EP2231673A1 - Method for the preparation of morphine compounds - Google Patents

Method for the preparation of morphine compounds

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Publication number
EP2231673A1
EP2231673A1 EP08871482A EP08871482A EP2231673A1 EP 2231673 A1 EP2231673 A1 EP 2231673A1 EP 08871482 A EP08871482 A EP 08871482A EP 08871482 A EP08871482 A EP 08871482A EP 2231673 A1 EP2231673 A1 EP 2231673A1
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EP
European Patent Office
Prior art keywords
compound
morphine
unsaturated
reaction
naloxone
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EP08871482A
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German (de)
French (fr)
Inventor
Alain Dlubala
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Sanofi SA
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Sanofi Aventis France
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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:
    • C07D489/06—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 a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B63/00—Purification; Separation; Stabilisation; Use of additives
    • C07B63/02—Purification; Separation; Stabilisation; Use of additives by treatment giving rise to a chemical modification
    • 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:

Definitions

  • the present invention relates to a process for the preparation of morphine compounds, especially naloxone, with a low content of unsaturated ⁇ - ⁇ compounds. It also relates to the compositions thus obtained.
  • Morphine and related compounds such as codeine, hydrocodone, hydromorphone, naloxone, naltrexone, oxycodone and oxymorphone are used as active ingredients in analgesics.
  • Naloxone base (CAS No. 465-65-5) is a morphine derivative used as a pharmaceutical active ingredient, particularly for the treatment of overdose: naloxone is administered to move the morphine receptors to stop its action.
  • This compound is accessible by total synthesis, but given the complexity of the molecule, the synthesis generally begins with plant extracts, especially poppy, either from the capsule or from the resin (opium ). These extracts usually comprise different structurally close compounds which give rise during the synthesis to the formation of species that are sometimes difficult to separate.
  • the morphine compounds it is sought to limit in the morphine compounds the presence of ⁇ - ⁇ unsaturated ketone compounds because of the supposed toxicity of some of them.
  • the morphine compounds have a content of ⁇ - ⁇ unsaturated compounds below 100 ppm.
  • WO 2006/084389 proposes to reduce the content of unsaturated ⁇ - ⁇ compounds by selective hydrogenation.
  • document WO 2006/084412 recommends that the ⁇ -ketonic hydroxyl group be preliminarily converted into a leaving group with acetic anhydride and then hydrogenated selectively.
  • the document US 2006/0111383 proposes to acidify the mixture to a pH of less than 6 and to possibly heat it above 55 ° C. before the hydrogenation.
  • hydrogenation most often involves the use of catalysts whose total absence in the final product is then very difficult to ensure.
  • WO2007 / 062184 proposes the elimination of ⁇ - ⁇ unsaturated electrophilic compounds of oxycodone by reaction with a thiol.
  • WO2007 / 103105 also uses a reaction with a thiol to remove unsaturated ⁇ - ⁇ compounds.
  • thiol is accompanied by significant odors, and toxicity for most of them. In addition, it must also ensure the absence of thiol in the active product.
  • the object of the present invention is to provide a process for the preparation of morphine compounds of high purity, and in particular comprising a low content of unsaturated ⁇ - ⁇ compounds.
  • the invention relates to a process for the preparation of morphine compounds with a low content of unsaturated ⁇ - ⁇ compounds comprising the steps of:
  • the invention provides a composition comprising at least 99%, preferably at least 99.5% by dry weight of morphine compound or a pharmaceutically acceptable salt thereof and an ⁇ - ⁇ -unsaturated compound in a lower content. at 100 ppm and preferably less than 50 ppm.
  • morphine compounds is understood to mean compounds of structure close to morphine, and in particular comprising a phenolic ring. These compounds may differ from morphine in particular by the nature of their substituents or the nature of the bonds. More specifically, these are 3-hydroxymorphinone derivatives corresponding to the following formula (I):
  • R1 represents a hydrogen atom or a hydroxyl group
  • R 2 represents a hydrogen atom or a (C 1 -C 6 ) alkyl, cyclo (C 3 -C 6 ) alkyl or (C 2 -C 6 ) alkenyl group.
  • a (C 1 -C 8) alkyl group a linear or branched saturated aliphatic group containing between 1 and 6 carbon atoms, for example methyl or ethyl groups may be mentioned; propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, etc .;
  • a cyclo (C 3 -C 6 ) alkyl group a cyclic alkyl group comprising between 3 and 6 carbon atoms.
  • cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups;
  • a (C 2 -C 6 ) alkenyl group a linear or branched, mono- or poly-unsaturated aliphatic group comprising, for example, one or two ethylenic unsaturations and containing between 2 and 6 carbon atoms.
  • the vinyl group Particularly targeted are hydromorphone, naloxone, naltrexone, noroxymorphone, oxymorphone and nalbuphone.
  • ⁇ - ⁇ -unsaturated compounds is intended to mean compounds comprising a double bond at position 7 and 8 of the morphine ring conjugated with a ketone at position 6. More precisely, these are 3-hydroxy-derivatives. 7,8-Didehydromorphinone corresponding to the following formula (II):
  • R1 and R2 have the same meanings as previously indicated.
  • R1 and R2 have the same meanings as previously indicated.
  • crude morphine compound is intended to mean a mixture of compounds essentially comprising a morphine compound or a derivative of 3-hydroxymorphinone as defined above and generally an ⁇ , ⁇ -unsaturated compound or 3-hydroxy derivative. , 8 didehydromorphinone as defined above in a smaller amount.
  • the ⁇ , ⁇ -unsaturated compound content is generally less than 1% and most often between 0.1% and 0.2% by weight.
  • product resulting from the aldolisation reaction is meant the dimer resulting from the reaction of the enolate with the ketone. More specifically, these are bis hydroxy morphinol-morphinone derivatives having the following formula (IV):
  • R1 and R2 have the same meanings as previously indicated.
  • product resulting from the crotonization reaction is meant the mother resulting from the dehydration reaction of aldol. More specifically, these are bis hydroxy morphinene-morphinone derivatives having the following formula (V):
  • R1 and R2 have the same meanings as previously indicated.
  • the invention is based on the surprising finding that the content of the morphine compounds can be reduced to ⁇ - ⁇ -unsaturated compounds, especially those having a double bond in position 7 and 8 of the ketone conjugated morphine ring at the 6-position. Michael addition of the hydroxide ion on the double bond.
  • the invention relates to a process for the preparation of morphine compounds with a low content of unsaturated ⁇ - ⁇ compounds comprising the steps of:
  • the method further comprises the subsequent step of:
  • step (i) of the described process is carried out:
  • the step (N) is carried out by precipitation, which is advantageously obtained by adding a neutralization agent, in particular an acid.
  • Step (iii) is preferably performed at the same time as step (iv).
  • the morphine compound is naloxone.
  • the unsaturated ⁇ - ⁇ compound is 7,8-didehydronaloxone.
  • the process according to the invention makes it possible, by a simple and rapid treatment, involving current and non-toxic reagents, to obtain a morphine compound of very high purity.
  • the process makes it possible to lower the presence of unsaturated ⁇ - ⁇ compounds below the regulatory thresholds, and most often below the detection threshold.
  • the addition compounds formed are hydrophilic and can therefore be easily removed.
  • this elimination takes place during the usual purification, and in particular during the transformation into a pharmaceutically acceptable salt, for example during the hydrochlorination.
  • the purification may comprise in particular a filtration step, for example on alumina.
  • the method described can therefore be implemented without major modifications of the procedures in place and recorded.
  • the process described makes it possible to transform the unsaturated ⁇ - ⁇ unsaturated compounds by a nucleophilic addition reaction called Michael type addition.
  • Michael type addition This reaction is well known as such, and is described for example in "Advanced Organic Chemistry” by Smith and March, 5 th Edition, (Chapter 15, p.976, 1022 to 1024).
  • the addition takes place on the double bond conjugated to the ketone function.
  • the adduct formed is therefore the corresponding hydroxylated saturated compound. These compounds are most often less toxic than ⁇ - ⁇ unsaturated compounds.
  • Reaction Scheme 1 illustrates the reaction to the base of the process for the particular example of naloxone.
  • Naloxone may contain as ⁇ - ⁇ -unsaturated impurity especially 7.8 didehydronaloxone. This compound is converted by basic treatment to 8-hydroxy naloxone.
  • Basic treatment
  • the compound formed by the reaction is more hydrophilic and may optionally be readily separated from the morphine compound.
  • the compounds formed by the Michael addition reaction are separated during the usual subsequent isolation and purification steps.
  • the Michael-type addition reaction proceeds in competition with secondary reactions, in particular the aldolization and crotonization reaction.
  • Reaction Scheme 2 illustrates the aldol reaction for the example of naloxone.
  • the dimeric product formed is relatively hydrophilic. It is therefore easily separable during subsequent isolation and purification steps.
  • naloxone Crotonization of naloxone leads to the corresponding dehydrated compound.
  • the reaction is illustrated in Reaction Scheme 3 above for the example of naloxone. It has been established by structural NMR analysis that only the compound with endocyclic unsaturation is formed.
  • Crotonization is an irreversible reaction, unlike the aldol reaction, which is in equilibrium with the reverse reaction called retroaldolisation. Furthermore, the compound resulting from the crotonization of the aldol product is not very water-soluble and therefore more difficult to separate from the reaction product.
