EP1805133A1 - Preparation of phenol-amide compounds with antioxidant properties - Google Patents

Preparation of phenol-amide compounds with antioxidant properties

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Publication number
EP1805133A1
EP1805133A1 EP05802436A EP05802436A EP1805133A1 EP 1805133 A1 EP1805133 A1 EP 1805133A1 EP 05802436 A EP05802436 A EP 05802436A EP 05802436 A EP05802436 A EP 05802436A EP 1805133 A1 EP1805133 A1 EP 1805133A1
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Prior art keywords
phenol
amino
preparation
formula
amide compounds
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EP05802436A
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German (de)
French (fr)
Inventor
Guy Adrian
Patrick Bigot
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CATALYS SARL
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CATALYS SARL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A61K2800/522—Antioxidants; Radical scavengers

Definitions

  • the present invention relates to the preparation of phenol-amide compounds with antioxidant properties derived from aromatic or heteroaromatic acids containing at least one hydroxy group and 2-amino-1-alkanols corresponding to formulas (I) and (E-)
  • R 1, R 2, R 3, R 4 - - OH, H or alkyl (C n H 2n + 1), n being understood to be between 1 and 4, R alkyl (-C n H 2n + ) or hydroxyalkyl (- C n H 2 n + 1 0 ), n being; c coommprize e enntrree 22 e etl 30.
  • R 5 alkyl (-C n H 2n + 1), n being between 1 and 4
  • R 8 , R 7 , R 8 -OH, H or alkyl (-C n H 2n + 1), n being between 1 and 4, R ⁇ alkyl or hydroxy alkyl of the same structure as in formula (I).
  • the compounds (I) and (D) amides derived from amino-2-alkanols-1 have antiradical antioxidant properties and can be used in the prevention of degenerative diseases and human aging: appearance of the skin (wrinkles), cardio- vascular diseases, neurodegenerative diseases and cancers, by efficiently capturing free radicals that degrade the cells and tissues concerned.
  • antioxidants for example ⁇ -tocopherol (vitamin E) plays a pivotal role in inhibiting the degradation of DNA, proteins and lipids by reacting with free radicals before they attack substrates and interrupting the propagation of radical oxidation chains (Halliwell B. and Gutteridge J. - Free radicals in Biology and Medicine - 1998).
  • antioxidant compounds Of the naturally occurring antioxidant compounds, many polyphenol derivatives are used, particularly gallic acid derivatives (IQ) - 3,4,5-trihydroxybenzoic acid and its methyl ester (IIIa).
  • IQ gallic acid derivatives
  • IIIa 3,4,5-trihydroxybenzoic acid and its methyl ester
  • antioxidants in particular QJX), (JEa) and (IVa), are active compounds in polar solvent media such as water or alcohol but not very effective in lipid media (Halliwell and Gutteridge).
  • the object of the invention is to obtain stable and non-toxic antioxidant structures that are miscible in lipidic media, in particular in view of a protective action on the dermis by penetration of the cutaneous barrier at the level of the stratum corneum. .
  • the 2-amino-1-alkanols (V) where R represents a linear or branched alkyl chain or hydroxyalkyl having 2 to 30 carbon atoms are prepared by methods known to those skilled in the art: for example by reduction of ⁇ -amino acids racemic compounds obtained by substitution with ammonia of the corresponding ⁇ -halo commercial acids.
  • the acylation reaction of the amino function of amino-2-alkanol-1 (V) provides advantageous access to compounds of type (J) and (JT) having an effective penetration of cutaneous tissues and low toxicity.
  • Formation of the amides from the 2-amino-1-alkanols (V) is carried out by activation of the carboxyl functions of the acids (1H) or (IV) to obtain an amide function, for example by formation of addition compounds on dicyclohexylcarbodiimide in the presence of hydroxy benzotriazole according to Chemische Berichte 1970, vol 103, p. 788-798.
  • the presence of free hydroxy groups in (III) or (IV) acids results in impure products (I) and (D) containing O-acylated phenol derivatives, which requires purification by pressure chromatography.
  • the compounds (I) and (H) are obtained after selective hydrolysis of the acetoxy groups by a basic agent and in particular cold sodium hydroxide.
  • the compounds (I) and (H) are isolated according to the appropriate techniques and purified by crystallization or by silica column chromatography.
