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WO1996028451A1 - Morphine-3-esters - Google Patents

Morphine-3-esters Download PDF

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Publication number
WO1996028451A1
WO1996028451A1 PCT/EP1996/001087 EP9601087W WO9628451A1 WO 1996028451 A1 WO1996028451 A1 WO 1996028451A1 EP 9601087 W EP9601087 W EP 9601087W WO 9628451 A1 WO9628451 A1 WO 9628451A1
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WO
WIPO (PCT)
Prior art keywords
morphine
ester
carbonyl
esters
moiety
Prior art date
Application number
PCT/EP1996/001087
Other languages
English (en)
Inventor
Christian Mignat
Dieter Heber
Albrecht Ziegler
Original Assignee
Euroceltique S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE1995108664 external-priority patent/DE19508664C2/de
Application filed by Euroceltique S.A. filed Critical Euroceltique S.A.
Priority to AU51085/96A priority Critical patent/AU5108596A/en
Publication of WO1996028451A1 publication Critical patent/WO1996028451A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone

Definitions

  • the present invention relates to morphine-3-esters, drugs containing morphine-3-esters, the use of the morphine-3- esters for preparing a morphine analgesic, for the pre ⁇ paration of a sustained release form of morphine and a process for preparing the morphine-3-esters.
  • Morphine is a frequently used analgesic which in particular is used for alleviating chronic pain. For a successful pain therapy it is required that the morphine plasma level is con ⁇ stant. Morphine, because of its very low half-life, is administered in the form of tablets capable of a controlled release of the active ingredient or by means devices, such as pumps, for a controlled release of the active ingredient. However, these application forms are subject to hard re ⁇ strictions in practice.
  • Slow-release morphine tablets are recognized as the most convenient option for treatment of chronic cancer pain. Adequate analgesia throughout the dosing interval with just twice- or thrice-a-day administration is achieved by incor ⁇ poration of morphine into a polymer matrix from which it is gradually released during the intestinal passage. The ad ⁇ ministration of these formulations is, however, not feasible in patients who are unable to swallow tablets. The alterna ⁇ tive use of subcutaneous or intravenous morphine infusions is limited, since sustained parenteral access and expensive pump-devices are required. These problems may be overcome by liquid slow-release morphine formulations, which would combine simplified oral or parenteral usage with pr perfumed pain relief .
  • Another drawbac of the long-term morphine administration is the occurrence of side-effects such as obstipations which may become so serious that the pain therapy using morphine will have to be discontinued or even abandoned.
  • Said object is attained by morphine-3-esters, the enzymatic hydrolysis of which has a half-life of from 0.5 to 12 hours under physiologic conditions and the non- enzymatic hydrolysis of which has a half-life in excess of 24 hours in an aqueous medium at pH values of 6-8, especially at pH 7, except for 3-pivaloyl morphine.
  • the morphine-3-esters according to the invention due to their structure, have only weak affinity or do not have any affinity at all to the morphine receptor.
  • the active com ⁇ pound is released and enabled to display its activity only after hydrolysis of the ester by specific or non-specific esterases present under physiological conditions.
  • the compounds according to the invention are relatively insensitive to a non-enzymatic hydrolysis at physiological pH values, as is evident from their half-lives in excess of 24 hours in an aqueous medium at pH values of 6-8, especially at pH 7.
  • WO 93/03051 describes 3-morphine esters synthesized as intermediates for the preparation of morphine-6-glucuronides.
  • WO 93/03051 fails to disclose any relevant data with respect to the activity of the 3-morphine ester derivatives described therein, especially 3-pivaloyl morphine, 3-propionyl and 3-isobutyryl morphine. Data on the rate of hydrolysis under physiological or other conditions have not been reported either.
