MXPA00009449A - Aspartyl dipeptide ester derivatives and sweeteners - Google Patents

Abstract

Novel aspartyl dipeptide ester derivatives (including those in the form of a salt) having an excellent sweetening effect and usable as sweeteners such as N-[N-[3-(3-methyl-4-hydoxyphenyl)propyl]-L-&agr;-aspartyl]- L-phenylalanine 1-methyl ester and N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-&agr;-aspartyl]- L-phenylalanine 1-methyl ester;and excellent sweeteners, etc. containing these novel derivatives. Thus, it becomes possible to provide low-caloric sweeteners which are superior particularly in degree of sweetness to the conventional ones.

Description

SWEETENERS AND DERIVATIVES OF ESTER DIPEPTIDE ASPARTI OR DESCRIPTION OF THE INVENTION The present invention relates to novel aspartyl dipeptide ester derivatives, and to a sweetener and to products such as foods having sweeteners, which contain the same as an active ingredient. In recent years, as eating habits have been improved to a high level, obesity caused by excessive consumption of sugar and diseases accompanied by obesity had been in question. As a result, the development of a low-calorie sweetener that replaces sugar has been in demand. As a sweetener that has been widely used today, there is aspartame that is excellent in taste and safety properties. However, it is a bit problematic in stability. In WO 94/11391, it is stated that the derivatives in which an alkyl group is introduced into an amino group of aspartic acid constituting the aspartame remarkably improves the sweetening potency and the stability is slightly improved. It is reported that the best compound described herein is N- [N- (3,3-dimethylbutyl) -L-α-aspartyl] -L-phenylalanine 1-methyl ester having a 3, 3-dimethylbutyl group as an alkyl group and the sweetening power of it is 10,000 times. Aspartame derivatives having introduced in the same 20 types of substituents other than the 3, 3-dimethylbutyl group are indicated herein and the sweetening potency thereof is reported to be less than 2,500 fold. Derivatives having a 3 (substituted phenyl) propyl group as an alkyl group are also shown. However, it is reported that the sweetening potency 1-methyl ester of N- [N- (3-phenylpropyl) -La-aspartyl] -L-phenylalanine is 1,500 times and that of 1-methyl ester of N- [N- [3- (3-methoxy-4-hydroxyphenyl) propyl] -La-aspartyl] -L-phenylalanine is 2,500 times. In this manner, they are much less than (10,000 times) 1-methyl ester of N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine. It is an object of the invention to provide novel aspartyl dipeptide ester derivatives which are excellent in safety and which have sweetening potency equal to or greater than that of N- [N- (3,3-dimethylbutyl) -l-1-methyl ester. aspartyl] -L-phenylalanine, and a low-calorie sweetener that contains the same as an active ingredient. To solve the problems, various aspartame derivatives have been synthesized in which several of the 3- (substituted phenyl) propyl groups are introduced into an amino group of aspartic acid constituting the aspartame derivatives by the use of cinamaldehyde having various substituents in 3-phenylpropianaldehyde having various substituents which can be easily derived therefrom from precursor aldehydes, and the sweetening potency thereof has been examined. It has therefore been found that with respect to the sweetening potency, the novel compounds that have been found are by far, higher than not only the N- [N- (3-phenylpropyl) -La-aspartyl] 1-methyl ester - L-phenylalanine which is reported to have a sweetening power of 1,500 times in WO 94/11391 but also 1-methyl ester of N- [N- (3, 3-dimethylbutyl) -La-aspartyl] -L-phenylalanine which is reported in the same for having the sweetening potency of 10,000 times, and especially the compounds represented by the following formula (1) are excellent as sweeteners. These discoveries have led to the completion of the invention. The present invention (Claim 1) is directed to novel aspartyl dipeptide ester derivatives (including those in the form of a salt) represented by the general formula (1): wherein i / R2 / - R3 - and 5 / independently of each other, represent a substituent selected from a hydrogen atom (H), a hydroxyl group (OH), an alkoxy group (OR, methoxy groups, ethoxy groups, groups propoxy, or the like) having from 1 to 3 carbon atoms, an alkyl group (R; methyl group, ethyl group, propyl groups or the like) having from 1 to 3 carbon atoms and a hydroxyalkyloxy group (for example, 0 (CH 2) 2 OH or OCH 2 CH (OH) CH 3) having 2 or 3 carbon atoms, or Ri and R2, or R2 and R3 together form a methylenedioxy group (OCH20) wherein R4 and R5 y, Ri or R3 which do not form the methylenedioxy group as a part thereof, independently of each other, represent any substituents as mentioned in previous designated for Ri, R2, R3, R, and R5, respectively, provided the case where Ri to R5 are all hydrogen atoms and in the case where R2 is excluded it is a methoxy group and R3 is a group hydroxyl and in the case where R 4 is a methoxy group and R 3 is a hydroxyl group, R b represents a hydrogen atom or a hydroxyl group, and R represents a substituent selected from a methyl group (CH 3), an ethyl group ( CH2CH3), an isopropyl group (CH (CH3) 2, an n-propyl group (CH2CH2CH3) and a t-butyl group ( C (CH 3) 3) The novel aspartyl dipeptide ester derivatives of the invention include the compounds represented by the formula (1) and salts thereof. The amino acids that constitute the derivatives are preferably L-isomers that are present in nature. With respect to the compounds of the invention, the following inventions are preferably included. [1] compounds of the formula (1) wherein R 3 is a substituent selected from a hydroxyl group, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 3 carbon atoms and a group hydroxyalkyloxy having 2 or 3 carbon atoms, Ri, R2, R4, and R5 are, independently of each other, each a substituent selected from a hydrogen atom, a hydroxyl group, an alkoxy group having from 1 to 3 carbon atoms, carbon, an alkyl group having 1 to 3 carbon atoms and a hydroxyalkyloxy group having 2 or 3 carbon atoms, or Ri and R2, or R2 and R3 together form a methylenedioxy group (0CH20) wherein R, R5 and Ri or R3, which do not form the methylenedioxy group as a part thereof, independently of one another, represent any substituents as mentioned above by Ri, R3, R4, and R5, R6 is a hydrogen atom or a group hydroxyl, and R is a substituent selected from a methyl group, an ethyl group or, an isopropyl group, an n-propyl group and a t-butyl group. [2] Compounds of the formula (1) wherein R3 is a hydrogen atom, Ri, R2, R4, and R5 are, independently of each other, each a substituent selected from a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms and a hydroxyalogyloxy group having 2 or 3 carbon atoms, or Ri 'and R2, or R2 and R3 together form a methylenedioxy group (OCH20) wherein R, R5 and Ri or R3 which do not form the methylenedioxy group as a part thereof, independently of each other, represent any substituent as mentioned above designated by Ri, R3, R, and R5, respectively, Re is a hydrogen atom or a hydroxyl group, and R7 is a substituent selected from a methyl group, an ethyl group, an isopropyl group, an n-propyl group and a t-butyl group. [3] Compounds of the formula (1) wherein R3 is a hydroxyl group, Ri, R2, R, and R5 are each a substituent selected from a hydrogen atom, a hydroxyl group, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms and a hydroxyalkyloxy group having 2 or 3 carbon atoms, or Ri and R2, or R2 and R3 together form a methylenedioxy group (OCH20) wherein R, R5, and Ri or R3 that do not form the methylenedioxy group as a part thereof, independently of one another, represent any substituents as mentioned above designated by Ri, R3, R4, and R5, respectively, R6 is an atom of hydrogen or a hydroxyl group, and R is a substituent selected from a methyl group, an ethyl group, an isopropyl group, an n-propyl group and a t-butyl group. [4] Compounds of the formula (1) wherein R2 is a hydroxyl group, R3 is a methoxy group, Ri, R4, R5 and R6 are each a hydrogen atom, and R is a methyl group. [5] Compounds of the formula (1) wherein R 2 and R 3 are each a methoxy group, R 1 R 4, R 5 and R 6 are each a hydrogen atom, and R 7 is a methyl group. [6] Compounds of the formula (1) wherein R2 and R3 together form a methylenedioxy group, Ri, R4, R5 and R6 are each a hydrogen atom, and R7 is a methyl group. [7] Compounds of the formula (1) wherein R3 is a hydroxyl group, Ri, R2, R, R5 and R6 are each a hydrogen atom, and R7 is a methyl group. [8] Compounds of the formula (1) wherein R3 is a methoxy group, Ri, R2, R4, R5 and Re are each a hydrogen atom, and R is a methyl group. [9] Compounds of the formula (1) wherein R3 is an ethoxy group, Ri, R2, R4, R5 and Re are each a hydrogen atom, and R is a methyl group. [10] Compounds of the formula (1) wherein R2 is a hydroxyl group, Ri, R3, R4, R5 and Re are each a hydrogen atom, and R is a methyl group. [11] Compounds of the formula (1) wherein R2 is a methoxy group, R1 R3, R, R5 and R? they are each a hydrogen atom, and R7 is a methyl group. [12] Compounds of the formula (1) wherein R3 is a methoxy group, R2 and R6 are each a hydroxyl group, Ri, R4 and R5 are each a hydrogen atom, and R7 is a methyl group. [13] Compounds of the formula (1) wherein Ri is a hydroxyl group, R3 is a methoxy group, R2, R4, R5 and R6 are each a hydrogen atom, and R7 is a methyl group. [14] Compounds of the formula (1) wherein Ri is a hydroxyl group, R2 is a methoxy group, R3, R4, R5 and R6 are each a hydrogen atom, and R7 is a methyl group. [15] Compounds of the formula (1) wherein R x is a hydroxyl group, R is a methoxy group, R 2, R 3, R 5 and R 1 are each a hydrogen atom, and R 7 is a methyl group. [16] Compounds of the formula (1) wherein Ri is a hydroxyl group, R3 and R are each a methyl group, and R2, R, R5 and Re are each a hydrogen atom. [17] Compounds of the formula (1) wherein Ri and R3 are each a methoxy group, R2 / R, R5 and R are each a hydrogen atom, and R7 is a methyl group. [18] Compounds of the formula (1) wherein Ri is an ethoxy group, R3 a methoxy group, R2, R, R5 and are each a hydrogen atom, and R7 is a methyl group. [19] Compounds of the formula (1) wherein R2 and R7 are each a methyl group, R3 is a hydroxyl group, and Ri, R, R5 and Re are each a hydrogen atom. [20] Compounds of the formula (1) wherein R2 is a hydroxyl group, R3 and R7 are each a methyl group, and Ri, R, R5 and R are each a hydrogen atom. [21] Compounds of the formula (1) wherein R2 and R7 are each a methyl group, R3 is a methoxy group, and Ri, R, R5 and Re are each a hydrogen atom. [22] Compounds of the formula (1) wherein R2 and R4 are each a methoxy group, Ri, R3, R5 and R are each a hydrogen atom, and R7 is a methyl group. [23] Compounds of the formula (1) wherein R3 is a 2-hydroxyethoxy group, Ri, R2, R4, R5 and Re are each a hydrogen atom, and R7 is a methyl group. [24] Compounds of the formula (1) wherein R3 and R7 are each a methyl group, and Ri, R2, R4, R5 and R6 are each a hydrogen atom. Examples of the salts of the compounds in the invention include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts with a onia; salts with amino acids such as licina and arginine; salts with inorganic acids such as hydrochloric acid and sulfuric acid; and salts with organic acids such as citric acid and acetic acid. These are included in the derivatives of the invention as described above.