  • an effective means for limiting the crotonization reaction is to limit the formation of aldol, which is the starting material of crotonization.
  • the crude morphine compound obtained by these processes generally has a content of ⁇ - ⁇ unsaturated compounds of less than 1%, most often between 0.1% and 0.2% by weight.
  • the process according to the invention allows the Michael-type addition reaction on the unsaturated ⁇ - ⁇ compounds present in the crude morphine compound.
  • the crude morphine compound is generally dissolved in a suitable solvent, advantageously in aqueous solution. It is preferable that the solution has a concentration between 5 and 25% by weight of crude morphine compound.
  • the base used is preferably a strong mineral base, such as alkali and alkaline earth metal hydroxides and in particular sodium or potassium hydroxide.
  • the amount of base is preferably in excess relative to the morphine compound employed. Generally, it represents at least 3, or even at least 5 equivalents calculated with respect to the morphine compound.
  • the reaction mixture has a pH greater than 13 or even greater than 14.
  • a base in concentrated solution will be used. Indeed, the retro-aldolization reaction is favored in a strongly basic medium, which limits the amount of aldol available for crotonization.
  • the morphine compound solution is introduced into the base and not vice versa.
  • This variant called reverse casting, provides a strongly basic reaction medium at any time.
  • the process according to the invention can be carried out in a simple manner and on conventional equipment.
  • the morphine compound is brought into contact with a basic medium, preferably with stirring.
  • the reaction medium is preferably maintained at a temperature of 20 to 25 ° C.
  • the contact time of the reaction mixture is preferably short in order to disadvantage the aldolization. This is not a problem in terms of conversion since the addition reaction of Michael is usually complete in 10 to 40 minutes, and most often in 20 to 30 minutes.
  • the reaction medium is neutralized.
  • the neutralizing agent will most often be a usual acid, strong or weak, organic or mineral. Particularly preferred are hydrochloric acid, sulfuric acid or acetic acid.
  • the morphine compound is neutralized until precipitation. Generally, the morphine product precipitates at neutral to moderately basic pH, for example between pH 8 and 10.
  • the solid product is then separated from the reaction mixture by conventional methods, for example by filtration.
  • Filtration on a polar medium such as alumina is particularly interesting because it allows affinity retention of the more hydroxylated compounds, especially the aldol products.
  • the morphine compound obtained, in the form of a solvent base is then converted into a pharmaceutically acceptable salt, especially hydrochloride, mucate, hydrobromide, stearate, pamoate, napsylate, 2-hydroxy (1, 1, 3, 3-tetramethylbutyl) benzoate, or else 3,5-bis (1,1-dimethylethyl) -2,6-dihydrobenzoate.
  • a pharmaceutically acceptable salt especially hydrochloride, mucate, hydrobromide, stearate, pamoate, napsylate, 2-hydroxy (1, 1, 3, 3-tetramethylbutyl) benzoate, or else 3,5-bis (1,1-dimethylethyl) -2,6-dihydrobenzoate.
  • This step can be carried out by reaction of the morphine compound obtained with the corresponding acid.
  • the base is poorly water soluble, and so a solution of the morphine compound is prepared in a suitable solvent, for example acetone.
  • the salt formed is separated, for example by precipitation.
  • the salts of the dimeric compounds from the aldolization and crustalization reactions are better soluble in water than the salt of the morphine compound. Their content can therefore be reduced during this step.
  • the morphine compound or its salt thus obtained can, if necessary, be further purified according to known methods, for example by recrystallization.
  • anhydrous morphine compound by removal of the solvent, especially by drying in an oven.
  • the compounds resulting from the reaction and the secondary reactions are thus separated by the subsequent purification steps, without the need for a step specifically provided for this purpose.
  • the invention relates to a composition comprising at least 99% by dry weight of morphine compound and an ⁇ - ⁇ -unsaturated compound content of less than 100 ppm.
  • the invention provides a composition comprising at least 99%, preferably at least 99.5% by dry weight of morphine compound or a pharmaceutically acceptable salt thereof and an ⁇ - ⁇ -unsaturated compound in a content of less than 100.
  • ppm preferably less than 50 ppm and more preferably less than 25 ppm.
  • the morphine compounds and their salts easily form solvates, and especially in the form of mono-, di- or trihydrates.
  • the contents of these compounds are therefore generally expressed relative to the dry compound, without taking into account the water content or solvents.
  • the contents indicated in the following, unless otherwise indicated, are therefore always in relation to the dry compound.
  • compositions when the morphine compound is naloxone, its hydrochloride or hydrochloride dihydrate are particularly targeted.
  • the unsaturated ⁇ - ⁇ compound is preferably 7,8-didehydronaloxone.
  • the composition also contains, in a small amount, compounds resulting from the aldolisation and crotonization reaction.
  • the subject of the present invention is in particular a composition comprising at least 99% by dry weight, preferably at least 99.5% by dry weight, of morphine compound or of a pharmaceutically acceptable salt thereof, an unsaturated ⁇ - ⁇ compound. in a content of less than 100 ppm and preferably less than 50 ppm, and further comprising at least one compound derived from the aldolization and crotonization reactions.
  • the compounds resulting from the aldolisation reaction and the crotonization reaction are generally present in a content of less than 1000 ppm and in particular less than or equal to 500 ppm in the compositions according to the invention
  • the compound resulting from the aldolization reaction is generally present in a content ranging from 20 to 200 ppm and in particular from 50 to 150 ppm.
  • the morphine compound when in the composition according to the invention the morphine compound is in salt form, the compound resulting from the crotonization reaction is generally present in a content ranging from 150 to 500 ppm and in particular from 200 to 350 ppm.
  • naloxone it is 6'-7-naloxol-naloxone and
  • compositions according to the invention comprising a pharmaceutically acceptable salt of morphine compound; in particular a naloxone hydrochloride.
  • morphine compounds or their salts are most often solvates, and in particular hydrates.
  • Particularly targeted is a composition comprising naloxone hydrochloride dihydrate.
  • the present invention relates to a composition
  • a composition comprising naloxone hydrochloride dihydrate, 7-8 didehydronaloxone, especially at a content of less than 90 ppm, 6'-7 naloxol naloxone especially in a content ranging from 50 to 150 ppm and 6'-7 'olefin of 6'-7-naloxol-naloxone especially in a content ranging from 200 to 350 ppm.
  • the composition will further contain solvent in a corresponding amount.
  • the composition may further contain up to 10% by weight of water relative to the total weight of the composition.
  • Fig. 1 HPLC analysis result of naloxone base with low content of ⁇ - ⁇ unsaturated compounds obtained in the example
  • 2 HPLC analysis result of naloxone hydrochloride with low content of ⁇ - ⁇ unsaturated compounds obtained in the example.
  • the medium is then loaded into a dropping funnel and then added dropwise into a three-necked flask containing 36 ml (0.27 mol; 8 eq) of concentrated sodium hydroxide (30%).
  • the initial ambient temperature of 21.6 ° C. of the reaction medium reaches, at the end of the casting, 21.5 ° C., the pH of the reaction medium then being 14.4.
  • the reaction medium has a temperature of 41.7 ° C. and a pH of 9.
  • the medium is cooled to 10.degree. C. and the precipitate is separated by filtration on sintered glass.
  • the separated solid product is dried in a ventilated oven at 60 ° C.
  • the treated crude base naloxone is isolated with a mass of 15.64 g dry.
  • the product obtained at the end of these operations is called "naloxone base treated" in Tables 1 to 4 below.
  • the naloxone base obtained is dissolved in acetone and then chlorhydrated by addition of concentrated hydrochloric acid.
  • the hydrochloride is precipitated by cooling, filtered and dried.
  • the product obtained after these operations is called "pure naloxone HCl" in Tables 1 to 4 below.
  • the product obtained is analyzed according to the HPLC method described by the European Pharmacopoeia after the basic treatment, and after hydrochlorination.
  • the process according to the invention makes it possible to obtain, by the basic treatment, naloxone with a low content of 7,8-didehydronaloxone.
  • the treatment makes it possible to lower the content of 7,8-didehydronaloxone from 0.8% by weight initially to less than 0.03% by weight, and therefore below the detection threshold.
  • a more specific HPLC method shows that the content of 7,8-didehydronaloxone, to be less than 100 ppm, has a usual value of 60 to 90 ppm.
  • Naloxone thus obtained at this stage meets the regulatory requirements for the content of 7,8-didehydronaloxone.

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Abstract

The present invention relates to a method for the preparation of morphine compounds comprising a low content of a,ß-unsaturated compounds, which comprises the steps of: (i) bringing the crude morphine compound into contact with a base, at a pH of greater than 13, under conditions which make possible the Michael addition reaction on the a,ß-unsaturated compound(s) present; (ii) separating the morphine compound from the reaction mixture; and (iii) if appropriate, separating the addition product formed, from the morphine compound. It also relates to a composition comprising at least 99% by dry weight of morphine compound, or of a pharmaceutically acceptable salt thereof, and an a,ß-unsaturated compound in a content of less than 100 ppm.

