Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-02-10
2001-07-24
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C252S399000, C252S401000, C252S404000, C426S442000, C426S546000, C514S617000, C564S139000, C564S142000
Reexamination Certificate
active
06265611
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to hydroxymandelic acid amides of phenolic amines, to a process for their preparation and to their use as antioxidants or free-radical scavengers, in particular, in cosmetic and pharmaceutical preparations and foods, and for protecting cells and tissue of mammals from the harmful effects of free radicals and reactive oxygen compounds which accelerate aging. The invention further relates to cosmetic and pharmaceutical preparations comprising such hydroxymandelic acid amides.
BACKGROUND OF THE INVENTION
It is desirable to find substances, which support the natural defense mechanisms in physiological systems against free radicals and reactive oxygen compounds or, in the form of protectants in cosmetics, pharmaceuticals or foods, protect their oxidation-sensitive constituents against autoxidation.
Antioxidants are substances which, in concentrations which are small compared with the oxidizable substrate, significantly delay oxidation, or prevent it completely. Many antioxidants also act as free-radical scavengers and/or as complexing agents for heavy metal ions.
The object of the present invention is to develop new antioxidants having a high specific free-radical-scavenging and/or antioxidative action.
SUMMARY OF THE INVENTION
The invention relates to hydroxymandelic acid amides of phenolic amines, their stereoilsomers or mixtures thereof, comprising the general formula I,
wherein
R
1
is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms;
R
2
is a hydrogen atom or an —O—R
8
group, in which R
8
is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms;
R
3
is a hydrogen atom, an acyl, alkyl or alkenyl radical having from 1 to 22 carbon atoms;
A
1
is a —CH
2
— group or a —CH
2
—CH
2
— group;
R
4
is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms; and
R
5
, R
6
and R
7
independently of one another are hydrogen atoms or —O—R
9
groups, where R
9
is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms.
DETAILED DESCRIPTION OF THE INVENTION
Preference is given to compounds of the general formula I
wherein
R
1
is a hydrogen atom or a methyl group;
R
2
is a hydrogen atom, a hydroxyl group or an —O—CH
3
group;
R
3
is a hydrogen atom;
A
1
is a —CH
2
— group or a —CH
2
—CH
2
— group;
R
4
is a hydrogen atom or a methyl group,
and
R
5
, R
6
and R
7
independently of one another are hydrogen atoms, hydroxyl groups or —O—CH
3
groups.
Particular preference is given to compounds in which A
1
is a —CH
2
— group.
The particularly preferred compounds of the general formula (I) include, for example:
N-(3,4-dihydroxyphenethyl)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)acetamide;
N-(3,4-dihydroxyphenethyl)-2-(3,4-dihydroxyphenyl)-2-hydroxyacetamide;
N-(3,4-dihydroxybenzyl)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)acetamide;
2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-N-(3,4,5-trihydroxybenzyl)acetamide;
2-(3,4-dihydroxyphenyl)-2-hydroxy-N-(4-hydroxy-3-methoxybenzyl)acetamide;
N-(3,4-dihydroxybenzyl)-2-(3,4-dihydroxyphenyl)-2-hydroxyacetamide;
2-(3,4-dihydroxyphenyl)-2-hydroxy-N-(3,4,5-trihydroxybenzyl)acetamide;
but are not limited thereto.
Surprisingly, we have now found that the hydroxymandelic acid amides of phenolic amines according to the present invention are particularly strong free-radical scavengers and antioxidants. In particular, they are significantly better antioxidants and free-radical scavengers than most customary antioxidants.
Compared to phenolic acid amides of hydroxyl-substituted benzylamines known from EP 0 900 781, the hydroxymandelic acid amides of phenolic amines according to the present invention have increased water solubility, meaning that they can be used more easily in cosmetic preparations.
Particularly advantageous antioxidants or free-radical scavengers are the compounds within the meaning of the invention having more than two hydroxyl groups.
