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Novel buprenorphine ester derivatives and process for preparing the same and medical compounds with long-acting analgesic effect

A technology of buprenorphine monocarboxylate and dibuprenorphine dicarboxylate, applied in the field of novel buprenorphine ester derivatives

Inactive Publication Date: 2004-06-02
CHI MEI MEDICAL CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] However, to date, no injectable long-acting dosage form of buprenorphine suitable for therapeutic use has been described.

Method used

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  • Novel buprenorphine ester derivatives and process for preparing the same and medical compounds with long-acting analgesic effect
  • Novel buprenorphine ester derivatives and process for preparing the same and medical compounds with long-acting analgesic effect
  • Novel buprenorphine ester derivatives and process for preparing the same and medical compounds with long-acting analgesic effect

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0117] The following examples are provided for illustrative purposes only, and are not intended to limit the scope of the present invention.

[0118] Table 1 below shows the chemical structures of preferred buprenorphine ester derivatives according to the present invention.

[0119] Table 1. Molecular structures of buprenorphine HCl, buprenorphine base and ester derivatives according to the present invention

[0120]

[0121] Bup: stands for buprenorphine

[0122] The buprenorphine ester derivatives listed in Table 1 can be synthesized by suitable known methods, such as those disclosed in US Pat. Nos. 5,750,534 and 6,225,321.

Synthetic example 1

[0123] Synthesis Example 1: Preparation of Buprenorphine Enanthate

[0124] 75 mL of dichloromethane (Mallinckrodt, Baker, U.S.A.) and 0.01 M of buprenorphine HCl or base were added to a 250 mL round bottom flask placed in an ice bath for cooling. The mixture was stirred, and 20 mL of dichloromethane containing 0.03 M of triethylamine (Sigma, MO, U.S.A.) was added slowly. Another 20 mL of dichloromethane containing 0.011 moles of heptanoyl chloride (Aldrich, Milwaukee, U.S.A.) was added dropwise with rapid stirring. After that, the mixture was stirred at room temperature for 1 hour. 20 ml of a 10% sodium carbonate was then added to neutralize residual acid and remove water soluble impurities. Sodium sulfate was used to dehydrate the solution. After drying under vacuum, the title compound (ie buprenorphine enanthate) was obtained. The product was purified by column chromatography.

[0125] The title compound was generated by figure 1 , figure 2 , image 3 and Figure ...

Synthetic example 2

[0131] Synthesis Example 2: Preparation of Buprenorphine Decanoate

[0132] The title compound was prepared according to the method described in Synthesis Example 1 above, except that 0.011 mol of decanoyl chloride (Fluka, Buchs, Switzerland) was used instead of heptanoyl chloride. Pure buprenorphine decanoate was obtained (see Figure 5 , Image 6 , Figure 7 and Figure 8 , these figures respectively show the 1 H-NMR spectrum, mass spectrum, UV spectrum and IR spectrum).

[0133] Measured properties of the title compound:

[0134] Representative 1 H-NMR (400MHz, CDCl 3 ): 6.76(d, 1H, J=8.0Hz), 6.58(d, 1H, J=8.1Hz), 5.91(s, 1H), 4.41(s, 1H), 3.45(s, 3H), 3.00(m .2H), 2.87(m, 1H), 2.50(t, 2H, J=7.4Hz), 2.33-2.10(m.5H), 2.00-1.78(m, 4H), 1.72-1.66(m.4H), 1.37-1.25(m, 18H), 1.04(m, 11H), 0.87(t, 3H, J=6.6Hz), 0.80(m, 1H), 0.69(m, 1H), 0.48(m, 2H), 0.11 (m, 2H).

[0135]Representative mass spectral fragments (amu): 622, 607, 565, 533, 521, 507, 380, 55 [determination p...

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Abstract

The present invention discloses novel monocarboxilic ester derivative of buprenorphine and dicarboxilic ester derivative of dibuprenorphine, which exhibit ever lasting pain relieving effect than the hydrochloride of buprenorphine. The present invention discloses also the synthesis process of these novel buprenorphine ester derivatives and long-acting pain relieving medicinal composition containing compound selected from buprenorphine alkaloid and these novel buprenorphine ester derivatives.

Description

field of invention [0001] The present invention relates to novel buprenorphine (buprenorphine) ester derivatives, particularly related to buprenorphine monocarboxylate derivatives and dibuprenorphine dicarboxylate derivatives, and buprenorphine hydrochloride In comparison, these derivatives exhibited a longer analgesic effect. The present invention also relates to processes for the preparation of these novel buprenorphine ester derivatives, and long-acting analgesic pharmaceutical combinations comprising a compound selected from buprenorphine base and these novel buprenorphine ester derivatives thing. Background technique [0002] Prolonged analgesia is particularly desirable for patients suffering from moderate to severe pain such as post-surgical pain and cancer pain. Currently, local anesthetics, weak analgesics and potent analgesics are used in this technical field, but all of them are short-acting drugs. [0003] Local anesthetics, such as xylocaine or bupivacaine, c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/485C07D489/12C07D519/00
CPCC07D489/12A61K31/485A61P25/04A61P29/00
Inventor 王志中
Owner CHI MEI MEDICAL CENT
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