FR2523962A1 - NOVEL ALDONIC ACID AMIDES, THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

NEW AMIDES OF FORMULA I: HO - CH - (CHOH) - CO - NH - R (I) IN WHICH M IS AN INTEGER NUMBER MAY VARY FROM 2 TO 6 AND R IS AN ALKYL, LINEAR OR BRANCHED GROUP, CONTAINING 6 TO 18ATOMS OF CARBON, AS WELL AS POLYOXYETHYLENE, POLYOXYPROPYLEN OR POLYGLYCEROL DERIVATIVES AND THE COMPOUNDS OF FORMULA I (USABLE AS SURFACTANTS); THEIR PREPARATION PROCESS AND COMPOSITIONS CONTAINING THEM.

Description

 The subject of the present invention is new amides of aldonic acids, their preparation and their application.

A more specific subject of the invention is the new amides of general formula I:
HO - CH2 - (CHOH) CO - NH - R (I) in which m is an integer which can vary from 2 to 6 and R is an alkyl group, linear or branched, containing 6 to 18 carbon atoms.

 The invention also extends to polyoxyethylenated, polyoxypropylenated or polyglycerolated derivatives of the compounds of formula I.

 A subject of the invention is in particular the compounds of formula I for which m is equal to 4, 5 or 6. Among the values of R, there may be mentioned in particular the heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl and octadecyl groups. Among the preferred compounds of formula I, mention will be made of those for which R has 8 to 12 carbon atoms.

 The invention also relates to a process for the preparation of the compounds of formula I.

This process is characterized by the fact that an aldonic acid of formula II is reacted:
HO - CH2 - (CHOH) m- COOH (II) optionally in the form of lactone, with an amine of formula RNH2.

 This process is carried out by applying the known methods for the preparation of amides.

 In particular, it is possible to proceed by activation of the carboxylic group of the starting acid using a carbodiimide, for example dicyclohexylcarbodiimide in an organic solvent or in the presence of N-ethoxycarbonyl-2-ethoxy1,2-dihydroquinoline ( EEDQ) in a hydroorganic environment. One can operate in the presence of hydroxybenzotriazole as catalyst.

It is also possible to activate the carboxylic group in the form of an ester of paranitrophenol, of hydroxysuccinimide or of any other active esters described in the literature and in particular in the work by GROSS, E. and
MEIENHOFFR, J., The peptides analysis synthesis and biology, I.

Major methods of peptide bond formation, Academic Press, 1979.

For example, to prepare the compounds of formula I derived from gluconic acid, it is possible to react the gluconic acid, in the form of an alkaline salt such as the sodium or potassium salt, with the amine RNH2 chosen, in solution in the
N-dimethylformamide in the presence of an equivalent of dicyclohexylcarbodiimide, an equivalent of hydroxybenzotriazole and an equivalent of paratoluenesulfonic acid.

The acids of formula II can be prepared by oxidation of the corresponding oses, for example by electrochemical oxidation, or by any other method described in the literature to obtain an aldonic acid from an aldose or an oligosaccharide. The acids of formula II are for example glycopentonic, glycohexonic, glycoheptonic and glycooctonic acids such as gluconic, mannonic, galactonic, lyxoni.que, arabinonic, xylonic, ribonic, glucoheptonic or glucooctonic acids. The compounds of formula I are obtained with these acids for which the group
HO-CH2- (CHOH) m-CO- represents the corresponding acyl residue.

 Among the amines used as starting materials, mention will be made of n-octylamine, tertio-octylamine, decylamine, dodecylamine or laurylamine, tetradecylamine or myristylamine, hexadecylamine or palmitylamine and octadecylamine or stearylamine.

 The process for the preparation of polyoxyethylenated, polyoxypropylenated or polyglycerolated derivatives of the compounds of formula I, which is also part of the invention, consists in reacting a compound of formula I with ethylene oxide, propylene oxide or glycidol, in the presence of an appropriate catalyst, in a manner known per se. The catalyst is generally a basic catalyst such as a hydroxide or an alkali metal alcoholate.

 Another subject of the invention is the use of the compounds of formula I as well as their polyoxyethylenated, polyoxypropylenated or polyglycerolated derivatives, as surfactants.

These non-ionic surfactants have the following characteristics in particular:
- they are neutral and stable over a wide range of pH and temperature;
- they resist oxidation by gaseous or dissolved oxygen;
- they are transparent in visible and near ultraviolet light;
- they have a high diffusibility, in particular they pass through dialysis membranes;
- they do not irritate the skin and mucous membranes;
- they are not very foaming and quickly biodegradable.

