AU605228B2

AU605228B2 - Sweetening agents derived from guanidinoacetic and ethanamidinoacetic acids, process for sweetening various products, and compositions containing such sweetening agents

Info

Publication number: AU605228B2
Application number: AU10271/88A
Authority: AU
Inventors: Claude Nofre; Farroudja Ouar; Jean-Marie Tinti
Original assignee: Universite Claude Bernard Lyon 1
Current assignee: Universite Claude Bernard Lyon 1
Priority date: 1987-01-15
Filing date: 1988-01-14
Publication date: 1991-01-10
Anticipated expiration: 2008-01-14
Also published as: NO880143D0; IL84983A0; DK16188D0; FR2609603A1; DE3869823D1; BR8800116A; KR880008760A; EP0289430A1; NO880143L; FI880160A0; ZA88208B; AU1027188A; PT86547B; ATE74496T1; JPS63188360A; FI880160A7; CN88100129A; PT86547A; NZ223180A; EP0289430B1

Abstract

Sweetening agents of the formula: <IMAGE> in which, in a preferred embodiment, R0 is: either a heterocyclic ring constructed on a cyclopentadienyl or phenyl group by replacement of 1 to 3 cyclic C with N, O or S, or an indanyl, indenyl, naphthyl or tetrahydronaphthyl group or a heterocyclic derivative constructed on these groups by replacement of 1 to 4 cyclic C with N, O or S; R1 is H or CH3; R2 is a 2-13 C hydrocarbon group in which up to 4 C may be replaced by N, O, S, Cl, Br and I and up to 5 H by F; R3 and R4 are H.

Description

COMMONWEALTH OF AUSTRALIA I I Patents Act 1952 C O M P L E T E SP E.C I F. I-JC-A T I O N

(ORIGINAL)

Application Number Lodged Complete Specification Lodged Accepted Published Tis <;cu r':n t cont ains the amendments made under Section 49 and is corect for printing Priority 15 January 1987 6 Related Art 21 A 91 A~ A

A-

A i-i 1,4 ii Name of Applicant Address of Applicant Actual Inventor/s Address for Service :UNIVERSITE CLAUDE BERNARD LYON 1 S43 boulevard du 11 novembre 1918, 69100 villeurbanne, France Claude NOFRE; Jean-Marie TINTI Farroudja OUAR.

F.B. RICE CO., Patent Attorneys, 28A Montague Street, Balmain N.S.W. 2041 Complete Specification for the invention entitled: Sweetening agents derived from guanidinoacetic and ethanamidinoacetic acids, process for sweetening various products, and compositions containing such sweetening agents The following statement is a full description of this invention including the best method of performing it known to us:- The present invention relates to new sweetening agents, which are useful in particular for sweetening foods, beverages, confectioneries, pastries, chewing gum, hygiene products, cosmetics, toiletries, pharmaceutical and veterinary products and their equivalents. It also relates to preparations and compositions containing such -sweetening agents.

In European Patent Application EP-A-0 195 730 of the Applicant, there are described, as new sweetening agents, compounds of the formula: A(B)m I NH-C-qNH-(CH)-COOH o 0 0, ttoso 0R01 *0 0* wherein: 9 *II 0 0 0 A is N and 0 O OVI a 0 0« m and n are equal to 1 or 2; I I -2- B is, when n 1

H,

CN,

NO

2

OCH

3 S OR,

SO

2

R,

SO

2 NHR and S0 2

N(R)

2 R being an alkyl, cycloalkyl or aryl group having up to 10 carbon atoms, 1 or 2 carbon atoms being capable of being replaced by 1 or 2 sulfur or oxygen atoms, 4 4 ft 1 4 20 *when n 2

H,

CN and

OCH

3 X, which is in the 4-position, is CN and

NO

2 when B is H, CN and OCH 3 and is *6fS ft *1 **t It

S

CF

3

CHO,

CN,

GOGH

3 F and

NO

2 when B is NO 2 SOR, SO 2 R, S0 2 NHR and S0 2 N 2'-

I

I~ l^-l;rX 1 -3- In European Patent Application EP-A-0241 395 of the Applicant, there are proposed as sweetening agents compounds of general formula

R

1 \A/R2 X4 14- C N C COOH 3 3 wherein X 3

X

4 and X 5 are the same or different and are selected from the group consisting of

U,

Br,

CF

3

CF

2

CF

3 1

CH

2

CF

3 000000

C

1

-C

4 alkyl, CH=NOCH3, o" o~3 CH=NOH, 0000s CHO,

*OOQ

oa, CoCH20CH3,

CH

2

OH,

C1, gOG* CN, o 00cj 0 00COCF 3

COC

1

-C

3 alkyl, 0 CONH 2

CONHC

1

-C

3 alkyl,

CON(C

1

-C

3 alkyl) 2

COOC

1

-C

3 alkyl,

COQE,

F,

I,

f -4-

NH

2

NHC

1

-C

3 alkyl,

N(C

1

-C

3 alkyl) 2

NHCHO,

NHCOCH3,

NHCONH

2

NHSO

2

CH

3

NO

2 OC1-C 3 alkyl,

OCOCH

3

OH,

SC

1

-C

3 alkyl,

SOCI-C

3 alkyl, SO2CI-C 3 alkyl,

SO

2

NH

2

SO

2

NHC

1

-C

3 alkyl, S02N(C1-C 3 alkyl) 2 and

SO

3

H;

oo0* f 0 'a wherein A is selected from the group consisting of N and C; 0o99 o wherein R 1 is a hydrogen atom or a hydrocarbon group or a modified hydrocarbon group which contain up to 4 carbon atoms and which can be saturated or unsaturated, acyclic, cyclic or mixed, and wherein, in the modified "0 hydrocarbon group 1 to 2 carbon atoms can be replaced by 1 to 2 heteroatoms, which may be identical or different, selected from the group consisting of nitrogen, oxygen, sulfur, chlorine, bromine and iodine atoms, and 1 to 3 hydrogen atoms can be replaced by 1 to 3 fluorine atoms; wherein R2 is a hydrocarbon group or a modified hydrocarbon group which contain 2 to 13 carbon atoms and which can be saturated or unsaturated, acyclic, cyclic or mixed, and wherein, in the modified hydrocarbon group 1 to 4 carbon atoms can be replaced by 1 to 4 heteroatoms, which may be identical or different, selected from the group consisting of nitrogen, oxygen, sulfur, chlorine, bromine and iodine atoms, 1U and 1 to 5 hydrogen atoms can be replaced by 1 to fluorine atoms; wherein R 1 and R 2 can be fused; wherein R 3 is selected from the group consisting of a hydrogen atom or a Cl-C 3 alkyl group; 9 wherein R 4 is selected from the group consisting of: H and

CH

3 with the proviso that when X 3

X

5

R

3 and R 4 are hydrogen atoms, and when X 4 is CN or NO2, that R 1 and R 2 may not be CN or OCH 3 and when X 4 is H, CF 3 CHO, C1, CN COCH 3 F or

NO

2 that R 1 may not be NO 2 or SOC -C 2 alkyl and that R 2 may not be NO 2 SOR, S0 2 R, S0 2 NHR. or S0 2

N(R)

2 R being an alkyl, cycloalkyl or aryl group having up to 10 atoms of carbon, 1 or 2 of which may be replaced by 1 or 2 atoms of sulfur or oxygen.

