Title of Invention

NOVEL ASPARTYL DIPEPTIDE ESTER DERIVATIVES

Abstract

There are provided novel aspartyl dipeptide ester derivatives (including salts thereof) such as N- [N- [3- (3- hydroxy-4-methoxyphenyl)propyl] -L-α-aspartyl] -L- (α - methyl)phenylalanine 1-methyl ester which are usable as sweeteners, and sweeteners, foods and the like containing the same. These derivatives are usable as low-calory sweeteners especially excellent in the degree of sweetness in comparison with the conventional products.

Full Text

SPECIFICATION NOVEL ASPARTYL DIPEPTIDE ESTER DERIVA^l^lES AND SWEETENERS TECHNICAL FIELD The present invention relates to novel aspartyl dipeptide ester derivatives, and sweeteners and products such as foods having a sweetness, which contain the same as an active ingredient. BACKGROUND ART In recent years, as eating habits have been improved to a high level, fatness caused by excessive intake of sugar and diseases accompanied by fatness have been at issue. Accordingly, the development of a low-calory sweetener that replaces sugar has been in demand. As a sweetener that has been widely used at present, there is aspartame which is excellent in a safety and taste properties. However, this is somewhat problematic in the stability. In WO 94/11391, it is stated that derivatives in which an alkyl group is introduced in an amino group of aspartic acid constituting aspartame markedly improves sweetening potency and the stability is slightly improved. It is reported that the best compound described in this document is N- [N- (3,3-dimethylbutyl)-L-a -aspartyl]-L-phenylalanine 1-methyl ester having a 3,3-dimethylbutyl group as an alkyl group and the sweetening potency thereof is 10,000 times that of sugar. Aspartame derivatives having introduced therein 20 types of substituents other than the 3,3-dimethylbutyl group are indicated therein, and the sweetening potency thereof is reported to be less than 2,500 times that of sugar. Derivatives having a 3-(substituted phenyl)propyl group as an alkyl group are also shown. However, it is reported that the sweetening potency of N-[N-(3-phenylpropyl)-L-a-aspartyl]-L-phenylalanine 1-methyl ester is 1,500 times that of sugar and that of N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-a-aspartyl]-L-phenylalanine 1-methyl ester is 2,500 times that of sugar. Thus, these are far less than that (10,000 times) of N-[N-(3,3-dimethylbutyl)-L-a-aspartyl]-L-phenylalanine 1-methyl ester. Furthermore, N-[N-(3,3-dimethylbutyl)-L-a-aspartyl] -L- tyrosine 1-methyl ester is stated therein as an example of the derivatives in which L-phenylalanine methyl ester is replaced by the other amino acid ester, and it is reported that its sweetening potency is 4,000 times that of sugar. Under these circumstances, development of a low-calory sweetener having fine sweetening potency is in demand. PROBLEM AND OBJECT OF THE INVENTION It is a problem to be solved by the present invention to provide novel aspartyl dipeptide ester derivatives which are excellent in the safety and which have sweetening potency equal to or higher than that of the N-[N-(3,3-dimethylbutyl)-L-α -aspartyl]-L-phenylalanine 1-methyl ester, a low-calory sweetener containing the same as an active ingredient and the like. DISCLOSURE OF THE INVENTION In order to solve the problem, the present inventors have synthesized several aspartame derivatives in which various 3 - (substituted phenyl)propyl group are introduced onto a nitrogen atom of aspartic acid constituting the aspartame derivatives, wherein a moiety of L-Phenylalanine methyl ester in the aspartame is replaced by another amino acid ester, through reductive alkylation by use of cinnamaldehydes having various substituent and easily avaialble, or 3-phenylpropionaldehyde having various substituent that can easily derived therefrom as precursor aldehyde, and have examined the sweetening potency of them. They have consequently found that with respect to the sweetening potency, the novel compounds that they have found are by far higher than not only N-[N-(3,3-dimethylbutyl)-L-a-aspartyl]-L-tyrosine 1-methyl ester which is reported to have the sweetening potency of 4,000 times that of sugar in WO 94/11391 but also N-[N-(3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine l-methyl ester which is reported therein to have the potency of 10,000 times that of sugar and that especially the compounds represented by the following formula (1) are excellent as sweeteners. These findings have led to the completion of the present invention. The present invention is directed to novel aspartyl