  • the antioxidant potential in solution of the amide-phenol compounds (I) and (H) is evaluated by measuring their reaction with the free radical diphenyl-picrylhydrazide (VHI) according to CT 1 Ho, J. Agric. Food Chem., 1999, p. 3975, taking as controls TROLOX (TVa) and methyl gallate (DIa), the compounds (I) and (II) have a similar activity to that of the reference products.
  • VHI free radical diphenyl-picrylhydrazide
  • the applicant has developed a process for preparing phenol-amide compounds with antioxidant properties; these compounds can be formed into tablets, capsules, or mixed in cosmetic preparations according to the usual techniques.
  • the reaction medium is filtered. 3 g of dicyclohexylurea are collected. The filter is concentrated under vacuum, redissolved in 100 ml of methyl tert-butyl ether and washed with 4 times 30 ml of 1N hydrochloric acid and then 30 ml of a 10% aqueous solution of sodium bicarbonate and then 2 times 30 ml of water. and concentrated under vacuum to provide 3.8 g of a pasty solid containing, by 1 H NMR, approximately 70% of the expected amide which could not be purified by crystallization in the usual solvents.
  • the medium is refluxed for 2 hours and then concentrated under reduced pressure.
  • the mixture is heated at 50 ° C. for 18 hours under stirring and then cooled to 20 ° C. and washed with 100 ml of water.
  • the organic phase is treated with 40 ml of ethanol, 30 ml of water and 5.6 g of a 50% aqueous solution of sodium hydroxide.
  • the stirred mixture is heated for 1 hour at 60 ° C. and then cooled to 20 ° C., concentrated in vacuo to remove the ethanol and taken up in 100 ml of methyl tert-butyl ether.
  • the mixture is heated for 3 hours at 60 ° C. and then concentrated under vacuum.
  • the medium is brought to 60 ° C. for 1 hour, then cooled to 20 ° C., diluted with 20 ml of methyl tert-butyl ether, and washed with 3 times 10 ml of hydrochloric acid N 3 10 ml of water and twice with 10 ml of water. ml of 10% sodium bicarbonate solution.
  • the claimed free radical inhibitory effect for compounds (Ia) and (Ea) was evaluated by measuring their absorbances in 517 nanometer UV spectrophotometry in the presence an excess of diphenylpicrylhydrazide radical (VIII). Ethanolic solutions containing 20 micromoles per liter of test compound and 100 micromoles per liter of radical (VIII) were stirred for 30 minutes at 20 ° C. and placed in a vessel 1 cm long.
  • the new compounds (Ia) and (IIa) have an inhibitory activity lower than TROLOX but comparable to that of methyl gallate.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
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  • Epidemiology (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Toxicology (AREA)
  • Engineering & Computer Science (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to the preparation of compounds comprising at least one phenol function and one amide function derived from amino-2 alkanol-1 having formula (I) and (II), which have antioxidant and antiradical properties and which are soluble in lipid media. The inventive compounds can be used as cosmetic or pharmaceutical preparations for the prevention of biological degradation caused by free radicals.

Description

i i
PREPARATION DE COMPOSES PHENOL-AMIDES A PROPRIETES ANTIOXYDANTESPREPARATION OF PHENOL-AMIDE COMPOUNDS WITH ANTIOXIDANT PROPERTIES
La présente invention concerne la préparation de composés phénol-amides à propriétés antioxydantes dérivés d'acides aromatiques ou hétéroaromatiques comportant au moins un groupe hydroxy et d'amino-2 alcanols-1 correspondant aux formules (I) et (E-)The present invention relates to the preparation of phenol-amide compounds with antioxidant properties derived from aromatic or heteroaromatic acids containing at least one hydroxy group and 2-amino-1-alkanols corresponding to formulas (I) and (E-)
où Ri, R2, R3, R4 - — OH, H ou alkyl (CnH2n+i), n étant com tnppiris entre 1 et 4, R = alkyl (-CnH2n+!) ou hydroxy-alkyl (-CnH2n+iO), n étant ; c coommpprriiss e ennttrree 22 e etl 30. where R 1, R 2, R 3, R 4 - - OH, H or alkyl (C n H 2n + 1), n being understood to be between 1 and 4, R = alkyl (-C n H 2n + ) or hydroxyalkyl (- C n H 2 n + 1 0 ), n being; c coommprize e enntrree 22 e etl 30.
où R5 = alkyl (-CnH2n+i), n étant compris entre 1 et 4 où Rδ, R7, R8 = — OH, H ou alkyl (-CnH2n+i), n étant compris entre 1 et 4, R ≈ alkyl ou hydroxy alkyl de même structure que dans la formule (I). where R 5 = alkyl (-C n H 2n + 1), n being between 1 and 4 where R 8 , R 7 , R 8 = -OH, H or alkyl (-C n H 2n + 1), n being between 1 and 4, R ≈ alkyl or hydroxy alkyl of the same structure as in formula (I).