L -6- The sweetening agents of the present invention have the general formula: 1 PR2 A R 4

H

R N C N-C-COOH o I

R

including the tautomeric forms and the physiologically acceptable salts thereof, wherein Ro is selected from the group consisting of: the heterocyclic groups derived from the 1,3-cyclopentadien-l-yl, 2,4-cyclopentadien-l-yl and phenyl parent hydrocarbon groups by replacement of 1 to 3 carbon atoms of the hydrocarbon parent ring by 1 to 3 nitrogen, oxygen and sulfur atoms, and wherein the hydrogen atoms of the 3and 4-positions' of the 1,3-cyclopentadien-l-yl and 2,4-cyclopentadien-l-yl parent groups and of the 4- and 5-positions the phenyl parent group can be substituted in the corresponding heterocyclic group by Br, CF 3

CH

3 Cl, CN, F, I, NH 2

NO

2

OCH

3 .or OH, I the indan-5-yl, inden-2-yl, inden-5-yl and inden-6-yl carbocyclic groups and the corresponding e heterocyclic groups obtained by replacement of 1 to 4 carbon atoms of the hydrocarbon parent ring by 1 to 4 nitrogen, oxygen or sulfur atoms and by the SO, CO and SO 2 groups for the 1- and 3-carbons of the indan-5-yl parent group, and by the NO or CCH 3 groups for the 3-carbon of 7 the 1H-inden-5-yl or for the 1- and 3-carbons of the parent group, and wherein the hydrogen atom of the 7position of the indan(or inden)-5-yl and of the 4-position of the inden-6-yl groups can be substituted in the carbocyclic group and in the corresponding heterocyclic group by Br, CF 3

CH

3 Cl, CN, F, I, NH 2

NO

2

OCH

3 or OH, .the 2-naphthyl and 5,6,7,8-tetrahydro-2naphthyl carbocyclic groups and the corresponding heterocyclic groups obtained by replacement of 1 to 4 carbon atoms of the hydrocarbon parent ring by 1 to 4 nitrogen, oxygen or sulfur atoms and by the SO, CO and SO 2 groups for the 5- and 8-carbons of the *5,6,7,8tetrahydronaphthyl parent group, and wherein the hydrogen atom of the 4position of the 2-naphthyl and 5,6,7,8-tetrahydro-2naphthyl groups can be substituted, both in the carbocyclic group and in the corresponding heterocyclic group, by Br, o CF 3

CH

3 Cl, CN, F, I, NH 2

NO

2

OCH

3 or OH; *j2 wherein A is selected from the group consisting of N and C; rrr ri r i.

Pi (ttSD

I

wherein R 1 is a hydrogen atom or a hydrocarbon group or a modified hydrocarbon group which contains up to 4 carbon atoms and which can be saturated or unsaturated, acyclic, cyclic or mixed, and wherein, in the modified hydrocarbon group 1 to 2 carbon atoms can be replaced by 1 to 2 heteroatoms, which may be identical or different, selected from the group consisting of nitrogen, oxygen, sulfur, chlorine, bromine and iodine atoms, and 1 to 3 hydrogen atoms can be replaced by 1 to 3 fluorine atoms; wherein R 2 is a hydrocarbon group or a modified hydrocarbon group which contain 2 to 13 carbon atoms and which can be saturated or unsaturated, acyclic, cyclic or mixed, and wherein, in the modified hydrocarbon group 1 to 4 carbon a'toms can be replaced by 1 to 4 heteroatoms, which may be identical or different, selected from the group consisting of nitrogen, oxygen, sulfur, chlorine, bromine and iodine atoms, 0 and 1 to 5 hydrogen atoms can be replaced by 1 to fluorine atoms; wherein R 1 and R 2 can be fused; wherein R 3 is selected from the group consisting of a hydrogen atom or a Cl-C 3 alkyl group; wherein R 4 is selected from the group consisting of: H and S0

CH

3 1 0* l- with the proviso, when A N, that R2 is not a SX4 group in which X 3

X

4 and X 5 are: Br,

CF.,

CF

2

CF,,

CH

2

CF

3 C,-C alkyl, CH=NOCH -9-

CH=NOH,

CHO,

CH OCH 3 f

CH

2

QHI

cl,

CN,

COCF31 COO -O alkyl, C0NH 2 OONHC -C 3 alkyl, CON(C-%3 alkyl)2, CoocI-C 3 alkyl,

OOOH,

F,

NH 21 NHC alkyl, N (C c alkyl) 2

NHOHO,

2o NHCOCHV, N HCONH 2

NHSO

2 CH31 NO2 OC 3 alkyl,

OCOCH,

OH,

SC- C alkyl,

SO

C 1 -C3 alkyl, so 2 C C alkyl,

SO

2

NH,

SO

2 NHCI- 3 alkyl,

SO

2

N(CI-C

3 alkyl) 2 and SO 4, 1 1 Advantageously, in practice -the heteroatoms, which in the parent hydrocarbon rings replace the carbon atoms to form a corresponding heterocyclic group R 0 are *N to replace CH, and *NH, 0, S, SO and SO 2 to replace CH 2

-R

0 when R 0 is a heterocyclic group, is selected from the group consisting of a pyrrolyl, pyrazolyl, imidazolyl, fury!, oxazolyl, isoxazolyl, oxadiazolyl, 1110 furazanyl, thienyl, thiazolyl, isothiazolyl, pyridyl, 2cyanopyridyl, pyridazinyl, pyrimidinyl, 2cyanopyrimidinyl, pyrazinyl. indolyl, isoindolyl, indolizinyl, 2.indazolyl, purinyl, isobenzofuranyl, 3,4methylenedioxyphenyl, benzisoxazolyl, benzofurazanyl, benzothiazQlyl, saccharin-5-yl, saccharin-6-yl, guinolyl, isocguinolyl, cinnolinyl, phthalazinyl, quinazolinyl, guinoxalinyl, naphthyridinyl, 1,5-naphthyridinyl, 1,6naphthyridinyl, l,7-naphthyridinyl, 1,4,5-triazanaphthyl, 1,2,8-triazanaphthyl, 1,3,8- 4 a"ORD triazanaphthyl, l,2,5-triazanaphthyl, pteridinyl and isocoumarinyl ring; A is a nitrogen atom; R, is selected from the group consisting of H and

CH

3 71 r I: iC.

-11-

R

2 is selected from the group consisting of normal alk(en)(yn)yl

C

2 -C13, branched alk(en)(yn)yl

C

3

-C

13 cycloalk(en)yl

C

3 -C13, alk(en)yl cycloalk(en)yl

C

4

-C

13 cycloalk(en)yl alk(en)yl

C

4

-C

13 alk(en)yl cycloalk(en)yl alk(en)yl

C

5

-C

13 alk(en)yi bicycloalk(en)yl

C

7

-C

13 fused bicycloalk(en)yl

C

7

-C

13 alk(en)yl fused bicycloalk(en)yl

C

8

-C

13 fused bicycloalk(en)yl alk(en)yl

C

8

-C

1 3 alk(en)yl fused bicycloalk(en)yl alk(en)yl c 9 -c 13 fused tricycloalk(en)yl

C

1 0

-C

1 3 alk(en)yl fused tricycloalk(en)yl

C

11 -C13, fused tricycloalk(en)yl alk(en)yl C1 1

-C

1 3 and alk(en)yl fused tricycloalk(en)yl alk(en)yl

C

13 wherein up to 4 carbon atoms can be replaced by heteroatoms, which may be the same or different, selected from the group consisting of: N to replace CH, NH, 0 and S to replace CH 2 and Cl, Br, and I to replace

CH

3 and wherein up to 5 hydrogen atoms can be replaced by fluorine atoms;

R

3 in one of the tautomeric forms of the molecule, is a hydrogen atom;

R

4 is a hydrogen atom.