dipeptide ester derivatives (including the salts thereof) represented by the following general formula (1) : wherein I Ri, R2, R3, R4 and R5, independently from each other, each represents a substituent selected from a hydrogen atom (H) , a hydroxyl group (OH), an alkoxy group having from 1 to 3 carbon atoms (OCH3, OCH2CH3, OCH2CH2CH3, etc.), an alkyl group having from 1 to 3 carbon atoms (CH3, CH2CH3, CH2CH2CH3, etc.) and a hydroxyalkyloxy group having 2 or 3 carbon atoms (0(CH2)20H, OCH2CH (OH) CH3, etc.) , or Ri and R2, or R2 and R3 together form a methylenedioxy group (OCH2O) wherein R4, R5, and Ri or R3 which does not form the methylenedioxy group, independently from each other, each represents any substituent as mentioned above designated for the R1, R3, R4 and R5, respectively; R6 represents a substituent selected from a hydrogen atom, a benzyl group (CH2C6H5), a p-hydroxybenzyl group (CH:2C6H4-P-OH) , a cyclohexylmethyl group (CHjCgHn) , a phenyl group (CsHs) , a cyclohexyl group (CgHn) , a phenylethyl group (CH2CH2C6H5) and a cyclohexylethyl group (CH2CH2C6HH) ; R7 represents a substituent selected from a hydrogen atom, a methyl group (CH3) , an ethyl group (CH2CH3) , and an isopropyl group (CH(CH3)2) ; Ra represents a substituent selected from a methyl group, an ethyl group, an isopropyl group, a n-propyl group (CH2CH2CH3) and a t-butyl group (0(cH3)3); provided the derivatives in which R6represents a benzyl group and R7 represents a hydrogen atom at the same time, and the derivatives in which R6 represents a p-hydroxybenzyl group and R? represents a hydrogen atom at the same time are excluded. EMBODIMENTS OF THE INVENTION The novel aspartyl dipeptide ester derivatives of the present invention include the compounds represented by the above general formula (1) and also the salts thereof. Asparic acid constituting the derivatives is L-isomer. and the other amino acid constituting them may be L- or D-isomer. In the compounds described above of the present invention, the following inventions are included as the embodiments for the preferable compounds. [1] In the compounds represented by the general formula (1) described above, the compounds wherein R7 is a substituent selected from a methyl group, an ethyl group and an isopropyl group; R1, R2, R3, R4 and R5, independently from each other, each is a substituent selected from a hydrogen atom, 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 hydroxyalkyloxy group having 2 or 3 carbon atoms (for examples, 0{CH2)20H, OCH2CH(OH) CH3, etc.), or R1 and R2, or R2 and R3 together form a methylenedioxy group (OCH2O) wherein R4, Rs and, R1 or R3 which does not form the methylenedioxy group, independently from each other, each is a substituent selected from any substituent as mentioned above designated or exemplified for the Ri, R3, R4 and R5; Rfi is a substituent selected from a hydrogen atom, a benzyl group, p-hydroxybenzyl group, a cyclohexylmethyl group, a phenyl group, a cyclohexyl group, a phenylethyl group and a cyclohexylethyl group; Rs is a substituent selected from a methyl group, an ethyl group, an isopropyl group, a n-propyl group and a t-butyl group. [2] In the compounds represented by the general formula (1) described above, the compounds wherein Rs is a substituent selected from a hydrogen atom, a cyclohexylmethyl group, a phenyl group, a cyclohexyl group, a phenylethyl group and a eyelohexylethyl group; Ri, Ra, R3/ R4 and R5, independently from each other, each is a substituent selected from a hydrogen atom, 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 hydroxyalkyloxy group having 2 or 3 carbon atoms (for examples, 0(CH2)20H, OCH2CH(OH)CH3, etc.), or Rj and R2, or R2 and R3 together form a methylenedioxy group (OCH2O) wherein R4, R5 and, Ri or R3 which does not form the methylenedioxy group, independently from each other, each is a substituent selected from any substituent as mentioned above designated or exemplified for the R1, R3, R4 and R5, respectively,-R7 is a substituent selected from a hydrogen atom , a methyl group, an ethyl group and an isopropyl group; R8 is a substituent selected from a methyl group, an ethyl group, an isopropyl group, a n-propyl group and a t-butyl group. [3] In the compounds represented by the general formula (1) described above, the compounds wherein R2 is a hydroxyl group, R3 is a methoxy group, Ri, R4 and R5 are hydrogen atoms. Re is a benzyl group, and R7 and Rs are methyl groups. [4] In the compounds represented by the general formula (1) described above, the compounds wherein R2 is a methoxy group, R3 is a