Les composés (I) et (D) amides dérivés d'amino-2 alcanols-1 présentent des propriétés antioxydantes antiradicalaires et peuvent être utilisés dans la prévention des maladies dégénératrices et du vieillissement humain : aspect de la peau (rides), maladies cardio- vasculaires, maladies neurodégénératrices et cancers, en captant efficacement les radicaux libres qui dégradent les cellules et les tissus concernés.The compounds (I) and (D) amides derived from amino-2-alkanols-1 have antiradical antioxidant properties and can be used in the prevention of degenerative diseases and human aging: appearance of the skin (wrinkles), cardio- vascular diseases, neurodegenerative diseases and cancers, by efficiently capturing free radicals that degrade the cells and tissues concerned.
En effet, les antioxydants, par exemple Pα-tocophérol (vitamine E) joue un rôle pivot dans l'inhibition des dégradations de l' ADN, des protéines et des lipides en réagissant avec les radicaux libres avant qu'ils n'attaquent les substrats et en interrompant la propagation des chaines radicalaires d'oxydation (B. Halliwell et J. Gutteridge - Free radicals in Biology and Medicine - 1998).Indeed, antioxidants, for example α-tocopherol (vitamin E) plays a pivotal role in inhibiting the degradation of DNA, proteins and lipids by reacting with free radicals before they attack substrates and interrupting the propagation of radical oxidation chains (Halliwell B. and Gutteridge J. - Free radicals in Biology and Medicine - 1998).
Parmi les composés antioxydants naturels, de nombreux dérivés de polyphénols sont utilisés, particulièrement les dérivés de l'acide gallique (IQ) - acide trihydroxy-3,4,5 benzoïque et son ester méthylique (ÏÏIa).Of the naturally occurring antioxidant compounds, many polyphenol derivatives are used, particularly gallic acid derivatives (IQ) - 3,4,5-trihydroxybenzoic acid and its methyl ester (IIIa).
fÊϋ'Iϋ! m REMPLACEMENT (tÈGii 2ù) Egalement utilisés sont les dérivés de l'hydroxy-6 dihydrochromane (JV) où R5J Re, R7, Rg sont des draines alkyles et particulièrement CH3, et X un groupe oxygéné par exemple acyle.f'ϋ ' Iϋ! m REPLACEMENT (wiII 2ù) Also used are the derivatives of 6-hydroxy dihydrochromane (JV) where R 5J Re, R 7 , R 8 are alkyl strains and particularly CH 3 , and X an oxygen group, for example acyl.
Un exemple bien connu de cette famille de composés est le TROLOX (TVa). (J. W. Scott, J. Am. OiI Chemist's Assoc. 1974, 51, p. 200).A well-known example of this family of compounds is TROLOX (TVa). (J. W. Scott, J. Am., Chemist's Assoc., 1974, 51, 200).
m (TV) (TVa) m (TV) (TVa)
Les antioxydants précités, notamment QJX), (JEa) et (IVa), sont des composés actifs dans les milieux solvants polaires tels que eau ou alcool mais peu efficaces dans les milieux lipidiques (Halliwell et Gutteridge).The aforementioned antioxidants, in particular QJX), (JEa) and (IVa), are active compounds in polar solvent media such as water or alcohol but not very effective in lipid media (Halliwell and Gutteridge).
Le but de l'invention est d'obtenir des structures antioxydantes stables et non-toxiques miscibles dans les milieux lipidiques, en particulier dans l'optique d'une action protectrice au niveau du derme par pénétration de la barrière cutanée au niveau du stratum corneum.The object of the invention is to obtain stable and non-toxic antioxidant structures that are miscible in lipidic media, in particular in view of a protective action on the dermis by penetration of the cutaneous barrier at the level of the stratum corneum. .