The aspartyl dipeptide ester derivatives of the invention can be easily formed by reductively alkylated aspartame derivatives with cinnamaldehydes having various substituents and a reducing agent (e.g., palladium hydrogen / carbon catalyst). Alternatively, the derivatives can be formed by subjecting aspartame derivatives (e.g., β-O-benzyl-α-L-aspartyl-L-phenylalanine methyl ester) which have a protecting group in a carboxylic acid in the β-position whose derivatives can be obtained by the method of usual peptide synthesis (Izumiya et al., Basis of Peptide Synthesis and Experiments Thereof, Naruzen, published January 20, 1985) for reductive alkylation with cinnamaldehydes having various substituents and a reducing agent (e.g., NaB (OAc) 3H) (AF Abdel-Magid et al., Tetrahedron Letters, 31, 5595 (1990)), and then the protecting group is removed. However, the method of forming the compounds of the invention is not limited thereto. 3-Phenylpropionaldehydes having various substituents or acetal derivatives thereof can, of course, be used as precursor aldehydes in the reductive alkylation instead of cinnamaldehydes having various substituents. As a result of a sensory evaluation, the compounds and salts thereof in the invention were found to have a strong sweetening potency and have taste properties similar to those of sugar. For example, the sweetening potency of 1-methyl ester N- [N- [3- (3-methyl-4-hydroxyphenyl) propyl] -L-aspartyl] -L-phenylalanine was about 35,000 times (relative to sugar), which of N- [N- [3- (2-hydroxy-4-methylphenyl) propyl] -L-aspartyl] -L-phenylalanine 1-methyl ester was about 30,000 times (relative to sugar), that of 1-methyl ester N - [N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -L-aspartyl] -L-phenylalanine was about 20,000 times that of N- [N- [3- (2-hydroxy) -methyl ester 4-methoxyphenyl) propyl] -L-aspartyl] -L-phenylalanine was approximately 20,000 times (relative to sugar), that of N- [N- [3- (3-hydroxy-4-methylphenyl) propyl) 1-methyl ester ] -La-aspartyl] -L-phenylalanine was approximately 15,000 times (relative to sugar), that of N- [N- [3- (3-hydroxyphenyl) propyl] -La-aspartyl] -L- 1-methyl ester phenylalanine was approximately 8,000 times (relative to sugar), that of N- [N- [3- (4-methoxyphenyl) propyl] 1-methyl ester] -La-aspartyl] -L-phenylalanine was approximately 6,500 times (relative to sugar), and that of N- [N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -La-aspartyl 1-methyl ester. ] -L-tyrosine was approximately 16,000 times (relative to sugar). With respect to the formed aspartyl dipeptide derivatives (represented by the formula (2)), the structures and the results of the sensory evaluation are shown in Table 1. H3 (2) Table 1 Structures and sweetening potency of aspartyl dipeptide ester derivatives. Compound Rt R2 R3 R4 R5 R6 power sweetener *} No. 1 H OH OCH. H H H 20000 3 H OCH .0 H H H 5000 4 H H OH H H H 5000 H H OCH a H H H 6500 7 H OH H H H H 8000 8 H OCHa H H H H 3500 9 H OH OCHa H H OH 16000 1 0 OH H OCHa H H H 20000 1 1 OH OCHa H H H H 10000 1 2 OH H H OCHa H H 1500 1 3 OH H CH, H H H 30000 15 OCH.CH- H OCHa H H H 2500 1 7 H OH CH. H H H 15000 H H OCHÍCHÍOH H H H 1000 *) With regard to the sweetening potency of a 4% sucrose aqueous solution. As understood from the results of Table 1, the novel derivatives in the present invention are excellent in the sweetening potency. When the compounds (including those in the form of a salt) of the invention are used as a sweetener, this can of course be useful in combination with other less attractive sweeteners than any special problems. When the derivatives of the invention are used as a sweetener, an appropriate carrier and / or an appropriate volume agent can be used when required. For example, a carrier is available which has been used so far. The derivatives of the invention can be used as a sweetener or an ingredient therefor, and also as a sweetener for products such as foods and the like to which a sweetener has to be imparted, for example, confectionery, chewing gum, products hygienic, toiletries, cosmetics, pharmaceuticals and veterinary products for animals. Furthermore, they can be used in a method for imparting a sweetener to the products. This method can be, for example, a conventional method for using a sweetening ingredient for a sweetener in sweeteners or the method for imparting a sweetener.

