Dipeptide derivatives of fatty acids, process for preparing them, pharmaceutical composition and use

Claim 2

A dipeptide derivative of fatty acid of formula (I) (wherein m is a number of 0, 1 or 2; n is a number of 0 to 12; R, is a saturated or unsaturated unbranched hydrocarbon group having 5 to 25 carbon atoms (the unsaturated carbon chain may include a plurality of double bonds); R 3 is a lower alkylester group of the formula: -COOR 4 (wherein R 4 is a lower alkyl group) or hydroxymethyl group or formyl group; R2 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R 2 is methyl group, phenyl group, hydroxyphenyl group, carboxyl group, formyl group, amino group, hydroxyl group or methylthio group (these groups may be substituted); R s is hydrogen atom, or when n is 3, R2 and R s together may represent a single bond between carbon atom and nitrogen atom).

Claim 3

A compound according to Claim 1, represented by the formula (Ia): (wherein n is an integer of 1 to 12; R, and R 3 represent the meaning given in Claim 1; R2 is methyl group, phenyl group, hydroxyphenyl group, carboxyl group, formyl group, amino group, hydroxyl group or methylthio group (these groups may be substituted)).

Claim 4

A compound according to Claim 1, represented by the formula (Ib): (wherein R, and R 3 represent the meaning given Claim 1).

Claim 5

A compound according to Claim 1, represented by the formula (Ic): (wherein m, R 1 and R 3 represent the meaning given in Claim 1; R 2 is:

Claim 6

A compound according to either one of Claims 1 and 2, wherein n represents a number of 1 to 6.

Claim 7

A compound according to any one of Claims 1 to 4, wherein R 3 represents formyl group.

Claim 8

A process for producing a compound of formula (I) (wherein m is a number of 0, 1 or 2; n is a number of 0 to 12; R, is a saturated or unsaturated unbranched hydrocarbon group having 5 to 25 carbon atoms (the unsaturated carbon chain may include a plurality of double bonds); R 3 is a lower alkylester group of the formula: -COOR4 (wherein R4 is a lower alkyl group) or hydroxymethyl group or formyl group; R 2 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R2 is methyl group, phenyl group, hydroxyphenyl group, carboxyl group, formyl group, amino group, hydroxyl group or methylthio group (these groups may be substituted); R s is hydrogen atom, or when n is 3, R 2 and R s together may represent a single bond between carbon atom and nitrogen atom), characterized in that (i) carboxylic acid, carboxylic acid anhydride or carbonyl chloride represented by the formula: or (wherein R, is a saturated or unsaturated unbranched hydrocarbon group having 5 to 25 carbon atoms (the unsaturated carbon chain may include a plurality of double bonds)), and peptide or amino acid, having a proline residue whose carboxyl group has been converted to a lower alkylester, of the formula (II): (wherein m is a number of 0, 1 or 2; R 7 is a lower alkyl group; R 6 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R6 is methyl group, phenyl group, hydroxyphenyl group whose hydroxyl group is protected, protected carboxyl group, protected amino group, protected hydroxy group or methylthio group; R s is hydrogen atom, or when n is 3, R 6 and R s together may represent a single bond between carbon atom and nitrogen atom), are reacted to form a compound of the formula (Id): (wherein R,, R 2 , R s , R 6 , n and m are as defined above), and if a compound of formula (Id) has a protected group, said group is removed to form a compound of formula (le): (wherein R,, R 2 , R s , R 7 , n and m are as defined above), or (ii) a compound of the formula (Id) is further reduced to form a compound of formula (If): (wherein R,, R s , n and m are as defined above; R 8 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R 8 is methyl group, phenyl group, hydroxyphenyl whose hydroxyl is protected, protected amino group, protected hydroxyl group, methylthio group or hydroxymethyl group, or when n is 3, R 8 and R s together may represent a single bond between carbon atom and nitrogen atom), and if a compound of formula (If) has a protected group, said group is removed to form a compound of formula (Ig): (wherein R,, R s , n and m are as defined above; R 9 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R 9 is methyl group, phenyl group, hydroxyphenyl group, amino group, hydroxyl group or methylthio group, or when n is 3, R 9 and R s together may represent a single bond between carbon atom and nitrogen atom) or (iii) a compound of the formula (If) is further oxidized to form a compound of formula (Ih): (wherein R,, R s , n and m are as defined above; R 10 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R, o is methyl group, phenyl group, hydroxyphenyl group whose hydroxy group is protected, protected amino group, protected hydroxyl group, methylthio group or formyl group, or when n is 3, R, o and R s together may represent a single bond between carbon atom and nitrogen atom), and if a compound of the formula (Ih) has a protected group, said group is removed to form a compound of formula (li): (wherein R,, R s , n and m are as defined above; R 11 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R,, is methyl group, phenyl group, hydroxyphenyl group, amino group, hydroxyl group, hydroxyalkyl group, methylthio group or formyl group, or when n is 3, R 11 and R s together may represent a single bond beween carbon atom and nitrogen atom).