Les amino-2 alcanols-1 (V) où R représente une chaîne alkyle linéaire ou branchée ou hydroxyalkyle comportant 2 à 30 atomes de carbone sont préparés par des méthodes connues de l'homme du métier : par exemple par réduction des α-amino acides racémiques obtenus par substitution avec l'ammoniac des α-halogéno acides commerciaux correspondants.The 2-amino-1-alkanols (V) where R represents a linear or branched alkyl chain or hydroxyalkyl having 2 to 30 carbon atoms are prepared by methods known to those skilled in the art: for example by reduction of α-amino acids racemic compounds obtained by substitution with ammonia of the corresponding α-halo commercial acids.
R-CH-CH2OH NH, (V)R-CH-CH 2 OH NH, (V)
La réaction d'acylation de la fonction aminé des amino-2 alcanol-1 (V) permet d'accéder avantageusement aux composés de type (J) et (JT) présentant une pénétration efficace au niveau des tissus cutanés et une faible toxicité. Pour les usages précités, on préfère Pamino-2 dodécanol-1, R = decyl (n-Ci0H2i) conduisant aux aminés (Ia) et (lia).The acylation reaction of the amino function of amino-2-alkanol-1 (V) provides advantageous access to compounds of type (J) and (JT) having an effective penetration of cutaneous tissues and low toxicity. For the aforementioned uses, 2-amino-1-dodecanol is preferred, R = decyl (n-C 0 H 2 i) leading to amines (Ia) and (IIa).
La formation des amides à partir des amino-2 alcanols-1 (V) est effectuée par activation des fonctions carboxyles des acides (IH) ou (JV) pour obtenir une fonction amide, par exemple par formation de composés d'addition sur la dicyclohexylcarbodiimide en présence d'hydroxy benzotriazole selon Chemische Berichte 1970, vol 103, p. 788-798. La présence de groupes hydroxy libres dans les acides (Iïï) ou (TV) conduit à des produits (I) et (D) impurs contenant des dérivés O-acylés de phénol, ce qui nécessite une purification par chromatographie sous pression.Formation of the amides from the 2-amino-1-alkanols (V) is carried out by activation of the carboxyl functions of the acids (1H) or (IV) to obtain an amide function, for example by formation of addition compounds on dicyclohexylcarbodiimide in the presence of hydroxy benzotriazole according to Chemische Berichte 1970, vol 103, p. 788-798. The presence of free hydroxy groups in (III) or (IV) acids results in impure products (I) and (D) containing O-acylated phenol derivatives, which requires purification by pressure chromatography.
On préférera une protection des fonctions phénols par l'anhydride acétique pour obtenir des acides O-acylés (VI) et (Vu), puis passage aux chlorures d'acides correspondants par action d'un agent d'halogénation et particulièrement le chlorure de thionyle, puis condensation sélective des chlorures d'acides aromatiques O-acylés sur la fonction aminé des aminoalcanols (V).It is preferable to protect the phenol functions with acetic anhydride to obtain O-acylated acids (VI) and (Vu), then to pass through the corresponding acid chlorides by the action of a halogenating agent and particularly thionyl chloride. , then selective condensation of O-acylated aromatic acid chlorides on the amine function of the aminoalkanols (V).
(VI) (Vu)(VI) (Vu)
Les composés (I) et (H) sont obtenus après hydrolyse sélective des groupes acétoxy par un agent basique et en particulier l'hydroxyde de sodium à froid.The compounds (I) and (H) are obtained after selective hydrolysis of the acetoxy groups by a basic agent and in particular cold sodium hydroxide.
Les composés (I) et (H) sont isolés selon les techniques appropriées et purifiés par cristallisation ou par chromatographie sur colonne de silice.The compounds (I) and (H) are isolated according to the appropriate techniques and purified by crystallization or by silica column chromatography.
Le potentiel antioxydant en solution des composés amide-phénols (I) et (H) est évalué par mesure de leur réaction avec le radical libre diphenyl-picrylhydrazide (VHI) selon CT1Ho, J. Agric. Food Chem., 1999, p. 3975, en prenant comme témoins le TROLOX (TVa) et le gallate de methyle (DIa), les composés (I) et (II) possèdent une activité similaire à celle des produits de référence .The antioxidant potential in solution of the amide-phenol compounds (I) and (H) is evaluated by measuring their reaction with the free radical diphenyl-picrylhydrazide (VHI) according to CT 1 Ho, J. Agric. Food Chem., 1999, p. 3975, taking as controls TROLOX (TVa) and methyl gallate (DIa), the compounds (I) and (II) have a similar activity to that of the reference products.