The invention is specifically illustrated by referring to the following examples. EXAMPLE 1 Synthesis of N- [N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -L-a-aspartyl] -L-phenylalanine 1-methyl ester. Five milliliters of a solution of 4N-HC1 and dioxane were added to 485 mg (1.0 mmol) of Nt-butoxycarbonyl-β-O-benzyl-α-L-aspartyl-L-phenylalanine methyl ester, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. Thirty milliliters of 5% aqueous sodium carbonate aqueous solution is added to the residue and the mixture is extracted twice with 30 ml of ethyl acetate. The organic layer is washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Then, the magnesium sulfate is removed by filtration, and the filtrate is concentrated under reduced pressure to obtain 385 mg of β-O-benzyl-α-L-aspartyl-L-phenylalanine methyl ester as a viscous oil. , The methyl ester of β-O-benzyl-a-L-aspartyl-L-phenylalanine (385 mg, 1.0 mmol) is dissolved in 15 ml of THF, a solution is maintained at 0 ° C. To this is added 268 mg (1.0 mmol) of 3-benzyloxy-4-methoxycinnamaldehyde, 0.060 ml (1.0 mmol) of acetic acid and 318 mg (1.5 mmol) of NaB (OAc) 3H. The mixture is stirred at 0 ° C for 1 hour and furthermore overnight at room temperature. To the solution is added 50 ml of saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted twice with 30 ml of ethyl acetate. The organic layer is washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The magnesium sulfate is then removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was purified with PTLC (Preparative Thin Layer Chromatography) to obtain 523 mg (0.82 mmoles) of N- [N- [3- (3-benzyloxy-4-methoxyphenyl) propenyl] -β- O-methyl ester. -benzyl-La-aspartyl] -L-phenylalanine as a viscous oil. 1-Methyl ester N- [N- [3- (3-benzyloxy-4-methoxyphenyl) propenyl] -β-O-benzyl-L-a-aspartyl] -L-phenylalanine (523 mg, 0.82 mmol) is dissolved in a mixed solvent of 30 ml of methanol and 1 ml of water, and 200 mg of 10% palladium carbon (50% water content) is added thereto. The mixture is reduced under an atmosphere of hydrogen at room temperature for 3 hours. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. To remove an adsorbed odor, the residue is purified with PTLC to obtain 228 mg (0.48 mmoles) of N- [N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -L-a- 1-methyl ester. aspartyl] -L-phenylalanine as a solid. 1HRMN (DMSO-d6) d: 1.50-1.60 (m, 2H), 2.15-2.40 (m, 6H), 2.87-2.97 (dd, 1H), 3.05-3.13 (dd, 1H), 3.37-3.43 (m, 1H), 3.62 (s, 3H), 3.71 (s, 3H), 4.50-4.60 (m, 1H), 6.52 (d, 1H), 6.60 (s, 1H), 6.79 (d, 1H), 7.18-7.30 (m, 5H), 8.52 (d, 1H), 8.80 (broad s, 1H). ESI-EM 459.2 (MH +) The sweetening potency (in relation to sugar): ,000-fold EXAMPLE 2 Synthesis of N- [N- [3- (3, -dimethoxyphenyl) -propyl] -L-aspartyl] -L-phenylalanine 1-methyl ester Example 1 was repeated except that 3,4-dimethoxycinnamaldehyde was used instead of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1 N- [N- [3- (3, 4-dimethoxyphenyl) ropil] -L-aspartyl] -L-phenylalanine methyl ester in a total yield of 48.7% as a solid. XHRMN (DMSO-de) d: 1.52-1.62 (m, 2H), 2.18-2.50 (m, 6H), 2.86-2.76 (dd, 1H), 3.04-3.12 (dd, 1H), 3.37-3.44 (m, 1H), 3.62 (s, 3H), 3.71 (s, 3H), 3.73 (s, 3H), 4.52-4.62 (m, 1H), 6.66 (d, 1H), 6.76 (s, 1H), 6.83 (d, 1H), 7.18-7.30 (m, 5H), 8.50 (d, 1H). ESI-EM 473.2 (MH +) The sweetening potency (in relation to sugar): 2,500 times EXAMPLE 3 Synthesis of N- [N- [3- (3,4-methylenedioxyphenyl) propyl] -L-aspartyl] -L-phenylalanine 1-methyl ester Example 1 was repeated except that 3,4-methylenedioxycinnamaldehyde was used instead of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1-methyl ester of N- [N- [3- (3, 4-methylenedioxyphenyl) propyl] -L-a-aspartyl] -L-phenylalanine in a total yield of 42.1% as a solid. XHRMN (DMSO-de) d: 1.48-1.60 (m, 2H), 2.14-2.48 (m, 6H), 2.86-2.96 (dd, 1H), 3.03-3.12 (dd, 1H), 3.37-3.43 (m, 1H), 3.62 (s, 3H), 4.54-4.59 (m, 1H), 5.94 (s, 1H), 5.95 (s, 1H), 6.61 (d, 1H), 6.74 (s, 1H), 6.78 (s) , 1H), 7.15-7.30 (m, 5H), 8.47 (d, 1H). ESI-EM 457.2 (MH +) The sweetening potency (relative to sugar): 5,000,000 EXAMPLE 4 Synthesis of N- [N- [3- (4-hydroxyphenyl) propyl] -La-aspartyl] -methyl ester - L-phenylalanine Example 1 was repeated except that 4-benzyloxycinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1 N- [N- [3- (4-hydroxyphenyl) propyl] -La-aspartyl methyl ester] -L-phenylalanine in a total yield of 40.6% as a solid. 1 HNRM (DMSO-d6) d: 1.48-1.60 (m, 2H), 2.14-2.43 (m, 6H), 2.86-2.96 (dd, 1H), 3.04-3.14 (dd, 1H), 3.37-3.42 (m, 1H), 3.62 (s, 3H), 4.52-4.62 (, 1H), 6.65 (d, 2H), 6.93 (d, 2H), 7.16-7.29 (m, 5H), 8.49 (d, 1H), 9.12 ( s broad, 1H).