  • the morphine esters according to the invention are preferably characterized in that the rate of hydrolysis and/or dispo ⁇ sition of the morphine ester for an esterolytic activity is adjusted by steric or electronic effects of the acid moiety of the morphine ester.
  • Morphine esters according to the invention are those having the following formula (I)
  • R either is a moiety having the following formula (ID
  • R 3 and/or R 4 H, if
  • R 3 and/or R 4 is not H, then the respective other residue independently or simultaneously has the following meaning:
  • R 3 and/or R 4 straight-chain or branched alkyl group (CH 2 ) n CH 3 with n being an integer between 0 and 10;
  • the phenyl moiety (II) can be substituted with R 3 and/or R 4 up to the maximum value as possible.
  • compounds having in each o-position to a carbonyl function an alkyl moiety and in p-position a hydroxyl moiety fall within the scope of the invention.
  • morphine esters wherein the substituents R 3 and R 4 are in the o- or p-positions relative to each other.
  • the morphine esters are characterized in that the moiety R in formula (I) is represented by the following formula (III)
  • R 1 has the meaning as defined for R 3 and R 4 , with the proviso that R 1 is either equal to R 3 and/or R 4 or different therefrom; R 3 and R 4 have the meaning defined above; R 2 stands for +M- , +1- or -I- substituents.
  • morphine esters wherein R 2 is a sub ⁇ stituted or free amino group to form S-aminocinnamic acid esters .
  • R 1 , R 3 and/or R 4 are as defined above, with the proviso that individual carbon atoms of the moiety R have been replaced by heteroatoms such as 0, N and/or S.
  • Morphine esters in a further embodiment, are characterized in that R is represented by the formula (V)
  • morphine -3 -esters there are to be mentioned 3- ( 2 -methylbenzoyl) morphine, 3- (2 -chlorobenzoyl) morphine, 3 - (2,6 -di chlorobenzoyl ) morphine , 3 - ( ⁇ -methylcinna- moyl ) morphine , 3- (2, 6 -dimethylbenzoyl) morphine, 3-(2,6-di- propylbenzoyl ) morphine , 3 - ( 2 , 6 -diphenylbenzoyl ) morphine , 3 - ( 2 -phenylbenzoyl ) morphine , 3 - ( 2 , 6 -dimethoxybenzoyl ) - morphine, 3- (2, 6 -diethoxybenzoyl) morphine, 3- (2-cyclohexyl- benzoyl) morphine, 3- ( ⁇ -methyl- ⁇ -dimethylamino
  • the morphine esters according to the invention can be used as medicaments.
  • the medicament according to the invention contains an effective amount of at least one of the morphine- 3-esters according to the invention, including 3-pivaloyl morphine. More particularly, the morphine-3-esters according to the invention may be present in the form of their pharma ⁇ ceutically compatible salts, optionally in combination with further auxiliary materials and carriers.
  • the morphine-3-esters according to the invention can be used for the preparation of a morphine analgesic which avoids the side-effects caused by the morphine analgesics of prior art.
  • a serious side-effect there is mentioned, by way of example, obstipation.
  • the morphine-3-esters according to the invention can be utilized as a sustained release form of morphine. This sustained release form of morphine may be enterally and/or parenterally administered.
  • the amount to be administered in a dosage unit of morphine-3- ester corresponds to from about 0.5 mg to about 10 mg per 1 kg of body weight.
  • the morphine derivatives according to the invention can be prepared by a method according to J. Org. Che . 19, 1409
  • a solution of morphine hydrochloride in water in the presence of sodium hydrogen- carbonate is admixed with the appropriate carboxylic acid component, preferably an excess amount thereof, of the ester to be formed in the form of an activated derivative thereof such as an acid halide, acid anhydride etc..
  • the mixture is stirred until the reaction is complete.
  • the reaction may be monitored, for example, by means of thin layer chromato ⁇ graphy.
  • the morphine-3-ester formed may be extracted, especially with water-immiscible organic solvents, such as, for example, methylene chloride.
