CA2209922A1 - Novel sweeteners derived from 3,4-disubstituted .alpha.-benzeneamide n-(4-cyanophenylcarbamoyl or 2-cyanopyrid-5-ylcarbamoyl)-l-aspartic or l-glutamic acids - Google Patents
Novel sweeteners derived from 3,4-disubstituted .alpha.-benzeneamide n-(4-cyanophenylcarbamoyl or 2-cyanopyrid-5-ylcarbamoyl)-l-aspartic or l-glutamic acidsInfo
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- CA2209922A1 CA2209922A1 CA002209922A CA2209922A CA2209922A1 CA 2209922 A1 CA2209922 A1 CA 2209922A1 CA 002209922 A CA002209922 A CA 002209922A CA 2209922 A CA2209922 A CA 2209922A CA 2209922 A1 CA2209922 A1 CA 2209922A1
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- Prior art keywords
- aspartic acid
- alpha
- cyanophenylcarbamoyl
- sweetening
- cyanopyrid
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/30—Artificial sweetening agents
- A23L27/31—Artificial sweetening agents containing amino acids, nucleotides, peptides or derivatives
- A23L27/32—Artificial sweetening agents containing amino acids, nucleotides, peptides or derivatives containing dipeptides or derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Proteomics, Peptides & Aminoacids (AREA)
- Health & Medical Sciences (AREA)
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- Engineering & Computer Science (AREA)
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- Polymers & Plastics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Peptides Or Proteins (AREA)
Abstract
Novel high-potency sweeteners of formula (I), wherein Y is a CH group or a nitrogen atom, A is an oxygen atom, n is 1 or 2, and R is a 3,4-disubstituted phenyl group, and physiologically acceptable salts thereof. Such compounds are useful as sweeteners.
Description
Novel sweeteners derived fronn 3,4~ ubstituted a-ben7~n~o~nnide N-(4-cy~nophenyl-~rb~moyl or ?-cy~nopyrid-5-ylr~rb~moyl)-T-;-~rtic or ~-glut~mic acids.
S The object of the present invention is novel sweetening agents derived from N-(4-cyanophenylcarbamoyl or 2-cyanopyrid-5-ylcarbamoyl)-L-aspartic or L-glutamic acid a-ben7~n~mides. These novel sweetening agents of very high sweetçning intensity are particularly useful for sweetening a variety of products, especially fizy drinks, foods, confectionery, pastries, chewing gums, hygiene products, cosmetics, toilet articles, ph~rm~-eutical and veterinary products, and their equivalents.
It is known that, in order to be usable on an industrial scale, a sweete~ing agent must possess notabl~ an intense sweetening potency, making it possible to limit the cost of its use.
The novel compounds in accordance with the present invention possess extremely high sweetening activities since they are, on a weight basis, up to 50,000 times more powerful than sucrose (table sugar). Amongst the artificial sweetçning agents currently on the market, the most used is a dipeptide derivative, N-L-a-aspartyl-L-phenylalanine 1-methyl ester, known better under the name of aspartame (US 3,49'',131). The principal advantages of this compound are its excellent organoleptic properties and its chemical constitution based on two natural amino acids, L-aspartic acid and L-phenyl~l~nine On the other hand, its sweetening potency is relatively weak since it is only 120 to 180 times higher than that of sucrose on a weight basis, this signifying that it is necessary to provide 1 gram of aspartame in order to replace 120 to 180 grams of sugar. The relatively weak ~weetenillg potency of aspartame, associated with its relatively high cost of manufacture due to its dipeptide structure, makes it therefore an expensive sweetening agent, this constituting its principal drawback within the context of its inclnctn~l use.
The e~tremely high sweetening potency of the compounds of the invention, associated with their ease of pl~pardlion, has as advantage the ~ aldtion of ' CA 02209922 1997-07-08 .
sweetçning agents of low cost price. The preferred sweete~in~ agents of the present invention are in fact up to 50,000 times sweeter than sugar on a weight basis, this meaning that 1 gram of the plGr~ d compounds of the invention is sufficient to replace up to 50 kilograms of sugar. The p,~rt;l.~d sweetening agents of the present invention being about 250 to 400 times more powerful than aspartame itself, their cost of use shall therefore be very low with respect to aspa,l~llle, this leaving it favourable to envisage their industrial application.
In the JP 86-26005' document, Tsuchiya et al. described sweetçnin~
agents having the following general formula:
O--NH~
~ --H R3 R1~=
S The object of the present invention is novel sweetening agents derived from N-(4-cyanophenylcarbamoyl or 2-cyanopyrid-5-ylcarbamoyl)-L-aspartic or L-glutamic acid a-ben7~n~mides. These novel sweetening agents of very high sweetçning intensity are particularly useful for sweetening a variety of products, especially fizy drinks, foods, confectionery, pastries, chewing gums, hygiene products, cosmetics, toilet articles, ph~rm~-eutical and veterinary products, and their equivalents.
It is known that, in order to be usable on an industrial scale, a sweete~ing agent must possess notabl~ an intense sweetening potency, making it possible to limit the cost of its use.