hydroxyl group, R1, R4 and R5 are hydrogen atoms, R6 is a benzyl group, and R7 and R6 are methyl groups. [5] In the compounds represented by the general formula (1) described above, the compounds wherein Rj is a hydroxyl group, R3 is amethoxy group, Ri, R4, Rs and R7 are hydrogen atoms. Re is a cyclohexylmethyl group, and Re is a methyl group. [6] In the compounds represented by the general formula (1) described above, the compounds wherein R2 is a methoxy group, R3 is a hydroxyl group, Ri, R4, Rs and R7 are hydrogen atoms, Rs is a cyclohexylmethyl group, and Re is a methyl group. [7] In the compounds represented by the general formula (1) described above, the compounds wherein R2 is a hydroxyl group, R3 is amethoxy group, Ri, R4, R5 and R? are hydrogen atoms, Rg is a phenyl group, and Rs is a methyl group. [8] In the compounds represented by the general formula (1) described above, the compounds wherein Rj is amethoxy group, R3 is a hydroxyl group, Ri, R4, R5 and R7 are hydrogen atoms, Rfi is a phenyl group, and Ra is a methyl group. [9] In the compounds represented by the general formula (1) described above, the compounds wherein R2 is a hydroxyl group, R3 is a methoxy group, Ri, R4, R5 and R7 are hydrogen atoms, Rg is a 2-phenylethyl group, and Re is a methyl group. [10] In the compounds represented by the general formula (1) described above, the compounds wherein R2 is a methoxy group, R3 is a hydroxyl group, Ri, R4, R5 and R7 are hydrogen atoms, Rs is a 2-phenylethyl group, and Ra is a methyl group. [11] In the compounds represented by the general formula (1) described above, the compounds wherein R2 is a hydroxy1 group, R3 is a methoxy group, R1, R4, Rs and R6 are hydrogen atoms, R7 is a methyl group, and R6 is a n-propyl group. [12] In the compounds represented by the general formula (1) described above, the compounds wherein R2 is a methoxy group, R3 is a hydroxy 1 group, Ri, R4, R5 and R6 are hydrogen atoms, R7 is a methyl group, and Re is a n-propyl group. [13] In the compounds represented by the general formula (1) described above, the compounds wherein Ri is a hydroxyl group, R3 is a methoxy group, R2, R4» and R5 are hydrogen atoms, Rs is a benzyl group, and R? and Rs are methyl groups. [14] In the compounds represented by the general formula (1) described above, the compounds wherein R2 and Rs are methyl groups, R3 is a hydroxyl group, Ri, R4, R5 and R? are hydrogen atoms, and Rg is a cyclohexylmethyl group. [15] In the compounds represented by the general formula (1) described above, the compounds wherein Ri is a hydroxyl group, R3 and Re are methyl groups, R2, R4, Rs and R? are hydrogen atoms, and Re is a cyclohexylmethyl group. [16] Sweeteners or products such as foods having a sweetness, comprising at least one derivative selected from the derivatives in the present invention as an active ingredient. The sweeteners or the products may further comprise a carrier or a bulking agent for sweeteners. [17] A method for imparting sweetness which comprises: incorporating or giving (adding, mixing, or the like) at least one selected from the derivatives in the present invention to products requiring the sweetness such as foods, drinks (beverages), pharmaceutical products, oral hygierie products and the like. [18] A method for producing compounds of the general formula (1) described above, which comprises the step of reacting an aldehyde represented by the following general formula (2) or (3) with an aspartame derivative represented by the following formula (4) under conditions for reductive alkylations. wherein R1, R2, R3, R4 and R5 have the same meanings as those in the Ri, R2, R3, R4 and R5 mentioned in the above formula (1) for the derivatives in the present invention. wherein Re* R? and Rs have the same meanings as those in the Re> R? and Rs mentioned in the above general formula (1) for the derivatives in the present invention; R9 represents a substituent selected from a hydrogen atom and a substituent which is convertible to a hydrogen atom under the condition for reductive alkylation; and R10 represents a substituent selected from a hydrogen atom and a substituent which can be used for protecting a carboxyl group, such as a benzyl group and a t-butyl group. Said method comprises the step of reacting under any condition for reductive alkylations, and may further comprise the other step (s) , for example, any steps to obtain the compound of general formula (1) such as steps for removing protective group and forming salts after the step of reacting under the condition for reductive alkylation, if necessary. As