 These properties make it possible in particular to use them as surfactants or detergents in the most diverse fields: household maintenance, automobile maintenance, cosmetology, as well as in the field of biological and microbiological sciences where the compounds of formula I can be used by example for the lysis of cell membranes or viral capsids, the solubilization of proteins, etc. These latter uses find their application in particular in the pharmaceutical industry, for example for the preparation of vaccines.

 The subject of the invention is in particular the compounds of formula I described below in the experimental part, as well as their polyoxyethylenated, polyoxypropylenated and polyglycerolated derivatives.

 The compounds of formula I are generally easily soluble in water, with the exception of long chain amine derivatives, the solubilization of which is facilitated by the presence of borate which considerably increases their solubility.

 The compounds of formula I can be used with advantage in place of detergents of the alkylphenoxypolyethylene glycol type (Triton X100 type, Nonidet NP40 ...) or of the alkyloxypolyethylene glycol type (Brij 30 type, Brij 52 etc ...).

 The compounds of formula I do not have an ether function and are therefore stable in the presence of air oxygen. They are not oxidized to peroxides.

 In addition, polyoloylaminoalkanes containing no aromatic nucleus are perfectly transparent in the visible and in ultraviolet light up to very short wavelengths, less than 250 nm.

 The subject of the invention is also new surfactant or detergent compositions comprising at least one product chosen from the compounds of formula I and the polyoxyethylenated, polyoxypropylenated or polyglycerolated derivatives of the compounds of formula I.

 When the compositions of the invention are surfactant or detergent compositions, they can be in the form of solid products such as powders, or in the form of a solution, in particular in the form of an aqueous solution.

They can also contain, in a proportion of 0 to 90% by weight, one or more conventional adjuvants such as borates.

 The surfactant or detergent compositions can also be liquids or aqueous solutions.

 When they are in the form of an aqueous solution, they are either concentrated solutions to be used after dilution, or ready-to-use solutions.

 The compositions of the invention generally contain from 0.5 to 100% by weight of compounds of formula I or their derivatives. They can also contain from 0 to 99.5% by weight of additives, including water. If desired, they also contain a pH modifying agent allowing the pH to be adjusted to the desired value, generally between 6 and 11.

 The compositions of the invention are in particular household detergents such as powders for washing clothes or dishes, liquids or solutions for cleaning windows or floors, etc.

 The compositions of the invention can also be cosmetic compositions. These are, for example, detergent cosmetic compositions (in particular powders or washing solutions for the skin and in particular for the hands, shampoos), compositions in the form of emulsions (in particular creams or milks) and more generally all cosmetic compositions capable of contain nonionic surfactants.

 The compositions of the invention may also be pharmaceutical compositions containing at least one active principle and the surface-active agent of the present application, the presence of which promotes the action of the active principle or makes it possible to present it in a particular form (for example example solution or emulsion).

 The pharmaceutical compositions are for example ointments or ointments containing said surfactants to facilitate the solubilization and penetration of the active principles, or solutions of membrane antigens or viral capsids, the presence of the surfactants of the invention allowing has these antigens to stay in solution.

The following examples illustrate the invention without however limiting it:
EXAMPLE 1
Preparation of gluconoylaminooctane. Formula I with m = 4 and
R = n-octyl.

 The gluconolactone (35.6 g; 0.2 mole) is dissolved in 50 ml of anhydrous dimethyl sulfoxide at 500C. To this solution, noctylamine (25.8 g; 0.2 mole) is added. The solution is kept at 65 ° C. with stirring. (The exothermic reaction increases the temperature). Crystals appear after a few minutes of incubation. The suspension is cooled to 20250C and then dispersed in dichloromethane (250ml). The detergent is washed with dichloromethane (250ml) and then wrung out.

 Yield: 60g (98%).

EXAMPLE 2
Preparation of gluconoylaminoheptane. Formula I with m = 4 and
R = n-heptyle.

 The gluconolactone (35.6 g; 0.2 mole) is dissolved in 50 ml of anhydrous dimethyl sulfoxide at 50 pu. To this solution, nheptylamine (22.34 g; 0.2 mole) is added. The solution is kept at 650C with stirring. Crystals appear after a few minutes of incubation. The suspension is cooled 20250C and then dispersed in dichloromethane (250ml). The detergent is washed with dichloromethane (250ml) and then wrung out.

 Yield: 55.7 g (95%).

EXAMPLE 3
Preparation of gluçpnoylaminodecane. Formula I with m = 4 and
R = n-decyl.

 This product is prepared under the same conditions as those described in Example 1.

 Gluconolactone (35.6 g; 0.2 mole) dissolved in 50 ml of dimethyl sulfoxide at 500 ° C. is mixed with decylamine (31.4 g; 0.2 mole). The reaction takes place at 650C.

Yield: 64.3g (96%)
EXAMPLE 4
Preparation of gluconoylaminododecane. Formula I with m = 4 and
R = n-dodecyl.