  • the organic solvent used for the extraction of the morphine-3-ester is evaporated, and the residue is purified, for example by column chromato ⁇ graphy using suitable carriers such as silica gel.
  • suitable carriers such as silica gel.
  • This method is not suitable for the preparation of 3-(2,6-di- methoxybenzoyl)morphine.
  • the latter compound may rather be prepared by a conventional method using pyridine as a base and removal of the mono-ester by column chromatography.
  • [ 3 H] DAMGO, [ 3 H] DPDPE, and [ 3 H]U69593 (specific activity 55, 46 and 47 Ci/mmol, respectively) were purchased from Du Pont NEN Research Products (Boston, MA, USA) . Un- labelled DAMGO, DPDPE, and U69593 as well as naloxone hydro ⁇ chloride were obtained from Sigma Chemicals (St. Louis, MO, USA) .
  • Brain homogenates were obtained from guniea pigs (250 - 350g b.w.) , which were killed by cervical dislocation. The brain was rapidly dissected, the cerebellum removed and the re ⁇ mainder homogenized in 9 volumes of iced 0.32 M sucrose solution in a Potter-Elvehjem homogenizer by 5 strokes of a teflon pestle, motor driven at 1,250 rpm. The homogenate was centrifuged at 3,400 x g for 10 min and the supernatant was recentrifuged for 30 min at 115,500 x g.
  • the pellet from the second centrifugation was suspended in 50 mM Tris-HCl buffer (pH 7.4, 4°C) by use of the Potter-Elvehjem homo ⁇ genizer.
  • the protein content of this membrane suspension was approximately 8 mg/ml, as determined by the method of Lowry et al. , with bovine serum albumin as the standard.
  • the temperature was maintained at 4°C throughout the homogeni- sation procedure and the membrane suspension was stored at -80°C until assay.
  • Brain homogenates (0.25 ml) were incubated for 60 min at 25°C in a final volume of 1.5 ml of 50 mM Tris- HCl buffer (pH 7.4) containing the radioligand.
  • the filters were washed twice with 5 ml of ice-cold 50 mM Tris- HCl buffer (pH 7.4) and transferred to scintillation vials containing 10 ml of scintillation cocktail (Ready Protein, Beckman Instruments, Fullerton, USA) . Radioactivity was determined by liquid-scintillation counting (Tri-Carb 460 CD, Packard Instruments, Downers Grove, USA) . Assays were performed in quadruplicate within an experiment and each experiment was replicated 4 times.
  • the samples were prepared immediately for HPLC analysis by the following procedure which was done within 60 seconds: the samples were diluted to 400 ⁇ l with water, vortexed, and filtrated through Millex-HV 13 filters (0.45 ⁇ m pore size, Millipore, Bedford, Mass., USA); the filtrate was then transferred to a vial for automatic injection and 10 ⁇ l of the solution was directly loaded onto the HPLC column without further processing.
  • Solvent A (pH 3.5) was 25% (v/v) acetonitrile in an aqueous solution of 20 mM sodium dihydrogenphosphate and 1 mM sodium dodecylsulphate.
  • Solvent B (pH 2.2) consisted of 40% (v/v) acetonitrile in 20 mM sodium dihydrogenphosphate buffer containing 1 mM sodium dodecylsulphate. The solvents were filtered using a 0.2 ⁇ m filter (Sartorius, G ⁇ ttingen, Germany) and degassed under vacuum by sonication.
  • the degradation of the morphine-3-esters was quantified by measuring the peak areas in relation to those of the initial peak at time zero. Half-lives for ester hydrolysis were determined from the slopes of linear plots of the logarithm of residual ester against time. At least four separate experiments were made to calculate the mean ⁇ S.E.M. values.
  • the pharmacologic activity of the morphine-3-esters might be also related to release of mor ⁇ phine by enzymatic degradation of the prodrug.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention décrit des morphine-3-esters de formule (I), dont l'hydrolyse enzymatique a une demi-vie comprise entre 0,5 et 12 heures à l'état physiologique et dont l'hydrolyse non enzymatique a une demi-vie de plus de 24 heures en milieu aqueux à des valeurs de pH de 6 à 8, spécialement à un pH de 7, à l'exception de la 3-pivaloyl morphine (I), R étant tel que défini dans le descriptif.
PCT/EP1996/001087 1995-03-14 1996-03-14 Morphine-3-esters WO1996028451A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU51085/96A AU5108596A (en) 1995-03-14 1996-03-14 Morphine-3-esters