said substituent which is convertible to a hydrogen atom under the condition for reductive alkylation, any substituent which meets said condition can be selected from known substituents therefor, for example, abenzyloxycarbonyl group. As said condition for reductive alkylation, appropriate reductive condition at present known per se or developed in later such as a condition using a metal hydride can be used. The present invention preferably includes as an embodiment the method according to the above [18] wherein one or more hydroxyl groups in the aldehyde represented by the above general formula (2) or (3) are protected by any appropriate protecting groups (for example, a benzyl group) in the case of the aldehyde having one or more hydroxyl groups. Examples of the salts of the compounds in the present invention include; salts with alkaline metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesivim; ammonium salts with ammonia; salts with amino acids such as lysine 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 present invention as described above. The aspartyl dipeptide ester derivatives of the present invention can easily be formed by reductively alkylating aspartame derivatives, wherein a moiety of L-phenylalanine methyl ester in the aspartame is replaced by another amino acid ester, with cinnamaldehydes having various substituents and a reducing agent (for example, hydrogen/palladium carbon catalyst). Alternatively, the derivatives can be formed by subjecting aspartame derivatives (for example, P-0-benzyl-a-L-aspartyl-L-amino acid methyl ester) having a protective group in a carboxylic acid in the B-position which derivatives can be obtained by the usual peptide synthesis method (Izumiya et al., Basis of Peptide Synthesis and Experiments Thereof, Maruzen, published January 20, 1985) to reductive alkylation with cinnamaldehydes having various substituents and a reducing agent (for example, NaB(0Ac)3H) (A. F. Abdel-Magid et al.. Tetrahedron Letters, 11, 5595 (1990)), and then removing the protective group. However, the method of forming the compounds of the present 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 an sensory evaluation, the compounds and the salts thereof in the present invention were found to have a strong sweetening potency and have sensory (organoleptic) properties similar to that of sugar. For example, the sweetening potency of N-[N-[3 - (3-hydroxy-4-methoxyphenyl)propyl]-L-a-aspartyl]-L-( a methyl)phenylalanine 1-methyl ester was approximately 18,000 times (relative to sugar), that of N-[N- [3 - (3-methoxy-4-hydroxyphenyl)propyl]-L-a-aspartyl]-L-(a- methy)phenylalanine 1-methyl ester was approximately 18,000 times (relative to sugar), that of N-[N-[3 -(3-hydroxy-4-methoxyphenyl)propyl] -L-a-aspartyl]- 3-cyclohexyl-L-alanine 1-methyl ester was approximately 25,000 times (relative to sugar), that of N-[N-[3 -(3-methoxy-4-hydroxyphenyl)propyl]-L-a-aspartyl]-3-cyclohexyl-L-alanine 1-methyl ester was approximately 25,000 times (relative to sugar), that of N-[N-[3 -(3-methyl•4-hydroxyphenyl)propyl]-L-a-aspartyl]-3-cyclohexyl-L-alanine 1-methyl ester was approximately 40,000 times (relative to sugar). With respect to the aspartyl dipeptide derivatives (represented by the following general formula (5) ) formed, the structures and the results of the sensory evaluation are shown in Table 1. As understood from the results of Table 1, the novel derivatives in the present invention are excellent in sweetening potency. When the derivatives (including compounds in the present invention and the salts thereof) of the present invention are used as sweeteners, these may of course be used in combination with other sweeteners unless inviting any special troubles. When the derivatives of the present invention are used as sweeteners, an appropriate carrier and/or an appropriate bulking agent may be used as required. For example, a carrier, a bulking agent or the like which has been known per se and so far used for the sweeteners is available. The derivatives of the present invention can be used as sweeteners or ingredients therefor, and further as sweeteners for products such as foods and the like to which a sweetness has to be imparted, for example, confectionery, chewing gum, hygiene products, toiletries, cosmetics, pharmaceutical products and veterinary products for animals. Still further, they can be used as a form of products having sweetness including the derivatives of the present invention and they can be used in a method of imparting sweetness to the products requiring sweetness. The method