84 4o 004* -12- In a preferred embodiment, the sweetening agents according to the invention consist of compounds of the formula R R

N

RO-N=-C-NH-CH

-COOH

wherein RO is selected from the group consisting of a 2- 2-cyanopyrimidin-5-yl, indazol-6-yl, benzisoxazol-5-yl, benzisoxazol-6-yl, isoquinol-6-yl, quinazolin-7-yl, 1,7-naphthyridin-3-yl or 1,3,5-triazanaphth-7-yl group,

R

1 is H or CH3,

R

2 is c-C 8

H

15

CH

2

C

6

H

5

CH

2 -c-C 6

H

11

CH(CH

3

)C

6 H5 or

CH(CH

3 )-c-C 6

H

11 The sweetening agents of the invention are also characterized in that they can be converted to salts by physiologically acceptable inorganic or organic acids or bases. Advantageously, these compounds are converted to salts in the form of hydrochlorides or of sodium, potassium, ammonium, calcium and magnesium salts.

In other words, the invention consists in having oo selected as the RO group derivatives of the following parent hydrocarbon groups: Ot o ote t00 CL 13 -1,.3-cyclopentadien-1-yl 2, 4-cyclopentadien-1-fl phenyl inden-2-yl k 44 7- 14

I'

~Ii S J eq tAt

A.,

-inden-6-y naphthyl: 15 5, 6,7,8-tetrahydro-2-naphthyl The invention also relates to the process which consists of sweetening the foods, beverages, confectioneries, pastries, chewing gum, hygiene products, cosmetics, toiletries, pharmaceutical and veterinary products and their equivalents, by adding thereto an adequate quantity of one or more sweetening agents according to the present invention. By "adequate quantity" «o 'there is designated a quantity of sweetening agent :tO o sufficient to produce the perception of a sweet taste.

The invention also relates to the preparations S which have been sweetened according to the process of the present invention.

°Oo The invention also relates to the sweetening 'o 1 compositions characterized in that they consist of an adequate quantity of at least one sweetening agent according to the present invention, and an appropriate carrier or bulking agent.

09« C -16- The invention also relates to the sweetening compositions which are characterized in that they consist of an adequate quantity of one or more sweetening agents according to the present invention, and one or more other sweetening agents.

The compounds of .the present invention are distinguished for the most part from the compounds described in European Patent Applications EP-A-0 195 730 or 0 241 395, often by their greater stability in solution and, for the nitrogen-containing heterocyclic derivatives, by a better solubility and by their faster rate of dissolution in the usual media (carbonated beverages...).

In addition, the present invention also makes it possible to synthesize sweetening agents which are among the most potent obtained heretofore, since it has been possible to obtain a sweetening agent which is 130,000 times sweeter than sucrose, and which therefore has nothing in common with the sweetening potency of the principal °sweetening agents which are currently used, which have been o0 proposed or developed or which are in the course of testing, and which are listed in Table I hereinafter.

torr The sweetening potency of the compounds of the present invention is therefore often very greatly enhanced relative to the compounds described heretofore, and this is completely unexpected considering that any modification, even slight, of the molecular structure of a sweetening agent can cause suppression of the sweetening activity, all the more so because the relationships between the structure and the sweetening activity are unpredictable (see, for example, M.G.J. BEETS, Structure-Activity Relationships in 2 1 -17- Human Chemoreception, Applied Science Pub., London, 1978, pp. 259-362).

TABLE I Sweetening agents Sweetening potency (sucrose 1) I0

I

4 -a a at a Xylitol Sodium cyclamate Glycyrrhizin Acesulfame-K Aspartame Stevioside Saccharin Neohesperidin dihydrochalcone Trichlorogalactosucrose Alitame Thaumatin Monellin 1 200 200 300 400 1000 2000 2000 2000 2000 a a Ua 4.

4;II a Another very important advantage of the sweetening agents of the present invention is to provide a very pure sweet taste, practically identical to that of sucrose, without liquorice aftertaste (as is the case, for example, for glycyrrhizin or thaumatin) and without metallic or bitter aftertaste (as is the case, for example, for saccharin or acesulfame-K).

The other advantages which ultimately can be expected of the sweetening agents of the present invention are directly related to their intensive sweetening I 1 1. I M- -18activity, viz. in particular their low cost and their safety of use, due to the very low concentrations necessary to obtain a sweet taste.

The compounds of the present invention can be prepared by various methods already described in the literature Med. Chem., 1978, 21, 773-781; Chem. Ber., 1966, 99, 1252-1257; Brit. Pat. No. 1 587 258; J. Org.

Chem., 1970, 35, 2067-2069; J. Org. Chem., 1986, 51, 1882- 1884; Chem. Ber., 1967, 100, 591-604; J. fur Prakt. Chemie, 1977, 319, 149-157; The Chemistry of Amidines and Imidates, S. Patai ed., Wiley-Interscience, 1975, p. 283-348).

The process for preparation of such sweetening agents consists in condensing a thioureido or thioamido derivative of general formula:

S

Gf -N C A-G 1 aG Ge ft .1 with a compound of general formula:

G

G6 wherein:

G

1 is RO or HOOCCHR 4

.G

2 is R 2 or HOOCCHR 4

G

3

G

4 and G 5 are H, R 1 or R 3

G

6 is RO, R 2 or HOOCCHR 4 is N or C, -19n is equal to 1 when A' is N, and is equal to 2 when A' is C; and wherein: G1, G2 and G 6 are not simultaneously identical, A and A' are not simultaneously carbon atoms, A' is N and G 3

G

4 and G 5 are H when G 1 or

G

2 or G 6 are HOOCCHR 4 and wherein RO, R 1

R

2

R

3

R

4 and A correspond to the definitions given hereinbefore.

The thioureido derivatives can be advantageously obtained by reaction of an isothiocyanate with an amine according to one of the reactions:

S

r

II

G--N C= C S +HN- G 2

G-N-C-N-G

z o I I I .1 S

G

3

G

3

H

The condensation of the thioureido or thioamido derivatives can be advantageously realized by activation of the sulfur atom by transforming it to an S-alkyl or SO 3

H

group, or by replacing it by an 0-alkyl or O-SO 2 aryl group or a halogen atom. In practice, the thioureido or

I

111"-'- 2 thioamido derivative is advantageously activated transforming it to an S-methylisothioureido or methylisothioamido derivative of general formula:

SCH

3

II

G- N zA-G 2 by the action of an alkylating agent selected from the group consisting of methyl iodide and dimethyl sulfate.

