WO2011104667A1 - Sels d'acides aminés basiques de polyphénols - Google Patents

Sels d'acides aminés basiques de polyphénols Download PDF

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Publication number
WO2011104667A1
WO2011104667A1 PCT/IB2011/050737 IB2011050737W WO2011104667A1 WO 2011104667 A1 WO2011104667 A1 WO 2011104667A1 IB 2011050737 W IB2011050737 W IB 2011050737W WO 2011104667 A1 WO2011104667 A1 WO 2011104667A1
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Prior art keywords
polyphenol
compound
formula
group
solution
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Ceased
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PCT/IB2011/050737
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English (en)
Inventor
Gavara Govinda Rajulu
Shivarudraiah Prasad
Sambasivam Ganesh
Nair Ayyappan
Koramangala Chandrappa Ravindra
Bhardwaj Ajay
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Anthem Biosciences Pvt Ltd
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Anthem Biosciences Pvt Ltd
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones

Definitions

  • the present disclosure relates to the basic amino acid salts of polyphenols that are having the general formula (I) with improved stability, solubility and pharmacological properties over parent polyphenols. More particularly, the present disclosure relates to L-Arginine salts of resveratrol and the methods of preparations thereof. The present disclosure also describes improved oral bioavailability of polyphenol derivatives.
  • the present disclosure also provides a process for the preparation of the above said compounds of the general formula (I).
  • Polyphenols such as resveratrol exhibits a wide variety of biological activities and are widely used as anti aging agent and also it is widely exploited as an antioxidant.
  • compositions containing unprotected polyphenols are not likely to deliver their complete biological potential and the provision of protective packaging or special handling necessary to preserve their activity is too costly to be commercially feasible on a large scale.
  • WO 2005/000780 Al describes about to compounds of general formula (I) having a trans configuration: wherein: R is selected from COOH and a group of formula (II):
  • Ri is H, OH or R 2 , and R 2 is independently selected from OH, linear or branched 0- (Cl- C6) alkyl optionally substituted with a group selected from OH or O- (C1-C6) alkyl; R 3 is independently selected from H and linear or branched (C1-C6) alkyl optionally substituted with a group selected from OH or O- (C1-C6) alkyl.
  • A is a substituted or unsubstituted, saturated or unsaturated alkyl radical having from 1 to 20 carbon atoms, which is bonded to the polyphenol by: a carboxylic ester function on a hydroxyl function of the said polyphenol; or by means of an A' spacer, in which A is bonded to A' via a carboxylic ester function, and A' is bonded to the polyphenol via a carboxylic ester function on a hydroxyl function of the said polyphenol;
  • n is an integer greater than or equal to 1 ;
  • B is a precursor of a biologically active molecule which is bonded to the polyphenol by: a carboxylic ester function on a hydroxyl function of the said polyphenol; or by means of a B' spacer, in which B is bonded to B' via a carboxylic ester function, and B' is bonded to the polyphenol via a carboxylic ester function on a hydroxyl function of the said polyphenol;
  • n is an integer greater than or equal to 1.
  • the present disclosure provides a information about polyphenolic derivatives which are more water soluble and enhanced in their activity.
  • PP polyphenol and R is selected from a group comprising;
  • PP polyphenol and R is selected from a group comprising
  • composition comprising acts of a) adding amino acid solution to a solution of polyphenol to obtain a mixture, b) heating the mixture to obtain the compound of formula (I) and c) optionally adding with pharmaceutically acceptable excipients; a composition comprising a compound of formula (I) along pharmaceutically acceptable excipients(s) to the compound of formula (I) to obtain a composition.
  • PP polyphenol and R is selected from a group comprising
  • Figure 1 shows comparison of pharmacokinetics parameters of Resveratrol and Resveratrol-L-Arginine salt.
  • Figure 2 provides a graph of Resveratrol standard calibration curve at ⁇ ⁇ 306nm.
  • Figure 3 provides a graph Resveratrol-L-arginine salt standard calibration curve at ⁇ max 306nm.
  • PP is polyphenol
  • R is selected from a group comprising
  • the polyphenol is Resveratrol and the R is
  • PP is polyphenol
  • R is selected from a group comprising
  • the amino acid is a basic amino acid, selected from a group comprising Arginine, Lysine and Histidine.
  • the amino acid solution is a solution in a solvent selected from a group comprising water, methanol, ethanol, propanol and butanol or combination thereof.
  • the polyphenol solution is a solution in ethanol.
  • the addition of amino acid solution is carried out at a temperature ranging from about 20°C to about 30°C, preferably at about 25°C .
  • the heating is carried out at a temperature ranging from about 60°C to about 80°C preferably at about 70°C.
  • the present disclosure is also in relation to a composition comprising a compound of formula (I) along with pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are selected but not limiting to a group comprising binders, disintegrants, diluents, lubricants, plasticizers, permeation enhancers and solubilizers.
  • the composition is in a form selected but not limiting to a group comprising tablet, capsule, powder, syrup, solution, aerosol and suspension.