therefor can be, method known per se, for example, conventional method for using a sweetening ingredient for a sweetener in the sweeteners or the method of imparting sweetness. PREFERREP EMBODIMENTS OF THE INVENTION The present invention is illustrated specifically by referring to the following Examples. These examples are not to limit the present invention. In the following examples, NMR spectra were measured by using " Varian Gemini-300 (300MHz)" and MS spectra were measured by using " Thermo Quest TSQ700". (EXAMPLE 1) Synthesis of N- [N- [3-(3-hydroxy-4-methoxyphenyl)propyl] -L-a-aspartyl]-L-( α -methyl) phenylalanine 1-methyl ester Twenty milliliters of methanol was cooled to 0"C . To this was added 1.09 ml (IS.Ommol) of thionyl chloride by dropping. Then l.Og (5.58mmol) of L-( a-methyl) phenylalanine was added to the mixture and stirred for 1 hour at 0*0 and further over night at TOtD. The solvent was removed under reduced pressure. An aqueous solution of 5% sodium hydrogen carbonate was added to the residue and extracted twice with 50ml of methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and magnesium sulfate was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 0.95g (4.92mmol) of L-( 05 -methyl)phenylalanine methyl ester as an oil. To 30ml of methylene chloride were added 0.95g (4.92inmol) of L-( a -methyl)phenylalanine methyl ester and 1.59g (4.92mmol) of N-t-butoxycarbonyl-L-aspartic acid /3 -benzyl ester. The mixture was cooled to O C. To the mixture, 73 0mg (5.41mmol) of 1-hydroxybenzotriazol hydrate (HOBt)"and 1.04g (5.41mmol) of water-soluble carbodiiroide hydrochloride were added and stirred at 0 "C for 1 hour and further at room temperature over night. The reaction mixture was concentrated under reduced pressure and 50ml of water was added to the residue and the mixture was extracted twice with 50ml of ethyl acetate. The organic layer was washed twice with 50ml of 5% aqueous solution of citric acid, once with 50ml of saturated aqueous solution of sodium chloride, twice with 50ml of 5% sodium hydrogen carbonate aqueous solution, then once 50ml of saturated aqueous solution of sodium chloride. Then the organic layer was dried over anhydrous magnesium sulfate and magnesium sulfate was removed by filtration. And the filtrate was concentrated to obtain 2.07g (4.15 mmol) of N-t-butoxycarbonyl- 0 -O-benzyl- a -L-aspartyl-L-( a methyl)phenylalanine methyl ester as a viscous oil. Ten milliliters of a solution of 4N-HCl/dioxane were added to 1.04g (2.08 mmol) of N-t-butoxycarbonyl-P-0-benzyl-a-L-aspartyl -L- ( a -methyl) phenylalanine methyl ester, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. Fifty milliliters of 5% sodium hydrogen carbonate aqueous solution was added to the residue, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Then, magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 822 mg (2.06mmol) of p-0-benzyl-a-L-aspartyl-L-( CK -methyl) phenylalanine methyl ester as a viscous oil. The P-0-benzyl-a-L-aspartyl-L-{ a methyl)phenylalanine methyl ester (822 mg, 2.06 mmol) was dissolved in 20 ml of tetrahydrofuran (THF), and the solution was maintained at 0°C. To this were added 554 mg (2.06 mmol) of 3-benzyloxy-4-methoxycinnamaldehyde, 0.11 ml (2.06 mmol) of acetic acid and 636 mg (3.0 mmol) of NaB (OAc) 3H. The mixture was stirred at O c for 1 hour and further overnight at room temperature. To the reaction solution was added 50 ml of a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Then, magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure . The residue was purified with PTLC ( Preparative Thin Layer Chromatography ) to obtain 1.17 g (1.80 mmol) of N-[N-[3- (3-benzyloxy-4-methoxyphenyl)propenyl]-P-0-benzyl-L-a-aspartyl]-L-( a -methyl)phenylalanine 1-methyl ester as a viscous oil. The N- [N- [3- (3-benzyloxy-4-methoxyphenyl)propenyl] -P"O-benzyl-L-a-aspartyl]-L-( Ot -methyl) phenylalanine 1-methyl ester (1.173 g, 1.78 nunol) was dissolved in a mixed solvent of 3 0 ml of methanol and 1 ml of water, and 350 mg of 10% palladium carbon (water content 50%) were added thereto. The mixture was reduced in a hydrogen stream at room temperature for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. In order to remove an odor adsorbed, the residue was purified with PTLC to obtain 553 mg (1.17 mmol) of N-[N-[3 -(3-hydroxy-4-methoxyphenyl)propyl]-L-α-aspartyl]-L-( a methyl)phenylalanine 1-methyl ester as a solid. ^HNMR (DMSO-de) 5:1.27 (s,3H), 1.60-1.72 (m,2H), 2.30-2.60 (m,6H), 3.10 (dd,2H), 3.50-3.62 (m,lH), 3.56 (s,3H), 3.71 (s,3H), 6.54 (dd,lH), 6.61 (d,lH), 6.79 (d,lH), 7.04-7.10 (m,2H), 7.22-7.34 (m,3H), 8.40 (s,lH), 8.80 (brs,lH). ESI (Electrospray Ionization)-MS 473.3 (MH*) Sweetening potency (relative to sugar): 18,000 times (EXAMPLE 2) Synthesis of N- [N- [3 - (3-methoxy-4-hydroxyphenyl)propyl] -L- a-aspartyl] -L-( Q!