Description

Procédé de préparation de composés morphiniques. Process for the preparation of morphine compounds
La présente invention concerne un procédé de préparation de composés morphiniques notamment la naloxone, à faible teneur en composés α-β insaturés. Elle vise également les compositions ainsi obtenues.The present invention relates to a process for the preparation of morphine compounds, especially naloxone, with a low content of unsaturated α-β compounds. It also relates to the compositions thus obtained.
La morphine et des composés analogues tels que la codéine, hydrocodone, hydromorphone, naloxone, naltrexone, oxycodone et oxymorphone sont utilisés comme principes actifs dans des analgésiques.Morphine and related compounds such as codeine, hydrocodone, hydromorphone, naloxone, naltrexone, oxycodone and oxymorphone are used as active ingredients in analgesics.
La naloxone base (n° CAS 465-65-5) est un dérivé morphinique utilisé comme principe actif pharmaceutique, notamment pour le traitement de l'overdose : la naloxone est administrée pour déplacer la morphine des récepteurs afin d'arrêter son action.Naloxone base (CAS No. 465-65-5) is a morphine derivative used as a pharmaceutical active ingredient, particularly for the treatment of overdose: naloxone is administered to move the morphine receptors to stop its action.
Ce composé est accessible par synthèse totale, mais étant donné la complexité de la molécule, la synthèse débute généralement d'extraits de plantes, no- tamment du pavot, soit à partir de la capsule, soit à partir de la résine (l'opium). Ces extraits comportent habituellement différents composés structurellement proches qui donnent lieu, au cours de la synthèse, à la formation d'espèces qu'il est parfois difficile de séparer.This compound is accessible by total synthesis, but given the complexity of the molecule, the synthesis generally begins with plant extracts, especially poppy, either from the capsule or from the resin (opium ). These extracts usually comprise different structurally close compounds which give rise during the synthesis to the formation of species that are sometimes difficult to separate.
En particulier, on cherche à limiter dans les composés morphiniques la pré- sence de composés α-β insaturés cétoniques en raison de la toxicité supposée de certains d'entre eux. De préférence, les composés morphiniques présentent une teneur en composés α-β insaturés en dessous de 100 ppm.In particular, it is sought to limit in the morphine compounds the presence of α-β unsaturated ketone compounds because of the supposed toxicity of some of them. Preferably, the morphine compounds have a content of α-β unsaturated compounds below 100 ppm.
Le document WO 2006/084389 propose de réduire la teneur en composés α-β insaturés par hydrogénation sélective. Dans ce cadre, le document WO 2006/084412 préconise de transformer au préalable le groupe hydroxyle β- cétonique en groupe partant avec l'anhydride acétique puis de l'hydrogéner de façon sélective. Par ailleurs, le document US 2006/0111383 propose d'acidifier le mélange à un pH inférieur à 6 et de le chauffer éventuellement au-delà de 55°C avant l'hydrogénation. Toutefois, l'hydrogénation implique le plus souvent l'utilisation de catalyseurs dont l'absence totale dans le produit final est ensuite très difficile à assurer.WO 2006/084389 proposes to reduce the content of unsaturated α-β compounds by selective hydrogenation. In this context, document WO 2006/084412 recommends that the β-ketonic hydroxyl group be preliminarily converted into a leaving group with acetic anhydride and then hydrogenated selectively. Furthermore, the document US 2006/0111383 proposes to acidify the mixture to a pH of less than 6 and to possibly heat it above 55 ° C. before the hydrogenation. However, hydrogenation most often involves the use of catalysts whose total absence in the final product is then very difficult to ensure.
Le document WO2007/062184 propose l'élimination des composés électro- philes α-β insaturés de l'oxycodone par réaction avec un thiol. Le document WO2007/103105 utilise également une réaction avec un thiol pour éliminer les composés α-β insaturés.WO2007 / 062184 proposes the elimination of α-β unsaturated electrophilic compounds of oxycodone by reaction with a thiol. WO2007 / 103105 also uses a reaction with a thiol to remove unsaturated α-β compounds.
L'utilisation d'un thiol s'accompagne d'odeurs importantes, et de toxicité pour la plupart d'entre eux. De plus, il faut également s'assurer de l'absence du thiol dans le produit actif.The use of a thiol is accompanied by significant odors, and toxicity for most of them. In addition, it must also ensure the absence of thiol in the active product.
Le but de la présente invention est de proposer un procédé de préparation de composés morphiniques de haute pureté, et comportant notamment une faible teneur en composés α-β insaturés.The object of the present invention is to provide a process for the preparation of morphine compounds of high purity, and in particular comprising a low content of unsaturated α-β compounds.
Ce but est atteint par le procédé selon l'invention, lequel comprend une étape de traitement du produit brut en milieu basique dans des conditions susceptibles de conduire à l'addition 1 ,4 sur la cétone conjuguée, aussi appelée addition de Michaël.This object is achieved by the process according to the invention, which comprises a step of treating the crude product in a basic medium under conditions which may lead to the addition 1, 4 to the conjugated ketone, also called Michael addition.
Aussi, selon un premier aspect, l'invention vise un procédé de préparation de composés morphiniques à faible teneur en composés α-β insaturés comportant les étapes de :Also, according to a first aspect, the invention relates to a process for the preparation of morphine compounds with a low content of unsaturated α-β compounds comprising the steps of:
(i) mise en contact du composé morphinique brut avec une base, à un pH supérieur à 13, dans des conditions permettant la réaction d'addition de Michaël sur le(s) composé(s) α-β insaturé(s) présent(s);(i) contacting the crude morphine compound with a base, at a pH greater than 13, under conditions permitting the Michael addition reaction on the unsaturated α-β compound (s) present ( s);
(ii) séparation du composé morphinique du mélange réactionnel ; et (iii) le cas échéant, séparation du produit d'addition formé du composé morphinique.(ii) separation of the morphine compound from the reaction mixture; and (iii) optionally, separating the adduct formed from the morphine compound.
Selon un deuxième aspect, l'invention vise une composition comprenant au moins 99 %, de préférence au moins 99,5 % en poids sec de composé morphinique ou un de ses sels pharmaceutiquement acceptables et un composé α-β- insaturé en une teneur inférieure à 100 ppm et de préférence inférieure à 50 ppm.According to a second aspect, the invention provides a composition comprising at least 99%, preferably at least 99.5% by dry weight of morphine compound or a pharmaceutically acceptable salt thereof and an α-β-unsaturated compound in a lower content. at 100 ppm and preferably less than 50 ppm.
DéfinitionsDefinitions
Dans l'exposé qui suit, on entend par l'expression « composés morphiniques », des composés de structure proche de la morphine, et comportant notamment un cycle phénolique. Ces composés peuvent différer de la morphine en particulier par la nature de leurs substituants ou par la nature des liaisons. Plus précisément, il s'agit de dérivés 3-hydroxymorphinone répondant à la formule (I) suivante : In the following description, the expression "morphine compounds" is understood to mean compounds of structure close to morphine, and in particular comprising a phenolic ring. These compounds may differ from morphine in particular by the nature of their substituents or the nature of the bonds. More specifically, these are 3-hydroxymorphinone derivatives corresponding to the following formula (I):
(I) dans laquelle : R1 représente un atome d'hydrogène ou un groupe hydroxyle et(I) wherein: R1 represents a hydrogen atom or a hydroxyl group and
R2 représente un atome d'hydrogène ou un groupe (CrC6)alkyle, cyclo(C3- C6)alkyle ou (C2-C6)alcényle.R 2 represents a hydrogen atom or a (C 1 -C 6 ) alkyl, cyclo (C 3 -C 6 ) alkyl or (C 2 -C 6 ) alkenyl group.
Dans le cadre de la présente invention, on entend par : - un groupe (Ci-Cβjalkyle: un groupe aliphatique saturé linéaire ou ramifié comportant entre 1 et 6 atomes de carbone. A titre d'exemple, on peut citer les groupes méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tertbutyle, pentyle, etc ;In the context of the present invention, the term: a (C 1 -C 8) alkyl group: a linear or branched saturated aliphatic group containing between 1 and 6 carbon atoms, for example methyl or ethyl groups may be mentioned; propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, etc .;
- un groupe cyclo(C3-C6)alkyle : un groupe alkyle cyclique comportant entre 3 et 6 atomes de carbone. A titre d'exemple, on peut citer les groupes cyclopropyle, cy- clobutyle, cyclopentyle et cyclohexyle ;a cyclo (C 3 -C 6 ) alkyl group: a cyclic alkyl group comprising between 3 and 6 carbon atoms. By way of example, mention may be made of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups;
- un groupe (C2-C6)alcényle : un groupe aliphatique mono- ou poly insaturé, linéaire ou ramifié, comprenant par exemple une ou deux insaturations éthyléni- ques et comportant entre 2 et 6 atomes de carbone. A titre d'exemple, on peut citer le groupe vinyle. Particulièrement visés sont I' hydromorphone, la naloxone, la naltrexone, la noroxymorphone, l'oxymorphone et la nalbuphone.a (C 2 -C 6 ) alkenyl group: a linear or branched, mono- or poly-unsaturated aliphatic group comprising, for example, one or two ethylenic unsaturations and containing between 2 and 6 carbon atoms. By way of example, mention may be made of the vinyl group. Particularly targeted are hydromorphone, naloxone, naltrexone, noroxymorphone, oxymorphone and nalbuphone.