  • the present disclosure is also in relation to a method for increasing the bioavailability of a polyphenol said method comprising an act of contacting an animal in need thereof with a compound of formula (I) or a pharmaceutical compositioncomprising compound of formula (I).
  • the polyphenol is Resveratrol and the R are;
  • PP represents polyphenols and polyphenols like Resveratrol, Quercetin, Luteolin, Curcumin as given below and each of them may be optionally substituted.
  • R is selected from basic amino acid side chain such as:
  • the poly phenols and amino acid may be optionally substituted with various substitutions possible for a person skilled in the art.
  • the compound of formula (I) is particularly arginine salt of Resveratrol.
  • the compounds are useful for methods for improving antioxidant properties by increasing the oral bioavailability of resveratrol andsolubility.
  • the disclosure also provides a method of delayed release of resveratrol as derivatives which can improve half life and bio availability of resveratrol.
  • Another embodiment of the present disclosure provides a method for rendering water- soluble an insoluble resveratrol which comprises salts of the insoluble polyphenol to an extent sufficient to render the polyphenol water-soluble.
  • the present disclosure is also in relation to a pharmaceutical composition, comprising a compound of formula (I) along with pharmaceutically acceptable excipient selected but not limiting to a group comprising of binders, disintegrants, diluents, lubricants, plasticizers, permeation enhancers and solubilizers.
  • the composition is in the form selected but not limiting to a group comprising of tablet, capsule, powder, syrup, solution, aerosol and suspension.
  • Optionally substituted means that substitution is optional and therefore it is possible for the designated atom or molecule to be unsubstituted. In the event a substitution is desired, then such substitution means that any number of hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the normal valency of the designated atom is not exceeded, and that the substitution results in a stable compound.
  • Pharmaceutically acceptable salts include base addition salts such as alkali metal salts like Li, Na, and K salts; alkaline earth metal salts like Ca and Mg, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, O-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine.
  • Salts may include acid addition salts where appropriate, which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates.
  • Pharmaceutically acceptable solvates may be hydrates or comprising of other solvents of crystallization such as alcohols.
  • the term analog includes a compound, which differs from the parent structure by one or more C, N, O or S atoms.
  • stereoisomer includes isomers that differ from one another in the way the atoms are arranged in space, but whose chemical formulas and structures are otherwise identical.
  • Stereoisomers include enantiomers and diastereoisomers.
  • tautomers include readily interconvertible isomeric forms of a compound in equilibrium.
  • polymorphs include crystallographically distinct forms of compounds with chemically identical structures.
  • pharmaceutically acceptable solvates includes combinations of solvent molecules with molecules or ions of the solute compound.
  • derivative refers to a compound obtained from a compound according to formula (I), an analog, tautomeric form, stereoisomer, polymorph, hydrate, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, by a simple chemical process converting one or more functional groups, such as, by oxidation, hydrogenation, alkylation, esterification, halogenation.
  • pharmacological properties includes but not limited to antioxidant properties, Type II diabetes or hyperglycemia, cancers including skin, breast, cervix, colon, lung, liver, lymphoma, prostate, heart diseases, optic neuritis and retinal degeneration, neurodegeneration, stroke and cardiac arrest, osteoporosis, kidney dysfunction and albuminuria, cataracts, inflammatory bowel diseases (e.g. colitis), COPD (emphysema).
  • Type II diabetes or hyperglycemia cancers including skin, breast, cervix, colon, lung, liver, lymphoma, prostate, heart diseases, optic neuritis and retinal degeneration, neurodegeneration, stroke and cardiac arrest, osteoporosis, kidney dysfunction and albuminuria, cataracts, inflammatory bowel diseases (e.g. colitis), COPD (emphysema).
  • the compounds of this disclosure may be prepared by the following process.
  • Resveratrol-L-Arginine salt showed about 6 times higher Cmax and about 5 times higher AUC as compared to parent Resveratrol
  • Resveratrol salt showed about 6 times increase in the maximum plasma concentrations (Cmax) and about 5 times increase in the AUC.
  • the figure 1 provides the comparative analysis of Resveratrol and Resveratrol-L-arginine salt.
  • Intrinsic solubility of Resveratrol and Resveratrol-L-arginine salt The test compound was allowed to saturate in an aqueous medium (Milli-Q water) and were equilibrated for about 8 hrs at 25° C. The equilibrated solution was centrifuged at 5,000 rpm for 15 min at 25° C and the supernatant was analyzed by UV spectrometer. A standard linearity curve was obtained at ⁇ max using UV spectrometer. The information is tabulated in table 2.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention porte sur des sels d'acides aminés basiques de composés polyphénoliques de formule (I) et sur des compositions de ceux-ci présentant des propriétés physicochimiques et pharmacologiques améliorées. L'invention porte également sur un procédé pour leur préparation. Formule (I).
PCT/IB2011/050737 2010-02-25 2011-02-23 Sels d'acides aminés basiques de polyphénols Ceased WO2011104667A1 (fr)