The novel compounds in accordance with the present invention possess extremely high sweetening activities since they are, on a weight basis, up to 50,000 times more powerful than sucrose (table sugar). Amongst the artificial sweetçning agents currently on the market, the most used is a dipeptide derivative, N-L-a-aspartyl-L-phenylalanine 1-methyl ester, known better under the name of aspartame (US 3,49'',131). The principal advantages of this compound are its excellent organoleptic properties and its chemical constitution based on two natural amino acids, L-aspartic acid and L-phenyl~l~nine On the other hand, its sweetening potency is relatively weak since it is only 120 to 180 times higher than that of sucrose on a weight basis, this signifying that it is necessary to provide 1 gram of aspartame in order to replace 120 to 180 grams of sugar. The relatively weak ~weetenillg potency of aspartame, associated with its relatively high cost of manufacture due to its dipeptide structure, makes it therefore an expensive sweetening agent, this constituting its principal drawback within the context of its inclnctn~l use.
The e~tremely high sweetening potency of the compounds of the invention, associated with their ease of pl~pardlion, has as advantage the ~ aldtion of ' CA 02209922 1997-07-08 .
sweetçning agents of low cost price. The preferred sweete~in~ agents of the present invention are in fact up to 50,000 times sweeter than sugar on a weight basis, this meaning that 1 gram of the plGr~ d compounds of the invention is sufficient to replace up to 50 kilograms of sugar. The p,~rt;l.~d sweetening agents of the present invention being about 250 to 400 times more powerful than aspartame itself, their cost of use shall therefore be very low with respect to aspa,l~llle, this leaving it favourable to envisage their industrial application.
In the JP 86-26005' document, Tsuchiya et al. described sweetçnin~
agents having the following general formula:
O--NH~
~ --H R3 R1~=
2 n ~H
in which:
Rl and R3 are hydrogen or halogen atoms, or CN, NO2, R' (R' being an alkyl group15 of 1 to 6 carbon atoms), COOR"~ R"CO, halomethyl, R"O, CONHR", SO2R" OR
SOR" groups (R" being an alkyl group of 1 to 4 carbon atoms);
R2 is an oxygen or sulphur atom;
nis0,1or ';
and the configuration of the carbon atom marked C*, bearing an amino group, 20 being L or DL.
In this document, indicative figures relative to the sweetening potency are only found for only ~ (two) compounds claimed, namely, N-(4-nitrophenylcarbamoyl)-L-aspartic acid-a-4-chlorobenzeneamide of formula:
O CO--NH~ C1 O2N~N~--C--NH ~ C~H
iH2 COOH
which is described as having a sweetçnin~ potency of 5,400 times that of sucrose, and N-(4-nitrophenylcarbamoyl)-L-aspartic acid-a-4-cyanob~ ide of 5 formula:
O CO--NH ~ CN
~2 N ~NH--C--NH ~ C _ H
i COOH
which is described as having a ~wcc;Lellillg potency of 4,800 times that of sucrose.
It was discovered, and this constitutes the basis of the invention, that the sw~Gte.~ g potency of some other derivatives of N-(4-cyanophenylcarbamoyl or 2-cyanopyrid-5-ylcarbamoyl)-L-aspartic or L-glutamic acid-a-benzeneamides was greatly increased, in an entirely unpredictable manner, when the bçn7çnç~mide group is substituted siml-lt~neously in positions 3 (met~) and 4 15 G~ara) with applop,iately selected substituents. Now, it is known that a modification, even minor, of the structure of a sweetening agent may lead to a total loss of its activity. It is therefore entirely unexpected that a double substitution on the ben_eneamide group is able not su~ s the sweetenin~ activity, but on the contrary to strongly increases it with respect to the activity of the monosubstituted 20 compounds described in the prior art.
CA 02209922 l997-07-08 Thus, the object of the invention is novel sweetening agents, characterised in that they have the following formula:
A CO--NH--R
NC ~NH--C--NH ~ C ~ H
y ( CH2 ) n COOH
in which:
Y is a CH group or a nitrogen atom, A is an oxygen atom, 10 n is equal to 1 or ', R is a 3,4-disubstituted phenyl radical selected from the groups:
in which:
Rl and R3 are hydrogen or halogen atoms, or CN, NO2, R' (R' being an alkyl group15 of 1 to 6 carbon atoms), COOR"~ R"CO, halomethyl, R"O, CONHR", SO2R" OR
SOR" groups (R" being an alkyl group of 1 to 4 carbon atoms);
R2 is an oxygen or sulphur atom;
nis0,1or ';
and the configuration of the carbon atom marked C*, bearing an amino group, 20 being L or DL.
In this document, indicative figures relative to the sweetening potency are only found for only ~ (two) compounds claimed, namely, N-(4-nitrophenylcarbamoyl)-L-aspartic acid-a-4-chlorobenzeneamide of formula:
O CO--NH~ C1 O2N~N~--C--NH ~ C~H
iH2 COOH
which is described as having a sweetçnin~ potency of 5,400 times that of sucrose, and N-(4-nitrophenylcarbamoyl)-L-aspartic acid-a-4-cyanob~ ide of 5 formula:
O CO--NH ~ CN
~2 N ~NH--C--NH ~ C _ H
i COOH
which is described as having a ~wcc;Lellillg potency of 4,800 times that of sucrose.
It was discovered, and this constitutes the basis of the invention, that the sw~Gte.~ g potency of some other derivatives of N-(4-cyanophenylcarbamoyl or 2-cyanopyrid-5-ylcarbamoyl)-L-aspartic or L-glutamic acid-a-benzeneamides was greatly increased, in an entirely unpredictable manner, when the bçn7çnç~mide group is substituted siml-lt~neously in positions 3 (met~) and 4 15 G~ara) with applop,iately selected substituents. Now, it is known that a modification, even minor, of the structure of a sweetening agent may lead to a total loss of its activity. It is therefore entirely unexpected that a double substitution on the ben_eneamide group is able not su~ s the sweetenin~ activity, but on the contrary to strongly increases it with respect to the activity of the monosubstituted 20 compounds described in the prior art.