-methyl) phenylalanine 1-methyl ester Example 1 was repeated except that 3-methoxy-4-hydroxycinnamaldehyde was used instead of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl] -L-a-aspartyl]-L-( a methyl)phenylalanine 1-methyl ester in a total yield of 42.7% as a solid in the same manner as above. ^HNMR (DMSO-de) 5:1.28 (s,3H), 1.60-1.72 (m,2H), 2.24-2.58 {m,6H), 3.14 {dd,2H), 3.43-3.50 (m,IH), 3.56 (s,3H), 3.74 (s,3H), 6.56 (d,lH), 6.65 (d.lH), 7.07 (d,2H), 7.20-7.32 (m,3H), 8.33 (s,lH), 8.65 (brs,lH). ESI-MS 473.3 (MH*) Sweetening potency (relative to sugar): 18,000 times (EXAMPLE 3) Synthesis of N-[N-[3 - (3-hydroxy-4-methoxyphenyl)propyl]-L-a-aspartyl]- 3-cyclohexyl-L-alanine 1-methyl ester Example 1 was repeated except that 3-cyclohexyl-L-alanine was used instead of L- ( Q! -methyl) -phenylalanine to obtain N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-a-aspartyl] -3 -cyclohexyl -L-alanine 1-methyl ester in a total yield of 30.0% as a solid in the same manner as above. ^HNMR (DMSO-de) 5:1.11 (m,2H), 1.64 (m.lOH), 2.27 (m, IH) , 2.3 8 (m,lH) , 2.45 (m,4H) , 3.3 8 (m, 2H) , 3.51 (m, IH) , 3.61 {s,3H) , 3.71 (s,3H) , 4.37 (m.lH) , 6.5 7 (m, 2H) . 6.78 (m, IH) , 8,47 {m,lH) . ESI-MS 465.3 (MH*) Sweetening potency (relative to sugar): 25,000 times (EXAMPLE 4) Synthesis of N-[N-[3 -(3-methoxy-4-hydroxyphenyl)propyl]-L- a-aspartyl]-3-cyclohexyl-L-alanine 1-methyl ester Example 1 was repeated except that 3-cyclohexyl-L-alanine was used instead of L-( α -methyl)-phenylalanine and that 3-methoxy -4-benzyloxycinnamaldehyde was used instead of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-a-aspartyl]-3-cyclohexyl-L-alanine 1-methyl ester in a total yield of 28.7% as a solid in the same manner as above. ^HNMR (DMSO-de) 5:1.10 (m,2H), 1.62 (m,10H), 2.25 {m,lH), 2.3 8 (m,lH), 2.49 (m,4H), 3.38 (m,2H), 3.52 (m,lH), 3.60 (s,3H), 3.73 (s,3H), 4.36 (m,lH), 6.63 (m,3H), 8.46 (m,lH). ESI-MS 465.3 (MH*) Sweetening potency (relative to sugar): 25,000 times (EXAMPLE 5) Synthesis of N- [N-[3 -(3-hydroxy-4-methoxyphenyl)propyl] -L-a-aspartyl]-L-phenylglycin 1-methyl ester Example 1 was repeated except that L-phenylglycin was used instead of L- (oi-methyl) -phenylalanine to obtain N-[N- [3- (3-hydroxy-4-methoxyphenyl)propyl] -L-a-aspartyl] -L-phenylglycin 1-methyl ester in a total yield of 19. 0% as a solid In the same manner as above. 1HNMR (DMSO-ds) 6:1.63 (m,2H), 2.30 (m,lH), 2.42 (m, IH) , 2.48 (m,4H), 3.38 (m.lH), 3.63 (s,3H), 3.71 (s,3H), 5.44 (m,lH), 6.55 (m,2H). 6.78 (m,lH), 7.38 (m,5H), 8.96 (m,lH). ESI-MS 445.3 (MH*) Sweetening potency (relative to sugar): 1,600 times (EXAMPLE 6) Synthesis of N- [N- [3-(3-methoxy-4-hydroxyphenyl)propyl] -L- a-aspartyl]-L-phenylglycin 1-methyl ester Example 1 was repeated except that L-phenylglycin was used instead of L-( a -methyl)-phenylalanine and that 3-methoxy-4-benzyloxycinnamaldehyde was used instead of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-a-aspartyl]-L-phenylglycin 1-methyl ester in a total yield of 23.5% as a solid in the same manner as above. ^HNMR (DMSO-ds) 5:1.65 (m,2H), 2.29 (m. IH) , 2.43 (m, IH) , 2.50 (m,4H) , 3.5 8 (m, IH) , 3.63 (s,3H) , 3.73 (s,3H) , 5.44 (m, IH) , 6.41 (m,3H), 7.38 (m,5H), 8.94 (m,lH). ESI-MS 445.3 (MH*) Sweetening potency (relative to sugar): 700 times (EXAMPLE 7) Synthesis of N- [N- [3-(3-hydroxy-4-methoxyphenyl)propyl] -L- a-aspartyl]-DL-homophenylalanine 1-methyl ester Example 1 was repeated except that DL-homophenylalanine was used instead of L- ( α -methyl) -phenylalanine to obtain N-[N-[3- ^HNMR (DMSO-de) 5:1.68 (m,2H), 1.96 (m,2H), 2.32 (m, IH) , 2.4 6 (m,lH), 2.5 8 {m,4H),3.37 (m,2H) ,3.52 (m,lH) , 3.60 (2s,3H) , 3.70 (2s,3H). 4.21 (m,IH), 6.68 (m,3H), 7.23 (m,5H), 8.58 (m,lH) . ESI-MS 473.3 (MH*) Sweetening potency (relative to sugar): 1,000 times (EXAMPLE 8) Synthesis of N- [N-[3 -(3-methoxy-4-hydroxyphenyl)propyl] -L-a-aspartyl]-DL-homophenylalanine 1-methyl ester Example 1 was repeated except that DL-homophenylalanine was used instead of L- ( a -methyl) -phenylalanine and that 3-methoxy-4-benzyloxycinnamaldehyde was used instead of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-a-aspartyl]-DL-homophenylalanine 1-methyl ester in a total yield of 18.4% as a solid in the same manner as above. 