Substituted sulphonamido phenoxybenzamides
View Patent ↗The present invention relates to substituted sulphonamido phenoxybenzamide compounds of general formula (I): in which A, R1, R2, R3, R4, R5, R6, R7, R8 and n are as defined in the claims, to pharmaceutical compositions and combinations containing said compounds, to methods of preparing said compounds, and to the use of said compounds or compositions for treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.
1. A compound of general formula (I) :
in which:
R1 is selected from the group consisting of halogen or —C≡C—H;
R2 is hydrogen, halogen or alkyl;
wherein at least one of R1 and R2 is halogen;
R3 is hydrogen or alkyl;
R4 is selected from the group consisting of halogen and cyano;
R5 is C2-C6 alkyl;
R6 is selected from the group consisting of hydrogen, halogen, cyano, alkoxy, amino, alkylamino, dialkylamirio;
R7 and R8 independently from each other are hydrogen, halogen or alkyl;
A is selected from the group consisting of aryl and heteroaryl;
n is an integer from 0 to 2.
2. The compound according to claim 1 , wherein:
R1 is halogen;
R2 is halogen;
R3 is hydrogen;
R4 is selected from the group consisting of halogen and cyano;
R5 is C2-C6 alkyl;
R6 is selected from the group consisting of hydrogen, halogen, cyano, alkoxy, amino, alkylamino, dialkylamino;
R7 and R8 independently from each other are hydrogen or halogen;
A is selected from the group consisting of aryl and heteroaryl;
n is an integer from 0 to 1.
3. The compound according to claims 1 , wherein:
R1 is halogen;
R2 is halogen;
R3 is hydrogen;
R4 is halogen;
R5 is C2-C6 alkyl;
R6 is hydrogen;
R7 and R8 are hydrogen;
A is phenyl or pyridyl;
n is an integer from 0 to 1.
4. The compound according to claims 1 , which is selected from the group consisting of:
2-(3-ethanesulfonylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;
4-fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(propane-2-sulfonylamino)-phenoxy]-benzamide;
4-fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[5-(propane-2-sulfonylamino)-pyridin-3-yloxy]-benzamide; and
2-(3-ethanesulfonylamino-benzyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide.
5. A method of preparing a compound of general formula (I) according to claim 1 , said method comprising the step of allowing an intermediate compound of general formula 8:
in which R1, R2, R3, R4, R5, R7, R8, A and n are as defined in claim 1 , to react in the presence of a base with an sulfonyl chloride of formula 9:
in which R5 is as defined claim 1 ;
to yield a compound of general formula (I):
in which R1, R2, R3, R4, R5, R6, R7, R8, A and n are as defined in claim 1 .
6. A method of preparing a compound of general formula (Ib), said method comprising the step of allowing an intermediate compound of general formula (Ia):
in which R2, R3, R4, R5, R7, R8, A and n are as defined in claim 1 , to react with an alkyne of formula 17:
in the presence of a Pd catalyst, copper iodide and a base optionally followed by desilylation to yield a compound of general formula (Ib):
in which R2, R3, R4, R5, R6, R7, R8, A and n are as defined in claim 1 .
7. A pharmaceutical composition comprising a compound according to claim 1 , or a tautomer, stereoisomer, physiologically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable diluent or carrier.
8. The pharmaceutical composition according to claim 7 wherein said compound is present in a therapeutically effective amount.
9. The pharmaceutical composition according to claim 8 which further comprises at least one further active compound.
10. The pharmaceutical composition according to claim 9 , in which said further active compound is an anti-hyperproliferative agent, an anti-angiogenic agent, a mitotic inhibitor, an alkylating agent, an anti-metabolite, a DNA-intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme inhibitor, a toposisomerase inhibitor, a biological response modifier, or an anti-hormone.
11. A packaged pharmaceutical composition comprising a container, the pharmaceutical composition of claim 7 , and instructions for using the pharmaceutical composition to treat a disease or condition in a mammal.