Phenylalanine dipeptide derivatives, compositions and use thereof
Disclosed are a compound of formula I, stereoisomers, pharmaceutically acceptable salts or hydrates thereof, a pharmaceutical composition comprising the same, a process for preparing the same and use thereof. The compound may also be used to prepare a medicament to treat viral infections, especially to prepare a medicament to treat hepatitis B virus and human immunodeficiency virus with little toxic side effects.
1. A compound of formula I and pharmaceutically acceptable salts thereof,
wherein,
each R 1 , R 2 and R 3 independently represent a single substituent, wherein R 1 is independently selected from the group consisting of H, NO 2 , NH 2 , NRR′, NHCOR, NHCO(CH 2 ) n COOH, OH, OCOR, OR and O(CH 2 ) n NRR′;
R 3 is selected from the group consisting of H, NO 2 , NH 2 , NRR′, NHCOR, NHCO(CH 2 ) n COOH, and CH 2 NRR′;
R 2 is selected from the group consisting of H, NO 2 , NH 2 , NRR′, NHCOR, NHCO(CH 2 ) n COOH, NHOC(CH 2 ) n NRR′; OH, OCOR, OR, O(CH 2 ) n NRR′, O(CH 2 ) n COOH, CN, CH 2 NRR′, COOH, C 1 -C 6 alkyl, halo, (1-pyrrolidyl) acetamido,
R 4 is selected from the group consisting of CH 2 OH, COOR, CH 2 OCOC 2 -C 6 (linear or branched alkyl), CH 2 OCOC 3 -C 7 cycloalkyl, CH 2 OCO(CH 2 ) n COOH, COONa and —COOH;
each R and R′ in the R 1 to R 4 described above represent identical or different, linear or branched C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl;
said alkyl and cycloalkyl may be further optionally substituted with one or two substituents selected from the group consisting of OH, NO 2 , CN, CF 3 and halo;
X is CH or N; and
n is an integral number of 1 to 4;
with the proviso that the following compounds are excluded where:
X is CH, R 1 is CH 2 N(CH 3 ) 2 , R 2 is H, R 3 is H, and R 4 is CH 2 OH or CH 2 OCOMe;
X is CH, R 1 is H, R 2 is NHCH 2 CH 2 N(CH 3 ) 2 , R 3 is H, and R 4 is CH 2 OH or CH 2 OCOMe;
X is CH, R 1 is H, R 2 is H, R 3 is CH 2 N(CH 3 ) 2 , and R 4 is CH 2 OH or CH 2 OCOMe;
X is CH, each R 1 , R 2 and R 3 are H, and R 4 is CH 2 OH.
2. The compound of claim 1 , wherein R 2 is selected from the group consisting of H, NO 2 , NHCOR, NHCO(CH 2 ) n COOH, OH, OCOR, O(CH 2 ) n NRR′, CH 2 NRR′, C 1 -C 6 alkyl, halo, (1-pyrrolidyl) acetamido,
and COOH.
3. The compound of claim 1 , wherein R 1 is selected from the group consisting of H, NO 2 , NHCOCH 3 , NHCOCH2CH3, N(CH 3 ) 2 , NHCO(CH 2 ) 2 COOH, OH, OCH 3 , OCOCH 3 , O(CH 2 ) 2 N(CH 3 ) 2 and OCH 2 COOH.
4. The compound of claim 1 , wherein R 3 is selected from the group consisting of H, NO 2 , NHCOCH 3 , and NHCOCH 2 CH 3 .
5. The compound of claim 1 , wherein R 2 is selected from the group consisting of H, F, C1, NO 2 , NHCOCH 3 , NHCOCH 2 C1, NHCOCH 2 CH 3 , NHCO(CH 2 ) 2 COOH, NHCOCH 2 N(CH 3 ) 2 , OH, OCOCH 2 CH 3 , O(CH 2 ) 2 N(CH 3 ) 2 , CH 3 , CH 2 N(CH 3 ) 2 , COOH, (1-pyrrolidyl)acetamido,
6. The compound of claim 1 , wherein R 4 is selected from the group consisting of CH 2 OH, COOCH 3 , CH 2 OCOCH 3 , CH 2 OCOCH 2 CH 3 , CH 2 OCOCH 2 COOH, CH 2 OCO(CH 2 ) 2 COOH, COONa and COOH.
7. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.