Applications Claiming Priority (2)

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IN498CH2010 2010-02-25
IN498/CHE/2010 2010-02-25

Publications (1)

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WO2011104667A1 true WO2011104667A1 (fr) 2011-09-01

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITPG20120030A1 (it) * 2012-06-27 2013-12-29 Bernard Fioretti Resveratrolo inorganico ibrido
CN105078944A (zh) * 2014-05-11 2015-11-25 复旦大学 Isopaucifloral F在制备抗骨质疏松药物中的用途
US9782375B2 (en) * 2015-10-28 2017-10-10 Shil Kothari Methods and compositions for improving microvascular function, suppressing cyclooxygenase activity, reducing platelet aggregation and increasing levels of resveratrol in plasma
US9844526B2 (en) * 2015-10-28 2017-12-19 Gateway Health Alliances, Inc. Methods and compositions for improving microvascular function, suppressing cyclooxygenase activity, reducing platelet aggregation and increasing levels of resveratrol in plasma
CN112218641A (zh) * 2018-04-23 2021-01-12 阿尔卑斯药品工业株式会社 O-糖苷基类黄酮的组成物
US10918654B1 (en) 2019-09-23 2021-02-16 Alps Pharmaceutical Ind. Co., Ltd. Rutin compositions
WO2021042001A1 (fr) * 2019-08-30 2021-03-04 Natural Extraction Systems, LLC Compositions et procédés associés à des oxydes dissous
WO2021158574A1 (fr) * 2020-02-03 2021-08-12 Natural Extraction Systems, LLC Compositions et procédés associés à des excipients pharmaceutiques
US11110109B2 (en) 2019-10-22 2021-09-07 Alps Pharmaceutical Ind. Co., Ltd. Water soluble O-glycosyl flavonoid compositions and methods for preparing same
US11241396B2 (en) * 2015-10-28 2022-02-08 Gateway Health Alliances, Inc. Methods and compositions for improving microvascular function, suppressing cyclooxygenase activity, reducing platelet aggregation and increasing levels of resveratrol in plasma
IT202100014966A1 (it) 2021-06-08 2022-12-08 S&R Farm S P A Uso di una miscela in combinazione stechiometrica di resveratrolo e acidi biliari per il trattamento topico dell’infiammazione neurogenica e del prurito
US12349706B2 (en) 2020-07-31 2025-07-08 Natural Extraction Systems, LLC Compositions and methods related to excipients and cannabinoid formulations

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2679243A1 (fr) 2012-06-27 2014-01-01 Bernard Fioretti Co-précipité de un ou plusieurs polyphénols de stilbène et leurs dérivés dans des solides anioniques lamellaires, ses applications et procédé de préparation correspondant
ITPG20120030A1 (it) * 2012-06-27 2013-12-29 Bernard Fioretti Resveratrolo inorganico ibrido
CN105078944A (zh) * 2014-05-11 2015-11-25 复旦大学 Isopaucifloral F在制备抗骨质疏松药物中的用途
US11241396B2 (en) * 2015-10-28 2022-02-08 Gateway Health Alliances, Inc. Methods and compositions for improving microvascular function, suppressing cyclooxygenase activity, reducing platelet aggregation and increasing levels of resveratrol in plasma
US9782375B2 (en) * 2015-10-28 2017-10-10 Shil Kothari Methods and compositions for improving microvascular function, suppressing cyclooxygenase activity, reducing platelet aggregation and increasing levels of resveratrol in plasma
US9844526B2 (en) * 2015-10-28 2017-12-19 Gateway Health Alliances, Inc. Methods and compositions for improving microvascular function, suppressing cyclooxygenase activity, reducing platelet aggregation and increasing levels of resveratrol in plasma
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