CA 02209922 l997-07-08 Thus, the object of the invention is novel sweetening agents, characterised in that they have the following formula:
A CO--NH--R
NC ~NH--C--NH ~ C ~ H
y ( CH2 ) n COOH
in which:
Y is a CH group or a nitrogen atom, A is an oxygen atom, 10 n is equal to 1 or ', R is a 3,4-disubstituted phenyl radical selected from the groups:
3,4-dimethylphenyl:
3,4-methylenedioxyphenyl:
~ , 2 3-hydroxy-4-methoxyphenyl:
OH
~ OCH3 3-chloro-4-methoxyphenyl:
~ OCH3 4-methyl-3-nitrophenyl:
NOz ~ CH3 indan-S-yl:
1,4-benzodioxan-6-yl:
o 20 and their physiologically acceptable salts.
The compounds of the invention for which n is equal to 1 represent a preferred form of the invention.
S A particularly advantageous embodiment form of the invention is N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3,4-dimethylb~ 7~l-e~.,.ide of formula:
O CO--NH ~ CH 3 NC~;3NH--C--NH _ C~H
COOH
whose sweetening potency, expressed on a weight basis, is 50,000 times higher than that of sucrose by colllpalison with a '~% sucrose solution.
Another particularly advantageous embodiment form of the invention is N-(?-cyanopyrid-5-ylcarbamoyl)-L-aspartic acid-a-3,4-dimethylben7~n~mide 15 of formula:
O CO--NH~ CH3 NC~3NH--C--NH _ C_H
I
COOH
whose sweetening potency, expressed on a weight basis, is 40,000 times higher than that of sucrose by co.,lpafison with a 2% sucrose solution.
Other preferred compounds of the invention are characterised in that it is N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3,4-methylenedioxybenzene-5 arnide, N-(~-cyanopyrid-S-ylcarbamoyl)-L-aspartic acid-a-3,4-methylenedioxy-benzeneamide, N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3-hydroxy-4-methoxybenzeneamide, ~V-(2-cyanopyrid-5-ylcarbamoyl~-L-aspartic acid-a-3-hydroxy-4-methoxybenzeneamide, N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3-chloro-4-methoxyb~l~el~ealllide, 10 N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-4-methyl-3-nitrobenzeneamide, lV-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-indan-S-ylamide, N-( -cyanopyrid-5-ylcarbamoyl)-L-aspartic acid-a-indan-S-ylamide, ~V~4-c~anophenylcarbamoyl~-L-aspartic acid-a-1,4-benzodi-oxan-6-ylamide and N-(''-cyanopyrid-5-ylcarbamoyl)-L-aspartic acid-a-1,4-15 benzodioxan-6-ylamide.
The compounds of the invention differ therefore from the compounds described in the JP 86-'60052 document by the very specific nature and the position of the substituents fixed onto the benzeneamide group. In fact, in this prior 20 art document, the benzene ring of the benzeneamide group of the compounds described and claimed is monosubstituted, and, for the examples mentioned, only in position 4 (para).
In accordance with the present invention, the phenyl group R is simultaneously substituted in positions 3 (meta) and 4 (para) with specific groups.
25 The selection in the compounds of the invention of this novel group R leads to a spect~c~ r increase in the sweetening potency, it being possible for this potency to reach 10 (ten) times that of the compounds of the prior art, and consequently a significant decrease in the cost of use of such compounds.
The sweetening agents of the present invention may be added to any edible 30 product to which it is desired to give a sweet taste, provided that it is added in sufficient proportions to attain the level of sweetness desired. The optimal use concentration of the sweeterling agent will depend upon a variety of factors such as, for example, the sweetening potency of the sweetçning agent, the conditions of storage and use of the products, the particular constituents of the products and the level of sweetness desired. Any qualified person can easily ~letçrmine the optimal S proportion of sweetening agent which must be employed in order to obtain an edible product by carrying out routine sensory analyses. The sweetening agents of the present invention is, in general, added to the edible products in proportions, according to the sweetening potency of the compound, ranging from 0.5 mg to 50 mg of sweetening agent per kilogram or per litre of edible product. The 10 concentrated products will obviously contain greater quantities of ~w~etellillg agent, and will then be diluted following the final intentions of use.
The sweetçning agents of the present invention may be added in the pure fomm to products to be swee~ened, but because of their high sweetening potency they are generally mixed with an app-o~liate carrier or bulking agent.
Advantageously, the applol.liate carriers or bulking agents are selected from the group consisting of polydextrose, starch, maltocle~trin~, cellulose, methyl cellulose, carboxymethyl cellulose and other derivatives of cellulose, sodium alginate, pectins, gums, lactose, maltose, glucose, leucine, glycerol, m~nnitol,sorbitol, sodium bicarbonate, phosphoric, citric, tartaric, fumaric, benzoic, sorbic and propionic acids and their sodium, potassium and calcium salts, and equivalents thereof.
A sweetening agent of the invention may, in an edible product, be employed as the only sweetening agent, or in combination with other sweetening agents such as sucrose, com syrup, fructose, sweet dipeptide analogues or derivatives (as~a,l;~,l,e, alitame), neohesperidin dihydrochalcone, hydrogenatedisomaltulose, stevioside, the L sugars, gly~;yl,l,iGhl, xylitol, sorbitol, m~nnitol, acesulfame-K, saccharin and its sodium, potassium, ammonium and calcium salts, cyclamic acid and its sodium, potassium and calcium salts, sucralose, monellin, th~llm~tin and equivalents thereof.
