Alpha-helical mimetics
View Patent ↗Benzoyl urea derivatives that are alpha helical peptides mimetics that mimic BH3-only proteins, compositions containing them, their conjugation to cell-targeting-moieties, and their use in the regulation of cell death are disclosed. The benzoyl urea derivatives are capable of binding to and neutralizing pro-survival Bcl-2 proteins. Use of benzoyl urea derivatives in the treatment and/or prophylaxis of diseases or conditions associated with deregulation of cell death are also described.
1. A compound of formula (I):
wherein
R 1 is selected from CO 2 H or a carboxylic acid or carboxylate bioisostere;
R 2 is selected from an amino acid side chain and a group
R a —(CHR′) x -A-(CH 2 ) y —
wherein A is a covalent bond or is selected from O, S, SO, SO 2 and NR 6 , R a is H, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl or R b where R b is
and R c is selected from heteroaryl, aryl, aryl(C 2-6 alkenyl), aryl(C 2-6 alkynyl), heteroaryl(C 2-6 alkenyl) and heteroaryl(C 2-6 alkynyl), R′ is H or C 1-6 alkyl, x and y are independently 0 or an integer from 1 to 6 provided that the sum of x and y is 1 to 6;
R 3 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and a group
R d —(CH 2 ) p —W—(CH 2 ) q —
wherein W is selected from a covalent bond, O, S and NR 6 , R d is selected from H, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl; p is an integer from 1 to 6, q is 0 or an integer from 1 to 5 provided that the sum of p and q is 1 to 6;
R 4 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, C 1-6 alkyloxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, cycloalkoxy, C 1-6 alkylthio, C 2-6 alkenylthio, C 2-6 alkynylthio, cycloalkylthio, halogen, aryl, aryl(C 1-6 alkyl)-, aryl(C 2-6 alkenyl), aryl(C 2-6 alkynyl), heterocyclyl, heterocyclyl(C 1-6 alkyl)-, heterocyclyl(C 2-6 alkenyl), heterocyclyl(C 2-6 alkynyl), heteroaryl, heteroaryl(C 1-6 alkyl)-, heteroaryl(C 2-6 alkenyl) and heteroaryl(C 2-6 alkynyl);
R 5 is selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyloxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 1-6 alkythio, C 2-6 alkenylthio, C 2-6 alkynylthio, CN and C(R 7 ) 3 or when R 5 is in the 2- or 5-position, R 5 and R 3 taken together may form a 5 to 10 membered ring;
R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
each R 7 is independently selected from H and halogen;
m is 0 or an integer from 1 to 6; and
n is 0 or an integer from 1 to 3;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one or more optional substituents;
and pharmaceutically acceptable salts and prodrugs thereof; with the proviso that when R 1 is COOH, R 2 is C 6 H 5 —CH 2 S—CH 2 —, R 4 is 3-C 6 H 5 and R 5 is H, R 3 is not CH 3 CH 2 —.
2. A compound according to claim 1 , wherein R 1 is CO 2 H, tetrazole, tetrazolate or an acylbenzenesulfonamide.
3. A compound according to claim 2 , wherein R 1 is CO 2 H.
4. A compound according to claim 1 , wherein R 2 is R a —(CHR′) x -A-(CH 2 ) y — in which R a is H, optionally substituted cycloalkyl or optionally substituted aryl, x is 0 or 1 to 4, R′ is H or C 1-3 alkyl, A is O, S or SO and y is 1 to 3.
5. A compound according to claim 1 , wherein R 2 is R a —(CHR′) x -A-(CH 2 ) y — in which R a is optionally substituted aryl or optionally substituted heteroaryl, R′ is H, the sum of x and y is 1 to 4 and A is a covalent bond.
6. A compound according to claim 1 , wherein R 3 is C 1-6 alkyl, optionally substituted cycloalkyl or a group R d —(CH 2 ) p —W—(CH 2 ) q — in which R d is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted heteroaryl, W is a covalent bond and the sum of p and q is 1 to 3, or R d is H, W is O or S and the sum of p; and q is 2 to 4.
7. A compound according to claim 1 , wherein R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- or 4-aryl, aryl(C 1-3 alkyl)-, aryl(C 2-3 alkenyl)- or aryl(C 2-3 alkynyl)- wherein aryl is optionally substituted with one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl, hydroxy(C 1-6 alkyl), CN or C 1-6 acyl.
8. A compound according to claim 7 , wherein R 4 is 3- or 4-phenyl, naphthyl or phenyl(ethynyl) in which the phenyl or naphthyl groups are optionally substituted.
9. A compound according to claim 1 , wherein R 5 is hydrogen, halogen, methyl or methoxy.
10. A compound according to claim 9 , wherein R 5 is hydrogen.
11. A compound according to claim 1 , wherein m is 0.
12. A compound according to claim 1 , wherein n is 0.
13. A compound according to claim 1 , wherein said compound is a compound of formula (II)
wherein R 2 and R 3 are as defined for formula (I) in claim 1 and R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-phenyl, 3-(2-naphthyl), 3-(1-naphthyl), 3-benzyl, 4-phenyl, 4-benzyl, 3-(phenylethynyl) or 4-(phenylethynyl), wherein each phenyl, naphthyl or benzyl group is optionally substituted with one or more substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkenyloxy and halogen, and pharmaceutically acceptable salts or prodrugs thereof, with the proviso that when R 2 is C 6 H 5 —CH 2 S—CH 2 — and R 4 is 3-phenyl, R 3 is not ethyl.
14. A compound according to claim 1 , wherein said compound is a compound of formula (IIa)
wherein R 2 is defined as above for formula (I) in claim 1 ,
R 3 is selected from C 3-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl and a group
R d —(CH 2 ) p —W—(CH 2 ) q —
wherein W is selected from a covalent bond, 0, S or NR 6 , R d is selected from H, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl; p is an integer from 1 to 6, q is 0 or an integer from 1 to 5 provided that the sum of p and q is 1 to 6;
R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-phenyl, 3-(2-naphthyl), 3-(1-naphthyl), 3-benzyl, 4-phenyl, 4-benzyl, 3-(phenylethynyl) or 4-(phenylethynyl), wherein each phenyl, naphthyl or benzyl group is optionally substituted with one or more substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkenyloxy and halogen, and pharmaceutically acceptable salts or prodrugs thereof.
15. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
16. A composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier.
17. A composition comprising a compound according to claim 3 and a pharmaceutically acceptable carrier.
18. A composition comprising a compound according to claim 4 and a pharmaceutically acceptable carrier.
19. A composition comprising a compound according to claim 5 and a pharmaceutically acceptable carrier.
20. A composition comprising a compound according to claim 6 and a pharmaceutically acceptable carrier.
21. A composition comprising a compound according to claim 7 and a pharmaceutically acceptable carrier.
22. A composition comprising a compound according to claim 8 and a pharmaceutically acceptable carrier.
23. A composition comprising a compound according to claim 9 and a pharmaceutically acceptable carrier.
24. A composition comprising a compound according to claim 10 and a pharmaceutically acceptable carrier.
25. A composition comprising a compound according to claim 11 and a pharmaceutically acceptable carrier.
26. A composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier.
27. A composition comprising a compound according to claim 13 and a pharmaceutically acceptable carrier.
28. A composition comprising a compound according to claim 14 and a pharmaceutically acceptable carrier.