WO1986001508A1 - Antagonistes d'opiate - Google Patents

Antagonistes d'opiate Download PDF

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Publication number
WO1986001508A1
WO1986001508A1 PCT/AU1985/000200 AU8500200W WO8601508A1 WO 1986001508 A1 WO1986001508 A1 WO 1986001508A1 AU 8500200 W AU8500200 W AU 8500200W WO 8601508 A1 WO8601508 A1 WO 8601508A1
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WO
WIPO (PCT)
Prior art keywords
formula
general formula
compound
group
opiate
Prior art date
Application number
PCT/AU1985/000200
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English (en)
Inventor
Kenneth Neville Wynne
Jaroslav Haman Boublik
Olaf Heino Drummer
Ian David Rae
John Watson Funder
Original Assignee
The Commonwealth Of Australia Care Of The Departme
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
Application filed by The Commonwealth Of Australia Care Of The Departme filed Critical The Commonwealth Of Australia Care Of The Departme
Publication of WO1986001508A1 publication Critical patent/WO1986001508A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom

Definitions

  • This invention relates to the identification and isolation of compounds having opiate receptor binding activity, to the synthesis thereof, and to the use of such compounds as opiate narcotic antagonists.
  • R, , R 2 and R_ groups represents a feruloyl or isoferuloyl group of the formula II or III, respectively:
  • R.. , R_ and R-. are as defined above.
  • Feruloylquinic acids of the general formula IV are known to occur in green coffee beans (Clifford, M.N. , Food Chem. 4, 146-149 (1961) ) .
  • Compounds of the general formula I may also be isolated directly from coffee beans which have been roasted, ground and extracted with water and from instant coffee. This process, which includes thes teps of adsorption on an ion exchange resin followed by chromatography to isolate fractions having the desired activity, is described in greater detail below.
  • the present invention also provides a process for the preparation of the compounds of the general formula I, above, which process comprises the reaction of quinic- 1,3-lactone (or quinide) of the formula V:
  • each R separately represents H or a removable hydroxy protecting group, with a ferulic or isoferulic acid of the formula VI or VII, respectively:
  • R. is an acetyl or other hydroxy protecting group, or a reactive derivative thereof, followed by removal of the group R. and, if necessary any hydroxy
  • the lactone of the formula V may be prepared from quinic acid by reaction with a condensing agent, for example dicyclohexylcarbodiimide (DCC) , or by other known methods, such as by reaction with gaseous HCl in acetone.
  • a condensing agent for example dicyclohexylcarbodiimide (DCC)
  • DCC dicyclohexylcarbodiimide
  • Removable hydroxy protective groups R may be added by methods known per se in the art.
  • acetylferuloylquinides or acetylisoferuloylquinides the acetyl group is removed by brief exposure to methanolic K 2 C0 3-
  • the process of the invention involves the reaction of quinic-1,3-lactone of the formula
  • R. is an acetyl or other hydroxy protecting group, followed by removal of the group R.. Similarly, the protecting isopropylidene or trichloroethoxy carbonyl groups are removed to give in the cases of VA, VB, and VC, the 1,5, and 4-substituted esters of quinic-l,3-lactone respectively.
  • Compounds of the general formula I exhibit significant opiate receptor binding activity, and thus have potential for use as opiate antagonists in reversing the toxic effects of opiate narcotic analgesics such as morphine, for example in the treatment of opiate narcotic overdosage and in the reversal of respiratory depression following the use of narcotics during surgery.
  • opiate narcotic analgesics such as morphine
  • the present invention therefore also extends to pharmaceutical compositions comprising a compound of the general formula I, together with one or more pharmaceutically acceptable carrier or diluent; as well as to methods of treatment of the conditions outlined above, which comprise administration to a patient of a compound of the general formula I, or a pharmaceutical composition containing a compound of the general formula I.