1 HNMR (DMSO-ds) 0 :1.70 (m,2H), 1.96 (m,2H), 2.34 (m,lH), 2.45 (m,lH), 2.56 (m,4H), 3.40 (m,2H), 3.55 (m,lH), 3.60 (2s,3H), 3.70(2s,3H), 4.21 (m, IH) , 6.68 (ni,3H), 7.23 (m,5H), 8.58 (m.lH). ESI-MS 473.3 (MH*) Sweetening potency (relative to sugar): 1,200 times (EXAMPLE 9) Synthesis of N-tN-[3 -(3-hydroxy-4-methoxyphenyl)propyl]-L-α -aspartyl]-D-alanine 1-n-propyl ester Example 1 was repeated except that D-alanine n-propyl ester hydrochloride was used instead of L- { α -methyl) -phenylalanine methyl ester to obtain N-[N-[3 -(3-hydroxy-4-methoxyphenyl)propyl]-L-a-aspartyl]-D-alanine 1-n-propyl ester in a total yield of 37.3% as a solid in the same manner as above. ^HNMR (DMSO-dg) (5:0.87 (t,3H), 1.28 (d.3H), 1.50-1.60 (m,2H), 1.60-1.70 (m,2H), 2.18-2.60 (m,6H), 3.43-3.51 (m,lH), 3.71 (s,3H), 3.95-4.02 (m,2H), 4.20-4.30 (m,IH), 6.54 (d,lH), 6.61 (s,lH), 6.78 (d,lH), 8.50 (d,IH), 8.80 (brs,lH). ESI-MS 411.4 (MH*) Sweetening potency (relative to sugar): 800 times (EXAMPLE 10) Synthesis of N- [N- [3 -(3-methoxy-4-hydroxyphenyl)propyl] -L- a-aspartyl]-D-alanine 1-n-propyl ester Example 1 was repeated except that D-alanine n-propyl ester hydrochloride was used instead of L- { (X -methyl) -phenylalanine methyl ester and that 3-methoxy-4-hydroxycinnamaldehyde was used instead of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N-[N-[3 -(3-methoxy-4-hydroxyphenyl)propyl] -L-a-aspartyl]-D-alanine i-n-propyl ester in a total yield of 27.8% as a solid in the same manner as above. ^HNMR (DMSO-de) 5:0.87 {t,3H), 1.28 {d,3H), 1.50-1.62 (m,2H), 1.62-1.73 (m,2H), 2.20-2.60 (m,6H), 3.45-3.51 {m,lH), 3.74 (s,3H), 3.94-4.02 (m,2H), 4.20-4.30 (m,IH), 6.56{dd,lH), 6.65 (d,lH), 6.74 (d,lH), 8.51 (d,lH), 8.60 (brs.lH). ESI-MS 411.4 (HH*) Sweetening potency (relative to sugar): 600 times (EXAMPLE 11) Synthesis of N-[N-[3 -(2-hydroxy-4-methoxyphenyl)propyl] -L-a-aspartyl]-L-( α -methyl) phenylalanine 1-methyl ester Example 1 was repeated except that 2-benzyloxy-4-methoxycinnamaldehyde was used instead of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N-[N-[3 - (2-hydroxy-4-methoxyphenyl) propyl]-L-a-aspartyl]-L-( α methyl)phenylalanine 1-methyl ester in a total yield of 44.0% as a solid in the same manner as above. ^HNMR (DMSO-de) 3.43-3.48 (in,lH), 3.56 (s,3H), 3.65 (s,3H), 6.28 {dd,lH), 6.35 (d,lH), 6.92 (d,lH), 7.05-7.10 (in,2H). 7.20-7.31 (m,3H), 8.35 (s,lH). ESI-MS 473.2 (MH*) Sweetening potency (relative to sugar): 15,000 times (EXAMPLE 12) Synthesis of N-[N-[3 -(3-methyl- 4-hydroxyphenyl)propyl]-L-a -aspartyl]-3-cyclohexyl-L-alanine 1-methyl ester Example 1 was repeated except that 3-cyclohexyl-L-alanine was used instead of L-( 0!-methyl)-phenylalanine and that 3-methyl-4-benzyloxycinnamaldehyde was used instead of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N-[N-[3-(3-methyl-4-hydroxyphenyl)propyl]-L-a-aspartyl]-3-cyclohexyl-L-alanine 1-methyl ester in a total yield of 35.6% as a solid in the same manner as above. ^HNMR (DMSO-ds) 5:0.83-1.65 (m,llH), 1.49-1.60 (m,2H), 1.63-1.68 (m,2H), 2.08 (s,3H), 2.24-2.40 (m,2H), 2.41-2.51 (m,4H), 3.49-3.53 (m,lH), 3.61 (s,3H), 4.33-4.50 (m,IH), 6.65 (d,lH), 6.78 (d,lH), 6.86 (s,lH), 8.48 (d,lH), 9.04 (brs,lH). ESI-MS 449.3 (MH") Sweetening potency (relative to sugar): 40,000 times (EXAMPLE 13) Synthesis of N- [N- [3 - (2-hydroxy-4-methylphenyl)propyl] -L-a -aspartyl]-3-cyclohexyl-L-alanine Example 1 was repeated except that 3-cyclohexyl-L-alanine was used instead of L-( α -methyl)-phenylalanine and that 2-benzyloxy-4-methylcinnamaldehyde was used instead of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N-[N-[3-(2-hydroxy-4-methylphenyl)propyl]-L-a-aspartyl]-3-cyclohexyl-L-alanine in a total yield of 2 6.2% as a solid in the same manner as above. ^HNMR (DMSO-ds) 5:0.82-1.65 (m,llH), 1.49-1.59 (m,2H), 1.61-1.66 (m,2H), 2.17 (s,3H), 2.23-2.41 (m,2H), 2.44-2.48 (m,4H), 3.47-3.53 (m,IH) , 3.61 (s,3H), 4.33-4.41 (m,IH) , 6.50 (d,lH), 6.59 (s.lH), 6.89 (d.lH), 8.50 (d,lH), 9.12 (brs.lH). ESI-MS 449.3 (MH*) Sweetening potency (relative to sugar): 25,000 times (EXAMPLE 14) Synthesis of N-[N-[3 -(3-hydroxy-4-methoxyphenyl)propyl] -L- α -aspartyl]-L-( α -methyl)phenylalanine 1-methyl ester The reaction and the treatment are carried out in the same manner as in Example 1 except that 3 - (3-benzyloxy-4-methoxyphenyl)propionaldehyde is used instead of 3-benzyloxy-4-methoxycinnamaldehyde to obtain N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-a-aspartyl]-L-( a methyl)phenylalanine 1-methyl ester. EFFECT OF THE INVENTION The novel aspartyl dipeptide ester derivatives of the present invention are low in calories. And the derivatives have especially an