CVTD)CVTD)
La demanderesse a mis au point un procédé de préparation de composés phénol-amides à propriétés antioxydantes ; ces composés peuvent être façonnés en comprimés, capsules, ou en mélange dans des préparations cosmétiques selon les techniques habituelles.The applicant has developed a process for preparing phenol-amide compounds with antioxidant properties; these compounds can be formed into tablets, capsules, or mixed in cosmetic preparations according to the usual techniques.
Bien entendu, diverses modifications peuvent être apportées par l'homme de l'art aux dispositifs ou procédés qui viennent d'être décrits uniquement à titre d'exemple non limitatif, sans sortir du cadre de l'invention. L'invention est illustrée par les exemples 1 à 3 suivants :Of course, various modifications may be made by those skilled in the art devices or methods that have just been described by way of non-limiting example, without departing from the scope of the invention. The invention is illustrated by the following Examples 1 to 3:
* Exemple 1 : Obtention de l'amide de formule (I), R = n Ci0H21 à partir d'acide gallique (HI).* Example 1: Obtaining the amide of formula (I), R = n Ci 0 H 21 from gallic acid (HI).
Une solution d'acide gallique 2,55 g (15 mmoles), d'hydroxybenzotriazole 4 g (30 mmoles) et d'amino-2 dodécanol-1 3 g (10 mmoles) dans 30 ml de tétrahydrorurane est refroidie à 0°C puis une solution de 3,1 g (15 mmoles) de dicyclohexylcarbodiimide dans 5 ml de THF est ajoutée en une fois.A solution of gallic acid 2.55 g (15 mmol), hydroxybenzotriazole 4 g (30 mmol) and 2-amino-1-dodecanol 3 g (10 mmol) in 30 ml of tetrahydrofuran is cooled to 0 ° C then a solution of 3.1 g (15 mmol) of dicyclohexylcarbodiimide in 5 ml of THF is added all at once.
Après une heure d'agitation à 0°C, puis 2 heures à 20°C, le milieu réactionnel est filtré. On recueille 3 g de dicyclohexylurée. Le filtrant est concentré sous vide, redissous dans 100 ml de méthyl tertiobutyl éther et lavé par 4 fois 30 ml d'acide chlorhydrique IN puis 30 ml d'une solution aqueuse à 10 % de bicarbonate de sodium puis 2 fois 30 ml d'eau et concentré sous vide pour fournir 3,8 g d'un solide pâteux contenant par RMN1H 70 % environ de l'amide attendu qui n'a pu être purifié par cristallisation dans les solvants courants.After stirring for 1 hour at 0 ° C. and then 2 hours at 20 ° C., the reaction medium is filtered. 3 g of dicyclohexylurea are collected. The filter is concentrated under vacuum, redissolved in 100 ml of methyl tert-butyl ether and washed with 4 times 30 ml of 1N hydrochloric acid and then 30 ml of a 10% aqueous solution of sodium bicarbonate and then 2 times 30 ml of water. and concentrated under vacuum to provide 3.8 g of a pasty solid containing, by 1 H NMR, approximately 70% of the expected amide which could not be purified by crystallization in the usual solvents.
* Exemple 2 :* Example 2:
Obtention de l'amide de formule (Ia), R = n Ci0H21 à partir de l'acide triacétoxy-3,4,5 benzoïque.Obtaining the amide of formula (Ia), R = n Ci 0 H 21 from 3,4,5-triacetoxy benzoic acid.
On prépare une solution de 5,9 g (20 mmoles) d'acide triacétoxy 3,4,5 benzoïque F = 170°C (Berichte der Deutschen Chemische Gesellschaft 1919, vol. 52, p. 829-833) dans 20 ml de dichloro-1,2 ethane à 20°C.A solution of 5.9 g (20 mmol) of 3,4,5-benzoic triacetoxy acid, mp = 170 ° C. (Berichte der Deutschen Chemische Gesellschaft 1919, vol 52, pp. 829-833) is prepared in 20 ml of 1,2-dichloroethane at 20 ° C.
On coule 1,73 g (24 mmoles) de chlorure de thionyle et 0,1 ml de triéthylamine.1.73 g (24 mmol) of thionyl chloride and 0.1 ml of triethylamine are poured.