  • GC-MS gas chromatogram-mass spectra
  • Principal total ion peaks of the gas chromatogram contained M/Z 249 (derivatized feruloyl ions) and five of these also exhibit the same molecular ion M/Z 566.
  • the five, with similar mass spectra, are from the possible feruloylquinides of general formula I. Some may be cis-isomers produced as artifacts by the conditions during gas chromatography.
  • Another five hidden peaks of derivatized caffeoyl ions M/Z 307, totalling 10% of the feruloyl ions were also observed and were assumed to represent demethylation that occurred during isolation.
  • Conversion of the roasted bean to instant coffee is estimated to double the concentration of active quinides - possibly to 2% of instant coffee. If this figure is applied to - the ED 50 for instant coffee set out in Table 1 (1.2 mg/ml) it would indicate that feruloylquinides have an ED 5Q of 0.024 mg/ml. The finding of 0.05 mg/ml for crude feruloylquinides indicates that one or more of the isomeric forms of feruloylquinide produce the predominant opiate receptor binding activity of instant coffee.
  • ED-.'s represent the concentration of material required to displace by 50% the binding of 3 H-naloxone in a crude rat brain membrane preparation as described in detail hereinafter. Samples were dissolved in 0.05 M Tris (HCl buffer at pH 7.4 and assayed in triplicate' at 3 to 5 concentrations. ED-, values are determined graphically on log transformed data.
  • Figure 2 shows mass chromatograms of (A) TMS derivatives of instant coffee extract (Fig.l) showing time profiles of total ion current, ions m/z 249 (feruloyl ion), and m/z 566 and (b) TMS derivatives of 4- and 5-caffeoylquinides showing time profiles of total ion current, ion m/z 307 (caffeoyl ion) , and m/z 624 (M+) .
  • Derivatives were prepared by reaction of sample with 100 ⁇ l trimethylsilylimidazole (Pierce) and
  • the receptor assay system was based on that of Pert and Snyder (Pert, C.B. & Snyder, S.H., Proc. Natu. Acad. Sci. U.S.A. 70, 2243-2247, (1973) ).
  • Male Sprague-Dawley rats were killed by decapitation, and brains minus cerebellum homogenized in 25x vol of 0.05 Tris-HCl, pH 7.4 buffer using a Brinkmarin Polytron on setting 4 for 5 s. The homogenate was centrifuged for 20 min at 18,000 g, and the pellet resuspended in 25x vol buffer.
  • Acetylferulic acid was prepared after the method of L.S.Fosdick & A.C.Starke, J.Am.Chem.Soc. 6J2, 3352-5 (1940).
  • Acetylferuloylquinide from the previous preparation was dissolved in methanol and K ⁇ CO ⁇ dissolved in aq.methanol was added.
  • acetylisoferulic acid prepared previously by J.Pacsu and C.Stieber, Ber. 62B, 2974-9 (1929)
  • acetylisoferuloylquinides may be prepared exactly as described previously • for acetylferuloylquinides.
  • the acetyl group may be removed by the method described previously to yield the 1-feruloyl ester of quinic-1,3-lactone.
  • the 1-isoferuloyl ester of quinic-l,3-lactone may be prepared.
  • Example 4 The general procedures of Example 4, may be repeated using 2,2,2-trichloroethoxycarboxy esters as protecting groups on the 1-, or 1- and 5-, hydroxy groups of quinic-1,3—lactone, following ' the methods for synthesis and facile hydrolysis described by T.B.Windolz and D.B.R.Johnston, Tetrahedron Lett. 2555 (1967) .

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

Abstract

Composés de formule générale (I), où l'un des groupes R1, R2 et R3 représente un groupe féruloyle ou isoféruloyle de formule (II) ou (III), respectivement, et les autres groupes R1, R2 et R3 représentent l'hydrogène. Ces composés présentent une activité de récepteurs d'opiate et peuvent être utilisés dans le traitement des effets toxiques d'analgésiques narcotiques à base d'opiate. Est décrite la préparation de ces composés par extraction du café et par des procédés de synthèse.
PCT/AU1985/000200 1984-08-24 1985-08-23 Antagonistes d'opiate WO1986001508A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPG6761 1984-08-24
AU676184 1984-08-24

Publications (1)

Publication Number Publication Date
WO1986001508A1 true WO1986001508A1 (fr) 1986-03-13

Family

ID=3697344

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU1985/000200 WO1986001508A1 (fr) 1984-08-24 1985-08-23 Antagonistes d'opiate