On entend par l'expression « composés α-β-insaturés », des composés comportant une double liaison en position 7 et 8 du cycle morphinique conjuguée à une cétone en position 6. Plus précisément, il s'agit de dérivés 3-hydroxy-7,8- didéhydromorphinone répondant à la formule (II) suivante : The expression "α-β-unsaturated compounds" is intended to mean compounds comprising a double bond at position 7 and 8 of the morphine ring conjugated with a ketone at position 6. More precisely, these are 3-hydroxy-derivatives. 7,8-Didehydromorphinone corresponding to the following formula (II):
(H) dans laquelle :(H) wherein:
R1 et R2 ont les mêmes significations qu'indiquées précédemment .R1 and R2 have the same meanings as previously indicated.
On entend par l'expression « produit d'addition de Michaël sur le composé α,3- insaturé », le composé saturé hydroxylé correspondant. Plus précisément, il s'agit de dérivés 3,8 dihydroxymorphinone répondant à la formule (III) suivante :By the term "Michael addition product on the α, 3-unsaturated compound" is meant the corresponding hydroxylated saturated compound. More precisely, these are dihydroxymorphinone 3,8 derivatives having the following formula (III):
(III) dans laquelle : (III) wherein:
R1 et R2 ont les mêmes significations qu'indiquées précédemment.R1 and R2 have the same meanings as previously indicated.
On entend par l'expression « composé morphinique brut », un mélange de com- posés comprenant essentiellement un composé morphinique ou dérivé de 3- hydroxymorphinone tel que défini ci-dessus et généralement un composé α,β- insaturé ou dérivé 3-hydroxy 7,8 didéhydromorphinone tel que défini ci-dessus en quantité plus faible.The expression "crude morphine compound" is intended to mean a mixture of compounds essentially comprising a morphine compound or a derivative of 3-hydroxymorphinone as defined above and generally an α, β-unsaturated compound or 3-hydroxy derivative. , 8 didehydromorphinone as defined above in a smaller amount.
Dans ce mélange, la teneur en composé α,β-insaturé est généralement inférieure à 1% et le plus souvent entre 0,1% et 0,2% en poids. On entend par l'expression « produit issu de la réaction d'aldolisation », le dimère issu de la réaction de l'énolate sur la cétone. Plus précisément, il s'agit de dérivés de bis hydroxy morphinol-morphinone répondant à la formule (IV) suivante :In this mixture, the α, β-unsaturated compound content is generally less than 1% and most often between 0.1% and 0.2% by weight. By the term "product resulting from the aldolisation reaction" is meant the dimer resulting from the reaction of the enolate with the ketone. More specifically, these are bis hydroxy morphinol-morphinone derivatives having the following formula (IV):
(IV) dans laquelle :(IV) wherein:
R1 et R2 ont les mêmes significations qu'indiquées précédemment.R1 and R2 have the same meanings as previously indicated.
On entend par l'expression « produit issu de la réaction de crotonisation », le di- mère issu de la réaction de déshydratation de l'aldol. Plus précisément, il s'agit des dérivés de bis hydroxy morphinène-morphinone répondant à la formule (V) suivante :By the term "product resulting from the crotonization reaction" is meant the mother resulting from the dehydration reaction of aldol. More specifically, these are bis hydroxy morphinene-morphinone derivatives having the following formula (V):
(V) dans laquelle :(V) in which :
R1 et R2 ont les mêmes significations qu'indiquées précédemment.R1 and R2 have the same meanings as previously indicated.
L'invention repose sur la constatation surprenante que l'on peut réduire la teneur des composés morphiniques en composés α-β-insaturés, notamment ceux comportant une double liaison en position 7 et 8 du cycle morphinique conjuguée à une cétone en position 6, par addition de type Michaël de l'ion hydroxyde sur la double liaison.The invention is based on the surprising finding that the content of the morphine compounds can be reduced to α-β-unsaturated compounds, especially those having a double bond in position 7 and 8 of the ketone conjugated morphine ring at the 6-position. Michael addition of the hydroxide ion on the double bond.
ProcédéProcess
Aussi, selon un premier aspect, l'invention vise un procédé de préparation de composés morphiniques à faible teneur en composés α-β insaturés comportant les étapes de :Also, according to a first aspect, the invention relates to a process for the preparation of morphine compounds with a low content of unsaturated α-β compounds comprising the steps of:
(i) mise en contact du composé morphinique brut avec une base dans des conditions permettant la réaction d'addition de Michaël sur le(s) composé(s) α-β insaturés présents ;(i) contacting the crude morphine compound with a base under conditions permitting the Michael addition reaction on the unsaturated α-β compound (s) present;
(ii) séparation du composé morphinique du mélange réactionnel ; et (iii) le cas échéant, séparation du produit d'addition formé du composé morphinique. Avantageusement, le procédé comporte en outre l'étape subséquente de:(ii) separation of the morphine compound from the reaction mixture; and (iii) optionally, separating the adduct formed from the morphine compound. Advantageously, the method further comprises the subsequent step of:
(iv) transformation du composé morphinique en sel pharmaceutiquement acceptable, notamment en chlorhydrate, correspondant.(iv) conversion of the morphine compound into a pharmaceutically acceptable salt, especially the corresponding hydrochloride salt.
Les conditions permettant la réaction de Michaël de l'étape (i), en particulier les conditions de température et de temps peuvent varier selon le composé morphini- que traité. Ces conditions peuvent être aisément déterminées par l'homme du métier en utilisant des techniques de routine. Sont données ci-après à titre illustratif les conditions de température et de temps relatives au traitement de la naloxone. De préférence, l'étape (i) du procédé décrit est réalisée :The conditions for the Michael reaction of step (i), particularly the temperature and time conditions, may vary depending on the morphine compound being treated. These conditions can be easily determined by those skilled in the art using routine techniques. The temperature and time conditions relating to the treatment of naloxone are given below by way of illustration. Preferably, step (i) of the described process is carried out:
- par introduction du composé morphinique brut dans la base ; - à une température de 20 à 25°C ;by introducing the crude morphine compound into the base; at a temperature of 20 to 25 ° C;
- avec un temps de contact de moins d'une heure ; et/ou- with a contact time of less than one hour; and or
- dans un milieu présentant un pH supérieur à 13, avantageusement supérieur à 14. De préférence, l'étape (N) est réalisée par précipitation, laquelle est avantageusement obtenue par ajout d'un agent de neutralisation, notamment un acide. L'étape (iii) est de préférence réalisée en même temps que l'étape (iv). Selon un mode de réalisation préféré du procédé, le composé morphinique est la naloxone. De préférence, le composé α-β insaturé est la 7,8- didéhydronaloxone.in a medium having a pH greater than 13, advantageously greater than 14. Preferably, the step (N) is carried out by precipitation, which is advantageously obtained by adding a neutralization agent, in particular an acid. Step (iii) is preferably performed at the same time as step (iv). According to a preferred embodiment of the process, the morphine compound is naloxone. Preferably, the unsaturated α-β compound is 7,8-didehydronaloxone.
Le procédé selon l'invention permet, par un traitement simple et rapide, impliquant des réactifs courants et non toxiques, d'obtenir un composé morphinique de pureté très élevée. Le procédé permet en particulier d'abaisser la présence en composés α-β insaturés en dessous des seuils réglementaires, et le plus souvent en dessous du seuil de détection.The process according to the invention makes it possible, by a simple and rapid treatment, involving current and non-toxic reagents, to obtain a morphine compound of very high purity. In particular, the process makes it possible to lower the presence of unsaturated α-β compounds below the regulatory thresholds, and most often below the detection threshold.
Les composés d'addition formés sont hydrophiles et peuvent de ce fait être éliminés aisément. Avantageusement, cette élimination a lieu pendant la purifica- tion habituelle, et notamment au cours de la transformation en sel pharmaceuti- quement acceptable, par exemple lors de la chlorhydratation. La purification peut comprendre en particulier une étape de filtration, par exemple sur alumine.The addition compounds formed are hydrophilic and can therefore be easily removed. Advantageously, this elimination takes place during the usual purification, and in particular during the transformation into a pharmaceutically acceptable salt, for example during the hydrochlorination. The purification may comprise in particular a filtration step, for example on alumina.
Le procédé décrit peut donc être mis en œuvre sans modifications majeures des procédures en place et enregistrées. Le procédé décrit permet de transformer les composés α-β insaturés indésirables par une réaction d'addition nucléophile appelée addition de type Michaël. Cette réaction est bien connue en tant que telle, et est décrite par exemple dans « Advanced Organic Chemistry » par Smith et March, 5th Edition, (Chapter 15, p.976, 1022-1024). L'addition a lieu sur la double liaison conjuguée à la fonction cétone. Le produit d'addition formé est donc le composé saturé hydroxylé correspondant. Ces composés sont le plus souvent moins toxiques que les composés α-β insaturés.The method described can therefore be implemented without major modifications of the procedures in place and recorded. The process described makes it possible to transform the unsaturated α-β unsaturated compounds by a nucleophilic addition reaction called Michael type addition. This reaction is well known as such, and is described for example in "Advanced Organic Chemistry" by Smith and March, 5 th Edition, (Chapter 15, p.976, 1022 to 1024). The addition takes place on the double bond conjugated to the ketone function. The adduct formed is therefore the corresponding hydroxylated saturated compound. These compounds are most often less toxic than α-β unsaturated compounds.