Le milieu est chauffé à reflux 2 heures, puis concentré sous pression réduite.The medium is refluxed for 2 hours and then concentrated under reduced pressure.
Le chlorure d'acide brut est redissous dans 20 ml de dichloro-1,2 éthane et 3,8 g (19 mmoles) d'amino-2 dodecanol-1 sont ajoutés à 2O0C suivi de de 27 ml (19 mmoles) de triéthylamine.The crude acid chloride is redissolved in 20 ml of 1,2-dichloroethane and 3.8 g (19 mmol) of 2-amino-1-dodecanol are added at 20 ° C. followed by 27 ml (19 mmol). of triethylamine.
Le mélange est chauffé à 50°C pendant 18 heures sous agitation puis refroidi à 200C et lavé par 100 ml d'eau.The mixture is heated at 50 ° C. for 18 hours under stirring and then cooled to 20 ° C. and washed with 100 ml of water.
La phase organique est additionnée de 40 ml d'éthanol, 30 ml d'eau et 5,6 g d'une solution aqueuse de soude à 50 %.The organic phase is treated with 40 ml of ethanol, 30 ml of water and 5.6 g of a 50% aqueous solution of sodium hydroxide.
Le mélange agité est porté 1 heure à 600C puis refroidi à 200C, concentré sous vide pour éliminer l'éthanol et repris par 100 ml de méthyl tertiobutyl éther.The stirred mixture is heated for 1 hour at 60 ° C. and then cooled to 20 ° C., concentrated in vacuo to remove the ethanol and taken up in 100 ml of methyl tert-butyl ether.
Le milieu est acidifié à pH = 2 par une solution aqueuse d'acide chlorhydrique N, lavé à l'eau et par une solution aqueuse de bicarbonate de sodium. On obtient après concentration de la phase organique un solide pâteux qui, par agitation avec 100 ml d'eau, cristallise pour donner 5,7 g d'un solide beige qui, après recristallisation dans 50 ml d'acétate d'éthyle, fournit 2,6 g d'un solide blanc crèmeThe medium is acidified to pH = 2 with an aqueous solution of N hydrochloric acid, washed with water and with an aqueous solution of sodium bicarbonate. After concentrating the organic phase, a pasty solid is obtained which, by stirring with 100 ml of water, crystallises to give 5.7 g of a beige solid which, after recrystallization in 50 ml of ethyl acetate, gives 2 , 6 g of a creamy white solid
F = IlO0C.F = 110 ° C.
Rdt = 38,8 % à partir de l'amino-2 dodécanol-1. Le spectre RMN 1H à 250 MHz dans le diméthyl sulfoxyde met en évidence 5 protons échangeables, 2 protons aromatiques à δ = 6,8 ppm et un ensemble de protons aliphatiques entre 0,8 et 1,8 ppm compatibles avec la structure (I). Le spectre de masse montre un pic (M + 1) = 354. * Exemple 3 :Yield = 38.8% from 2-amino-1-dodecanol. The 1 H NMR spectrum at 250 MHz in dimethyl sulfoxide shows 5 exchangeable protons, 2 aromatic protons at δ = 6.8 ppm and a set of aliphatic protons between 0.8 and 1.8 ppm compatible with the structure (I ). The mass spectrum shows a peak (M + 1) = 354. * Example 3:
Obtention de l'amide (Ha)3 R : : n C10H21, R5 ≈ R5 = R7 = Rs = CH3. Une solution de TROLOX (acide 2H-1 benzopyran-2 carboxylique-6-hydroxy-2,5,7,8 tetraméthyl) 2,5 g (10 mmoles) dans 10 ml de dichloro-1,2 éthane est mélangé avec 2 ml d'anhydride acétique et 10 μl de triéthylamine.Fetching amide (IIa) R 3:: n -C 10 H 21, R 5 ≈ R 5 = R 7 = R = CH 3. A solution of TROLOX (2H-1-benzopyran-2-carboxylic acid-6-hydroxy-2,5,7,8-tetramethyl) 2.5 g (10 mmol) in 10 ml of 1,2-dichloroethane is mixed with 2 ml. acetic anhydride and 10 μl of triethylamine.
Le mélange est chauffé 3 heures à 60°C puis concentré sous vide.The mixture is heated for 3 hours at 60 ° C. and then concentrated under vacuum.
