EP2365956A2 - Curcumine comportant des groupes fonctionnels naturels conservés, à action prolongée - Google Patents

Curcumine comportant des groupes fonctionnels naturels conservés, à action prolongée

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Publication number
EP2365956A2
EP2365956A2 EP08878223A EP08878223A EP2365956A2 EP 2365956 A2 EP2365956 A2 EP 2365956A2 EP 08878223 A EP08878223 A EP 08878223A EP 08878223 A EP08878223 A EP 08878223A EP 2365956 A2 EP2365956 A2 EP 2365956A2
Authority
EP
European Patent Office
Prior art keywords
curcumin
natural
novel
conserved
derivatives
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP08878223A
Other languages
German (de)
English (en)
Other versions
EP2365956A4 (fr
Inventor
El-Sayed Ameen Mahmoud Rezq
Mohammad Talaat Abdel-Aziz Mansour
Taha Abdullah Kumosani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP2365956A2 publication Critical patent/EP2365956A2/fr
Publication of EP2365956A4 publication Critical patent/EP2365956A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/02—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides
    • C07C245/06—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings
    • C07C245/08—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings with the two nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings, e.g. azobenzene

Definitions

  • This invention relates to the synthesis of a novel curcumin-protein conjugate with conserved natural functional groups necessary for curcumin biochemical, physiological and pharmacological functionality. It also relates to the novel intermediate essential for the synthesis of the abovementioned curcumin-protein conjugate.
  • novel derivatives relate to conveying lacking essential properties on natural curcumin such as; free water solubility, easy digestibility, free intestinal absorption, long serum half-life and improved original biochemical, physiological and pharmacological potencies of natural curcumin towards certain pre-studied effects in humans and experimental animal models.
  • Curcumin, l,7-Bis(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione is a component of turmeric, a yellow spice from the rhizome of the herb Curcuma longa L. (Zingiberaceae), that is widely used as a food flavoring and coloring agent.
  • Curcumin has a long history of medicinal use for a wide variety of medical conditions. It is insoluble in water but soluble in ethanol, alkalis, glacial acetic acid and chloroform.
  • additives as Piperine, (from black pepper), Quercetin (from various plants), Genistein (from soy) were used with the aim to inhibit the natural pumps that expel curcumin out of the intestinal and/or other cells.
  • Microemulsions e.g. natural oils such as peppermint oil, different surfactants such as lecithin, monoolein, Tween-20 were used with the aim to facilitate intestinal curcumin absorption in larger amounts.
  • Chemical derivatives e.g., tetrahydro curcumin, demethoxy curcumin, tetrahydrodemethoxy curcumin, bisdemethoxy curcumin, tetrahydro bisdemethoxy curcumin, hexahydrocurcumin, acetate, phosphate, gluconate, ..., etc. were used with the aim to avoid the abovementioned action of the intestinal enzymes/pumps and liver enzymes. But all such chemical derivatives were made through the use of the curcumin natural functional groups required for full biological activity, (biochemical, physiological and pharmacological potencies).
  • curcumin Long acting, conserved natural functional group curcumin, of free water solubility, easy digestibility, free intestinal absorption, long serum half-life should help getting the utmost possible beneficial effects of this historical, albeit promising treatment of several acute and chronic illnesses.
  • Nitrous acid was generated by the addition of a solution of 0.85 niEq of sodium nitrite to an excess of HCl. The reaction was maintained at a temperature of 5°C. A solution of 0.85 niEq of 4-aniinobenzoic acid in IN HCl chilled to 5 0 C was prepared with continuous stirring in ice bath for 20 minutes, the pH of 1.0 was never exceeded. Diazotized 4-minobenzoic acid was added dropwise to an equivalent concentration, (0.85 mEq) of curcumin, (I) dissolved in ethanol at pH 11.0 with continuous stirring at 5 0 C.
  • the curcumin-bovine serum albumin conjugate (III), of this invention was synthesized in a medium of 1% NaCl/dioxane/NaOH solution of pH 8-10, at 5 0 C, by adding 0.1M solution of l-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluene sulfonate to purified crystalline l,7-bis(5-carboxyphenylazo-4-hydroxy-3- methoxyphenyl)-l,6-heptadiene-3,5-dione, (II) in the same medium with continuous stirring.
  • Bovine serum albumin was added to the foregoing mixture at 5 0 C, pH 8-10 with continuous stirring for 1 hr until the intermediate azopseudourea has conjugated to bovine serum albumin, after which the mixture was centrifuged off, acidified to pH 4.2, salted out, recentrifuged, redissolved then dialyzed for 24 hr at 5 0 C against 0.5M sodium carbonate, pH 8.2 until any color no longer appears in dialysis solution. A final dialysis is performed against bi-distilled water for 24 hours at 5°C, after which the protein conjugate (III) was lyophilized.
  • novel curcumin derivatives (II) and (III) were characterized by IR Spectroscopy, GC/MS, NMR, EM, TLC, Gel Filtration, Continuous Flow Electrophoresis and Isoelectric Focusing whenever applicable.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

