β-benzyloxyaspartate derivatives with amino group on benzene ring

1. An L-threo-β-benzyloxyaspartate derivative having a substituent on the benzene ring, represented by the following formula (1):

or a salt thereof,

wherein R is hydrogen, a linear or branched lower aliphatic acyl group with the acyl portion optionally substituted, an alicyclic acyl group, an aromatic acyl group with a substituent on the aromatic ring, an amino acid-derived group or a biotin derivative-derived group.

2. A compound according to claim 1 , wherein R is hydrogen, an optionally thiol-substituted linear or branched lower aliphatic acyl group, an alicyclic acyl group, an aromatic acyl group optionally with a substituent on the aromatic ring, or a hydroxyl- or thiol-containing amino acid-derived group.

3. A compound according to claim 1 , wherein R is acetyl, propionyl, n-butanoyl, sec-butanoyl, n-pentanoyl, pivaloyl, phenylacetyl, cyclohexylcarbonyl, benzoyl, substituted benzoyl, naphthoyl or pyridylcarbonyl.

4. A compound according to claim 1 , wherein R is glycyl, alanyl, β-alanyl or cysteinyl.

5. A compound according to claim 1 , wherein R is biotinyl or biotinyl-β-alanyl.

6. A compound according to claim 3 , wherein R is a benzoyl group substituted with one or more substituents selected from the group consisting of an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, a cyano group, a nitro group, and a halogen atom.

7. A compound according to claim 6 , wherein said substituent on the benzoyl group contains an isotope.

8. A method for producing an L-threo-nitrobenzylated (2S,3R) compound represented by the following formula (7):

wherein Boc represents t-butoxycarbonyl and TBS represents t-butyldimethylsilyl, wherein a compound of formula (6) as defined in claim 6 is reacted with nitrobenzyl bromide in the presence of sodium hydride and tetra-n-butylammonium iodide without altering the stereospecificity.

9. The method of claim 8 , wherein the yield of the L-threo-nitrobenzylated (2S,3R) compound represented by formula (7) is at least 70%.

10. The method of claim 8 , which further comprises a step of producing a an L-threo-β-benzyloxyaspartate derivative having a substituent on the benzene ring, represented by the following formula (1):

or a salt thereof,

wherein R is hydrogen, a linear or branched lower aliphatic acyl group with the acyl portion optionally substituted, an alicyclic acyl group, an aromatic acyl group with a substituent on the aromatic ring, an amino acid-derived group or a biotin derivative-derived group, by converting the NO 2 group on the benzene ring of the compound of formula (7) to an NHR group, and removing any protecting groups.

11. A compound represented by the following formula (7):

wherein Boc represents t-butoxycarbonyl and TBS represents t-butyldimethylsilyl.

12. A method for treating an L-glutamate-transporter-related neurodegenerative disease in a mammal, comprising administering to said mammal a pharmaceutical composition comprising an effective amount of a compound or a salt thereof as defined in formula (1) in claim 1 , and a pharmaceutically acceptable carrier, wherein the L-glutamate-transporter-related neurodegenerative disease is selected from the group consisting of epilepsy, amyotrophic lateral sclerosis and Alzheimer's disease.

13. A pharmaceutical composition comprising an effective amount of a compound or a salt thereof as defined in formula (1) in claim 1 , and a pharmaceutically acceptable carrier.

14. A method for inhibiting an L-glutamate-transporter, comprising administering an effective amount of a compound or a salt thereof as defined in claim 12 .

15. A method for inhibiting L-glutamate uptake, comprising administering an effective amount of a compound or a salt thereof as defined in claim 12 .