Claim 9

A process for producing a compound of formula (I) (wherein m is a number of 0, 1 or 2; n is a number of 0 to 12; R, is a saturated or unsaturated unbranched hydrocarbon group having 5 to 25 carbon atoms (the unsaturated carbon chain may include a plurality of double bonds); R 3 is a lower alkylester group of the formula: -COOR4 (wherein R4 is a lower alkyl group) or hydroxymethyl group or formyl group; R 2 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R2 is methyl group, phenyl group, hydroxyphenyl group, carboxyl group, formyl group, amino group, hydroxyl group or methylthio group (these groups may be substituted); R s is hydrogen atom, or when n is 3, R 2 and R s together may represent a single bond between carbon atom and nitrogen atom), characterized in that (i) carboxylic acid, carboxylic acid anhydride or carbonyl chloride represented by the formula: or (wherein R, is a saturated or unsaturated unbranched hydrocarbon group having 5 to 25 carbon atoms (the unsaturated carbon chain may include a plurality of double bonds)), and peptide or amino acid, having a proline residue whose carboxyl group has been converted to a lower alkylester, of the formula (II): (wherein m is a number of 0, 1 or 2; R 7 is a lower alkyl group; R 6 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R6 is methyl group, phenyl group, hydroxyphenyl group whose hydroxyl group is protected, protected carboxyl group, protected amino group, protected hydroxy group or methylthio group; R s is hydrogen atom, or when n is 3, R 6 and R s together may represent a single bond between carbon atom and nitrogen atom), are reacted to form a compound of the formula (Id): (wherein R,, R 2 , R s , R 6 , n and m are as defined above), and if a compound of formula (Id) has a protected group, said group is removed to form a compound of formula (le): (wherein R,, R 2 , R s , R 7 , n and m are as defined above), or (ii) a compound of the formula (Id) is further reduced to form a compound of formula (If): (wherein R,, R s , n and m are as defined above; R 8 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R 8 is methyl group, phenyl group, hydroxyphenyl whose hydroxyl is protected, protected amino group, protected hydroxyl group, methylthio group or hydroxymethyl group, or when n is 3, R 8 and R s together may represent a single bond between carbon atom and nitrogen atom), and if a compound of formula (If) has a protected group, said group is removed to form a compound of formula (Ig): (wherein R,, R s , n and m are as defined above; R 9 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R 9 is methyl group, phenyl group, hydroxyphenyl group, amino group, hydroxyl group or methylthio group, or when n is 3, R 9 and R s together may represent a single bond between carbon atom and nitrogen atom) or (iii) a compound of the formula (If) is further oxidized to form a compound of formula (Ih): (wherein R,, R s , n and m are as defined above; R 10 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R, o is methyl group, phenyl group, hydroxyphenyl group whose hydroxy group is protected, protected amino group, protected hydroxyl group, methylthio group or formyl group, or when n is 3, R, o and R s together may represent a single bond between carbon atom and nitrogen atom), and if a compound of the formula (Ih) has a protected group, said group is removed to form a compound of formula (li): (wherein R,, R s , n and m are as defined above; R 11 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R,, is methyl group, phenyl group, hydroxyphenyl group, amino group, hydroxyl group, hydroxyalkyl group, methylthio group or formyl group, or when n is 3, R 11 and R s together may represent a single bond beween carbon atom and nitrogen atom).

