 2.3g, HPLC content 99.1%.

[0085] GC-MS (m / z): 415.6.

Embodiment 3

[0086] The synthesis of embodiment 3 pentazocine prodrug (compound 1)

[0087] 1, Synthesis of 2-acetyl-2-methyl-butyrolactone (intermediate 1)

[0088] N 2 Protection, 4L of anhydrous dichloromethane solution of 2-acetylbutyrolactone (510g, 4mol), was added dropwise into [Me 2 Cl][Al(OTeF 5 ) 4 ] (8mol) solution, stirred at room temperature overnight, filtered, the solid was washed with an appropriate amount of dichloromethane, and concentrated under reduced pressure to obtain 523 g of light yellow oil, with a yield of 91.8%.

[0089] 2. Synthesis of 5-chloro-3-methylpentan-2-one (intermediate 2)

[0090] 2-Acetyl-2-methyl-butyrolactone (520g, 3.4mol), concentrated hydrochloric acid (1.3L, 32%, 10.7mol), distilled water 1500ml, heated carefully until the gas ceased, and the reaction compound was distilled to collect 1400ml distillate , the residue was added to 900ml of distilled water, and 800ml of distillate was collected by distillation, the organic layer was separated...

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Abstract

The invention discloses a pentazocine prodrug shown as a formula (I), a preparation method thereof and medical application of a pharmaceutical preparation containing the pentazocine prodrug, wherein Ris hydrogen or deuterium. The water solubility of the prodrug compound is improved by 20 times or above at room temperature, the prodrug compound is chemically stable, the onset time is delayed, thedrug effect is prolonged, meanwhile, the same parent drug blood concentration is generated at a low dosage, and the prodrug compound has a wide clinical application prospect.

Description

[0001] 1. Technical field [0002] The invention relates to the field of medicinal chemistry, in particular to a pentazoctine axetil, its preparation method, including its pharmaceutical preparation and its medical use. [0003] 2. Background technology [0004] Pentazocine was successfully developed and launched by British SteringWinthropGroup LTD in 1967. Pentazocine (pentazocine, also known as tebuconazole, analgesic new) is a derivative of benzomorphinane, which has mixed agonistic and antagonistic effects on opioid receptors, mainly activating opioid κ receptors, with a large It can stimulate the σ receptor at a certain dose, and has partial agonism or weak antagonistic effect on the μ receptor. Pentazocine is suitable for analgesia of moderate to severe pain, and has a wide range of clinical applications, such as auxiliary intraoperative analgesia, postoperative analgesia, chronic pain treatment, cancer pain treatment, etc. Oral pentazocine tablets are currently the onl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/09A61K31/675A61P29/00
CPCC07F9/096A61P29/00
Inventor 徐奎刘逸凡
Owner ANHUI HEALSTAR PHARM CO LTD
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