Derivatives of squaric acid with anti-proliferative activity
View Patent ↗The present invention provides derivatives of squaric acid, in particular derivatives of 3,4-diamino-cyclobut-3-ene-1,2-dione and tautomers and isomers thereof, as a single stereoisomer or a mixture of stereoisomers, or as a pharmaceutically acceptable salt thereof. These compounds show anti-proliferative activity, including against tumor cells, and are useful in the treatment of diseases including cancer.
1. A compound of general formula (Ia):
wherein
R 1 is 3-pyridyl or 4-pyridyl;
R 2 and R 3 are each hydrogen;
R 4 is CH 2 —;
R 5 is a linker moiety selected from the group consisting of C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, which linker moiety is substituted by p substituents R 9 (where p is an integer from 0 to 10);
X is absent or selected from the group consisting of —O—, —S— and —NH—;
R 6 is phenyl wherein said phenyl is substituted with 0-10 substituents R 10 ;
each R 9 and R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, heterocyclylalkyl, halo, nitro, cyano, hydroxy, amino, carboxy, —OR 11 , —NHR 11 , —NR 11 R 12 , —C(O)H, —C(O)R 11 , —OC(O)R 11 , —C(O)OR 11 , —C(O)NHR 11 , —C(O)NR 11 R 12 , —S(O)xR 11 (where X is 0 to 2), —S(O) 2 OR 11 , —R 13 -nitro, —R 13 -cyano, —R 13 -hydroxy, —R 13 -amino, —R 13 -carboxy, —R 13 —OR 11 , —R 13 —NHR 11 , —R 13 —NR 11 R 12 , —R 13 —C(O)H, —R 13 —C(O)R 11 , —R 13 —OC(O)R 11 , —R 13 —C(O)OR 11 , —R 13 —C(O)NHR 11 , —R 13 —C(0)NR 11 R 12 , —R 13 —S(O)xR 11 (where X is 0 to 2), —R 13 —S(O) 2 OR11; —O—R 13 -nitro, —O—R 13 -cyano, —OR 13 -hydroxy, —O—R 13 -amino, —O—R 13 -carboxy, —O—R 13 —OR 13 , —O—R 13 —NHR 11 , —O—R 13 —NR 11 R 12 , —O—R 13 —C(O)H, —OR 13 —C(O)R 11 , —O—R 13 —OC(O)R 11 , —O—R 13 —C(O)OR 11 , —O—R 13 —C(O)NHR 11 , —O—R 13 —C(O)NR 11 R 12 , —O—R 13 —S(O)xR 11 (where X is 0 to 2), —O—R 13 —S(O) 2 OR 11 ; —N(R 14 )—R 13 -nitro, —N(R 14 )—R 13 -cyano, —N(R 14 )—R 13 -hydroxy, —N(R 14 )—R 13 -amino, —N(R 14 )—R 13 -carboxy, —N(R 14 )—R 13 —OR 11 , —N(R 14 )—R 13 —NHR 11 , —N(R 14 )—R 13 —NR 11 R 12 , —N(R 14 )—R 13 —C(O)H, —N(R 14 )—R 13 —C(O)R 11 , —N(R 14 )—R 13 —OC(O)R 11 , —N(R 14 )C(O)R 11 —, —O—R 13 —N(R 14 )—C(O)R 11 —, —N(R 14 )—R 13 —C(O)OR 11 , —N(R 14 )—R 13 —C(O)NHR 11 , —N(R 14 )—R 13 —C(O)NR 11 R 12 , —N(R 14 )—R 13 —S(O)xR 11 (where X is 0 to 2), —N(R 14 )—R 13 —S(O) 2 OR 11 , (morpholin-4-yl) C 1 -C 6 alkyl or (morpholin-4-yl) C 1 -C 6 alkoxy;
R 11 , R 12 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, heterocyclylalkyl, or if R 11 and R 12 are both bound to a nitrogen atom, together with the nitrogen atom form a 5-7 membered ring consisting of carbon and 0-2 additional heteroatoms selected from the group consisting of O, S and N (where the N is bound to a further substituents selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl), which ring system may be partially unsaturated;
each R 13 is independently selected from the group consisting of C 1 -C 6 alkylene, C 1 -C 6 alkenylene, C2-C 6 alkynylene;
each R 14 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, heterocyclylalkyl; or tautomers thereof;
as a single stereoisomer or a mixture of stereoisomers;
or as a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 1 is 3-pyridyl.