The preferred S-methylisothioureido derivative corresponds to the general formula:

SCH

3

R

0 -N =C N-R 2 I I

R

3

RI

When A is N and when G 3 and G 4 are hydrogen atoms, the condensation can be advantageously realized by activating the thioureido derivative by transformation to a carbodiimide intermediate: o 09 9 0 9* 9 9*~ 99 9 9r 9 00

S

II

GI- N -C-N-G 2 H

H

Cl CO or Ph 3

P-C

C

4 Et 3

N

G

1 N- G 2 either by treatment, by phosgene or by the action of an equimolar mixture of (C 6

H

5 3 P, CC1 4 and (C 2

H

5 3

N.

1 -21- Finally, when A and A' are N and when G 3 or G 4 or

G

5 is H, the condensation of the thioureido derivative with the amine can be advantageously realized by 'action of dicyclohexylcarbodiimide (DCC) according to the reaction:

G

5

G

6 S N II G iG 1 5

DCC

G

1

N-C-N-G

2 HN G-N C N-G 2 1 1 G6 I

G

3

G

4

G

3

G

4 Advantageously, in practice: One of the preferred methods of synthesis for obtaining the thioureido derivatives consists in making an alkyl or aryl isothiocyanate react with an appropriately chosen amine. The reaction is conducted at room o o temperature or at boiling depending on the reactivity of the two compounds which have been brought together, and it is effected in an organic solvent such as ethanol, methanol, chloroform or acetone. The following reactions can-therefore be realized:

R

1

R

R1 Rz N R -N=C=S N RO -NH-C=S

H

H R,

N

Ro-NHR3 R-N=C=S R 0

-N-C=S

R, 3 -22- R1

/R

2 C1l R\

R

O -N-C=S N

R

3

H

3

N

RO-N- C= S

R

3 S Sa S S The condensation of the thioureido derivatives can then be advantageously realized either by replacing the sulfur atom by an activated ligand (designated by the letter L in the formulas hereinafter) or by transforming the thioureido derivative to a carbodiimide derivative.

In the first method of activation, the activated ligand is preferably selected from the group consisting of the S-alkyl, S0 3 H, O-alkyl and OS02aryl groups and the halogens. The condensation then consists in making the thusly activated intermediate react with an appropriately selected amine, by bringing into contact:

R

i

R,

A

il

R

o C="L and H N-CHR--COOH

R

3 eta *:at StA S 4 R1 R

A

R

O

-NHR

3 and L -C N-CHR 4

-COOH,

-23-

L

I

RO NZ -C=NCHR 4 f COOH and R3 R, /R2

N

H

4 0 00 F 4e 4,4.

I'o 0,, 2L).

In a particularly advantageous method of realization, the preferred activated ligand L is an S-alkyl group, preferably an S-CH 3 group, such as, for example, in the following S-methylisothioureido derivative:

R

I

R

2

N

RO- N =C-S-CH 3 The activated intermediate is advantageously obtained by treating the thioureido derivative by an alkylating agent (methyl iodide, dimethyl sulfate) in solution in an organic solvent such as acetone or 2-butanone, at a temperature between room temperature and boiling. The S-methylisbthioureido derivative is obtained in the form of a salt (iodide, sulfate). The salt is treated by a sodium hydroxide or potassium hydroxide solution to liberate the base form. Condensation with the alpha-amino acid is then effected in an ethanol-water mixture, in the presence of a base such as sodium hydroxide, potassium hydroxide or a tertiary amine (such as, for example, triethylamine), at temperatures between room temperature and boiling.

7 i; -24- In the second method of activation, the carbodiimide intermediate is advantageously obtained by action of phosgene, or by action of an equimolar mixture of triphenylphosphine, carbon tetrachloride and tertiary amine (triethylamine, for example) in solution in an organic solvent such as carbon tetrachloride or dichloromethane, at temperatures between 0 OC and boiling. The condensation then consists of making the carbodiimide intermediate react with an appropriately selected amine, by bringing into contact: R1 /R2

R

0 C=-N-CHR -COOH and N

H

4 *t 0 *4.

#1 OI; R -N=C:=N-R2and H 2

N-CHR-COOH

RO '-NHR 3 andR 2 -N C=N-CHR,-COOH These condensations can be effected in water or in organic solvents such as ethanol, methanol, acetone, chloroform,

II

4*44 carbon tetrachloride or pyridine, at a temperature which can vary from room temperature to boiling.

In certain reactions (reactions 2 to it can be advantageous to provide the carboxyl group of the alphaamino acid with initial protection in the form, for example, of an ester (methyl, ethyl, tert-butyl, benzyl ester). To obtain the compounds of the invention, it is then necessary to eliminate the protective group by the most appropriate means, which can be, for example, saponification by sodium hydroxide solution or hydrolysis by hydrogen chloride solution.

The compounds of the invention can exist, depending on the nature of R 1

R

2

R

3 and A, in zwitterion form or in acid form. They can therefore be converted to salts by physiologically acceptable inorganic or organic 2 acids or bases. One of the methods of choice for preparing these salts consists in concentrating to dryness under vacuum a mixture, in aqueous solution, of a compound of the invention and one equivalent of an inorganic or organic acid or base. The preferred salts of the invention are the 00*r hydrochlorides and the sodium, potassium, ammonium, calcium and magnesium salts.

The purification of the compounds of the invention was realized by standard techniques such as i recrystallization or chromatography. Their structure and their purity was checked by classical techniques (thinlayer chromatography, high-performance liquid Schromatography, infrared spectrometry, nuclear magnetic resonance, elemental analysis).

-7 -26- The present sweetening agents can exist as equilibrium mixture of tautomeric forms. Thus, example, when A is N and R, and R 3 are H, there obtained: an for are H R 2 H /R 2 N When A is N, R, is CH 3 and R 3 is H, there are obtained: a a a a a a#a a~ a a a a a a.

a *a a a *44 a @4 4a a a a CH3 CH3 /R 2

C--N

When A is N, Rl is H and R 3 is CH 3 there are obtained: a a, a ~4 4 0 4 a a4M.a o a a '*54 a -N-C N

CI

/R

i'V i i -27- When A is C and R 3 is H, there are obtained:

R

2 RI R

-H

I R o 0 j 0D n

II

C--C H H H H This is why the sweetening agents of the present invention are represented, in the general formula, by a resonance hybrid, and, in the descriptive part, by one of their tautomeric forms, in the full knowledge that the tautomeric form shown is necessarily in equilibrium with the other tautomeric forms, the respective proportions of the tautomers varying depending on the nature of the substituents R 0

R

1

R

2 and R 3 and depending on the pH.

The sweetening agents of the present invention have the advantage that they can be added to any comestible product to which it is desired to impart a sweet taste, provided they are added in proportions sufficient to attain the desired level of sweetness. The optimum utilization concentration of the sweetening agent will depend on diverse factors such as, for example, the sweetening potency of the sweetening agent, the conditions of storage and utilization of the products, the particular constituents of the products, the flavor profile of the comestible products and the desired level of sweetness.

Any person skilled in the art can easily determine the optimum proportion of sweetening agent which must be employed to obtain a comestible product by realizing routine sensory analyses. The sweetening agents of the present invention are generally added to comestible flr

IL

II

-28products in proportions of around 0.0001 to around 0.2 weight percent of the comestible product, advantageously of around 0.0005 to around 0.15 weight percent and preferably of around 0.001 to around 0.1 weight percent. The concentrated products obviously will contain higher percentages of sweetening agent(s), and will then be diluted according to the ultimate utilization purposes.