ESI-EM 429.2 (MH +) The sweetening potency (relative to sugar): 5,000 times EXAMPLE 5 Synthesis of N- [N- [3- (4-hydroxyphenyl) propyl] -La-aspartyl] -l-methyl ester phenylalanine (1) Example 1 was repeated except that 4-methoxycinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N- [N- [3- (4-hydroxyphenyl) propyl] -methyl ester. aspartyl] -L-phenylalanine in a total yield of 50.0% as a solid. 1 HNMR (DMSO-d6) d: 1.50-1.62 (m, 2H), 2.16-2.48 (m, 6H), 2.84-2.94 (dd, 1H), 3.04-3.12 (dd, 1H), 3.38-3.44 (m, 1H), 3.62 (s, 3H), 3.71 (s, 3H), 4.52-4.62 (m, 1H), 6.83- (d, 2H), 7.08 (d, 2H), 7.17-7.29 (m, 5H), 8.50 (d, H). ESI-MS 443.3 (MH +) The sweetening potency (relative to sugar): 5,000 times EXAMPLE 6 Synthesis of N- [N- [3- (4-methoxyphenyl) propyl] -La-aspartyl] -l-methyl ester phenylalanine (2) 4-methoxycinnamaldehyde (405 mg, 2.5 mmol), 735 mg (2.5 mmol) of aspartame and 350 mg of palladium carbonate (50% water content) were added to a mixed solvent of 15 ml of methanol and 5 ml of water, and the mixture was stirred under a hydrogen atmosphere overnight at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added 30 ml of ethyl acetate and the mixture was stirred for a moment. Then, the soluble material was collected by filtration. The collected insoluble material was washed with a small amount of ethyl acetate. To this was added 50 ml of a mixed solvent of ethyl acetate and methanol (5: 2) and the mixture was stirred for a moment. The soluble material was removed by filtration, and the filtrate was concentrated. Then, the total residue solidified. This was dried under reduced pressure, and then recrystallized from a mixed solvent of a methanol and water to obtain N- [N- [3- (4-methoxyphenyl) propyl] -La-aspartyl] -l-methyl ester. -phenylalanine in a total yield of 43.4% as a solid. EXAMPLE 7 Synthesis of N- [N- [3- (4-ethoxyphenyl) propyl] -L-aspartyl] -L-phenylalanine 1-methyl ester Example 1 was repeated except that 4-methoxycinnamaldehyde was used in place of 3-benzyloxy -4-methoxycinnamaldehyde to obtain N- [N- [3- (4-ethoxyphenyl) propyl] -L-aspartyl] -L-phenylalanine 1-methyl ester in a total yield of 57.1% as a solid. 1HRMN (DMSO-de) d: 1.30 (t, 3H), 1.50-1.62 (m, 2H), 2.16-2.48 (m, 6H), 2.85-2.95 (dd, 1H), 3.02-3.12 (dd, 1H) , 3. 39-3.44 (m, 1H), 3.62 (s, 3H), 3.96 (c, 2H), 4.52-4.59 (m, 1H), 6.81 (d, 2H), 7.05 (d, 2H), 7.17-7.28 (m, 5H), 8.50 (d, 1 HOUR) . ESI-EM 457.2 (MH +) EXAMPLE 8 Synthesis of N- [N- [3- (3-hydroxyphenyl) propyl] -L-aspartyl] -L-phenylalanine 1-methyl ester Example 1 was repeated except that 3-benzyloxycinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1 N- [N- [3- (3-hydroxyphenyl) propyl] -L-aspartyl] -L-phenylalanine methyl ester in a total yield of 40.6% as a solid . XHRMN (DMSO-d6) d: 1.50-1.62 (m, 1H), 2.10-2.48 (m, 6H), 2.87-2.96 (dd, 1H), 3.40-3.12 (dd, 1H), 3.33-3.38 (m, 1H), 3.62 (s, 3H), 4.52-4.60 (m, 1H), 6.53-6.60 (m, 3H), 7.04 (t, 1H), 7.17-7.30 (m, 5H), 8.50 (d, 1H), 9.40 (s broad, 1 HOUR) . ESI-MS 429.2 (MH +) Sweetened potency (relative to sugar): 8,000 times EXAMPLE 9 Synthesis of N- [N- [3- (3-methoxyphenyl) propyl] -La-aspartyl] -L-phenylalanine 1-methyl ester Example 1 was repeated except that 3-benzyloxycinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1 N- [N- [3- (3-methoxyphenyl) propyl] -L-aspartyl] -L- methyl ester. phenylalanine in a total yield of 55.6% as a solid. 1HRMN (DMSO-d6) d: 1.54-1.66 (m, 2H), 2.18-2.50 (m, 6H), 2.86-2.96 (dd, 1H), 3.02-3.12 (dd, 1H), 3.40-3.46 (m, 1H), 3.62 (s, 3H), 3.73 (s, 3H), 4.53-4.61 (m, 1H), 6.70-6.78 (m, 3H), 7.13-7.30 (m, 5H), 8.50 (d, 1H). ESI-EM 443.1 (MH +) Sweetened potency (relative to sugar): 3,500 times EXAMPLE 10 Synthesis of N- [N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -La-aspartyl 1-methyl ester] -L-tyrosine Example 1 was repeated except that methyl ester of Nt-butoxycarbonyl-β-O-benzyl-α-L-aspartyl-L-tyrosine was used instead of Nt-butoxycarbonyl-β-O-benzyl-α-L-aspartyl-L-phenylalanine methyl ester to obtain N-methyl-1-methyl ester N- [3- (3-hydroxy-4-methoxyphenyl) propyl] -La-aspartyl] -L-tyrosine in a total yield of 45.4% as a solid. ^ • HRMN (DMSO-de) d: 1.52-1.64 (m, 2H), 2.24-2.48 (m, 6H), 2.74-2.84 (dd, 1H), 2.91-2.99 (dd, 1H), 3.47-3.54 ( m, 1H), 3.61 (s, 3H), 3.72 (s, 3H), 4.45-4.53 (m, 1H), 6.54 (d, 1H), 6.60 (s, lH), 6.65 (d, 2H), 6.79 (d, 1H), 6.98 (d, 2H), 8.54 (d, 1H), 8.78 (broad s, 1H), 9.25 (broad s, 1H).