Le schéma réactionnel 1 ci-dessous illustre la réaction à la base du procédé pour l'exemple particulier de la naloxone. La naloxone peut contenir comme impureté α-β-insaturée en particulier la 7,8 didéhydronaloxone. Ce composé est transformé par traitement basique en 8-hydroxy naloxone. Traitement Basique Reaction Scheme 1 below illustrates the reaction to the base of the process for the particular example of naloxone. Naloxone may contain as α-β-unsaturated impurity especially 7.8 didehydronaloxone. This compound is converted by basic treatment to 8-hydroxy naloxone. Basic treatment
8 Hydroxy Naloxone Schéma réactionnel 1 : Addition de type Michaël sur la 7,8 didéhydronaloxone8 Hydroxy Naloxone Reaction Scheme 1: Michael addition to 7.8 didehydronaloxone
Du fait de la présence d'un groupe hydroxyle supplémentaire, le composé formé par la réaction est plus hydrophile et peut le cas échéant être séparé facilement du composé morphinique.Due to the presence of an additional hydroxyl group, the compound formed by the reaction is more hydrophilic and may optionally be readily separated from the morphine compound.
Selon un mode de réalisation particulier, les composés formés par la réaction d'addition de type Michaël sont séparés lors des étapes d'isolement et de purification subséquentes habituelles.According to a particular embodiment, the compounds formed by the Michael addition reaction are separated during the usual subsequent isolation and purification steps.
La réaction d'addition de type Michaël se déroule en compétition avec des réactions secondaires, notamment la réaction d'aldolisation et de crotonisation.The Michael-type addition reaction proceeds in competition with secondary reactions, in particular the aldolization and crotonization reaction.
Le schéma réactionnel 2 ci-dessous illustre la réaction d'aldolisation pour l'exemple de la naloxone. Le produit dimère formé est relativement hydrophile. Il est de ce fait facilement séparable lors des étapes d'isolement et de purification subséquentes.Reaction Scheme 2 below illustrates the aldol reaction for the example of naloxone. The dimeric product formed is relatively hydrophilic. It is therefore easily separable during subsequent isolation and purification steps.
aldolisationaldolization
rétroaldolisation rétroaldolisation
"Aldol""Aldol"
Naloxone ( 6',7 Naloxol-Naloxone)Naloxone (6 ', 7 Naloxol-Naloxone)
Schéma réactionnel 2 : Aldolisation de la naloxone crotonisationReaction Scheme 2: Aldolization of naloxone crotonization
"Crotonisé""Crotonisé"
"Aldol" 6', 7' oléfine de 6',7 naloxol -naloxone) ; 6',7 Naloxol-Naloxone)"Aldol" 6 ', 7' olefin 6 ', 7 naloxol-naloxone); 6 ', 7 Naloxol-Naloxone)
Schéma réactionnel 3 : Crotonisation de la naloxoneReaction Scheme 3: Crotonization of naloxone
La crotonisation de la naloxone conduit au composé déshydraté correspondant. La réaction est illustrée sur le schéma réactionnel 3 ci-dessus pour l'exemple de la naloxone. Il a été établi par analyse RMN structurale que seul le composé avec l'insaturation endocyclique est formé.Crotonization of naloxone leads to the corresponding dehydrated compound. The reaction is illustrated in Reaction Scheme 3 above for the example of naloxone. It has been established by structural NMR analysis that only the compound with endocyclic unsaturation is formed.
La crotonisation est une réaction irréversible, contrairement à la réaction d'aldolisation, qui est en équilibre avec la réaction inverse appelée rétroaldolisa- tion. Par ailleurs, le composé issu de la crotonisation du produit aldol est peu hy- drosoluble et de ce fait plus difficile à séparer du produit réactionnel.Crotonization is an irreversible reaction, unlike the aldol reaction, which is in equilibrium with the reverse reaction called retroaldolisation. Furthermore, the compound resulting from the crotonization of the aldol product is not very water-soluble and therefore more difficult to separate from the reaction product.
De manière surprenante, il a été constaté qu'il était possible de limiter l'impact des réactions secondaires en sélectionnant certains paramètres du procédé de manière appropriée.Surprisingly, it has been found that it is possible to limit the impact of side reactions by selecting certain process parameters appropriately.
En particulier, il s'est révélé qu'un moyen efficace pour limiter la réaction de crotonisation est de limiter la formation d'aldol, qui est le produit de départ de la crotonisation.In particular, it has been found that an effective means for limiting the crotonization reaction is to limit the formation of aldol, which is the starting material of crotonization.
Or il a été constaté que la réaction d'aldolisation est défavorisée à basse température, en milieu fortement basique, et à faible temps de contact.However, it has been found that the aldolisation reaction is disadvantaged at low temperature, in a strongly basic medium, and at a low contact time.
Par conséquent, il est préférable de réaliser la réaction à basse tempéra- ture. Cependant, il a été observé que l'addition de Michaël est ralentie lorsque la température est trop basse.Therefore, it is preferable to carry out the reaction at low temperature. However, it has been observed that the addition of Michael is slowed down when the temperature is too low.
Une température réactionnelle de 10 à 400C, en particulier de 20 à 25°C constitue généralement un bon compromis. Il est particulièrement préféré de mettre en œuvre la réaction à température ambiante, sans moyens de chauffage ou de refroidissement.A reaction temperature of 10 to 40 ° C., in particular 20 to 25 ° C., generally constitutes a good compromise. It is particularly preferred to implement the reaction at room temperature without heating or cooling means.
L'étape particulière décrite est réalisée sur le composé morphinique brut, accessible par l'un des procédés classiques connus, par exemple décrits dans « Chemistry of the Opium Alkaloids », par Lyndon F. Small et Robert E. Lutz,The particular step described is carried out on the crude morphine compound, accessible by one of the known conventional processes, for example described in "Chemistry of the Opium Alkaloids", by Lyndon F. Small and Robert E. Lutz,
Supplément n° 108 to the Public Health Reports, US Government Printing Office,Supplement No. 108 to the Public Health Reports, US Government Printing Office,
1982.1982.
Le composé morphinique brut obtenu par ces procédés présente généralement une teneur en composés α-β insaturés inférieure à 1%, le plus souvent entre 0,1 % à 0,2% en poids.The crude morphine compound obtained by these processes generally has a content of α-β unsaturated compounds of less than 1%, most often between 0.1% and 0.2% by weight.
Le procédé selon l'invention permet la réaction d'addition de type Michaël sur les composés α-β insaturés présents dans le composé morphinique brut.The process according to the invention allows the Michael-type addition reaction on the unsaturated α-β compounds present in the crude morphine compound.
Le composé morphinique brut est généralement mis en solution dans un solvant approprié, avantageusement en solution aqueuse. Il est préférable que la solution présente une concentration entre 5 et 25 % en poids de composé morphinique brut.The crude morphine compound is generally dissolved in a suitable solvent, advantageously in aqueous solution. It is preferable that the solution has a concentration between 5 and 25% by weight of crude morphine compound.
La base utilisée est de préférence une base minérale forte, telles que les hydroxydes de métaux alcalins et alcalino-terreux et en particulier l'hydroxyde de sodium ou de potassium. La quantité de base est de préférence en excès par rapport au composé morphinique engagé. Généralement, elle représente au moins 3, voire au moins 5 équivalents calculé par rapport au composé morphinique. De préférence, le mélange réactionnel présente un pH supérieur à 13 ou même supérieur à 14. De préférence, on utilisera donc une base en solution concentrée. En effet, la réaction de rétro-aldolisation est favorisée en milieu fortement basique, ce qui limite la quantité d'aldol disponible pour la crotonisation.The base used is preferably a strong mineral base, such as alkali and alkaline earth metal hydroxides and in particular sodium or potassium hydroxide. The amount of base is preferably in excess relative to the morphine compound employed. Generally, it represents at least 3, or even at least 5 equivalents calculated with respect to the morphine compound. Preferably, the reaction mixture has a pH greater than 13 or even greater than 14. Preferably, therefore, a base in concentrated solution will be used. Indeed, the retro-aldolization reaction is favored in a strongly basic medium, which limits the amount of aldol available for crotonization.
Selon un mode de réalisation préféré, la solution de composé morphinique est introduite dans la base et non l'inverse. Cette variante, appelée coulée inverse, assure un milieu réactionnel fortement basique à tout moment. Le procédé selon l'invention peut être réalisé de manière simple et sur un équipement classique. On met le composé morphinique en contact avec un milieu basique, de préférence sous agitation. Le milieu réactionnel est de préférence maintenu à une température de 20 à 25°C.According to a preferred embodiment, the morphine compound solution is introduced into the base and not vice versa. This variant, called reverse casting, provides a strongly basic reaction medium at any time. The process according to the invention can be carried out in a simple manner and on conventional equipment. The morphine compound is brought into contact with a basic medium, preferably with stirring. The reaction medium is preferably maintained at a temperature of 20 to 25 ° C.
Le temps de contact du mélange réactionnel est de préférence court afin de défavoriser l'aldolisation. Cela ne pose pas de problème en termes de conversion car la réaction d'addition de Michaël est généralement complète en 10 à 40 minutes, et le plus souvent en 20 à 30 minutes.The contact time of the reaction mixture is preferably short in order to disadvantage the aldolization. This is not a problem in terms of conversion since the addition reaction of Michael is usually complete in 10 to 40 minutes, and most often in 20 to 30 minutes.