Country Status (2)

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EP (1) EP0190296A1 (fr)
WO (1) WO1986001508A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0581979A1 (fr) * 1992-08-03 1994-02-09 Societe Des Produits Nestle S.A. Dérivés de l'acide quinique et procédé de préparation de dérivés de l'acide quinique
EP0581980A1 (fr) * 1992-08-03 1994-02-09 Societe Des Produits Nestle S.A. Dérivés de l'acide quinique 3- et/ou 4-substitués et procédé de préparation de dérivés de l'acide quinique 3- et/ou 4-substitués
WO2002060462A2 (fr) * 2001-01-30 2002-08-08 Laboratórios Biosintética Ltda. Moyen d'obtention d'un extrait aux proprietes d'antidepresseur et d'antagonistes des opioides et produits pharmaceutiques obtenus a partir de celui-ci
US6693128B2 (en) 2001-05-11 2004-02-17 Vanderbilt University Substituted dicinnamoylquinides and their use in augmentation of adenonsine function
WO2007002112A3 (fr) * 2005-06-20 2007-02-15 Procter & Gamble Methodes destinees a isoler des composes amers utilisables dans des produits alimentaires ou a boire
CN108003027A (zh) * 2017-12-25 2018-05-08 北京微医智慧信息技术有限责任公司 1-o-咖啡酰奎宁酸、其衍生物、制备方法及其用途

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0581979A1 (fr) * 1992-08-03 1994-02-09 Societe Des Produits Nestle S.A. Dérivés de l'acide quinique et procédé de préparation de dérivés de l'acide quinique
EP0581980A1 (fr) * 1992-08-03 1994-02-09 Societe Des Produits Nestle S.A. Dérivés de l'acide quinique 3- et/ou 4-substitués et procédé de préparation de dérivés de l'acide quinique 3- et/ou 4-substitués
US5395950A (en) * 1992-08-03 1995-03-07 Nestec S.A. Production of quinic acid derivatives
US5401858A (en) * 1992-08-03 1995-03-28 Nestec S.A. Preparation of quinic acid derivatives
AU662231B2 (en) * 1992-08-03 1995-08-24 Societe Des Produits Nestle S.A. 3- and/or 4-substituted derivatives of quinic acid and a process for the production of 3- and/or 4-substituted derivatives of quinic acid
AU662430B2 (en) * 1992-08-03 1995-08-31 Societe Des Produits Nestle S.A. Derivatives of quinic acid and a process for their production
WO2002060462A2 (fr) * 2001-01-30 2002-08-08 Laboratórios Biosintética Ltda. Moyen d'obtention d'un extrait aux proprietes d'antidepresseur et d'antagonistes des opioides et produits pharmaceutiques obtenus a partir de celui-ci
WO2002060462A3 (fr) * 2001-01-30 2002-12-19 Laboratorios Biosintetica Ltda Moyen d'obtention d'un extrait aux proprietes d'antidepresseur et d'antagonistes des opioides et produits pharmaceutiques obtenus a partir de celui-ci
US6693128B2 (en) 2001-05-11 2004-02-17 Vanderbilt University Substituted dicinnamoylquinides and their use in augmentation of adenonsine function
WO2007002112A3 (fr) * 2005-06-20 2007-02-15 Procter & Gamble Methodes destinees a isoler des composes amers utilisables dans des produits alimentaires ou a boire
JP2008543336A (ja) * 2005-06-20 2008-12-04 ザ プロクター アンド ギャンブル カンパニー 食料及び飲料製品に使用するための苦味化合物の単離方法
CN108003027A (zh) * 2017-12-25 2018-05-08 北京微医智慧信息技术有限责任公司 1-o-咖啡酰奎宁酸、其衍生物、制备方法及其用途
WO2019128113A1 (fr) * 2017-12-25 2019-07-04 北京微医智慧信息技术有限责任公司 Acide 1-o-caféoylquinique, dérivé de celui-ci, procédé de préparation associé et utilisation correspondante
CN108003027B (zh) * 2017-12-25 2021-07-06 北京微医智慧信息技术有限责任公司 1-o-咖啡酰奎宁酸、其衍生物、制备方法及其用途

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