The compounds of the invention can also be used either in the acid fomm or in their fomm of salts obtained with the aid of physiologically acceptable inorganic or organic bases, this having as effect to increase their solubility. Advantageously, these compounds are salified in the form of salts of sodium, potassium, ammonium, calcium or m~gn~cillm The pl~paldlion of the compounds of the invention makes use notably of 5 the methods commonly used in peptide synthesis (see for example M. Bodansky and A. Bodansky, The Practice of Peptide Synthesis, Springer Verlag, Berlin, 1984).
The pl~pa~dtion of the compounds according to the invention can thus be carried out from precursors of commercial origin, such as for example, N-10 benzyloxycarbonyl-L-aspartic acid 13-benzyl ester (n = 1), N-benzyloxycarbonyl-L-glutamic acid y-benzyl ester (n = ), and the amine R-NH2 wherein R is a disubstituted phenyl group such as defined above, in following the following reaction scheme:
COOH
C6HsCH2OCO-NH ~ C ~ H
(CH2)n isobutyl chloroformate HzN-R
N-methylmorpholine CO - NH - R
C6H5CH2OCO-NH ~ C ~ H
(CH2)n COOCH2C6Hs H2, Pd/C 10%
CO - NH - R
HzN ~ C ~ H
(CH2)n COOH
NC ~ N=C=O
y O CO - NH - R
NC ~ NH - C - NH - C ~ H
Y
(CH2)n COOH
The purification of the compounds of the invention is p~ lroll~led according to the standard techniques such as recryst~ tion and chromatography. Their structure and their purity have been checked by classical techniques (thin layerchromatography, high pelrol,llance liquid chromatography, infrared specLlollletry, S nuclear m~gnetic resonance, elementary analysis).
The sweetening potency of the compounds described in the Examples has been evaluated by a group of eight experienced people. For this, the compounds, in aqueous solution at ~ar~ing concentrations, are compared, with respect to taste, to 10 a control solution of sucrose of concentration '%. The sweetening potency of the test compound compared with sucrose then corresponds to the weight ratio between the compound and sucrose for equal ~w~ tlling h~lellsily, i. e. when thesweet tastes of the solution of the test compound and the control solution of sucrose are considered by a majority of people to ha~e the same sweetening 15 illttllSily.
The manner in which the invention may be carried out and the advantages resulting therefrom shall emerge better from the non-limiting implementation Examples that follow.
FXAl~PT F~
Preparation of N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3,4-di-methylbenzeneamide:
s O CO--NH ~ CH 3 NC ~3NH--C--NH ~ 1 ~ H
!
lH2 COOH
1. Plepaldlion of N-benzylox~carbonyl-L-aspartic acid-a-3,4-dimethyl-benzeneamide ,~-benzylester:
10To a solution of 3 g (8.4 mmoles) of N-benzyloxycarbonyl-L-aspartic acid ,13-benzyl ester (Bachem product No. C-1350) in 50 cm3 of tetrahydrofuran cooled to -15~C are added successively 0.84 g (8.4 mmoles) of N-methylmorpholine and 1.14 g (8.4 mmoles) of isobutyl chloroformate. After 2 min~ltes~ stirring at this ~ eldture, 1 g (8.4 mmoles) of 3,4-dimethylaniline 15(Aldrich product No. 1',637-3) is added. The reaction mixture is slowly warmed up and then is stirred for hours at ambient temperature. The N-methylmorpholine hydrochloride pl~:ci~ilate is removed by filtration, and then washed with 0 cm3 of tetrahydrofuran. The filtrate is concentrated to dryness under vacuum and the residue obtained is triturated in 50 cm3 of diethyl ether. The 20 white solid obtained is separated off by filtration and then washed again with 20 cm3 of diethyl ether. 3.3 g of N-benzyloxycarbonyl-L-aspartic acid-a-3,4-dimethylbenzeneamide ,B-benzylester are thus obtained (85% yield) whose melting point is 146~C.
2. Preparation of L-aspartic acid-a-3,4-dimethylbenzeneamide:
A solution of 3 g (5.6 mmoles) of lV-benzyloxycarbonyl-L-aspartic acid-a-3,4-dimethylbenzeneamide ,B-benzylester obtained above in 100 cm3 of methanol is submitted, in the presence of 10% palladium on activated charcoal, to S hydrogen under atmospheric pressure for 18 hours. After removing the catalyst by filtration, the solution is concentrated under vacuum and the white solid obtained is washed by trituration in acetone. 1.3 g of L-aspartic acid-a-3,4-dimethylbenzeneamide (85% yield) are thus obtained as a white solid whose melting point is 204~C. ~ts purity is monitored by thin layer chromatography on G
1060 silica gel (Merck No. 1.05554 silica support), eluent butanol-acetic acid-water (8-2-. ), vi.c~ tion with ninhydrin, Rf = 0.49.
3. Preparation of N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3,4-dimethylbenzeneamide:
15To a solution of 0.7 g (3 mmoles) of L-aspartic acid-a-3,4-dimethylbenzeneamide and 0.63 g (6 mmoles) of sodium carbonate in 30 cm3 of water, is added, under vigorous stirring, 0.47 g (3. mmoles) of 4-cyanophenylisocyanate in solution in 30 cm3 of benzene. The solution is stirred for 30 minutes at ambient temperature before being washed with thrice 30 cm3 of 20 diethyl ether. Acidifying to pH '-3 by a 6N hydrochloric acid solution leads to the formation of a white precipitate which is filtered off and washed with 5-6 cm3 of water. After filtration and drying, 0.98 g of N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3,4-dimethylbenzeneamide (86% yield) are obtained whose melting point is 17 ~C after recrystallisation from 95% ethanol.