Le résidu est dissous dans 10 ml de dichloroéthane. On ajoute 2 ml de chlorure de thionyle ; on porte 2 heures à reflux ; on concentre à sec et redissout dans 10 ml de dichloroéthane.The residue is dissolved in 10 ml of dichloroethane. 2 ml of thionyl chloride are added; we bring 2 hours to reflux; it is concentrated to dryness and redissolved in 10 ml of dichloroethane.
Une solution de 2,04 g (10 mmoles) d'amino-2 dodécanol-1 et de 1,4 ml de triéthylamine dans 5 ml de dichloroéthane est ajoutée et le milieu porté à 50°C sous agitation pendant 18 heures, puis concentré à nouveau. Au mélange brut précédent on ajoute 10 ml d'éthanol et 10 ml de soude 2N.A solution of 2.04 g (10 mmol) of 2-amino-1-dodecanol and 1.4 ml of triethylamine in 5 ml of dichloroethane is added and the medium is brought to 50 ° C. with stirring for 18 hours and then concentrated. again. To the previous crude mixture are added 10 ml of ethanol and 10 ml of 2N sodium hydroxide.
Le milieu est porté à 600C pendant 1 heure, puis refroidi à 200C, dilué par 20 ml de méthyl tertiobutyl éther, et lavé par 3 fois 10 ml d'acide chlohydrique N3 10 ml d'eau et 2 fois 10 ml de solution de bicarbonate de sodium à 10 %.The medium is brought to 60 ° C. for 1 hour, then cooled to 20 ° C., diluted with 20 ml of methyl tert-butyl ether, and washed with 3 times 10 ml of hydrochloric acid N 3 10 ml of water and twice with 10 ml of water. ml of 10% sodium bicarbonate solution.
La phase organique est séparée, séchée sur sulfate de magnésium et concentrée dans un évaporateur rotatif pour obtenir une cire blanche 2,7 g qui est chromatographiée surThe organic phase is separated, dried over magnesium sulfate and concentrated in a rotary evaporator to obtain a white wax 2.7 g which is chromatographed on
60 g de silice Fluka (40-60 micromètres) au moyen d'un mélange éluant cyclohexane60 g of Fluka silica (40-60 microns) using a cyclohexane eluent mixture
3 parts - acétate d'éthyle 2 parts, pour obtenir 1,35 g.3 parts - 2 parts ethyl acetate, to obtain 1.35 g.
Rdt= 31 %. Le spectre RMN 1H à 250 MHz dans le diméthylsulfoxyde montre 3 protons échangeables, 4 groupes CH3 à 2,0 - 2,1 - 2,6 et 3,2 ppm et les protons aliphatiques entre 0,8 et 1,6 ppm.Yield = 31%. The 1 H NMR spectrum at 250 MHz in dimethyl sulfoxide shows 3 exchangeable protons, 4 CH 3 groups at 2.0-2.1-2.6 and 3.2 ppm and the aliphatic protons between 0.8 and 1.6 ppm .
Le spectre de masse montre un pic principal (M + 1) = 434. L'effet inhibiteur des radicaux libres revendiqué pour les composés (Ia) et (Ea) a été évalué par mesure de leurs absorbances en spectrophotométrie UV à 517 nanomètres en présence d'un excès de radical diphénylpicrylhydrazide (VIII). On a préparé des solutions éthanoliques contenant 20 micromoles par litre de composé à tester et 100 micromoles par litre de radical (VHI) agitées 30 minutes à 200C et placées dans une cuve de 1 cm de longueur.The mass spectrum shows a principal peak (M + 1) = 434. The claimed free radical inhibitory effect for compounds (Ia) and (Ea) was evaluated by measuring their absorbances in 517 nanometer UV spectrophotometry in the presence an excess of diphenylpicrylhydrazide radical (VIII). Ethanolic solutions containing 20 micromoles per liter of test compound and 100 micromoles per liter of radical (VIII) were stirred for 30 minutes at 20 ° C. and placed in a vessel 1 cm long.
Les composés nouveaux (Ia) et (Ha) présentent une activité inhibitrice inférieure au TROLOX mais comparable à celle du gallate de méthyle. The new compounds (Ia) and (IIa) have an inhibitory activity lower than TROLOX but comparable to that of methyl gallate.