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19508664.3 1995-03-14
DE1995108664 DE19508664C2 (de) 1995-03-14 1995-03-14 Verwendung von Morphin-3-estern, Morphin-3-ester als solche und Verfahren zu deren Herstellung
AUPCT/EP95/01480 1995-04-19
PCT/EP1995/001480 WO1996028450A1 (fr) 1995-03-14 1995-04-19 Morphine-3-esters

Publications (1)

Publication Number Publication Date
WO1996028451A1 true WO1996028451A1 (fr) 1996-09-19

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Family Applications (1)

Application Number Title Priority Date Filing Date
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AU (1) AU5108596A (fr)
WO (1) WO1996028451A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064430A3 (fr) * 1998-06-06 2000-02-03 Cenes Ltd Synthese de morphine-6-glucuronide
EP1422230A1 (fr) * 2002-11-25 2004-05-26 Chi Mei Foundation Medical Center Dérivés estérifiés de buprenorphine, procédé pour leur préparation, et médicaments analgésiques à action prolongée
JP2004175706A (ja) * 2002-11-26 2004-06-24 Chi Mei Foundation Medical Center 新規なブプレノルフィンのエステル誘導体及びそれらの調製方法、及び長時間効力持続性鎮痛薬剤組成物
KR100704085B1 (ko) * 2002-12-02 2007-04-05 치 메이 파운데이션 메디칼 센터 신규한 부프레노핀 에스테르 유도체, 그의 제조 방법 및지속성 진통제 약학 조성물
WO2013093931A2 (fr) 2011-09-19 2013-06-27 Sun Pharma Advanced Research Company Ltd. Nouveaux promédicaments de médicaments phénoliques
US10799496B2 (en) 2018-07-13 2020-10-13 Alkermes Pharma Ireland Limited Naphthylenyl compounds for long-acting injectable compositions and related methods
US10807995B2 (en) 2018-07-13 2020-10-20 Alkermes Pharma Ireland Limited Thienothiophene compounds for long-acting injectable compositions and related methods
US10975099B2 (en) 2018-11-05 2021-04-13 Alkermes Pharma Ireland Limited Thiophene compounds for long-acting injectable compositions and related methods

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992008459A1 (fr) * 1990-11-16 1992-05-29 Kabi Pharmacia Ab Compositions a administration locale destinees a l'asministration transdermique de derives de promedicament de morphine
WO1993003051A1 (fr) * 1991-08-06 1993-02-18 Salford Ultrafine Chemicals And Research Limited Procede de preparation de morphine-6-glycuroconjuguee ou de morphine-6-glycuroconjuguee substituee

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992008459A1 (fr) * 1990-11-16 1992-05-29 Kabi Pharmacia Ab Compositions a administration locale destinees a l'asministration transdermique de derives de promedicament de morphine
WO1993003051A1 (fr) * 1991-08-06 1993-02-18 Salford Ultrafine Chemicals And Research Limited Procede de preparation de morphine-6-glycuroconjuguee ou de morphine-6-glycuroconjuguee substituee

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 57, no. 3, 6 August 1962, Columbus, Ohio, US; abstract no. 19532, LEGOSTEV ET AL: "Some pharmaceutical characteristics of morphine derivatives containing acid groups on phenol hydroxy groups." column 2; XP002001996 *
CHEMICAL ABSTRACTS, vol. 70, no. 19, 12 May 1969, Columbus, Ohio, US; abstract no. 88011h, SELMECI ET AL: "Synthesis of new morphine derivatives." page 366; column 2; XP002001995 *
DRUSTRUP ET AL: "Utilization of prodrugs to enhance the transdermal absorption of morphine", INT. J. OF PHARM., vol. 71, pages 105 - 116, XP002001993 *
HUGHES ET AL: "Lipidic Peptides.", J.PHARM.SCI, vol. 80, no. 12, pages 1103 - 1105, XP002001994 *
KHIM.-FARM.ZH., vol. 2, no. 7, RUSSIA, pages 19 - 23 *
LENINGR. MED. INST., pages 291 - 298 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064430A3 (fr) * 1998-06-06 2000-02-03 Cenes Ltd Synthese de morphine-6-glucuronide
US6566510B1 (en) 1998-06-06 2003-05-20 Genes Limited Morphine-6-glucuronide synthesis
US6693179B2 (en) * 1998-06-06 2004-02-17 Cenes Limited Morphine-6-glucuronide synthesis
EP1422230A1 (fr) * 2002-11-25 2004-05-26 Chi Mei Foundation Medical Center Dérivés estérifiés de buprenorphine, procédé pour leur préparation, et médicaments analgésiques à action prolongée
JP2004175706A (ja) * 2002-11-26 2004-06-24 Chi Mei Foundation Medical Center 新規なブプレノルフィンのエステル誘導体及びそれらの調製方法、及び長時間効力持続性鎮痛薬剤組成物
KR100704085B1 (ko) * 2002-12-02 2007-04-05 치 메이 파운데이션 메디칼 센터 신규한 부프레노핀 에스테르 유도체, 그의 제조 방법 및지속성 진통제 약학 조성물
WO2013093931A2 (fr) 2011-09-19 2013-06-27 Sun Pharma Advanced Research Company Ltd. Nouveaux promédicaments de médicaments phénoliques
US10799496B2 (en) 2018-07-13 2020-10-13 Alkermes Pharma Ireland Limited Naphthylenyl compounds for long-acting injectable compositions and related methods
US10807995B2 (en) 2018-07-13 2020-10-20 Alkermes Pharma Ireland Limited Thienothiophene compounds for long-acting injectable compositions and related methods
US10975099B2 (en) 2018-11-05 2021-04-13 Alkermes Pharma Ireland Limited Thiophene compounds for long-acting injectable compositions and related methods

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