Molecular formula: C20H20N404.
Thin layer chromatography: Silica gel G 60 F;~54 on aluminium sheets (Merck No.
1.05554), eluent: chloroform-methanol (6:4), vi~ tion with ninhydrin, Rf =
0.30.
NMR (lH, ppm), DMSO D6: '2.15 (s, 3H), ~.5 (s, 3H), 7.7 (m, '2H), 4.6 (m, lH), 6.9 (d, lH), 7.0 (d, lH), 7.3 (rn, H), 7.6 (m, 4H), 9.5 (s, lH), 9.9 (s, lH).
High performance liquid chromatography on a Merck "Lichrospher 100 RP-18 endcapped" type column, length '~44 mm, diameter 4.6 mm, eluent: ammonium acetate 65 mM - acetonitrile (65:35), flow rate of 1 ml/minute, detector:
refractometer, retention time 13.6 min~ltes s N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3,4-dimethylbenzene-amide has a sweetening potency which is, on a weight basis, 50,000 times higher than that of sucrose by comparison with a '~o sucrose solution.
As examples, the sweetcning potency of other compounds according to the invention, obtained following an experimental protocol similar to that describedabove and that the person skilled in the art shall easily find, is given in Table 1.
The approximate sweetening potencies, e~pressed in rounded-off values, are givencompared to a % sucrose solution.
Table 1 O CO - NH - R
NC ~ NH - C - NH ~ C ~ H
Y
(CH~)n COOH
R n Y Sweetçnin~
potency CH3 1 CH 50,000 ~CH3 C H3 1 N 40,000 O'CH2 1 CH 50,000 ~0 O'CH2 1 N 40,000 ~0 OH 1 CH 40,000 ~OMe OH 1 N 50,000 ~OMe CA 02209922 l997-07-08 Table 1 (continued) R n Y Sweet~nin~
potency Cl 1 CH 40,000 ~OMe NO2 1 CH 40,000 ~CH3 1 CH 30,000 1 N 20,000 O~ 1 CH 30,000 ~0 O~ 1 N 20,000 ~0 CH ~ CH 4 000 ~o2
3,4-methylenedioxyphenyl:
~ , 2 3-hydroxy-4-methoxyphenyl:
OH
~ OCH3 3-chloro-4-methoxyphenyl:
~ OCH3 4-methyl-3-nitrophenyl:
NOz ~ CH3 indan-S-yl:
1,4-benzodioxan-6-yl:
o 20 and their physiologically acceptable salts.
The compounds of the invention for which n is equal to 1 represent a preferred form of the invention.
S A particularly advantageous embodiment form of the invention is N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3,4-dimethylb~ 7~l-e~.,.ide of formula:
O CO--NH ~ CH 3 NC~;3NH--C--NH _ C~H
COOH
whose sweetening potency, expressed on a weight basis, is 50,000 times higher than that of sucrose by colllpalison with a '~% sucrose solution.
Another particularly advantageous embodiment form of the invention is N-(?-cyanopyrid-5-ylcarbamoyl)-L-aspartic acid-a-3,4-dimethylben7~n~mide 15 of formula:
O CO--NH~ CH3 NC~3NH--C--NH _ C_H
I
COOH
whose sweetening potency, expressed on a weight basis, is 40,000 times higher than that of sucrose by co.,lpafison with a 2% sucrose solution.
Other preferred compounds of the invention are characterised in that it is N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3,4-methylenedioxybenzene-5 arnide, N-(~-cyanopyrid-S-ylcarbamoyl)-L-aspartic acid-a-3,4-methylenedioxy-benzeneamide, N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3-hydroxy-4-methoxybenzeneamide, ~V-(2-cyanopyrid-5-ylcarbamoyl~-L-aspartic acid-a-3-hydroxy-4-methoxybenzeneamide, N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3-chloro-4-methoxyb~l~el~ealllide, 10 N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-4-methyl-3-nitrobenzeneamide, lV-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-indan-S-ylamide, N-( -cyanopyrid-5-ylcarbamoyl)-L-aspartic acid-a-indan-S-ylamide, ~V~4-c~anophenylcarbamoyl~-L-aspartic acid-a-1,4-benzodi-oxan-6-ylamide and N-(''-cyanopyrid-5-ylcarbamoyl)-L-aspartic acid-a-1,4-15 benzodioxan-6-ylamide.
The compounds of the invention differ therefore from the compounds described in the JP 86-'60052 document by the very specific nature and the position of the substituents fixed onto the benzeneamide group. In fact, in this prior 20 art document, the benzene ring of the benzeneamide group of the compounds described and claimed is monosubstituted, and, for the examples mentioned, only in position 4 (para).
In accordance with the present invention, the phenyl group R is simultaneously substituted in positions 3 (meta) and 4 (para) with specific groups.
25 The selection in the compounds of the invention of this novel group R leads to a spect~c~ r increase in the sweetening potency, it being possible for this potency to reach 10 (ten) times that of the compounds of the prior art, and consequently a significant decrease in the cost of use of such compounds.