La présente invention concerne la curcumine, un constituant du curcuma, une épice jaune extraite du rhizome de l’herbe Curcuma longa L. (Zingiberaceae), qui est largement utilisée comme aromatisant et colorant alimentaires. La curcumine possède de longs antécédents d’utilisation médicale pour une grande variété de pathologies. Elle est insoluble dans l’eau mais soluble dans l’éthanol, les alcali, l’acide acétique glacial et le chloroforme. Une administration par voie orale est bien tolérée, mais la biodisponibilité est très faible. Moins de 1 % de la curcumine atteint la circulation sanguine, le foie la détruisant rapidement presque totalement. Généralement, trois approches différentes étaient utilisées pour améliorer la biodisponibilité de la curcumine, à savoir : des additifs, des microémulsions et des dérivés chimiques, mais il s’est avéré qu’aucune de ces approches ne surmontait le problème. Les additifs et les microémulsions présentent le risque d’autres interactions médicamenteuses et tous les dérivés chimiques étaient préparés en utilisant les groupes fonctionnels naturels de la curcumine, nécessaires à une activité biologique complète (puissances biochimique, physiologique et pharmacologique). La curcumine comportant des groupes fonctionnels naturels conservés, dont l’action est prolongée, l’hydrosolubilité libre, la digestibilité aisée, l’absorption intestinale libre, la demi-vie sérique longue, devrait permettre d’obtenir les meilleurs effets bénéfiques possibles de ce traitement historique, bien que prometteur, de plusieurs maladies aiguës et chroniques. La curcumine naturelle pure, insoluble dans l'eau, a été convertie en nouveaux dérivés comportant des groupes fonctionnels naturels conservés, hydrosolubles, ne présentant aucune modification des groupes chimiques moléculaires naturels fonctionnels originaux et actifs nécessaires à des puissances biochimique, physiologique et pharmacologique complètes, décrits auparavant pour la curcumine naturelle. Les nouveaux dérivés de curcumine ont été caractérisés par spectroscopie IR, GC/MS, RMN, EM, TLC, filtration sur gel, électrophorèse en flux continu et électrofocalisation, le cas échéant. Des études animalières en laboratoire sur les nouveaux dérivés de curcumine ont démontré qu’ils conservaient toute la fonctionnalité naturelle de la curcumine, en plus de la nouvelle hydrosolubilité libre, de la digestibilité aisée, de l’absorption intestinale libre, de la longue demi-vie sérique, outre les puissances biochimique, physiologique et pharmacologique originales améliorées de la curcumine naturelle vis-à-vis de certains effets préalablement étudiés avec des modèles humains et animaliers expérimentaux, par exemple, le dysfonctionnement érectile, le diabète sucré.
EP08878223A 2008-11-20 2008-11-20 Curcumine comportant des groupes fonctionnels naturels conservés, à action prolongée Withdrawn EP2365956A4 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EG2008/000044 WO2010057503A2 (fr) 2008-11-20 2008-11-20 Curcumine comportant des groupes fonctionnels naturels conservés, à action prolongée

Publications (2)

Publication Number Publication Date
EP2365956A2 true EP2365956A2 (fr) 2011-09-21
EP2365956A4 EP2365956A4 (fr) 2012-07-25

Family

ID=42198568

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08878223A Withdrawn EP2365956A4 (fr) 2008-11-20 2008-11-20 Curcumine comportant des groupes fonctionnels naturels conservés, à action prolongée

Country Status (2)

Country Link
EP (1) EP2365956A4 (fr)
WO (1) WO2010057503A2 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140271923A1 (en) 2013-03-14 2014-09-18 Christopher Brian Reid Compositions & formulations for preventing and treating chronic diseases that cluster in patients such as cardiovascular disease, diabetes, obesity, polycystic ovary syndrome, hyperlipidemia and hypertension, as well as for preventing and treating other diseases and conditions
WO2014192024A1 (fr) * 2013-05-20 2014-12-04 Sree Chitra Tirunal Institute For Medical Sciences And Technology Développement de curcumine albuminée soluble pour application en thérapie anticancéreuse
US20160045454A1 (en) * 2014-08-12 2016-02-18 Tianxin Wang Therapeutical methods, formulations and nutraceutical formulations
WO2018102233A1 (fr) * 2016-11-30 2018-06-07 Wang tian xin Méthodes thérapeutiques, formulations et formulations nutraceutiques
US10639341B2 (en) 2017-04-24 2020-05-05 Muniyal Ayurvedic Research Centre Herbo-mineral formulation for prevention, treatment and management of diabetes and method of preparation thereof
CN112245414A (zh) * 2020-10-15 2021-01-22 四川大学华西医院 姜黄素或其载药体系在制备治疗阴茎勃起功能障碍的药物中的用途

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
A. BARIK ET AL: "Photophysical Studies on Binding of Curcumin to Bovine Serum Albumin", PHOTOCHEMISTRY AND PHOTOBIOLOGY, vol. 77, no. 6, 1 June 2003 (2003-06-01), pages 597-603, XP55029537, ISSN: 0031-8655, DOI: 10.1562/0031-8655(2003)0770597PSOBOC2.0.CO 2 *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 9 April 2008 (2008-04-09), MITRA, SANKAR P.: "Binding and stability of curcumin in presence of Bovine Serum Albumin", XP002677523, retrieved from STN Database accession no. 2008:437388 *
KUMAR VIRENDER ET AL: "Biodegradable microspheres of curcumin for treatment of inflammation", INDIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, ASSOCIATION OF PHYSIOLOGISTS AND PHARMACOLOGISTS OF INDIA, IN, vol. 46, no. 2, 1 April 2002 (2002-04-01), pages 209-217, XP009117434, ISSN: 0019-5499 *
See also references of WO2010057503A2 *

Also Published As

Publication number Publication date
EP2365956A4 (fr) 2012-07-25
WO2010057503A2 (fr) 2010-05-27
WO2010057503A3 (fr) 2010-07-15

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