ESI-EM 459.3 (MH +) Sweetened potency (relative to sugar): 16,000 fold EXAMPLE 11 Synthesis of N- [N- [3- (2-hydroxy-4-ethoxyphenyl) propyl] -La-aspartyl 1-methyl ester] -L-phenylalanine Example 1 was repeated except that 2-benzyloxy-4-methoxycinnamaldehyde was used in place of 3-benzyloxy-4-ethoxycinnamaldehyde to obtain 1-methyl ester of N- [N- [3- (2-hydroxy-4 -methoxyphenyl) propyl] -La-aspartyl] -L-phenylalanine in a total yield of 54.4% as a solid. XHRMN (DMSO-d6) d: 1.52-1.57 (m, 2H), 2.20-2.31 (m, 2H), 2.26-2.41 (m, 4H), 2.88-3.11 (m, 2H), 3.41-3.44 (m, 1H), 3.62 (s, 3H), 3.65 (s, 3H), 4.53-4.59 (m, 1H), 6.28-6.36 (m, 2H), 6.88-6.90 (d, 1H), 7.19-7.29 (m, 5H), 8.55 (d, 1H). ESI-EM 459.3 (MH +) Sweetened potency (relative to sugar): 20,000 fold EXAMPLE 12 N- [N- [3- (2-hydroxy-3-methoxyphenyl) propyl] -l-methyl ester of 1-methyl ester aspartyl] -L-phenylalanine Example 1 was repeated except that 2-benzyloxy-3-methoxycinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1-methyl ester of N- [N- [3- (2-hydroxy -3-methoxyphenyl) propyl] -La-aspartyl] -L-phenylalanine in a total yield of 33.4% as a solid. XHRMN (DMSO-de) d: 1.53-1.58 (m, 2H), 2.04-2.25 (m, 2H), 2.26-2.32 (m, 4H), 2.90-3.12 (m, 2H), 3.51-3.53 (m, 1 HOUR) , 3. 61 (s, 3H), 3.76 (s, 3H), 4.52-4.58 (m, 1H), 6.64-6.78 (m, 3H), 7.18-7.29 (m, 5H), 3.52 (d, 1H). ESI-EM 459.4 (MH +) Sweetened potency (relative to sugar): 10,000 fold EXAMPLE 13 Synthesis of N- [N- [3- (2-hydroxy-5-methoxyphenyl) propyl] -La-aspartyl 1-methyl ester] -L-phenylalanine Example 1 was repeated except that 2-benzyloxy-5-methoxycinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1-methyl ester of N- [N- [3- (2-hydroxy-5 -methoxyphenyl) propyl] -La-aspartyl] -L-phenylalanine in a total yield of 57.6% as a solid. XHRMN (DMSO-d6) d: 1.52-1.63 (m, 2H), 2.19-2.35 (m, 2H), 2.27-2.47 (m, 4H), 2.89-3.14 (m, 2H), 3.47-3.50 (m, 1 HOUR) , 3. 62 (s, 3H), 3.65 (s, 3H), 4.50-4.58 (m, 1H), 6.57-6.71 (m, 3H), 7.19-7.30 (m, 5H), 8.62 (d, 1H) 8.84 (s) broad, 1H). ESI-EM 459.3 (MH +) Sweetened potency (relative to sugar): 1,500 times EXAMPLE 14 Synthesis of N- [N- [3- (2-hydroxy-4-methylphenyl) propyl] -La-aspartyl 1-methyl ester] -L-phenylalanine Example 1 was repeated except that 2-benzyloxy-4-methylcinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1-methyl ester of N- [N- [3- (2-hydroxy-4 -methylphenyl) propyl] -La-aspartyl] -L-phenylalanine in a total yield of 35.7% as a solid. 1HRMN (DMSO-de) d: 1.52-1.58 (m, 2H), 2.17 (s, 3H), 2.19-2.32 (m, 2H), 2.37-2.44 (m, 4H), 2.87-3.11 (m, 2H) , 3.39-3.42 (m, 1H), 3.62 (s, 3H), 4.53-4.58 (m, 1H), 6.50 (d, 2H), 6.58 (s, 1H), 6.80 (d, 1H), 7.15-7.29 (m, 5H), 8.54 (d, 1H). ESI-EM 443.3 (MH +) Sweetened potency (relative to sugar): 30,000 fold EXAMPLE 15 Synthesis of N- [N- [3- (2,4-dimethyloxyphenyl) propyl] -La-aspartyl] -L 1-methyl ester phenylalanine Example 1 was repeated except that 2,4-dimethoxycinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N- [N- [3- (2,4-dimethoxyphenyl) propyl] 1-methyl ester - La-aspartyl] -L-phenylalanine in a total yield of 32.4% as a solid. XHRMN (DMSO-de) d: 1.50-1.54 (m, 2H), 2.20-2.31 (m, 2H), 2.25-2.43 (m, 4H), 2.88-3.12 (m, 2H), 3.44-3.82 (m, 1H), 3.62 (s, 3H), 3.72 (s, 3H), 3.75 (s, 3H) , 4.54-4.59 (m, 1H), 6.40-6.50 (m, 2H), 6.96-6.98 (m, 1H), 7.19-7.29 (m, 5H), 8.51 (d, 1H). ESI-MS 473.3 (MH +) Sweetened potency (relative to sugar): 4,000 fold EXAMPLE 16 Synthesis of N- [N- [3- (2-ethoxy-4-methoxyphenyl) propyl] -La-aspartyl] 1-methyl ester] -L-phenylalanine Example 1 was repeated except that 2-ethoxy-4-methoxycinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1-methyl ester of N- [N- [3- (2-ethoxy-4 -methoxyphenyl) propyl] -La-aspartyl] -L-phenylalanine in a total yield of 35.6% as a solid. XHRMN (DMSO-d6) d: 1.30-1.34 (t, 3H), 1.50-1.57 (m, 2H), 2.19-2.41 (m, 2H), 2.24-2.43 (m, 4H), 2.87-3.11 (m, 2H), 3. 38-3.42 (m, 1H), 3.62 (s, 3H), 3.71 (s, 3H), 3.70-4.03 (c, 2H), 4.53-4.60 (m, 1H), 6.40-6.48 (, 2H), 6.96-6.98 (m, 1H), 7. 