Claim 10

A pharmaceutical composition consisting essentially of dipeptide derivative of fatty acid of formula (I): (wherein m is a number of 0, 1 or 2; n is a numer of 0 to 12; R, is a saturated or unsaturated unbranched hydrocarbon group having 5 to 25 carbon atoms (the unsaturated carbon chain may include a plurality of double bonds); R 3 is a lower alkylester group of the formula: -COOR, (wherein R 4 is a lower alkyl group) or hydroxymethyl group or formyl group; R2 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R2 is methyl group, phenyl group, hydroxyphenyl group, carboxyl group, formyl group, amino group, hydroxyl group or methylthio group (these groups may be substituted); R s is hydrogen atom, or when n is 3, R2 and R s together may represent a single bond between carbon atom and nitrogen atom), as an active ingredient together with an acceptable carrier..

Claim 11

A pharmaceutical composition consisting essentially of dipeptide derivative of fatty acid of formula (I): (wherein m is a number of 0, 1 or 2; n is a numer of 0 to 12; R, is a saturated or unsaturated unbranched hydrocarbon group having 5 to 25 carbon atoms (the unsaturated carbon chain may include a plurality of double bonds); R 3 is a lower alkylester group of the formula: -COOR, (wherein R 4 is a lower alkyl group) or hydroxymethyl group or formyl group; R2 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R2 is methyl group, phenyl group, hydroxyphenyl group, carboxyl group, formyl group, amino group, hydroxyl group or methylthio group (these groups may be substituted); R s is hydrogen atom, or when n is 3, R2 and R s together may represent a single bond between carbon atom and nitrogen atom), as an active ingredient together with an acceptable carrier..

Claim 12

Use of a dipeptide derivative of fatty acid of formula (I): (wherein m is a number of 0, 1 or 2; n is a number of 0 to 12; R, is a saturated or unsaturated unbranched hydrocarbon group having 5 to 25 carbon atoms (the unsaturated carbon chain may include a plurality of double bonds); R, is a lower alkylester group of the formula: -COOR 4 (wherein R 4 is a lower alkyl group) or hydroxymethyl group or formyl group; R2 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R2 is methyl group, phenyl group, hydroxyphenyl group, carboxyl group, formyl group, amino group, hydroxyl group or methylthio group (these groups may be substitued); R 5 is hydrogen atom, or when n is 3, R z and R s together may represent a single bond between carbon atom and nitrogen atom), for the preparation of a medicament for the treatment of amnesia.

Claim 13

Use of a dipeptide derivative of fatty acid of formula (I): (wherein m is a number of 0, 1 or 2; n is a number of 0 to 12; R, is a saturated or unsaturated unbranched hydrocarbon group having 5 to 25 carbon atoms (the unsaturated carbon chain may include a plurality of double bonds); R, is a lower alkylester group of the formula: -COOR 4 (wherein R 4 is a lower alkyl group) or hydroxymethyl group or formyl group; R2 represents, when n is 0, an unbranched or branched alkyl group having 1 to 5 carbon atoms, whereas, when n is an integer of 1 to 12, R2 is methyl group, phenyl group, hydroxyphenyl group, carboxyl group, formyl group, amino group, hydroxyl group or methylthio group (these groups may be substitued); R 5 is hydrogen atom, or when n is 3, R z and R s together may represent a single bond between carbon atom and nitrogen atom), for the preparation of a medicament for the treatment of amnesia.