The products amenable to being sweetened by the sweetening agents of the present invention comprise all the products for which a component with sweet taste is desired, especially, and in non-limitative manner, food products (for human or animal consumption), beverages (alcoholic beverages, non-alcoholic beverages, juices, carbonated beverages), confectioneries, pastries, chewing gum, hygiene products, cosmetics, pharmaceutical and veterinary products and their equivalents.

ro a.4 3001 .4 I It o ir cr~ 30 444 The sweetening agents of the present invention can be added in pure form to comestible products to impart a sweet taste thereto. Nevertheless, by virtue of the high sweetening potency of the present sweetening agents, they are generally admixed with an appropriate carrier or bulking agent. Advantageously, the appropriate carriers or bulking agents are selected from the group consisting of polydextrose, starch, maltodextrins, cellulose, methylcellulose, carboxymethylcellulose and other cellulose derivatives, sodium alginate, pectins, gums, lactose, maltose, glucose, leucine, glycerol, mannitol, sorbitol, sodium bicarbonate, phosphoric, citric, tartaric, fumaric, benzoic, sorbic and propionic acids, and their sodium, potassium and calcium salts and the equivalents thereof.

rlchi Cr rt i -29- The present sweetening agents can be employed in a comestible product alone, as the sole sweetening agent, or in the form of mixtures of two or more sweetening agents of the present invention. The present sweetening agents can in addition be used in combination with other sweetening agents such as the sugars (sucrose), corn syrups, fructose, sweet dipeptide derivatives (aspartame, alitame), glycyrrhizin, xylitol, sorbitol, mannitol, acesulfame-K, saccharin and its sodium, potassium, ammonium and calcium salts, cyclamic acid and its sodium, potassium and calcium salts, trichlorogalactosucrose, monellin thaumatin and the equivalents thereof.

The sweetening potency of the compounds prepared in the following examples was evaluated by a group of eight experienced tasters. For this purpose, the compounds, in aqueous solution in variable concentrations, are compared in terms of taste with a control solution of sucrose in a *concentration of 2% and in certain cases of 5% and S in concentrations corresponding to those used in a t t S«,3 common application. The sweetening potency of the synthetic sweetening agents actually varies as a function of the concentration of the sucrose solution used as reference. The sweetening potency of the compound tested by comparison with sucrose then corresponds to the weight ratio which exists between the compound and sucrose at equal sweetening intensity, when the sweet tastes of the solution of the tested compound and of the control solution of sucrose are considered by a majority of tasters to have the same sweetening intensity.

i 20 The manner in which the invention can be realized and the advantages which derive therefrom will be trs* ti L i understood more clearly and will be further explained by, but not limited to, the practical examples which follow.

j t I- ii S -31- EXAMPLE 1: Synthesis of N-[N-cyclooctylamino(1pyrrolylimino)methyl]-2-aminoethanoic acid: H c-C 8

H

1

N

N-N =C-NH-CH-COOH Stage 1: Preparation of N-cyclooctyl-N'-(lpyrrolyl)thiourea: A solution of 1 g (12.1 mmol) of 1-aminopyrrole and 2.06 *g (12.1 mmol) of cyclooctylisothiocyanate in cm 3 of acetonitrile is heated for 30 hr to boiling.

After concentration to dryness under vacuum, the residue obtained is dissolved in 30 cm 3 of ethyl ether then is washed by a 1 N hydrochloric acid solution (3 x 10 cm 3 The ethereal solution is dried over anhydrous sodium sulfate then concentrated to dryness under vacuum. There is obtained 2.2 g of an oil which is purified by column chromatography (silica gel 60; eluant: chloroform); there is obtained finally 0.75 g (yield 25%) of a solid, the melting point of which is 125 oC.

Stage 2: Preparation of N-[N-cyclooctylamino(lpyrrolylimino)methyl]-2-aminoethanoic acid in hydrochloride form: A suspension of 0.75 g (2.99 mmol) of the thiourea obtained in the preceding, of 0.52 g (4 mmol) of glycine tert-butyl ester and of 0.82 g (4 mmol) of dicyclohexylcarbodiimide in 30 cm 3 of ethyl acetate is heated for 15 hr to 75 OC. The solution is concentrated to i -32dryness under vacuum and the residue is dissolved in 50 cm 3 of ethyl ether. The ethereal solution obtained is extracted by 0.25 N hydrochloric acid solution (4 x cm 3 This aqueous solution is thereafter washed by ethyl ether (2 x 30 cm 3 then brought to pH 10 by addition of 1 N sodium hydroxide solution. The oily precipitate formed is extracted by ethyl ether (5 x 30 cm 3 The solution in ethyl ether is dried over anhydrous sodium sulfate then is concentrated to dryness. There is obtained 0.75 g (yield 69%) of tert-butyl N-[N-cyclooctylamino(lpyrrolylimino)methyl]-2-aminoethanoate in the form of an oil which crystallizes slowly (melting point 102 OC).

To 2.8 cm 3 of a 7.5 N HC1 solution in dioxane there is added 0.75 g of the compound obtained in the preceding. The solution is stirred for 2 hr at 0 OC, then minutes at 20 oC, and concentrated under vacuum. The oily residue obtained is triturated in anhydrous ethyl ether for several hours, which permits 0.5 g of an S' amorphous product to be obtained (yield 71%; melting point O 100 0

C).

V* i S t 8 The sweetening potency of this compound corresponds approximately, on a weight basis, to 1000 (one thousand) times that of sucrose (by comparison with a 2% sucrose solution).

EXAMPLE 2: Synthesis of N-[N-cyclooctylamino(2thiazolylimino)methyl]-2-aminoethanoic acid: H c-C 8

H

1

N

N=C-NH-CH-COOH

N

i -33- This compound is obtained from N-cyclooctyl-N'- (2-thiazolyl)thiourea and glycine tert-butyl ester by following the experimental protocol described in Example 1 (yield 90%; melting point 140 OC).

The sweetening potency of this compound corresponds approximately, on a weight basis, to 150 (one hundred fifty) times that of sucrose (by comparison with a 2% sucrose solution).

EXAMPLE .3: Synthesis of N-[N-(S)-alpha-methylbenzylamino(2pyridylimino)methyl]-2-aminoethanoic acid: H CH(CH 3

)CH

5

(S)

\3 6 5

N

N -C-NH-CH -COOH

N

This compound is obtained from glycine and alpha-methylbenzyl-N'-(2-pyridyl)-S-methylisothiourea by following the experimental protocol described in Example 9 (yield 28%; melting point 160 oC).

The sweetening potency of this compound is, on a weight basis, less than 10 (ten) times that of sucrose (by comparison with a 2% sucrose solution) with a bitter aftertaste.