19-7.29 (m, 5H), 8.51 (d, 1H). ESI-MS 487.4 (MH +) Sweetened potency (relative to the auger): 2,500 times EXAMPLE 17 Synthesis of N- [N- [3- (3-methyl-4-hydroxyphenyl) propyl] -La-aspartyl 1-methyl ester] -L-phenylalanine Example 1 was repeated except that 3-methyl-4-benzyloxycinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1-methyl ester of N- [N- [3- (3-methyl-4 -hydroxyphenyl) propyl] -La-aspartyl] -L-phenylalanine in a total yield of 32.2% as a solid. XHRMN (DMSO-de) d: 1.50-1.58 (m, 2H), 2.08 (s, 3H), 2. 09-2.30 (m, 2H), 2.26-2.38 (m, 4H), 2.89-3.09 (m, 2H), 3.35-3.42 (m, 1H), 3.62 (s, 3H), 4.54-4.59 (m, 1H) ), 6.65-6.83 (m, 3H), 7.19-7.28 (m, 5H), 8.52 (d, 1H), 9.04 (broad s, 1H). ESI-EM 443.4 (MH +) Sweetened potency (relative to sugar): 35,000 fold EXAMPLE 18 Synthesis of N- [N- [3- (3-hydroxy-4-ethylphenyl) propyl] -La-aspartyl 1-methyl ester] -L-phenylalanine Example 1 was repeated except that 3-benzyloxy-4-methylcinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1-methyl ester of N- [N- [3- (3-hydroxy-4 -methylphenyl) propyl] -La-aspartyl] -L-phenylalanine in a total yield of 46.9% as a solid. 1H NMR (DMSO-d6) d: 1.51-1.58 (m, 2H), 2.06 (s, 3H), 2.18-2.32 (m, 2H), 2.24-2.39 (m, 4H), 2.87-3.11 (m, 2H) , 3.39-3.43 (m, 1H), 3.62 (s, 3H), 4.54-4.60 (m, 1H), 6.47-6.58 (m, 2H), 6.90-6.93 (m, 1H), 7.12-7.29 (, 5H) ), 8.52 (d, 1H), 9.12 (broad s, 1H).

ESI-EM 443.4 (MH +) Sweetened potency (relative to sugar): 15,000 fold EXAMPLE 19 Synthesis of N- [N- [3- (3-methyl-4-methoxyphenyl) propyl] -La-aspartyl 1-methyl ester] -L-phenylalanine Example 1 was repeated except that 3-methyl-4-methoxycinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1-methyl ester of N- [N- [3- (3-methyl-4 -methoxyphenyl) propyl] -La-aspartyl] -L-phenylalanine in a total yield of 34.0% as a solid. XHRMN (DMSO-d6) d: 1.52-1.59 (m, 2H), 2.11 (s, 3H), 2.20-2.38 (m, 2H), 2.26-2.43 (m, 4H), 2.89-3.10 (m, 2H) , 3.39-3.43 (m, 1H), 3.62 (s, 3H), 3.73 (s, 3H), 4.52-4.59 (m, 1H), 6.79-6.82 (, 1H), 6.92-6.94 (m, 2H), 7.19-7.28 (m, 5H), 8.53 (d, 1H). ESI-EM 457.4 (MH +) Sweetened potency (relative to sugar): 8,000 times EXAMPLE 20 Synthesis of N- [N- [3- (3,5-dimethoxyphenyl) propyl] -La-aspartyl] -L 1-methyl ester phenylalanine Example 1 was repeated except that 3,5-dimethoxycinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N- [N- [3- (3,5-dimethoxyphenyl) propyl] 1-methyl ester - La-aspartyl] -L-phenylalanine in a total yield of 41.0% as a solid. . XHRMN (DMSO-de) d: 1.56-1.62 (m, 2H), 2.18-2.38 (, 2H), 2.25-2.47 (m, 4H), 2.88-3.11 (m, 2H), 3.38-3.44 (m, 1H ), 3.62 (s, 3H), 3.71 (s, 6H), 4.53-4.59 (m, 1H), 6.30-6.35 (m, 3H), 7.19-7.28 (m, 5H), 8.58 (d, 1H). ESI-EM 473.3 (MH +) Sweetened potency (relative to sugar): 800 times EXAMPLE 21 Synthesis of N- [N- [3- (4- (2-hydroxyethoxy) phenyl) propyl] -methyl ester-La-aspartyl ] -L-phenylalanine Example 1 was repeated except that 4- (2-hydroxyethoxy) cinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain 1-methyl ester of N- [N- [3- (4- ( 2-hydroxyethoxy) phenyl) propyl] -La-aspartyl] -L-phenylalanine in a total yield of 33.8% as a solid. XHRMN (DMSO-d6) d: 1.52-1.60 (m, 2H), 2.18-2.35 (m, 2H), 2.24-2.47 (m, 4H), 3.38-3.43 (m, 1H), 3.62 (s, 3H), 3.67-3.71 (, 2H), 3.92-3.95 ( m, 2H), 4.53-4.59 (m, 1H), 6.82-6.85 (d, 2H), 7.05-7.07 (d, 2H), 7.19-7.29 (m, 5H), 8.51 (d, 1H). ESI-EM 473.3 (MH +) Sweetened potency (relative to sugar): 1,000 times EXAMPLE 22 Synthesis of N- [N- [3- (4-methylphenyl) propyl] -La-aspartyl] -L-phenylalanine 1-methyl ester Example 1 was repeated except that 4-methylcinnamaldehyde was used in place of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N- [N- [3- (4-methylphenyl) propyl] -La-aspartyl] -l-methyl ester. -phenylalanine in a total yield of 54.1% as a solid. 1HRMN (DMSO-de) d: 1.50-1.63 (m, 2H), 2.18-2.39 (m, 2H), 2.25 (s, 3H), 2.29-2.46 (m, 4H), 2.87-3.11 (m, 2H) , 3.41-3.47 (m, 1H), 3.61 (s, 3H), 4.53-4.61 (m, 1H), 7.03-7.09 (m, 4H), 7.17-7.29 (m, 5H), 8.58 (d, 1H) . ESI-EM 427.4 (MH +) Sweetened potency (relative to sugar): 4,000 times The novel aspartyl dipeptide ester derivatives of the invention have especially excellent sweetening potency compared to conventional sweeteners. The invention can provide novel chemical substances that have excellent flavor properties as a sweetener. Accordingly, such novel derivatives in the present invention can be used as a sweetener, and they can also impart a sweetener for products such as beverages and foods that require a sweetener.