A l'issue de la réaction, généralement au bout de moins d'une heure, le milieu réactionnel est neutralisé. Afin de limiter la montée de la température et donc les réactions de crotonisation, il est préféré de neutraliser le mélange réactionnel par ajout progressif d'un agent de neutralisation.At the end of the reaction, generally after less than one hour, the reaction medium is neutralized. In order to limit the rise in temperature and therefore the crotonization reactions, it is preferred to neutralize the reaction mixture by progressive addition of a neutralization agent.
L'agent de neutralisation sera le plus souvent un acide usuel, fort ou faible, organique ou minéral. Particulièrement préférés sont l'acide hydrochlorique, l'acide sulfurique ou l'acide acétique. On neutralise jusqu'à précipitation du com- posé morphinique. Généralement, le produit morphinique précipite à pH neutre à modérément basique, par exemple compris entre pH 8 et 10.The neutralizing agent will most often be a usual acid, strong or weak, organic or mineral. Particularly preferred are hydrochloric acid, sulfuric acid or acetic acid. The morphine compound is neutralized until precipitation. Generally, the morphine product precipitates at neutral to moderately basic pH, for example between pH 8 and 10.
Le produit solide est ensuite séparé du mélange réactionnel par les méthodes classiques, par exemple par filtration.The solid product is then separated from the reaction mixture by conventional methods, for example by filtration.
La filtration sur un milieu polaire comme l'alumine est particulièrement inté- ressante car elle permet une rétention par affinité des composés davantage hy- droxylés, notamment les produits d'aldolisation.Filtration on a polar medium such as alumina is particularly interesting because it allows affinity retention of the more hydroxylated compounds, especially the aldol products.
Le plus souvent, le composé morphinique obtenu, sous forme de base sol- vatée, est ensuite transformé en sel pharmaceutiquement acceptable, notamment en chlorhydrate, mucate, bromhydrate, stéarate, pamoate, napsylate, 2-hydroxy 5(1 ,1 ,3,3-tétraméthylbutyl)benzoate, ou encore 3,5- bis(1 ,1-diméthyléthyl)-2,6 di- hydrobenzoate.Most often, the morphine compound obtained, in the form of a solvent base, is then converted into a pharmaceutically acceptable salt, especially hydrochloride, mucate, hydrobromide, stearate, pamoate, napsylate, 2-hydroxy (1, 1, 3, 3-tetramethylbutyl) benzoate, or else 3,5-bis (1,1-dimethylethyl) -2,6-dihydrobenzoate.
Cette étape peut être réalisée par réaction du composé morphinique obtenu avec l'acide correspondant. Généralement, la base est peu hydrosoluble, et on prépare donc une solution du composé morphinique dans un solvant approprié, par exemple l'acétone. Après ajout de l'acide, on sépare le sel formé, par exemple par précipitation. Les sels des composés dimères issus des réactions d'aldolisation et de cro- tonisation sont mieux solubles dans l'eau que le sel du composé morphinique. Leur teneur peut donc être réduite lors de cette étape.This step can be carried out by reaction of the morphine compound obtained with the corresponding acid. Generally, the base is poorly water soluble, and so a solution of the morphine compound is prepared in a suitable solvent, for example acetone. After adding the acid, the salt formed is separated, for example by precipitation. The salts of the dimeric compounds from the aldolization and crustalization reactions are better soluble in water than the salt of the morphine compound. Their content can therefore be reduced during this step.
Le composé morphinique ou son sel ainsi obtenu peut si nécessaire être purifié davantage selon les méthodes connues, par exemple par recristallisation.The morphine compound or its salt thus obtained can, if necessary, be further purified according to known methods, for example by recrystallization.
Par ailleurs, il est possible d'obtenir le composé morphinique anhydre par élimination du solvant, notamment par séchage à l'étuve.Furthermore, it is possible to obtain the anhydrous morphine compound by removal of the solvent, especially by drying in an oven.
Selon un aspect avantageux de l'invention, les composés issus de la réaction et des réactions secondaires sont donc séparés par les étapes de purification subséquentes, sans nécessité d'une étape spécialement prévue à cet effet.According to an advantageous aspect of the invention, the compounds resulting from the reaction and the secondary reactions are thus separated by the subsequent purification steps, without the need for a step specifically provided for this purpose.
CompositionComposition
Selon un second aspect, l'invention concerne une composition comprenant au moins 99 % en poids sec de composé morphinique et une teneur en composé α-β-insaturé inférieure à 100 ppm. En particulier, l'invention vise une composition comprenant au moins 99 %, de préférence au moins 99,5 % en poids sec de composé morphinique ou un de ses sels pharmaceutiquement acceptables et un composé α-β-insaturé en une teneur inférieure à 100 ppm, de préférence infé- heure à 50 ppm et encore préféré inférieure à 25 ppm.According to a second aspect, the invention relates to a composition comprising at least 99% by dry weight of morphine compound and an α-β-unsaturated compound content of less than 100 ppm. In particular, the invention provides a composition comprising at least 99%, preferably at least 99.5% by dry weight of morphine compound or a pharmaceutically acceptable salt thereof and an α-β-unsaturated compound in a content of less than 100. ppm, preferably less than 50 ppm and more preferably less than 25 ppm.
Les composés morphiniques ainsi que leurs sels forment facilement des solvates, et notamment sous forme de mono-, di- ou trihydrates. Les teneurs de ces composés sont donc généralement exprimées par rapport au composé sec, sans tenir compte de la teneur en eau ou en solvants. Les teneurs indiquées dans ce qui suit, sauf indications contraires, s'entendent donc toujours par rapport au composé sec.The morphine compounds and their salts easily form solvates, and especially in the form of mono-, di- or trihydrates. The contents of these compounds are therefore generally expressed relative to the dry compound, without taking into account the water content or solvents. The contents indicated in the following, unless otherwise indicated, are therefore always in relation to the dry compound.
Particulièrement visées sont de telles compositions lorsque le composé morphinique est la naloxone, son chlorhydrate ou encore le dihydrate du chlorhydrate. Dans ces compositions, le composé α-β insaturé est de préférence la 7,8- didéhydronaloxone.Particularly targeted are such compositions when the morphine compound is naloxone, its hydrochloride or hydrochloride dihydrate. In these compositions, the unsaturated α-β compound is preferably 7,8-didehydronaloxone.
Selon un mode de réalisation particulier, la composition contient par ailleurs en faible quantité des composés issus de la réaction d'aldolisation et de crotonisa- tion. Ainsi la présente invention a notamment pour objet une composition comprenant au moins 99% en poids sec, de préférence au moins 99,5 % en poids sec, de composé morphinique ou d'un de ses sels pharmaceutiquement acceptables, un composé α-β insaturé en une teneur inférieure à 100 ppm et de préférence in- férieure à 50 ppm, et comprenant en outre au moins un composé issu des réactions d'aldolisation et de crotonisation.According to one particular embodiment, the composition also contains, in a small amount, compounds resulting from the aldolisation and crotonization reaction. Thus, the subject of the present invention is in particular a composition comprising at least 99% by dry weight, preferably at least 99.5% by dry weight, of morphine compound or of a pharmaceutically acceptable salt thereof, an unsaturated α-β compound. in a content of less than 100 ppm and preferably less than 50 ppm, and further comprising at least one compound derived from the aldolization and crotonization reactions.
Ces composés issus des réactions d'aldolisation et de crotonisation ne présentent plus de risque potentiel de génotoxicité associé aux structures cétoniques α-β insaturées. Les composés issus de la réaction d'aldolisation et de la réaction de crotonisation sont généralement présents en une teneur inférieure à 1000 ppm et en particulier inférieure ou égale à 500 ppm dans les compositions selon l'inventionThese compounds resulting from the aldolization and crotonization reactions no longer present a potential risk of genotoxicity associated with α-β-unsaturated ketone structures. The compounds resulting from the aldolisation reaction and the crotonization reaction are generally present in a content of less than 1000 ppm and in particular less than or equal to 500 ppm in the compositions according to the invention
Lorsque dans la composition selon l'invention le composé morphinique est sous forme de sel, le composé issu de la réaction d'aldolisation est généralement présent en une teneur allant de 20 à 200 ppm et en particulier de 50 à 150 ppm.When in the composition according to the invention the morphine compound is in salt form, the compound resulting from the aldolization reaction is generally present in a content ranging from 20 to 200 ppm and in particular from 50 to 150 ppm.
Lorsque dans la composition selon l'invention le composé morphinique est sous forme de sel, le composé issu de la réaction de crotonisation est généralement présent en une teneur allant de 150 à 500 ppm et en particulier de 200 à 350 ppm. Pour ce qui est de la naloxone, il s'agit de la 6'-7-naloxol-naloxone et de laWhen in the composition according to the invention the morphine compound is in salt form, the compound resulting from the crotonization reaction is generally present in a content ranging from 150 to 500 ppm and in particular from 200 to 350 ppm. In the case of naloxone, it is 6'-7-naloxol-naloxone and
6'-7' oléfine correspondante.6'-7 'corresponding olefin.