The sweetening agents of the present invention may be added to any edible 30 product to which it is desired to give a sweet taste, provided that it is added in sufficient proportions to attain the level of sweetness desired. The optimal use concentration of the sweeterling agent will depend upon a variety of factors such as, for example, the sweetening potency of the sweetçning agent, the conditions of storage and use of the products, the particular constituents of the products and the level of sweetness desired. Any qualified person can easily ~letçrmine the optimal S proportion of sweetening agent which must be employed in order to obtain an edible product by carrying out routine sensory analyses. The sweetening agents of the present invention is, in general, added to the edible products in proportions, according to the sweetening potency of the compound, ranging from 0.5 mg to 50 mg of sweetening agent per kilogram or per litre of edible product. The 10 concentrated products will obviously contain greater quantities of ~w~etellillg agent, and will then be diluted following the final intentions of use.
The sweetçning agents of the present invention may be added in the pure fomm to products to be swee~ened, but because of their high sweetening potency they are generally mixed with an app-o~liate carrier or bulking agent.
Advantageously, the applol.liate carriers or bulking agents are selected from the group consisting of polydextrose, starch, maltocle~trin~, cellulose, methyl cellulose, carboxymethyl cellulose and other derivatives of cellulose, sodium alginate, pectins, gums, lactose, maltose, glucose, leucine, glycerol, m~nnitol,sorbitol, sodium bicarbonate, phosphoric, citric, tartaric, fumaric, benzoic, sorbic and propionic acids and their sodium, potassium and calcium salts, and equivalents thereof.
A sweetening agent of the invention may, in an edible product, be employed as the only sweetening agent, or in combination with other sweetening agents such as sucrose, com syrup, fructose, sweet dipeptide analogues or derivatives (as~a,l;~,l,e, alitame), neohesperidin dihydrochalcone, hydrogenatedisomaltulose, stevioside, the L sugars, gly~;yl,l,iGhl, xylitol, sorbitol, m~nnitol, acesulfame-K, saccharin and its sodium, potassium, ammonium and calcium salts, cyclamic acid and its sodium, potassium and calcium salts, sucralose, monellin, th~llm~tin and equivalents thereof.
The compounds of the invention can also be used either in the acid fomm or in their fomm of salts obtained with the aid of physiologically acceptable inorganic or organic bases, this having as effect to increase their solubility. Advantageously, these compounds are salified in the form of salts of sodium, potassium, ammonium, calcium or m~gn~cillm The pl~paldlion of the compounds of the invention makes use notably of 5 the methods commonly used in peptide synthesis (see for example M. Bodansky and A. Bodansky, The Practice of Peptide Synthesis, Springer Verlag, Berlin, 1984).
The pl~pa~dtion of the compounds according to the invention can thus be carried out from precursors of commercial origin, such as for example, N-10 benzyloxycarbonyl-L-aspartic acid 13-benzyl ester (n = 1), N-benzyloxycarbonyl-L-glutamic acid y-benzyl ester (n = ), and the amine R-NH2 wherein R is a disubstituted phenyl group such as defined above, in following the following reaction scheme:
COOH
C6HsCH2OCO-NH ~ C ~ H
(CH2)n isobutyl chloroformate HzN-R
N-methylmorpholine CO - NH - R
C6H5CH2OCO-NH ~ C ~ H
(CH2)n COOCH2C6Hs H2, Pd/C 10%
CO - NH - R
HzN ~ C ~ H
(CH2)n COOH
NC ~ N=C=O
y O CO - NH - R
NC ~ NH - C - NH - C ~ H
Y
(CH2)n COOH
The purification of the compounds of the invention is p~ lroll~led according to the standard techniques such as recryst~ tion and chromatography. Their structure and their purity have been checked by classical techniques (thin layerchromatography, high pelrol,llance liquid chromatography, infrared specLlollletry, S nuclear m~gnetic resonance, elementary analysis).
The sweetening potency of the compounds described in the Examples has been evaluated by a group of eight experienced people. For this, the compounds, in aqueous solution at ~ar~ing concentrations, are compared, with respect to taste, to 10 a control solution of sucrose of concentration '%. The sweetening potency of the test compound compared with sucrose then corresponds to the weight ratio between the compound and sucrose for equal ~w~ tlling h~lellsily, i. e. when thesweet tastes of the solution of the test compound and the control solution of sucrose are considered by a majority of people to ha~e the same sweetening 15 illttllSily.
The manner in which the invention may be carried out and the advantages resulting therefrom shall emerge better from the non-limiting implementation Examples that follow.
FXAl~PT F~
Preparation of N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3,4-di-methylbenzeneamide:
s O CO--NH ~ CH 3 NC ~3NH--C--NH ~ 1 ~ H
!
lH2 COOH
1. Plepaldlion of N-benzylox~carbonyl-L-aspartic acid-a-3,4-dimethyl-benzeneamide ,~-benzylester:
10To a solution of 3 g (8.4 mmoles) of N-benzyloxycarbonyl-L-aspartic acid ,13-benzyl ester (Bachem product No. C-1350) in 50 cm3 of tetrahydrofuran cooled to -15~C are added successively 0.84 g (8.4 mmoles) of N-methylmorpholine and 1.14 g (8.4 mmoles) of isobutyl chloroformate. After 2 min~ltes~ stirring at this ~ eldture, 1 g (8.4 mmoles) of 3,4-dimethylaniline 15(Aldrich product No. 1',637-3) is added. The reaction mixture is slowly warmed up and then is stirred for hours at ambient temperature. The N-methylmorpholine hydrochloride pl~:ci~ilate is removed by filtration, and then washed with 0 cm3 of tetrahydrofuran. The filtrate is concentrated to dryness under vacuum and the residue obtained is triturated in 50 cm3 of diethyl ether. The 20 white solid obtained is separated off by filtration and then washed again with 20 cm3 of diethyl ether. 3.3 g of N-benzyloxycarbonyl-L-aspartic acid-a-3,4-dimethylbenzeneamide ,B-benzylester are thus obtained (85% yield) whose melting point is 146~C.