Claims (23)

1. CLAIMS 1. Novel aspartyl dipeptide ester derivatives (which include salts thereof) represented by the formula (1) characterized in that Ri, Rz, R3-R4 and Rs, independently of each other, represent a substituent selected from a hydrogen atom, a hydroxyl group, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms and a hydroxyalkyloxy group having 2 or 3 carbon atoms, or Ri and R2, or R2 and R3 together form a methylenedioxy group wherein R4 and R5 y, Ri or R3 which do not form the methylenedioxy group as part thereof, independently of each other, each represents any substituents as mentioned above designated for Ri, R2, R3, > and Rd, respectively, R represents a hydrogen atom or a hydroxyl group, and R7 represents a substituent selected from a methyl group, an ethyl group, an isopropyl group, an n-propyl group and a t-butyl group, providing the derivatives in which Ri to R5 are all hydrogen atoms, and the derivatives in which R2 or R4 are a methoxy group and R3 is a hydroxyl group, are included.
2. 2. The derivative according to claim 1, characterized in that R2 is a hydroxyl group, R3 is a methoxy group, Ri, R4, R5 and R6 are hydrogen atoms, and R7 is a methyl group.
3. 3. The derivative according to claim 1, characterized in that R2 and R are methoxy groups, Ri, R4, R5 and Re are hydrogen atoms, and R7 is a methyl group.
4. 4. The derivative according to claim 1, characterized in that R2 and R3 together form a methylenedioxy group, Ri, R4, R5 and R are hydrogen atoms, and R7 is a methyl group.
5. 5. The derivative according to claim 1, characterized in that R3 is a hydroxyl group, Ri, R2, R4, R5 and Re are hydrogen atoms, and R7 is a methyl group.
6. 6. The derivative according to claim 1, characterized in that R3 is a methoxy group, R2 R4 / R5 and Re are hydrogen atoms, and R7 is a methyl group.
7. 7. The derivative according to claim 1, characterized in that R3 is an ethoxy group, Ri, R2, R4, R5 and Re are hydrogen atoms, and R7 is a methyl group.
8. 8. The derivative according to claim 1, characterized in that R2 is a hydroxyl group, Ri, R3, R4, R5 and R6 are hydrogen atoms, and R7 is a methyl group.
9. 9. The derivative according to claim 1, characterized in that R2 is a methoxy group, Ri, R3, R4, R5 and R6 are hydrogen atoms, and R7 is a methyl group.
10. 10. The derivative according to claim 1, characterized in that R3 is a methoxy group, R2 and R6 are hydroxyl groups, Ri, R4 and R5 are hydrogen atoms, and R7 is a methyl group.
11. 11. The derivative according to claim 1, characterized in that Ri is a hydroxyl group, R3 is a methoxy group, R2, R4, R5 and Re are hydrogen atoms, and R7 is a methyl group.
12. 12. The derivative according to claim 1, characterized in that Ri is a hydroxyl group, R2 is a methoxy group, R3, R4, R5 and Re are hydrogen atoms, and R7 is a methyl group.
13. 13. The derivative according to claim 1, characterized in that Ri is a hydroxyl group, R4 is a methoxy group, R2, R3, 5 and e are hydrogen atoms, and R7 is a methyl group.
14. 14. The derivative according to claim 1, characterized in that Ri is a hydroxyl group, R3 and R7 are methyl groups, R2, R4, R5 and R are hydrogen atoms.
15. 15. The derivative according to claim 1, characterized in that Ri and R3 are methoxy groups, R2, R4, R5 and Re are hydrogen atoms, and R7 is a methyl group.
16. 16. The derivative according to claim 1, characterized in that Ri is an ethoxy group, R3 is a methoxy group, R2, R4 R5 and Re are hydrogen atoms, and R7 is a methyl group.
17. 17. The derivative according to claim 1, characterized in that R2 and R7 are a methyl group, R3 is a hydroxy group, and Ri, R4, R5 and Re are hydrogen atoms.
18. 18. The derivative according to claim 1, characterized by R2 is a hydroxyl group, R and R7 are methyl groups, and Rx, R4, R5 and R are hydrogen atoms.
19. 19. The derivative according to claim 1, characterized in that R2 and R7 are methyl groups, R3 is a methoxy group, and Ri, R4, R5 and Re are hydrogen atoms.
20. 20. The derivative according to claim 1, characterized in that R2 and R4 are a methoxy group, Ri, R3, R5 and are hydrogen atoms, and R7 is a methyl group.
21. 21. The derivative according to claim 1, characterized in that R3 is a 2-hydroxyethoxy group, R, R2, R4, R5 and R are hydrogen atoms, and R7 is a methyl group.
22. 22. The derivative according to claim 1, characterized in that R3 and R7 are methyl groups, and Ri, R2, R4, R5 and e are hydrogen atoms.
23. 23. A sweetener or products such as foods having a sweetener, characterized in that it comprises at least one derivative selected from the derivatives according to claim 1 as an active ingredient. The sweetener or products may further comprise a carrier and / or volume agent for sweeteners.