Particulièrement préférées sont les compositions selon l'invention comprenant un sel pharmaceutiquement acceptable de composé morphinique ; en particulier un chlorhydrate de naloxone. Les composés morphiniques ou leurs sels sont le plus souvent des solvates, et en particulier des hydrates. Particulièrement visée est une composition comprenant le dihydrate de chlorhydrate de naloxone. En particulier la présente invention vise une composition comprenant du dihydrate de chlorhydrate de naloxone, de la 7-8 didéhydronaloxone, notamment en une teneur inférieure à 90 ppm, de la 6'-7 naloxol naloxone notamment en une teneur allant de 50 à 150 ppm et de la 6'-7' oléfine de 6'-7 naloxol-naloxone notamment en une teneur allant de 200 à 350 ppm. Lorsque le composé morphinique est sous forme de solvate, la composition contiendra en outre du solvant en une quantité correspondante. Pour le cas du dihydrate de chlorhydrate de la naloxone, la composition peut en outre contenir jusqu'à 10% en poids d'eau par rapport au poids total de la composition.Particularly preferred are the compositions according to the invention comprising a pharmaceutically acceptable salt of morphine compound; in particular a naloxone hydrochloride. The morphine compounds or their salts are most often solvates, and in particular hydrates. Particularly targeted is a composition comprising naloxone hydrochloride dihydrate. In particular, the present invention relates to a composition comprising naloxone hydrochloride dihydrate, 7-8 didehydronaloxone, especially at a content of less than 90 ppm, 6'-7 naloxol naloxone especially in a content ranging from 50 to 150 ppm and 6'-7 'olefin of 6'-7-naloxol-naloxone especially in a content ranging from 200 to 350 ppm. When the morphine compound is in solvate form, the composition will further contain solvent in a corresponding amount. In the case of the hydrochloride dihydrate of naloxone, the composition may further contain up to 10% by weight of water relative to the total weight of the composition.
L'invention sera expliquée plus en détail au moyen des exemples suivants, et des figures, lesquelles montrent :The invention will be explained in more detail by means of the following examples, and figures, which show:
Fig. 1 : Résultat d'analyse par HPLC de naloxone base à faible teneur en composés α-β insaturés obtenue à l'exemple ; et Fig. 2 : Résultat d'analyse par HPLC de chlorhydrate de naloxone à faible teneur en composés α-β insaturés obtenue à l'exemple.Fig. 1: HPLC analysis result of naloxone base with low content of α-β unsaturated compounds obtained in the example; and 2: HPLC analysis result of naloxone hydrochloride with low content of α-β unsaturated compounds obtained in the example.
EXEMPLESEXAMPLES
EXEMPLE : Préparation de naloxone à faible teneur en composés α-3 insa- turésEXAMPLE: Preparation of naloxone with low content of unsaturated α-3 compounds
Dans un tricol de 250 ml équipé d'un thermomètre et d'un barreau aimanté 15,08g (0,046 mole) de naloxone base brute obtenue par N-allylation du chlorhydrate de noroxymorphone dans le diméthylformamide par le bromure d'allyle en présence de NaHCθ3 à 600C suivie d'une précipitation dans l'eau sont introduits, suivi par 105 ml d'eau et 9 ml (0,06 mol, 2 eq) de soude concentrée (30%). Le milieu est agité à température ambiante jusqu'à dissolution totale.In a 250 ml three-necked flask equipped with a thermometer and a magnetized bar 15.08 g (0.046 mol) of naloxone crude base obtained by N-allylation of noroxymorphone hydrochloride in dimethylformamide with allyl bromide in the presence of NaHCO 3 3 to 60 0 C followed by precipitation in water are introduced, followed by 105 ml of water and 9 ml (0.06 mol, 2 eq) of concentrated sodium hydroxide (30%). The medium is stirred at room temperature until complete dissolution.
Le milieu est ensuite chargé dans une ampoule de coulée, puis ajouté goutte à goutte dans un tricol contenant 36 ml (0,27 mol ; 8 eq) de soude concentrée (30%). La température ambiante initiale de 21 ,60C du milieu réactionnel at- teint en fin de coulée 21 ,5°C, le pH du milieu réactionnel étant alors de 14,4.The medium is then loaded into a dropping funnel and then added dropwise into a three-necked flask containing 36 ml (0.27 mol; 8 eq) of concentrated sodium hydroxide (30%). The initial ambient temperature of 21.6 ° C. of the reaction medium reaches, at the end of the casting, 21.5 ° C., the pH of the reaction medium then being 14.4.
L'agitation est encore maintenue pendant 30 minutes à cette température. On ajoute ensuite 39 ml (0,37 mol ; 8,2 eq) d'acide chlorhydrique concentré (à 37%) goutte à goutte afin de minimiser l'élévation de la température.Stirring is further maintained for 30 minutes at this temperature. 39 ml (0.37 mol, 8.2 eq) of concentrated hydrochloric acid (37%) are then added dropwise in order to minimize the rise in temperature.
En fin d'ajout, le milieu réactionnel présente une température de 41 ,7°C et un pH 9. Le milieu est refroidi à 100C et le précipité est séparé par filtration sur verre fritte. Le produit solide séparé est séché à l'étuve ventilée à 600C. La naloxone base brute traitée est isolée avec une masse de 15,64 g sèche. Le produit obtenu à l'issue de ces opérations est appelé « naloxone base traitée » dans les tableaux 1 à 4 ci-après.At the end of the addition, the reaction medium has a temperature of 41.7 ° C. and a pH of 9. The medium is cooled to 10.degree. C. and the precipitate is separated by filtration on sintered glass. The separated solid product is dried in a ventilated oven at 60 ° C. The treated crude base naloxone is isolated with a mass of 15.64 g dry. The product obtained at the end of these operations is called "naloxone base treated" in Tables 1 to 4 below.
Le produit obtenu est ensuite mis en solution dans l'acétone, filtré sur alumine et recristallisé dans le toluène. Le produit obtenu à l'issue de ces opérations est appelé « naloxone base pure » dans les tableaux 1 à 4 ci-après.The product obtained is then dissolved in acetone, filtered through alumina and recrystallized from toluene. The product obtained after these operations is called "naloxone pure base" in Tables 1 to 4 below.
La naloxone base obtenue est mise en solution dans l'acétone puis chlor- hydratée par ajout d'acide chlorhydrique concentré. Le chlorhydrate est précipité par refroidissement, filtré et séché. Le produit obtenu à l'issue de ces opérations est appelé « naloxone HCI pure » dans les tableaux 1 à 4 ci-après. Le produit obtenu est analysé selon la méthode HPLC décrite par la pharmacopée européenne après le traitement basique, et après chlorhydratation.The naloxone base obtained is dissolved in acetone and then chlorhydrated by addition of concentrated hydrochloric acid. The hydrochloride is precipitated by cooling, filtered and dried. The product obtained after these operations is called "pure naloxone HCl" in Tables 1 to 4 below. The product obtained is analyzed according to the HPLC method described by the European Pharmacopoeia after the basic treatment, and after hydrochlorination.
L'essai est répété deux fois selon le même protocole opératoire. Les résultats des analyses sont rassemblés dans les tableaux 1 et 2 ci-dessous.The test is repeated twice according to the same operating procedure. The results of the analyzes are summarized in Tables 1 and 2 below.
On remarque que le procédé selon l'invention permet l'obtention, par le trai- tement basique, de naloxone à faible teneur en 7,8-didéhydronaloxone. En effet, le traitement permet d'abaisser la teneur en 7,8-didéhydronaloxone de 0,8 % en poids initialement à moins de 0,03 % en poids, donc en dessous du seuil de détection. Une méthode HPLC plus spécifique permet de constater que la teneur en 7,8-didéhydronaloxone, devant être inférieure à 100 ppm, présente une valeur habituelle de 60 à 90 ppm.It is noted that the process according to the invention makes it possible to obtain, by the basic treatment, naloxone with a low content of 7,8-didehydronaloxone. Indeed, the treatment makes it possible to lower the content of 7,8-didehydronaloxone from 0.8% by weight initially to less than 0.03% by weight, and therefore below the detection threshold. A more specific HPLC method shows that the content of 7,8-didehydronaloxone, to be less than 100 ppm, has a usual value of 60 to 90 ppm.
La naloxone ainsi obtenue répond donc à ce stade aux exigences réglementaires en ce qui concerne la teneur en 7,8-didéhydronaloxone.Naloxone thus obtained at this stage meets the regulatory requirements for the content of 7,8-didehydronaloxone.
On note par ailleurs après traitement de la naloxone l'apparition du produit d'addition, la 8-hydroxy naloxone, ainsi que de petites quantités des produits des réactions concurrentes d'aldolisation et de crotonisation. Ces composés sont toutefois très largement éliminés au cours des étapes subséquentes de purification et de transformation en chlorhydrate.Furthermore, after the treatment of naloxone, the appearance of the addition product, 8-hydroxy naloxone, as well as small amounts of the products of the competing aldolization and crotonization reactions are noted. These compounds are, however, largely eliminated during the subsequent steps of purification and conversion to hydrochloride.