-34- EXAMPLE 4: Synthesis of N-[N-benzylamino(3pyridylimino)methyl]-2-aminoethanoic acid:

H\/CH

2

C

6

H

N

N/ C-NH-CH-COOH N2 Stage 1: Preparation of N-benzyl-N'-(3pyridyl)thiourea: I 0 4.41 g (46.8 mmol) of 3-aminopyridine and 7 g (46.8 mmol) of benzylisothiocyanate are mixed in 50 cm 3 of ethanol. After 4 hours of stirring at 20 OC, 300 cm 3 of ethyl ether is added. After filtration and washing by ethyl ether of the precipitate formed, 10.4 g (yield 91%) of the thioureido derivative (melting point 137 OC) is obtained.

Stage 2: Preparation of N-benzyl-N'-(3pyridyl)carbodiimide: 4.86 g (20 mmol) of the thiourea obtained in the I 0 preceding, in solution in anhydrous tetrahydrofuran (THF) cm 3 is added dropwise, with stirring and at a temperature of 0 OC,to 19 cm 3 of a 20% solution of phosgene in toluene. After 5 hours at 0 0 C, the mixture is evaporated under vacuum. The residue, taken up by THF cm 3 and by diisopropylethylamine (6.8 cm 3 at 0 oC, is evaporated to dryness- then extracted by hexane (3x50cm 3 The extracts lead after evaporation, to the carbodiimide, -which is recovered in the form of an oil (3.84 g; yield 91%).

Stage 3: Preparation of N-[N-benzylamino(3pyridylimino)methyl]-2-aminoethanoic acid: A solution in pyridine (10 cm 3 of 1 g (4.7 mmol) of the carbodiimide obtained in the preceding and of 0.85 g mmol) of glycine methyl ester is stirred for 2 hours at 20 The mixture, treated by water (100 cm 3 and by a 5% NaHCO 3 solution (10 cm 3 is extracted by ethyl ether (3 x 50 cm 3 The extracts are dried over sodium sulfate and concentrated to dryness to give 0.78 g of an oil, which crystallizes rapidly. The solid, treated by ethyl ether and filtered (0.42 g; melting point 156 OC), is dissolved in a mixture of a 1 *N sodium hydroxide solution (1.4 cm 3 and methanol (3 cm 3 After 12 hours at 35 OC, the mixture I is concentrated to dryness and taken up in 10 cm 3 of water, and the solution thus obtained is washed by dichloromethane (3 x 15 cm 3 After neutralization to pH 7 by a 1 N HC1 solution and concentration of the solution to dryness, the residue obtained is extracted by boiling acetone (2 x cm3).

After concentration to dryness, 0.24 g (yield 17%) of the desired product is obtained (melting point 146 Oc).

The sweetening potency of this compound corresponds approximately, on a weight basis, to 4000 (four thousand) times that of sucrose (by comparison with a 2% sucrose solution).

-36- EXAMPLE Synthesis of N-LN-(S) -alpha-methylbenzylamino(4 ,6dimethyl-2-pyrimidinylimino)methylj -2-aminoethanoic a#did: H CH(CH 3 )C H 5

(S)

C

3

N

N zC -NHCH

-COOH

This compound is obtained from glycine and alpha-methylbenzyl-N- 6-dimethyl-2-pyrimidinyl) Smethylisothiourea by following the experimental protocol described in Example 9 (yield melting point 150 OC).

The sweetening potency of this compound is, on a weight basis, less than 10 (ten) times that of sucrose (by aftertaste.

EXAMPLE 6: Synthesis of indanylimino)methyl)-2-aminoethanoic acid: H CH (CH 3

)C

6

H

5

(S)

N

S/ N -C-H-CH-COOH

I

-37- This compound is obtained from glycine and by following the experimental protocol described in Example 9 (yield 18%; melting point 165 oC).

The sweetening potency of this compound corresponds approximately, on a weight basis, to 2000 (two thousand) times that of sucrose (by comparison with a 2% sucrose solution).

EXAMPLE 7: Synthesis of N-[N-(S)-alpha-methylbenzylamino(lHindazol-5-ylimino)methyl]-2-aminoethanoic acid: S00" H /CH(CH 3

)C

6 H (S)

N

HN N=C-NH-CH -COOH I N This compound is obtained from glycine and by following the experimental protocol described in Example 9 (yield 54%; melting point 176 OC).

The sweetening potency of this compound corresponds approximately, on a weight basis, to 1100 (one Sthousand one hundred) times that of sucrose (by comparison with a 2% sucrose solution).

AO!; I** -38- EXAMPLE 8: Synthesis of -alpha-methylbenzylamino (lHindazol-6-ylimino)methyl] -2-aminoethanoic acid: H NrN

NN

H

This compound is obtained from glycine and alpha-methylbenzyl-N' (Ii-indazol-6-yl) -S-methylisothiourea by following the experimental protocol described in Example 9 (yield 43%; melting point 188 OC).

aThe sweetening potency of this compound corresponds approximately, on a weight basis, to 24, 000 (twenty-four thousand) times that of sucrose (by comparison with a 2% sucrose solution).

o EXAMPLE 9: Synthesis -of N-[N4-cyclooctylamino(lH-indazol-6ylimino)methyl)-2-aminoethanoic acid: H \C 9

CH

1 N4 9 0 0 0/ N C N H C H C O O H

H

-39- Stage 1: Preparation of N-cyclooctyl-N'-(1Hindazol-6-yl)thiourea: 4.81 g (37.8 mmol) of cyclooctylamine and 6 g (34.2 mmol) of 1H-indazol-6-yl isothiocyanate are mixed in cm 3 of 95% ethanol. After 4 hours of stirring at 20 OC, the solution is concentrated to dryness under vacuum. The residue is dissolved in 20 cm 3 of acetone and the solution is treated by addition of 300 cm 3 of ethyl ether. After filtration and washing by ethyl ether of the precipitate thus formed, 2.6 g (yield 54%) of the thioureido derivative (melting point 160 is obtained.

Stage 2: Synthesis of N-cyclooctyl-N'-(1Hindazol-6-yl)-S-methylisothiourea: A mixture of 2.6 g (8.6 mol) of the compound obtained in the preceding and of 1.83 g (12.9 mmol) of methyl iodide is stirred in 20 cm 3 of butanone at 20 OC for S' 48 hours. After filtration of the precipitate formed and washing by ethyl ether, 2.2 g (yield 58%; melting point 198 OC) of the S-methylisothioureido derivative is obtained in hydroiodide form.

This salt is then dissolved in 40 cm 3 of a 1 N sodium hydroxide solution. The resulting alkaline mixture is extracted by dichloromethane (3 x 50 cm 3 After drying over anhydrous sodium sulfate and concentration to dryness, 1.4 g (yield 89%; melting point 132 OC) of the isothioureido derivative is obtained.

Stage 3: Preparation of N-[N-cyclooctylamino(lHindazol-6-ylimino)methyl-2-aminoethanoic acid: A mixture of 0.5 g (6.6 mmol) of glycine and of 30, 0.26 g (6.6 mmol) of sodium hydroxide in 5 cm 3 of water is added to a solution of 1.4 g (4.4 mmol) of N-cyclooctyl-N'- (1H-indazol-6-yl)-S-methylisothiourea in 20 cm 3 of l° ethanol. The mixture is heated to 70 OC for 20 hours.

After cooling, the solution is concentrated to dryness and the residue is dissolved in 30 cm 3 of water. The resulting solution is washed by dichloromethane (3 x 30 cm 3 then acidified by a 2 N HC1 solution until a pH of 7 is obtained. The guanidino derivative precipitates and is then isolated by filtration. 0.78 g of the product (yield 51%; melting point 138 OC) is obtained.