2. Preparation of L-aspartic acid-a-3,4-dimethylbenzeneamide:
A solution of 3 g (5.6 mmoles) of lV-benzyloxycarbonyl-L-aspartic acid-a-3,4-dimethylbenzeneamide ,B-benzylester obtained above in 100 cm3 of methanol is submitted, in the presence of 10% palladium on activated charcoal, to S hydrogen under atmospheric pressure for 18 hours. After removing the catalyst by filtration, the solution is concentrated under vacuum and the white solid obtained is washed by trituration in acetone. 1.3 g of L-aspartic acid-a-3,4-dimethylbenzeneamide (85% yield) are thus obtained as a white solid whose melting point is 204~C. ~ts purity is monitored by thin layer chromatography on G
1060 silica gel (Merck No. 1.05554 silica support), eluent butanol-acetic acid-water (8-2-. ), vi.c~ tion with ninhydrin, Rf = 0.49.
3. Preparation of N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3,4-dimethylbenzeneamide:
15To a solution of 0.7 g (3 mmoles) of L-aspartic acid-a-3,4-dimethylbenzeneamide and 0.63 g (6 mmoles) of sodium carbonate in 30 cm3 of water, is added, under vigorous stirring, 0.47 g (3. mmoles) of 4-cyanophenylisocyanate in solution in 30 cm3 of benzene. The solution is stirred for 30 minutes at ambient temperature before being washed with thrice 30 cm3 of 20 diethyl ether. Acidifying to pH '-3 by a 6N hydrochloric acid solution leads to the formation of a white precipitate which is filtered off and washed with 5-6 cm3 of water. After filtration and drying, 0.98 g of N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3,4-dimethylbenzeneamide (86% yield) are obtained whose melting point is 17 ~C after recrystallisation from 95% ethanol.
Molecular formula: C20H20N404.
Thin layer chromatography: Silica gel G 60 F;~54 on aluminium sheets (Merck No.
1.05554), eluent: chloroform-methanol (6:4), vi~ tion with ninhydrin, Rf =
0.30.
NMR (lH, ppm), DMSO D6: '2.15 (s, 3H), ~.5 (s, 3H), 7.7 (m, '2H), 4.6 (m, lH), 6.9 (d, lH), 7.0 (d, lH), 7.3 (rn, H), 7.6 (m, 4H), 9.5 (s, lH), 9.9 (s, lH).
High performance liquid chromatography on a Merck "Lichrospher 100 RP-18 endcapped" type column, length '~44 mm, diameter 4.6 mm, eluent: ammonium acetate 65 mM - acetonitrile (65:35), flow rate of 1 ml/minute, detector:
refractometer, retention time 13.6 min~ltes s N-(4-cyanophenylcarbamoyl)-L-aspartic acid-a-3,4-dimethylbenzene-amide has a sweetening potency which is, on a weight basis, 50,000 times higher than that of sucrose by comparison with a '~o sucrose solution.
As examples, the sweetcning potency of other compounds according to the invention, obtained following an experimental protocol similar to that describedabove and that the person skilled in the art shall easily find, is given in Table 1.
The approximate sweetening potencies, e~pressed in rounded-off values, are givencompared to a % sucrose solution.
Table 1 O CO - NH - R
NC ~ NH - C - NH ~ C ~ H
Y
(CH~)n COOH
R n Y Sweetçnin~
potency CH3 1 CH 50,000 ~CH3 C H3 1 N 40,000 O'CH2 1 CH 50,000 ~0 O'CH2 1 N 40,000 ~0 OH 1 CH 40,000 ~OMe OH 1 N 50,000 ~OMe CA 02209922 l997-07-08 Table 1 (continued) R n Y Sweet~nin~
potency Cl 1 CH 40,000 ~OMe NO2 1 CH 40,000 ~CH3 1 CH 30,000 1 N 20,000 O~ 1 CH 30,000 ~0 O~ 1 N 20,000 ~0 CH ~ CH 4 000 ~o2
Claims (8)
1. Sweetening compounds, characterised in that they have the following formula:
in which:
Y is a CH group or a nitrogen atom, A is an oxygen atom, n is equal to 1 or 2, R is a 3,4-disubstituted phenyl radical selected from the groups:
3,4-dimethylphenyl:
3,4-methylenedioxyphenyl:
3-hydroxy-4-methoxyphenyl:
3-chloro-4-methoxyphenyl:
4-methyl-3-nitrophenyl:
indan-5-yl:
1,4-benzodioxan-6-yl:
and their physiologically acceptable salts.
in which:
Y is a CH group or a nitrogen atom, A is an oxygen atom, n is equal to 1 or 2, R is a 3,4-disubstituted phenyl radical selected from the groups:
3,4-dimethylphenyl:
3,4-methylenedioxyphenyl:
3-hydroxy-4-methoxyphenyl:
3-chloro-4-methoxyphenyl:
4-methyl-3-nitrophenyl:
indan-5-yl:
1,4-benzodioxan-6-yl:
and their physiologically acceptable salts.
