Method for preparing phenylalanine derivatives having quinazoline-dione skeleton and intermediates for use in the preparation of derivatives

1. A method for preparing a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, comprising:

wherein R1 represents either a phenyl group which may have a substituent or a pyridyl group which may have a substituent; R2 represents an alkyl group which may have a substituent; R3 represents an alkyl group substituted with a di-alkylamino group, an alkyl group substituted with a mono-alkylamino group or an alkyl group substituted with an amino group; and R4 represents a hydrogen atom, an alkyl group or a benzyl group which may have a substituent;

(a) reacting a compound represented by the following formula (2) or a chemically acceptable salt thereof:

wherein R1 and R2 are the same as those defined above,

with a carbonyl group-introducing reagent and a compound represented by the following formula (3) or a chemically acceptable salt thereof:

wherein R3′ represents an alkyl group substituted with a dialkylamino group, an alkyl group substituted with a mono-alkylamino group which may have a protective group or an alkyl group substituted with an amino group which may have a protective group,

to thus form a compound represented by the following formula (4) or a chemically acceptable salt thereof:

wherein R1, R2 and R3′ are the same as those defined above;

(b) converting the compound of Formula (4) into a quinazoline-dione compound represented by the following formula (5) or a pharmaceutically acceptable salt thereof, in the presence of a carboxyl group-activating agent:

wherein R1 to R3′ are the same as those defined above; and

(c) if desired, substituting an N-alkyl group for the hydrogen atom bonded to the nitrogen atom present in the quinazoline-dione ring of the compound of Formula (5) using an N-alkylation agent and then deprotecting the resulting product, when the substituent R3′ is protected.

2. The method as set forth in claim 1 , wherein R3 appearing in Formula (1) is a methylamino-methyl group, an ethylamino-methyl group or a dimethylamino-methyl group; R3′ appearing in Formulas (3) to (5) is a methyl group substituted with a methylamino group having a protective group, a methyl group substituted with an ethylamino group having a protective group, a dimethylamino-methyl group or a diethylamino-methyl group.

3. The method as set forth in claim 1 , wherein, in Formulas (1) to (5), R1 is a 2,6-dichlorophenyl group, a 2-chloro-6-methylphenyl group, a 2-chloro-6-fluorophenyl group, a 2,6-difluorophenyl group or a 2-fluoro-6-methylphenyl group; R4 represents either a methyl group or an ethyl group; and the quinazoline-dione substituent present on the benzene ring of the phenylalanine moiety is present at p-position of the benzene ring.

4. The method as set forth in claim 1 , wherein the carbonyl group-introducing reagent is 1,1′-carbonyl-diimidazole, 1,1′-carbonyl-ditriazole, or a chloroformate ester.

5. The method as set forth in claim 1 , wherein the carboxyl group-activating agent is 1,1′-carbonyl-diimidazole, a chloroformate ester, an alkylsulfonic acid chloride, N,N′-dicyclohexyl-carbodiimide (DCC) or 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide.

6. The method as set forth in claim 1 , wherein the N-alkylation agent is methyl p-toluene-sulfonate, methyl methane-sulfonate, methyl iodide, methyl bromide, or methyl chloride.

7. The method as set forth in claim 1 , wherein the compound of Formula (2) is first reacted with the carbonyl group-introducing reagent and then the resulting product is reacted with the compound of Formula (3).

8. The method as set forth in claim 1 , wherein the compound of formula (4) is not isolated.

9. The method as set forth in claim 1 , wherein a compound of Formula (2) in which R1 of Formula (2) is a 2,6-dichlorophenyl group and R2 is an isopropyl group, is reacted with 1,1′-carbonyl-diimidazole as a carbonyl group-introducing reagent and a compound of Formula (3) in which R3′ is an N-formyl-N-methyl-aminomethyl group to thus form 2-(3-{4-[2(S)-2-(2,6-dichlorobenzoylamino)-2-isopropoxycarbonylethyl)-phenyl}ureido)-5-(N-formyl-N-methyl-aminomethyl)-benzoic acid of Formula (4) in which R1 is a 2,6-dichlorophenyl group, R2 is an isopropyl group, and R3′ is an N-formyl-N-methyl-aminomethyl group; then the resulting compound is reacted with 1,1′-carbonyl-diimidazole as a carboxyl group-activating agent to thus convert the former into N α -(2,6-dichlorobenzoyl)-4-{6-(N-formyl-N-methyl-aminomethyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester of Formula (5) in which R1 is a 2,6-dichlorophenyl group, R2 is an isopropyl group and R3′ is an N-formyl-N-methyl-aminomethyl group; subsequently N-alkylation of the resulting product is carried out using methyl p-toluene-sulfonate to thus convert the product into N α -(2,6-dichlorobenzoyl)-4-{1-methyl-6-(N-formyl-N-methylamino-methyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester; and finally the N-alkylated product is treated with hydrogen chloride to thus deprotect the formyl group thereof to thus give N α -(2,6-dichlorobenzoyl)-4-[1-methyl-6-(N-methylamino-methyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester of Formula (1) or a hydrochloride thereof, in which R1 is a 2,6-dichlorophenyl group, R2 is an isopropyl group, R3′ is an N-methyl-aminomethyl group and R4 is a methyl group.

10. The method as set forth in claim 1 , wherein R1 is a phenyl group which may have a substituent or a pyridyl group which may have a substituent, wherein the substituent is selected from the group consisting of halogen atoms, alkyl groups, halogenoalkyl groups, alkoxy groups, halogenoalkoxy groups, alkylthio groups, nitro group, alkyl-sulfonylamino groups, and a tetrazolyl group.

11. The method as set forth in claim 1 , wherein R1 is an unsubstituted phenyl group.

12. The method as set forth in claim 1 , wherein R1 is an unsubstituted pyridyl group.

13. The method as set forth in claim 10 , wherein R1 is an substituted phenyl group.

14. The method as set forth in claim 10 , wherein R1 is an substituted pyridyl group.

15. The method as set forth in claim 1 , wherein R2 represents an alkyl group which may have a substituent selected from the group consisting of substituted or unsubstituted lower alkyl-carbonyloxy groups, substituted or unsubstituted lower alkoxy-carbonyloxy groups, substituted or unsubstituted amino groups, lower alkoxy groups, halogen atoms, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups and substituted or unsubstituted carbamoyl groups.

16. The method as set forth in claim 1 , wherein R2 represents an unsubstitued alkyl group.

17. The method as set forth in claim 1 , wherein R2 represents an substitued alkyl group.

18. The method as set forth in claim 1 , wherein R4 represents a hydrogen atom, an alkyl group or a benzyl group which may have a substituent selected from the group consisting of alkyl groups, alkoxy groups and halogen atoms.

19. The method as set forth in claim 18 , wherein R4 represents a hydrogen atom.

20. The method as set forth in claim 18 , wherein R4 represents an alkyl group.

21. The method as set forth in claim 18 , wherein R4 represents a benzyl group which may have a substituent selected from the group consisting of alkyl groups, alkoxy groups and halogen atoms.