The sweetening potency of this compound corresponds approximately, on a weight basis, to 130,000 (one hundred thirty thousand) times that of sucrose (by comparison with a 2% sucrose solution), to 100,000 (one hundred thousand) times relative to a 5% solution, and to 90,000 (ninety thousand) times relative to a 10% solution.

a a oo EXAMPLE Synthesis of N-[N-(S)-alphamethylbenzylamino(3,4-methylenedioxyphenylimino)methyl]-2aminoethanoic acid: H .CH(CH 3

)C

6

H

5

(S)

4 4'20 N 4 .4

N=C-NH-CH-COOH

I 0 This compound is obtained from glycine and alpha-methylbenzyl-N'-(3,4-methylenedioxyphenyl)-S- Smethylisothiourea by following the experimental protocol described in Example 9 (yield 41%; melting point 213 0

C).

-41- The sweetening potency of this compound corresponds approximately, on a weight basis, to- 3500 (three thousand five hundred) times that of sucrose (by comparison with a 2% sucrose solution).

EKAM.PLE 11: Synthesis of methyl-2-aminoethanoic acid: H /c-CH1i

N

N N= C-NH-CHi-COOH 0 4 0 0 This compound is obtained from tert-butyl N-[Ncyclooctylamino(5-benzofurazanylimino)methyl]-2-aminoethanoate o O (obtained by following the experimental protocol described in Example I) by treatment for 1 hour by trifluoroacetic acid solution followed by trituration in ethyl ether (yield 26%; melting S point 235 0 C; in the form of trifluoroacetic acid salt).

The sweetening potency of this compound corresponds approximately, on a weight basis, to 40,000 (forty thousand) times that of sucrose (by comparison with a 2% sucrose solution).

J 42 EXAMPLE 12: Synthesis of N-[N-(S)-alpha-methylbenzylamino(2naphthylimino)methyl]-2-aminoethanoic acid: H CH(CH 3

)C

6 H (S)

N

SN C-NH-CH COOH This compound is obtained from glycine and alpha-methylbenzyl-N'-(2-naphthyl)-S-methylisothiourea by following the experimental protocol described in Example 9 :o (yield 19%; melting point 164 C).

i The sweetening potency of this compound corresponds approximately, on a weight basis, to 9000 (nine thousand) times that of sucrose (by comparison with a 2% sucrose solution).

I 'p

'I

I ti -43- EXAMPLE 13: Synthesis of -alpha-methylbenzylamino(3quinolylimino)methyl]-2-aminoethanoic acid: H /CH(CH 3

)C

6

H

5

(S)

N

N -NC- H-CH-COOH 2 This compound is obtained from glycine and alpha-methylbenzyl-N'-(3-quinolyl)-S-methylisothiourea by following the experimental protocol described in Example 9 (yield 26%; melting point 188 The sweetening, potency of this compound corresponds approximately, on a weight basis, to 15,000 (fifteen thousand) times that of sucrose (by comparison with a 2% sucrose solution).

E o EXAMPLE 14: Synthesis of -alpha-methylbenzylamino(6quinolylimino)methyl]-2-aminoethanoic acid: H /CH(CH 3 )CH 5 (S)

N

N N =N C-NH-CH

-COOH

This compound is obtained from glycine and alpha-methylbenzyl-N'-(6-quinolyl)-S-methylisothiourea by 44 following the experimental protocol described in Example 9 (yield 15%; melting point 161 The sweetening potency of this compound corresponds approximately, on a weight basis, to 5000 (five thousand) times that of sucrose (by comparison with a 2% sucrose solution).

I

EXAMPLE 1.5 Synthesis of N-[N-cyclooctyl(6quinolylimino)methyl]-2-aminoethanoic acid: H,

N

N C-NH-CH

-COOH

o f i* i This compound is obtained from glycine and Ncyclooctyl-N'-(6-quinolyl)-S-methylisothiourea by following the experimental protocol described in Example 9 (yield melting point 150 oC).

The sweetening potency of this compound corresponds approximately, on a weight basis, to 10,000 (ten thousand) times that of sucrose (by comparison with a 2% sucrose solution).

45 EXAMPLE 16: Synthesis of N-[N-(S)-alphamethylbenzylamino(1,4-benzodioxan-6-ylimino)methyl]-2- H /CH(CH 3

)C

6

H

5

(S)

N Iq 0 N =-C-NH-CH-COOH 0 This compound is obtained from glycine and alpha-mexhylbenzyl-N'-(1,4-benzodioxan-6-yl)-Smethylisothiourea by following the experimental protocol described in Example 9 (yield 41%; melting point 205 oC).

The sweetening potency of this compound

I

corresponds approximately, on a weight basis, to 700 (seven hundred) times that of sucrose (by comparison with a 2% sucrose solution).

The sweetening potencies obtained with the different compounds cited in Examples 1 to 16 are summarized in Table II hereinafter; the sweetening potencies given therein were evaluated, on a weight basis, relative to a 2% sucrose solution.

46- TABLE ,I I A R4 H Ro- N C Iq-C -COOH Compound 0 B Sweetening R83 R 4 Potency 2/ H c-CO 1 5 H 1 000 H C-CSH 15

H

1 Hi H (S)CH(CH 3 C 6H 5 N H CH 2

C

6 H 5 H 1~ 000

CH

3 H H (S)CH(CH 3

C

6

H

5

CH

3 -7 I t 4 7 compound

R

0 A R I R R R Sweetening 3 4 Potency 7 HN-

N

H

H (S)CH(CH 3

C

6 Hs H (S)CH(CH 3

C

6

HS

H (S)CH(CH 3 )C 6 H 5 H 2 000 H 1 100 H 21 000 H H c-CaH 15 H 130 000 H H (S)CH(CH 3

C

6 HS H 3 500 H H c-CH 15 H 10 000 2 48- Compound R A R 1 R2 R 3 R 4 Sweetening Potency 12 13 H (S)CH(CH 3

)C

6 H 5 H (S)CH(CH 3

)C

6

HS

H 9 000 H 15 000 ~4 ft# 0 .0 0 00 4 tt~ 0 1 #1 0

II

04*I 4£ 0 H H (S)CH(CH 3

)C

6 H 5 H 5 000 H H c-C 8 H 15 H 10 000 H H (S)CH(CI1 3

)C

6 H 5 H 700 4* 1 I £4t

Claims

1. A compound, when used as a sweetening agent, characterized in that it has the general formula R1/R A R 4 H II ~t I 4 i '.4*4 .4 *4.4I .4 4, *4 .4 .4.44, o