 This product is prepared under the same conditions as in the previous examples. Gluconolactone (35.6 g; 0.2 mole) dissolved in 50 ml of dimethyl sulfoxide at 500 ° C. is mixed with dodecylamine (37.1 g; 0.2 mole) heated to 500 ° C. The reaction takes place at 65 "C.

Yield: 70.5g (97%)
EXAMPLE 5
In the same way, we prepared:
- Gluconoylamlnooctadecane, compound of formula I, with m = 4 and R = -octadecyle1 from gluconolactone and octadecylamine;
- Glucoheptanoylaminodecane, compound of formula I, with m = 5 and R = n-decyl, starting from glucoheptonolactone and decylamine;
- Glucooctanoylaminodecane, compound of formula I, with m = 6 and R = n-decyl, starting from glucooctonolactone and decylamine.

PROPERTIES OF COMPOUNDS OF FORMULA I
Product of Example 1 2 3 4
Molecular mass 307.35 293.31 335.40 363.46
Melting point 1590C 1590C 1590C 1580C
Infrared spectrum 1645 1645 1645 1645
(in cm-1) 1530 1530 1530 1530
Magnetic resonance 7.6 7.6 7.6 7.6 (1H, NH) nuclear (in ppm) 1.5 to 1.1 1.5 to 1.1 1.5 to 1.1 1.5 to 1 , 1 (CH2)
(12H) (10H) (14H) (16H)
0.90 0.90 0.90 0.90 (CH3)
Absorbance
250 to 700nm 0 0 0 0
213nm 220 220 220 220
Fluorescence
260 to 700nm 0 0 0 0
Solubility in
water (g / l)>10> 15 8 6
Solubility in a
solution
0.05M sodium borate (g / l)>25>33>16> 14
EXAMPLES OF USE
1.Lysis of animal cells
a) A suspension of human erythrocytes (group A +) (107 / ml) in sodium phosphate buffer (p: 0.15, pH 7.2) is lysed in less than five minutes by adding a volume of a 2% solution of gluconoylaminooctane in 0.05M sodium borate buffer, 0.10M sodium chloride, pH 8.5. Under the same conditions, the erythrocytes are stable when the detergent-free borate buffer is added to the suspension in the phosphate buffer.

 b) A pellet of ten million human erythrocytes (group A) obtained by centrifugation at 500 g, (l-Omin.) is suspended in 2 ml of gluconoylaminooctane dissolved at a concentration of 2 g / l in a sodium borate buffer 0 0.05M 0.1M sodium chloride, pH 8.5. In less than five minutes at room temperature, the erythrocytes are lysed and a clear, red solution is obtained.

2. Determination of fluorescent antibodies fixed on animal cells
Rabbit antibodies to mouse immunoglobulins are made fluorescent by reaction with an activated derivative of fluorescein (fluorescein isothiocyanate or dichlorotriazinylaminofluorescein). Five million cells of the spleen of mice are incubated in physiological saline (lml) containing the fluorescent rabbit antibodies (60pu) for 1 hour at 250C. The spleen cells are isolated by centrifugation at 1000 g for 10 minutes and then washed in isotonic phosphate buffer. The pellet is suspended in 1 ml of gluconoylaminooctane dissolved at a concentration of 2 g / l in 0.05M sodium borate, chloride. 0.1M sodium, pH 8.5, to lyse the cells and dissolve the membrane proteins. After 30 min. at 250C the suspension is centrifuged and the supernatant is analyzed by spectrofluorimetry: excitation wavelength: 495nm, emission wavelength: 520nm.

 All the fluorescence fixed on the cells is found in the supernatant which is clear. This method makes it possible to measure the quantity of antibodies present on the surface of B lymphocytes.

3. Determination of fluorescent glycoproteins (or neoglycoproteins) fixed on human cells
Glycoproteins (thyroglobulin) or neoglycoproteins (serum albumin substituted by reaction with glucosylphenyl isothiocyanate) are made fluorescent by reaction with a derivative of fluorescein. Five million lymphocytes from human blood (group A +) are incubated in the presence of a fluorescent glycoprotein 100 g in ml, for 1 hour at 250C. The cells are washed and suspended in a buffer containing gluconoylaminooctane, then the supernatant is analyzed by spectrofluorimetry under the same conditions as those described in ≈2. All the fluorescent material previously fixed on the lymphocytes is dissolved in the supernatant which is clear .

 This method makes it possible to measure the quantity of membrane lectins present on the surface of human lymphocytes.

4. Demonstration of intracellular lectins in animal cells
Mouse myeloma cells (SP2) are fixed on a coverslip covered with polylysine. One batch of coverslips (A) is incubated in a solution of 0.05M sodium borate, 0.1M sodium chloride, pH 8.5 and another batch (B) is incubated in the same buffer containing gluconoylaminooctane (20g / l). The cells on the coverslips of lot (B) are made fluorescent after incubation with fluorescent neoglycoproteins containing B-galactose, while the cells of lot (A) are not made fluorescent under the same conditions.