2. Sweetening compounds according to claim 1, characterised in that n is equal to 1.
3. Sweetening compound according to claim 1, characterised in that it is N-(4-cyanophenylcarbamoyl)-L-aspartic acid-.alpha.-3,4-dimethylbenzeneamide of formula:
4. Sweetening compound according to claim 1, characterised in that it is N-(2-cyanopyrid-5-ylcarbamoyl)-L-aspartic acid-.alpha.-3,4-dimethylbenzeneamideof formula:
5. Sweetening compounds according to claims 1 and 2, characterised in that it is N-(4-cyanophenylcarbamoyl)-L-aspartic acid-.alpha.-3,4-methylenedioxybenzeneamide, N-(2-cyanopyrid-5-ylcarbamoyl)-L-aspartic acid-.alpha.-3,4-o methylenedioxybenzeneamide,N-(4-cyanophenylcarbamoyl)-L-aspartic acid-.alpha.-3-hydroxy-4-methoxybenzeneamide, N-(2-cyanopyrid-5-ylcarbamoyl)-L-aspartic acid-.alpha.-3-hydroxy-4-methoxybenzeneamide, N-(4-cyanophenylcarbamoyl) -L-aspartic acid-.alpha.-3-chloro-4-methoxybenzeneamide, N-(4-cyanophenylcarbamoyl)-L-aspartic acid-.alpha.-4-methyl-3-nitrobenzeneamide, N-(4-cyanophenylcarbamoyl)-L-aspartic acid-.alpha.-indan-5-ylamide, N-(2-cyanopyrid-5-ylcarbamoyl)-L-aspartic acid-.alpha.-indan-5-ylamide, N-(4-cyanophenylcarbamoyl)-L-aspartic acid-.alpha.-1,4-benzodioxan-6-ylamide and N-(2-cyanopyrid-5-ylcarbamoyl)-L-aspartic acid-.alpha.-1,4-benzodioxan-6-ylamide .
6. Sweetening composition characterised in that it contains at least one of the sweetening compounds according to any one of claims 1 to 5.
7. Use of the compounds according to any one of claims 1 to 5 as sweetening agents.
8. Method of preparing the compounds according to any one of claims 1 to 5, characterised in that it consists in condensing a compound of formula:
with a compound of formula:
in which compounds, n, R and Y are such as defined in claim 1.
with a compound of formula:
in which compounds, n, R and Y are such as defined in claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR95/00878 | 1995-01-26 | ||
| FR9500878A FR2729950B1 (en) | 1995-01-26 | 1995-01-26 | NOVEL SWEETENING AGENTS DERIVING N- (4- CYANOPHENYLCARBAMOYL OR 2-CYANOPYRID-5-YLCARBAMOYL) -L- ASPARTIC OR L-GLUTAMIC ALPHA-BENZENAMIDES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2209922A1 true CA2209922A1 (en) | 1996-08-01 |
Family
ID=9475512
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002209922A Abandoned CA2209922A1 (en) | 1995-01-26 | 1996-01-25 | Novel sweeteners derived from 3,4-disubstituted .alpha.-benzeneamide n-(4-cyanophenylcarbamoyl or 2-cyanopyrid-5-ylcarbamoyl)-l-aspartic or l-glutamic acids |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0805799A1 (en) |
| JP (1) | JPH10512872A (en) |
| AU (1) | AU689698B2 (en) |
| CA (1) | CA2209922A1 (en) |
| FR (1) | FR2729950B1 (en) |
| WO (1) | WO1996022971A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2744122B1 (en) * | 1996-01-25 | 1998-04-30 | Univ Claude Bernard Lyon | NOVEL SWEETENING AGENTS DERIVING N- (4-CYANOPHENYLCARBAMOYL OR 2-CYANOPYRID-5-YLCARBAMOYL) -L- ASPARTIC ALPHA-BENZENAMIDE 3-MONOSUBSTITUTE ACID |
| KR100583547B1 (en) * | 1998-04-09 | 2006-05-26 | 아지노모토 가부시키가이샤 | Aspartyl dipeptide ester derivatives, sweeteners comprising them and food comprising the sweeteners |
| JP2020055751A (en) * | 2017-02-13 | 2020-04-09 | 味の素株式会社 | Novel compound and taste-improving agent containing that compound |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61260052A (en) * | 1985-05-14 | 1986-11-18 | Ajinomoto Co Inc | Novel amino acid derivative and sweetener |
| AU636853B2 (en) * | 1988-08-23 | 1993-05-13 | Nutrasweet Company, The | Substituted aryl ureas as high potency sweeteners |
-
1995
- 1995-01-26 FR FR9500878A patent/FR2729950B1/en not_active Expired - Lifetime
-
1996
- 1996-01-25 EP EP96901851A patent/EP0805799A1/en not_active Withdrawn
- 1996-01-25 WO PCT/FR1996/000124 patent/WO1996022971A1/en not_active Application Discontinuation
- 1996-01-25 JP JP8522682A patent/JPH10512872A/en active Pending
- 1996-01-25 CA CA002209922A patent/CA2209922A1/en not_active Abandoned
- 1996-01-25 AU AU46267/96A patent/AU689698B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP0805799A1 (en) | 1997-11-12 |
| AU4626796A (en) | 1996-08-14 |
| WO1996022971A1 (en) | 1996-08-01 |
| JPH10512872A (en) | 1998-12-08 |
| FR2729950A1 (en) | 1996-08-02 |
| AU689698B2 (en) | 1998-04-02 |
| FR2729950B1 (en) | 1997-04-18 |
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