Claims

REVENDICATIONS
1) Nouveaux composés phénol-amides dérivés d'acides aromatiques comportant au moins un groupe hydroxy et d'amino-2-alcanols-l correspondant à la formule (I)1) Novel phenol-amide compounds derived from aromatic acids having at least one hydroxyl group and amino-2-alkanols-1 corresponding to formula (I)
où R1, R2, R3, R4 - — OH, H ou alkyl (CnIi2n+!), n étant compris entre 1 et 4, R = alkyl (-CnH2^1), n étant compris entre 2 et 30. where R 1 , R 2 , R 3 , R 4 - - OH, H or alkyl (C n Ii 2n + 1), n being between 1 and 4, R = alkyl (-C n H 2 ^ 1 ), n being between 2 and 30.
2) Préparation de composés phénol-amides dérivés d'acides aromatiques comportant au moins un groupe hydroxy et d'arnino-2-alcariols-l correspondant à la formule (T), cette préparation est caractérisée selon l'exemple 1 par le fait quelle comprend les étapes selon lesquelles on fait réagir l'acide gallique avec un amino-2-alcanol-l.2) Preparation of Phenol Amide Compounds Derived from Aromatic Acids Comprising at Least One Hydroxy Group and 2-Arnino-1-Alkariols corresponding to Formula (T), This Preparation Is Characterized According to Example 1 by the fact that comprises the steps of reacting gallic acid with an amino-2-alkanol-1.
3) Préparation de composés phénol-amides dérivés d'acides aromatiques comportant au moins un groupe hydroxy et d'amino-2-alcanols-l correspondant à la formule (I), cette préparation est caractérisée selon l'exemple 2 par le fait quelle comprend les étapes selon lesquelles on fait réagir le chlorure de l'acide triacétoxy-3,4,5 benzoïque avec un amino-2 alcanol-1.3) Preparation of phenol-amide compounds derived from aromatic acids having at least one hydroxyl group and amino-2-alkanols-1 corresponding to formula (I), this preparation is characterized according to Example 2 by the fact that comprises the steps according to which trifetoxy-3,4,5-benzoic acid chloride is reacted with a 2-amino-1-alkanol.
4) Procédé selon les revendications 2) et 3) caractérisé en ce que les àmino-2 alcanols-1 comportent une chaine linéaire ou branchée contenant 2 à 30 atomes de carbone. 5) Procédé d'obtention et de purification de N-[2(hydroxy-l dodecyl)] trihydroxy-3,4,5 benzamide - formule (Ea), R = n-CioHai, selon la revendication 3), caractérisé par le fait qu'une solution aqueuse de soude est ajoutée au milieu réactionnel et que la phase obtenue est acidifiée, séparée, concentrée et cristallisée de l'eau.4) Process according to claims 2) and 3) characterized in that 1'mino-2-alkanols-1 comprise a linear or branched chain containing 2 to 30 carbon atoms. 5) Process for obtaining and purifying N- [2 (hydroxy-1-dodecyl)] trihydroxy-3,4,5-benzamide - formula (Ea), R = n-CioHai, according to claim 3), characterized by the an aqueous solution of sodium hydroxide is added to the reaction medium and that the phase obtained is acidified, separated, concentrated and crystallized from water.
6) Utilisation de dérivés phénol-amides tels que définis à l'une des revendications6) Use of phenol-amide derivatives as defined in one of the claims
1) à 5) pour la fabrication de préparations cosmétiques ou pharmaceutiques destinées à la prévention des dégradations biologiques dues aux radicaux libres. 1) to 5) for the manufacture of cosmetic or pharmaceutical preparations for the prevention of biological damage due to free radicals.
EP05802436A 2004-09-24 2005-09-22 Preparation of phenol-amide compounds with antioxidant properties Withdrawn EP1805133A1 (en)

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PCT/FR2005/002351 WO2006035142A1 (en) 2004-09-24 2005-09-22 Preparation of phenol-amide compounds with antioxidant properties

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EP3456707B1 (en) 2007-11-06 2020-04-15 PTC Therapeutics, Inc. 4- (p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases
FR2928370B1 (en) * 2008-03-07 2017-07-14 Catalys PREPARATION OF HYDROQUINONE-AMIDE COMPOUNDS WITH ANTI-OXIDANT PROPERTIES
US8895032B2 (en) * 2009-03-27 2014-11-25 Central Michigan University Dendritic nano-antioxidants
RU2770091C2 (en) 2014-12-16 2022-04-14 ПиТиСи ТЕРАПЬЮТИКС, ИНК. Polymorphous and amorphous forms of (r)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
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