1-[6,7-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives
View Patent ↗The present invention related to a novel urea derivative for formula (I): which is useful as an anti-cancer agent, its pharmaceutically acceptable acid addition salt or stereoisomer, and to a process for preparing the urea derivative and an anti-cancer composition comprising the same as an active ingredient.
1. A compound of the formula (1), or pharmaceutically acceptable salts thereof,
wherein
X is C—R 7 ;
Y is C—H;
for the combination of variables R 1 and R 2 :
R 1 is hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl or halogen and R 2 is F; or
R 1 is F and R 2 is hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl or halogen;
R 3 is C 1 -C 3 alkyl;
R 4 is hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, or halogen;
R 5 is H;
R 6 is H, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl; and
R 7 is H or C 1 -C 3 alkoxy.
2. The compound of claim 1 , wherein:
for the combination of variables R 1 and R 2 :
R 1 is F and R 2 is hydrogen or CH 3 ;
R 3 is CH 3 ;
R 4 is H, OCH 3 , CH 3 , or Cl;
R 5 is H;
R 6 is H, OCH 3 , or CH 3 ; and
R 7 is H or OCH 3 .
3. The compound of claim 2 , wherein
R 1 is F,
R 2 is H;
R 3 is CH 3 ;
R 4 is OCH 3 or CH 3 ;
R 5 is H;
R 6 is H, OCH 3 , or CH 3 ; and
X is C—H.
4. The compound of claim 3 , wherein
R 1 is F,
R 2 is H;
R 3 is CH 3 ;
R 4 is OCH 3 or CH 3 ;
R 5 is H;
R 6 is OCH 3 , or CH 3 ; and
X is C—H.
5. The compound of claim 4 , wherein
R 1 is F,
R 2 is H;
R 3 is CH 3 ;
R 4 and R 6 are both OCH 3 or CH 3 ;
R 5 is H; and
X is C—H.
6. The compound of claim 1 , wherein:
for the combination of variables R 1 and R 2 :
R 1 is hydrogen, OCH 3 , Cl or F and R 2 is F; or
R 1 is F and R 2 is hydrogen, OCH 3 , Cl or F;
R 3 is CH 3 ;
R 4 is H, OCH 3 , CH 3 , or Cl;
R 5 is H;
R 6 is H, OCH 3 , or CH 3 ; and
R 7 is H or OCH 3 .
7. A pharmaceutical composition which comprises a compound of the formula (1) as claimed in claim 1 , or pharmaceutically-acceptable salts thereof, in association with a pharmaceutically-acceptable diluent or carrier.
8. The compound of claim 1 , wherein the compound is
9. A pharmaceutical composition which comprises a compound of the formula (1) as claimed in claim 8 , or pharmaceutically-acceptable salts thereof, in association with a pharmaceutically-acceptable diluent or carrier.
10. The compound of claim 1 , wherein the compound is selected from the group consisting of
11. A pharmaceutical composition which comprises a compound of the formula (1) as claimed in claim 10 , or pharmaceutically-acceptable salts thereof, in association with a pharmaceutically-acceptable diluent or carrier.
12. A process for the preparation of a compound of claim 1 , comprising
reacting a compound of formula (6) with 1.0-5.0 equivalents of 2,4-dimethoxybenzylamine in dimethylsulfoxide to give a compound of formula (7);
reacting the compound of formula (7) with trifluoroacetic acid (TFA) in dichloromethane to give a compound of formula (2);
reacting the compound of formula (2) with 1.0-1.5 equivalents of L-C(═O)-L′ in an organic solvent in the presence of a base at room temperature to 100° C. to obtain a compound of formula (3); and
reacting the compound of formula (3) with 1.0-1.5 equivalents of a compound of formula (4) in an organic solvent in the presence of a base at 50° C. to 100° C., to give the compound of formula (1);
wherein L and L′ are independently imidazole, Cl, ethoxy, phenoxy or 4-nitrophenoxy.