3. The compound of claim 1 , wherein R 1 is 4-pyridyl.
4. The compound of claim 1 , wherein R 5 is C 2 -C 10 alkylene.
5. The compound according to claim 1 , wherein X is selected from the group consisting of —O—, —S— and NH—.
6. The compound according to claim 1 , wherein X is absent or —O—.
7. The compound according to claim 1 , wherein X is selected from the group consisting of —O— and —S—.
8. The compound according to claim 1 , wherein X is absent.
9. The compound according to claim 1 , wherein R 6 is substituted with 0-5 substituents R 10 .
10. The compound according to claim 1 , wherein R 6 is phenyl.
11. The compound according to claim 1 , wherein R 6 is substituted with halo, alkyl, alkoxy, cyano, (morpholin-4-yl) C 1 -C 6 alkyl or (morpholin-4-yl) C 1 -C 6 alkoxy.
12. The compound of claim 1 , wherein the compound is selected from:
3-[6-(4-Chloro-phenoxy)-hexylamino]-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione,
3-[6-(4-Chloro-phenoxy)-hexylamino]-4-(pyridine-3-ylamino)-cyclobut-3-ene-1,2-dione,
3-[5-(4-Chloro-phenoxy)-pentylamino]-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione,
3-[8-(4-Chloro-phenoxy)-octylamino]-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione,
3-[4-(4-Chloro-phenoxy)-butylamino]-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione,
3-[7-(4-Chloro-phenoxy)-heptylamino]-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione,
3-(7-Phenoxy-heptylamino)-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione,
3-[5-(4-Chloro-phenoxy)-pentylamino]-4-(pyridine-3-ylamino)-cyclobut-3-ene-1,2-dione,
3-(6-Phenoxy-hexylamino)-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione,
3-(Pyridin-4-ylamino)-4-(6-p-tolyloxy-hexylamino)-cyclobut-3-ene-1,2-dione,
3-[6-(4-Methoxy-phenoxy)-hexylamino]-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione,
3-[6-(3,4-Dichloro-phenoxy)-hexylamino]-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione,
3-(6-Phenoxy-hexylamino)-4-(pyridine-3-ylamino)-cyclobut-3-ene-1,2-dione,
3-[6-(4-Chloro-phenylamino)-hexylamino]-4-(pyridine-3-ylamino)-cyclobut-3-ene-1,2-dione,
3-[6-(4-Chloro-phenylamino)-hexylamino]-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione,
3-(7-Phenyl-heptylamino)-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione,
3-[4-(4-Chloro-phenoxy)-benzylamino]-4-(pyridine-3-ylamino)-cyclobut-3-ene-1,2-dione,
3-[4-(4-Chloro-phenoxymethyl)-benzylamino]-4-(pyridine-3-ylamino)-cyclobut-3-ene-1,2-dione,
3-[3-(4-Chloro-phenoxy)-benzylamino]-4-(pyridine-3-ylamino)-cyclobut-3-ene-1,2-dione,
3-[4-(4-Chloro-phenoxy)-benzylamino]-4-(pyridine-2-ylamino)-cyclobut-3-ene-1,2-dione,
3-(4-Phenoxy-benzylamino)-4-(pyridine-3-ylamino)-cyclobut-3-ene-1,2-dione,
3-[3-(4-Chloro-phenoxymethyl)-benzylamino]-4-(pyridine-3-ylamino)-cyclobut-3-ene-1,2-dione,
3-{2-[4-(4-Chloro-phenoxy)-phenyl]-ethylamino}-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione,
3-{2-[4-(4-Chloro-phenoxy)-phenyl]-ethylamino}-4-(pyridine-3-ylamino)-cyclobut-3-ene-1,2-dione,
3-[2-(4-Phenoxy-phenyl)-ethylamino]-4-(pyridine-4-ylamino)-cyclobut-3-ene-1,2-dione, and
3-[2-(4-Phenoxy-phenyl)-ethylamino]-4-(pyridine-3-ylamino)-cyclobut-3-ene-1,2-dione.
13. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to claim 1 and a pharmaceutically acceptable carrier and/or diluent.