The hydroxymandelic acid amides of phenolic amines according to the present invention and of the general formula I can be prepared using the customary amide synthesis processes known per se, by reacting an activated hydroxymandelic acid, optionally protected on the OH groups, with a phenolic amine, optionally protected on the phenolic OH groups, or its ammonium salt, optionally in the presence of solvents and auxiliary bases. Activated acid derivatives which may be used are the acid chlorides, the acid anhydrides or acid esters of, for example, optionally substituted phenols, N-hydroxysuccinimide or N-hydroxybenzotriazole. The protective groups are preferably acyl, carbamate or ether groups, e.g. acetyl, benzoyl, methoxycarbonyl, tert-butoxycarbonyl, allyl or benzyl groups. Solvents which can be used are, for example, water, acetone, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, chloroform or else mixtures of the last-named solvents. Auxiliary bases which can be used are, for example, the carbonates, hydrogencarbonates and hydroxides of ammonium, alkali metals or alkaline earth metals, tertiary amines, and inorganic or organic basic ion exchangers.
The hydroxymandelic acid amides of phenolic amines according to the present invention and of the general formula I are particularly preferably prepared from N-succinimidyl hydroxy mandelates, optionally blocked on the hydroxyl groups with acetyl or methoxycarbonyl groups, with a phenolic amine or its ammonium salt in a hydro-solvent mixture, preferably a water/1,4-dioxane mixture with one of the above-mentioned auxiliary bases at from 5 to 100° C. Advantageously, the N-succinimidyl hydroxymandelate, optionally blocked on the hydroxyl groups with acetyl or methoxycarbonyl groups, are synthesized from the corresponding free acid and N-hydroxysuccinimide using a carbodiimide, preferably N,N′-dicyclohexylcarbodiimide, in an aprotic solvent, preferably 1,4-dioxane, diethyl ether, tert-butyl methyl ether, ethyl acetate or tetra-hydrofuran, at from 0 to 50° C., preferably from 5 to 30° C., the dissolved crude product is separated from the residue by filtration, and the filtrate is reacted directly within the meaning of the invention with the phenolic amine, initially introduced into water, or its ammonium salt and one of the above-mentioned auxiliary bases.
The hydroxymandelic acids are, in particular, 2-(4-hydroxy-3-methoxyphenyl)-2-hydroxyacetic acid (vanillomandelic acid) and 2-(3,4-dihydroxyphenyl)-2-hydroxyacetic acid (3,4-dihydroxymandelic acid) and their stereoisomers or mixtures.
The phenolic amines are, in particular, 2-(3,4-dihydroxyphenyl)-ethylamine, 3,4-dihydroxybenzylamine, 4-hydroxy-3-methoxybenzylamine or 3,4,5-trihydroxybenzylamine or the respective ammonium salts.
The hydroxymandelic acid amides according to the present invention can, however, also be obtained by direct condensation of the free acids with the free amines with or without solvent. Condensing agents which may be used are, for example, carbodiimides, preferably N,N′-dicyclohexyl-carbodiimide, and solvents which may be used are, for example, 1,4-dioxane, diethyl ether, tert-butyl methyl ether, ethyl acetate or tetrahydrofuran.
The hydroxymandelic acid amides of phenolic amines according to the present invention are obtained from these reaction mixtures by purification stages known per se; if necessary, any protective groups which are present must be cleaved off using methods known per se.
The hydroxymandelic acid amides of phenolic amines according to the present invention and of the general formula I, their stereoisomers and mixtures thereof can be used as antioxidants or free-radical scavengers for protecting against oxidation and photooxidation. They can be used preferably in cosmetic, pharmaceutical or dermatological formulations or in foods. Particularly preferably, the hydroxy-mandelic acid amides of phenolic amines according to the present invention are used in cosmetic and dermatological formulations, which have the customary composition and are used for the treatment, protection, care and cleansing of the skin, of the nails and/or of the hair and a
Cheung Noland J.
Gil Joseph C.
Haarmann & Reimer GmbH
Kumar Shailendra
LandOfFree
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