4.4*4 *444 .4 44 wherein R0is selected from the group consisting of a pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, furazanyl, thienyl, thiazolyl, isothiazolyl, pyridyl, 2-cyanopyridyl, pyridazinyl, pyrimidinyl, 2-cyanopyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, isobenzofuranyl, 3,4-methylenedioxyphenyl, benzisoxazolyl, benzofurazanyl, benzothiazolyl, saccharin-5-yl, saccharin-6-yl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,3,5-triazanaphthyl, 1,4,5-triazanaphthyl, 1,2,8-triazanaphthyl, 1,3,8-triazanaphthyl, 1,2,5-triazanaphthyl, pteridinyl and isocoumarinyl, indanyl, ind~nyl, and radicals derived therefrom by replacement of one to three hydrogen atoms of the group by Br, CF 3 ;CH 3 1 Cl, CN, F, I, NH 2 NO 2 OCH 3 or OH; wherein A is selected from the group consisting of N and C wherein RIis a hydrogen atom or a hydrocarbon group which contains up to 4 carbon atoms; wherein R2is a hydrocarbon group which contains 2 to 13 carbon atoms and which can be saturated or unsaturated, acyclic or cyclic wherein R3is selected from the group consisting of a hydrogen atom and a C 1 -C 3 alkyl group; wherein R4is selected from the group consisting of H and CH 3 with the proviso, when A that Ris t a x wherein X 3 X 4 arnd X>5 are: 04 H, C~8 COBr, CF 3 CtF CF1 CP 2 CFq/ C_4al.kyl, CC~*CH=NOCH 3 CH=NOH, -CHO, CH 2 0CH 3 CH 2 0H, Cl, CN, COCF 3 COC 1 alkyl, CONH 2 CONHC 1 -C 3 alkyl, CON (C 1 -C 3 alkyl) 2' -1 tb P A -51- C00C 1 C al kyl, COOH, F, I NH 2 14HC 1 -C 3 alkyl, 14(C I- C alkyl) 2 N4H CHO, NHCOCH, NqHCONH 2 P H S 0 2 C H 3 OC- -CI alkyl, OCOCH.3 OH, 1C C 3 alkyl, SOC C alkyl, so C -C 3 alkyl, 2 1 3 so0 2 NH 2 1 so 2 NHC 1 -C 3 a lkyl, soN C alkyl) 2 and SO-H and physiologically acceptable salts thereof. 2. A compound according to claim 1, wherein A is a nitrogen atom. 3. A compound according to claim 1 or 2, wherein RIis selected from the group consisting of H aind CH 3 4. A compound according to one of claims 1 to 3, whereinR2 is selected from the group consisting of normal alk(en) (yn)yl C 2 -C 1 3 branched alk(en).(yn)yl C 3 -c 13 cycloalk(en) yl C 3 -C 1 3, ;0 RA 35 alk(en)yl cycloalk(en)yl C 4 -C 13 cycloalk(en)y. alk(en)y. C 4 -C 13 -52- alk(en)yl cycloalk(en)yl alk(en)yl C 5 -C 1 3, alk(en)yl bicycloalk(en)yl C 7 -C 1 3 fused bicycloalk(en)yl C 7 -CI3, alk(en)yl fused bicycloalk(en)yl C 8 -C 1 3 fused bicycloalk(en)yl alk(en)yl C 8 -C 1 3 alk(en)yl fused bicycloalk(en)yl alk(en)yl C 9 -C1 3 fused tricyclaalk(ei)yl C1 0 -C13, alk(en)y. fused tricycloalk(en)yl C 1 1 -C 1 3 fused tricycloalk(en)y. alk(en)yl C 1 1 -C 1 3 and alk(en~yl fused tricycloalk(en)yl alk(en)yl

6. A compound according to one of claims 1 to 4, wherein R is a hydrogen atom. 00%7. A compound according to claim 1, wherein it consists of 0 compounds of the formula R R-N C-N H CO wherein RO, R 1 R 2 have the same meaning as indicated in claim 1.

8. A compound according to claim 7, wherein R1is H or CH 3

9. A compound according to claim 7 or 8 wherein R2is c-C 8 H 15 CH 2 C 6 H 5 CH 2 -c-C 6 H ill CH(CH 3 )C 6 H 5 or CH(CH 3 )-c-C 6 H 11 A compound according to claims 7, 8 or 9 wherein ROis selected from the group consisting of a indazol-6-yl, benzisoxazol-6-yl, benzofurazan-5-yl, isoquinol-6-yl, quinazolin-7-yl, 1,7-naphthyridin-3-yl or 1,3,5-triazanaphth-7-yl -53- group.

11. A compound according to claim 7, selected from the group consisting of N- N-cyclooctylamino (I-pyrrolylimino)methylj-2- aminoethanoic acid N-LN-cyclooctylamino(2-thiazolylimino)methy aminoethanoic N-[N-(S)-alpha-methylbenzylamino (2-pyridylimino)methyl] -2-aminoethanoic acid N-LN-benzylamino(3-pyridylimino)methylj-2-aminoethanoic acid N-fCN- -aipha-methylbenzylamino 6-dimethyl-2-pyrimidinylimin3r) methyl]-2-aminoethanoic acid N-UN- -alpha-methylbenzylamino (5-indanylimino)me'thy2I -2-aminoethanoic acid N- methyl]-2-aminoethanoic acid N-LN-(S)-alpha-methylbenzylamino(1H-indazol-6-ylimino) methyl]-2-.aminoethanoic acid; N-UN-cyclooctylamino (1H-indazol-6-ylimino) methyl] -2-aminoethanoic acid 4 04aN-(N-(S)-alpha-methylbenzylamino(3,4-methylenedioxyphenylimino) methylj-2-aminoethanoic acid -2-aminoethanoic acid N-[N-(S)-alpha-methylbenzylamino(2-naphthylimino)methyl] -2-aminoethanoic acid N-[N-(S)-alpha-methylbenzylamino(3-quinolylimino)methyl3 -2-aminoethanoic acid N-EN- (3)-alpha-methylbenzylamino (6-quinolylimino) methyl.] -2-aminoethanoic acid N-CN-cyclooctyl(6-quinolylimino)methylj-2-aminoethanoic acid N-EN-(S)-alpha-methylbenzylamino(1,4-benzodioxan-6-ylimino)meh,!yl -2-aminoethanoic acid.

12. A process for sweetening foods, beverages, ccnfectioneries, pastries, chewing gum, hygiene products, cosmetics, toiletries and pharmaceutical and veterinary products, characterized in that it consists of adding to these products a -54- sweetening amount of at least one compound according to one of claims 1 to 11.

13. A product obtained from the process of claim12

14. Sweetening compositions, characterized in that they consist of a sweetening amount of one or more compound according to one of claims 1 to 11 and a carrier or bulking agent selected from the group consisting of polydextrose, starch, maltodextrins, cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, microcrystalline cellulose sodium alginate, pectins, gums, lactose, maltose, glucose, leucine, glycerol, mannitol, sorbitol, sodium bicarbonate, phosphoric, citric, tartaric, fumaric, benzoic, sorbic and propionic acids, and their sodium, potassium and calcium salts and mixtures thereof. Sweetening agents characterized in that they consist of a compound according to one of claims 1 to 11 and at least one other compound selected from the group consisting of sucrose, corn syrup, fructose, aspartame alitame, neohesperidin dihydrochalcone, hydrogenated isomaltulose, stevioside, L-sugars, glycyrrhizin, xylitol, acesulfame-K, saccharin and its sodium, potassium or calcium salts, cyclamic acid and its sodium, potassium or calcium salts, trichlorogalactosucrose, monellin, thaumatin and mixtures thereof. Dated this 27th day of September 1990 UNIVERSITE CLAUDE BERNARD LYON 1 Patent Attorneys for the Applicant F.B. RICE CO. at-. RCp p<