Les résultats des analyses HPLC des tableaux 1 et 2, traités selon des méthodes de quantification plus précises, conduisent aux valeurs présentées respec- tivement dans les tableaux 3 et 4 ci-dessous. Tableau 1 : Analyse HPLC essai 1The results of the HPLC analyzes in Tables 1 and 2, processed according to more precise quantification methods, lead to the values presented respectively in Tables 3 and 4 below. Table 1: HPLC Analysis Test 1
+ méthode HPLC de quantification de la 7,8 didéhydronaloxone selon la pharmacopée européenne ; * méthode d'expertise HPLC dédiée à la quantification précise de la 7,8 didéhydronaloxone. La différence entre les deux valeurs est due notamment à une différence de coefficient de réponse dans la pharmacopée européenne. + HPLC method of quantification of 7.8 didehydronaloxone according to the European Pharmacopoeia; * HPLC expertise method dedicated to accurate quantification of 7.8 didehydronaloxone. The difference between the two values is due in particular to a difference in response coefficient in the European pharmacopoeia.
Tableau 2 : Analyse HPLC essai 2Table 2: HPLC Analysis Test 2
+ méthode HPLC de quantification de la 7,8 didéhydronaloxone selon la pharmacopée européenne ; * méthode d'expertise HPLC dédiée à la quantification précise de la 7,8 didéhydronaloxone. La différence entre les deux valeurs est due notamment à une différence de coefficient de réponse dans la pharmacopée européenne. Tableau 3 : Analyse HPLC avec méthode de quantification différente de l'essai 1 + HPLC method of quantification of 7.8 didehydronaloxone according to the European Pharmacopoeia; * HPLC expertise method dedicated to accurate quantification of 7.8 didehydronaloxone. The difference between the two values is due in particular to a difference in response coefficient in the European pharmacopoeia. Table 3: HPLC Analysis with Quantification Method Different from Test 1
+ méthode HPLC de quantification de la 7,8 didéhydronaloxone selon la pharmacopée européenne ; * méthode d'expertise HPLC dédiée à la quantification précise de la 7,8 didéhydronaloxone. La différence entre les deux valeurs est due notamment à une différence de coefficient de réponse dans la pharmacopée européenne. + HPLC method of quantification of 7.8 didehydronaloxone according to the European Pharmacopoeia; * HPLC expertise method dedicated to accurate quantification of 7.8 didehydronaloxone. The difference between the two values is due in particular to a difference in response coefficient in the European pharmacopoeia.
Tableau 4 : Analyse HPLC avec méthode de quantification différente de l'essai 2Table 4: HPLC Analysis with Quantification Method Different from Test 2
+ méthode HPLC de quantification de la 7,8 didéhydronaloxone selon la pharmacopée européenne ; * méthode d'expertise HPLC dédiée à la quantification précise de la 7,8 didéhydronaloxone. La différence entre les deux valeurs est due notamment à une différence de coefficient de réponse dans la pharmacopée européenne. + HPLC method of quantification of 7.8 didehydronaloxone according to the European Pharmacopoeia; * HPLC expertise method dedicated to accurate quantification of 7.8 didehydronaloxone. The difference between the two values is due in particular to a difference in response coefficient in the European pharmacopoeia.

Claims

REVENDICATIONS
1.- Procédé de préparation de composés morphiniques à faible teneur en composés α-β insaturés, comportant les étapes de : (i) mise en contact du composé morphinique brut avec une base, à pH supérieur à 13, dans des conditions permettant la réaction d'addition de Michaël sur le(s) composé(s) α-β insaturé(s) présent(s) ; (ii) séparation du composé morphinique du mélange réactionnel ; et (iii) le cas échéant, séparation du produit d'addition formé du composé morphinique.1. A process for the preparation of morphine compounds with a low content of unsaturated α-β compounds, comprising the steps of: (i) bringing the crude morphine compound into contact with a base, at a pH greater than 13, under conditions permitting the reaction of Michael's addition to the unsaturated α-β compound (s) present; (ii) separation of the morphine compound from the reaction mixture; and (iii) optionally, separating the adduct formed from the morphine compound.
2. Procédé selon la revendication 1 , comportant à titre d'étape subséquente :2. Method according to claim 1, comprising as a subsequent step:
(iv) transformation du composé morphinique en sel pharmaceutiquement acceptable correspondant.(iv) conversion of the morphine compound to the corresponding pharmaceutically acceptable salt.
3. Procédé selon la revendication 1 ou 2, dans lequel l'étape (i) est réalisée par introduction du composé morphinique brut dans la base.3. The method of claim 1 or 2, wherein step (i) is performed by introducing the crude morphine compound into the base.
4. Procédé selon l'une des revendications 1 à 3, dans lequel l'étape (ii) est réalisée par précipitation obtenue par ajout d'un agent de neutralisation.4. Method according to one of claims 1 to 3, wherein step (ii) is carried out by precipitation obtained by adding a neutralization agent.
5. Procédé selon l'une des revendications 1 à 4, dans lequel l'étape (iii) est réalisée en même temps que l'étape (iv).5. Method according to one of claims 1 to 4, wherein step (iii) is carried out at the same time as step (iv).
6. Procédé selon l'une des revendications 1 à 5, dans lequel le composé morphinique est la naloxone et le composé α-β insaturé est la 7,8- didéhydronaloxone.6. Method according to one of claims 1 to 5, wherein the morphine compound is naloxone and the unsaturated α-β compound is 7,8-didehydronaloxone.
7. Procédé selon la revendication 6, dans lequel l'étape (i) est réalisée à une température de 20 à 25°C. The process of claim 6 wherein step (i) is conducted at a temperature of 20 to 25 ° C.
8. Procédé selon la revendication 6 ou 7, dans lequel l'étape (i) est réalisée avec un temps de contact de moins d'une heure.The method of claim 6 or 7, wherein step (i) is performed with a contact time of less than one hour.
9. Composition comprenant au moins 99% en poids sec de composé mor- phinique ou d'un de ses sels pharmaceutiquement acceptables et un composé α-β insaturé en une teneur inférieure à 100 ppm.9. Composition comprising at least 99% by dry weight of morphine compound or a pharmaceutically acceptable salt thereof and an unsaturated α-β compound in a content of less than 100 ppm.
10. Composition selon la revendication 9, comprenant au moins 99,5 % en poids sec de composé morphinique ou d'un de ses sels pharmaceutiquement ac- ceptable.10. Composition according to claim 9, comprising at least 99.5% by dry weight of morphine compound or a pharmaceutically acceptable salt thereof.
11. Composition selon la revendication 9 ou 10, présentant une teneur en composé α-β insaturé inférieure à 50 ppm.11. Composition according to claim 9 or 10, having a content of unsaturated α-β compound of less than 50 ppm.
12. Composition selon l'une des revendications 9 à 11 , comprenant en outre au moins un composé issu de la réaction d'aldolisation.12. Composition according to one of claims 9 to 11, further comprising at least one compound derived from the aldolization reaction.
13. Composition selon la revendication 12, dans laquelle la teneur en composé issu de la réaction d'aldolisation est inférieure à 1000 ppm.13. Composition according to claim 12, wherein the content of the compound resulting from the aldolisation reaction is less than 1000 ppm.
14. Composition selon l'une des revendications 9 à 13, comprenant en outre au moins un composé issu de la réaction de crotonisation.14. Composition according to one of claims 9 to 13, further comprising at least one compound derived from the crotonization reaction.
15. Composition selon la revendication 14, dans laquelle la teneur en com- posé issu de la réaction de crotonisation est inférieure à 1000 ppm.15. The composition of claim 14 wherein the compound content from the crotonization reaction is less than 1000 ppm.
16. Composition selon l'une des revendications 9 à 15, dans laquelle le composé morphinique est la naloxone et le composé α-β insaturé est la 7,8- didéhydronaloxone.16. Composition according to one of claims 9 to 15, wherein the morphine compound is naloxone and the unsaturated α-β compound is 7,8-didehydronaloxone.
17. Composition selon l'une des revendications 9 à 15, dans laquelle le sel pharmaceutiquement acceptable du composé morphinique est le chlorhydrate de naloxone et le composé α-β insaturé est la 7,8-didéhydronaloxone. 17. Composition according to one of claims 9 to 15, wherein the pharmaceutically acceptable salt of the morphine compound is naloxone hydrochloride and the unsaturated α-β compound is 7,8-didehydronaloxone.
18. Composition selon l'une des revendications 9 à 15, dans laquelle le sel pharmaceutiquement acceptable du composé morphinique est le dihydrate de chlorhydrate de naloxone et le composé α-β insaturé est la 7,8- didéhydronaloxone.18. Composition according to one of claims 9 to 15, wherein the pharmaceutically acceptable salt of the morphine compound is naloxone hydrochloride dihydrate and the unsaturated α-β compound is 7,8-didehydronaloxone.
19. Composition selon l'une des revendications 16 à 18, comportant en outre du 6'-7 naloxol-naloxone.19. Composition according to one of claims 16 to 18, further comprising 6'-7 naloxol-naloxone.
20. Composition selon l'une des revendications 16 à 19, comportant en ou- tre la 6'-7' oléfine de 6'-7 naloxol-naloxone. 20. Composition according to one of claims 16 to 19, further comprising the 6'-7 'olefin of 6'-7 naloxol-naloxone.
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ZA201003241B (en) 2011-08-31
EA201070589A1 (en) 2010-10-29
MX2010005124A (en) 2010-05-27
IL205601A0 (en) 2010-11-30
SG186591A1 (en) 2013-01-30

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