This method makes it possible to demonstrate a membrane lectin specific for galactose inside the myeloma cells of mice.

5. Determination of fluorescent glycoproteins (neoglycoproteins) fixed on mouse lewis pulmonary carcinoma (LLC) cells
LLC cells have a membrane lectin specific for the aD-glucose residue. The cells (106) are first incubated in the presence of serum albumin substituted by fluoresceinylisothiocyanate (controls): FTC-SAB or in the presence of serum albumin substituted by fluoresceinylisothiocyanate and α-glucopyranosyl phenylisothiocyanate Glc-FTC
SAB. After 1 h 30 min incubation at 370C, the excess reagent is removed by centrifugation and the cells are washed in isotonic phosphate buffer. Finally, the cells are lysed with a solution of detergent according to the invention or of triton X100. The solutions obtained are used to determine the concentration of fluorescein initially present in the cells, under the conditions described in the application 1 above.

The results obtained are collated in the following table:
Detergent Concentration FTC-SAB FTC-Glc SAB
detergent pg / cell pg / cell
Triton X100 1% 0.17 1.2
Product of Example 1 0.5% 0.1 1.7
Product of Example 2 0.58 0.056 0.7
Product of Example 3 0.5% 0.14 2.7
Product of Example 4 0.5% 0.14 3.4 NB: pg = picogram = 10 12g.

 The detergent solutions contain 0.05M sodium borate, pH 8.5 in order to ensure a pH allowing optimum efficiency of fluorescein fluorescence. Among the detergents used, the product of Example 4 makes it possible to dissolve a maximum quantity of fluorescent compounds initially fixed on the cells. The optimal concentration of this detergent is around 0.5%. At 1% and 0.1% the quantities of fluorescent material dissolved are 70% and 948 respectively of those obtained using the concentration of 0.5%.

6. Use of gluconoylaminooctane as a surfactant for automobile windshields
The gluconoylaminooctane (1 g) is dissolved in 1 liter of water containing 1 g of boric acid and brought to pH 8.5 by addition of ammonia. This solution is an effective agent for cleaning windshields. It eliminates the traces left by insects, without leaving spite promoting the diffusion of light.

Claims (13)

 1. New amides of general formula I:  HO - CH2 - (CHOH) - CO - NH - R (I) in which m is an integer which can vary from 2 to 6 and R is an alkyl group, linear or branched, containing 6 to 18 carbon atoms, thus than the polyoxyethylenated, polyoxypropylenated or polyglycerolated derivatives of the compounds of formula I.  2. New amides according to claim 1, characterized in that the group HO-CH2- (CHOH) m-CO- represents, in formula I, the acyl residue of gluconic, mannonic, galactonic, lyxonic acid, arabinonic, xylonic, ribonic, glucoheptonic or glucooctonic.  3. New amides according to claim 1 or 2, characterized in that m is equal to 4, 5 or 6.  4. New amides according to any one of claims 1 to 3, characterized in that R is a heptyl, decyl, dodecyl, tetradecyl, hexadecyl or octadecyl group.  5. New amides according to any one of the preceding claims, characterized in that R has 8 to 12 carbon atoms.  6. New amides according to any one of the preceding claims, characterized in that they are chosen from gluconoylaminooctane, gluconoylaminoheptane, gluconoylaminodecane, gluconoylaminododecane, gluconoylaminooctadecane, glucoheptonoylaminodecane and glucooctanoylaminodecane, as well as polyethylene derivatives, and polyoxypropylenated and polyglycerolated from these compounds.  7. Process for the preparation of an amide as defined in any one of the preceding claims, characterized in that an aldonic acid of formula II is reacted:  HO - CH2 - (CHOH) - COOH (II) optionally in the form of lactone, with an amine of formula RNH2, then reacting, if desired, the product of formula I obtained with ethylene oxide, propylene oxide or glucidol, in the presence of a catalyst.  8. Compositions, characterized in that they comprise, as surfactant or detergent, at least one product chosen from the compounds defined in any one of claims 1 to 6.  9. Compositions according to claim 8, characterized in that they constitute detergent compositions.  10. Compositions according to any one of claims 8 and 9, characterized in that they are in the form of powders.  11. Compositions according to any one of claims 8 and 9, characterized in that they are in the form of liquids or aqueous solutions.  12. Compositions according to any one of claims 8 to 11, characterized in that they contain from 0.5 to 100% by weight of compounds of formula I or their derivatives.  13. Compositions according to claim 8, characterized in that they constitute cosmetic or pharmaceutical compositions.