excellent sweetening potency in comparison with conventional sweeteners. The present invention can provide novel chemical substances having excellent properties as sweeteners. Accordingly, such novel derivatives in the present invention can be used as sweeteners, and also can impart a sweetness to products such as drinks (beverages) and foods requiring a sweetness. We claim: 1. Novel aspartyl dipeptide ester derivatives (including salts thereof) represented by formula (1) wherein; R1, R2, R3, R4 and R5, independently from each other, each represents a substituent selected from a hydrogen atom (H), a hydroxy 1 group (OH), an alkoxy group (OCH3, OCH2CH3, OCH2CH2CH3, etc.) having from 1 to 3 carbon atoms, an alkyl group (CH3, CH2CH3, CH2CH2CH3, etc.) having from 1 to 3 carbon atoms and a hydroxyalkyloxy group ( 0(CH2)20H, OCH2CH(OH)CH3, etc.) having 2 or 3 carbon atoms, or R1 and R2, or R2 and R3 together form a methylenedioxy group (OCH2O) wherein R4, R5, and Ri or R3 which does not form the methylenedioxy group, independently from each other, each represents any substituents as mentioned above designated for the R1, R3, R4 and R5, respectively; R6 represents a substitutent selected from a hydrogen atom, a benzyl group (CH2C6H5), a p-hydroxybenzyl group (CH2C6H4-P-OH), a cyclohexylmethyl group (CH2C6Hn), a phenyl group (CgHj), a cyclohexyl group (C6Hn), a phenylethyl group (CH2CH2C6H5) and a cyclohexylethyl group (CH2CH2C6H11); R7 represents a substituent selected from a hydrogen atom, a methyl group (CH3), an ethyl group (CH2CH3) and an isopropyl group (CH(CH3)2); R.g represents a substituent selected from a methyl group, an ethyl group, an isopropyl group, a n-propyl group (CH2CH2CH3) and a t-butyl group (C(CH3)3); provided the derivatives in which R6, represents a benzyl group and R7 represents a hydrogen atom at the same time, and the derivatives in which R6 represents a p-hydroxybenzyl group and R.7 represents a hydrogen atom at the same time are excluded. 2. The derivative as claimed in claim 1, wherein R2 is a hydroxyl group, R3 is a methoxy group, R1, R4 and R5 are hydrogen atoms, R6 is a benzyl group, and R7 and R8 are methyl groups. 3. The derivative as claimed in claim 1, wherein R2 is a methoxy group, R3 is a hydroxyl group, R), R4 and R5 are hydrogen atoms, R6 is a benzyl group, and R7 and R8 are methyl groups. 4. The derivative as claimed in claim 1, wherein R2 is a hydroxyl group, R3 is a methoxy group, Ri, R4, R5 and R? are hydrogen atoms, R^is a cyclohexylmethyl group, and Rg is a methyl group. 5. The derivative as claimed in claim 1, wherein R2 is a methoxy group, R3 is a hydroxyl group, Ri, R4, R5 and R7 are hydrogen atoms, R^ is a cyclohexylmethyl group, and Rg is a methyl group. 6. The derivative as claimed in claim 1, wherein R2 is a hydroxyl group, R3 is a methoxy group, R1, R4, R5 and R7 are hydrogen atoms, Rg is a phenyl group, and Rg is a methyl group. 7. The derivative of claim 1, wherein R2is a methoxy group, R3 is a hydroxyl group, Ri, R4, R5 and R7 are hydrogen atoms, R^ is a phenyl group, and R8 is a methyl group. 8. The derivative claim 1, wherein R2 is a hydroxyl group, R3 is a methoxy group, R1, R4, R5 and R7 are hydrogen atoms, R6 is a 2-phenylethyl group, and Rg is a methyl group. 9. The derivative as claimed in claim 1, wherein R2 is a methoxy group, Rsis a hydroxyl group, Ri, R4 R5 and R7 are hydrogen atoms, R^ is a 2-phenylethyl group, and R.g is a methyl group. 10. The derivative as claimed in claim 1, wherein R2 is a hydroxyl group, R32is a methoxy group, R1, R4, R5 and R6 are hydrogen atoms, Ryis a methyl group, and Rg is a n-propyl group. 11. The derivative as claimed in claim 1, wherein R2 is a methoxy group, R3 is a hydroxyl group, Ri, R4, R5 and Rg are hydrogen atoms, R7 is a methyl group, and Rg is a n-propyl group. 12. The derivative as claimed in claim 1, wherein Ri is a hydroxyl group, R3 is a methoxy group, R2, R4, and R5 are hydrogen atoms. Re is a benzyl group, and R7 and Rg are methyl groups. 13. The derivative as claimed in claim 1, wherein R2 and Rg methyl groups, R3 is a hydroxyl group, Ri, R4, R5 and R7 are hydrogen atoms, and R6 is a cyclohexylmethyl group. 14. The derivative of claim 1, wherein R1 is a hydroxyl group, R3 and Rg are methyl groups, R2, R4, R5 and R7 are hydrogen atoms, and R6 is a cyclohexylmethyl group. 15. A composition comprising at least one derivative of claim 1 and a carrier or bulking agent. 16. Novel aspartyl dipetide ester derivates substantially as hereinabove described and exemplified.

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