Neuroprotective agents for treatment of neurodegenerative diseases
A compound having formula I is useful for treating a neurodegenerative disease: R 1 is an C 1-12 organyl group; is a C 1-12 heterocyclic ring system containing 5 to 12 ring atoms and up to three heteroatoms individually selected from the group consisting of N, O, S, and Se; R 2 are C 1-12 organyl groups; R 7 , R 8 are each independently, hydrogen (H), hydroxyl, oxo (i.e., carbonyl), C 1-8 alkyl, C 1-8 alkoxyl, C 2-8 alkenyl, C 2-10 alkynyl, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, halo, C 1-4 aldehyde, or —NR 4 q where R 4 is H, C 1-8 alkyl, C 2-8 alkenyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, or C 6-10 aryl; o is 0, 1, 2, 3, or 4; A is a C 6-12 aryl group, C 5-12 heteroaryl group, or an optionally substituted 3-hydroxypyridin-4(1H)-one; p is an integer from 1 to 6; and Z m is absent or a divalent linking moiety; and m is an integer representing the number of time Z is repeated.
1. A compound having formula IA or IB for treating neurodegenerative and other related CNS diseases:
or a pharmaceutically acceptable salt or ester thereof,
wherein
R 1 is an optionally substituted C 1-8 alkyl, C 1-8 alkoxyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, or C 6-10 aryl;
R 2 are hydroxyl, C 1-4 alkoxyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, C 6-10 aryl, —NR 3 q or C 1-10 hydrocarbon groups containing one or more O, N, S, or Se heteroatoms where R 3 individually are H or organyl groups and q is 2 or 3, with the proviso that when q is 3, the group bears a positive formal charge;
R 7 , R 8 are each independently, hydrogen (H), hydroxyl, ═O, C 1-8 alkyl, C 1-8 alkoxyl, C 2-8 alkenyl, C 2-10 alkynyl, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, halo, C 1-4 aldehyde, or —NR 4 q where R 4 is H, C 1-8 alkyl, C 2-8 alkenyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, or C 6-10 aryl;
A is optionally substituted bipyridyl;
p is an integer from 1 to 6;
Z m is absent; and
o is 0, 1, 2, 3, or 4 for formula IA and 0 for formula IB.
2. The compound of claim 1 wherein R 1 is substituted with a component selected from the group consisting of C 1-8 alkoxy, C 1-4 acyloxy, C 1-4 acyl, —C(O)—R 4 , —R 5 —NH—SO 2 —NR 4 r , —R 5 —NH—C(O)—R 4 ; —R 5 —NR 4 r , and —R 5 —Ar where
R 4 is H, C 1-8 alkyl, C 2-8 alkenyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, or C 6-10 aryl;
R 5 is C 2-8 alkenyl;
r is 2 or 3; and
Ar is a C 6-10 aryl ring system, optionally including one or more heteroatoms or C 5-10 heteroaryl;
with the proviso that when r is 3, the nitrogen of the NR 4 r group will bear a positive formal charge.
3. The compound of claim 2 wherein Ar is an optionally substituted phenyl, thienyl, pyridyl, bipyridyl, biphenylyl, or naphthyl.
4. The compound of claim 1 wherein R 2 are C 1-8 alkyl, C 1-8 alkoxyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl; C 6-10 aryl, or —NR 3 q , where R 3 individually are H, C 1-8 alkyl, C 2-8 alkenyl, C 2-10 alkynyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, or C 6-10 aryl where q is 2 or 3, with the proviso that when q is 3, the group bears a positive formal charge and wherein hydrocarbon groups in each case are optionally substituted with —CN, C 1-8 alkyl, —OR 3 , —OH, halo, or —CF 3 .
5. The compound of claim 4 wherein two R 2 together form an alicyclic or aromatic fused five or six membered ring, optionally containing heteroatoms O, N, S, or Se.
6. The compound of claim 1 wherein A is substituted with C 1-8 alkyl, —CN, halo, OH, C 1-8 alkoxyl, NH 2 SO 2 R 3 , CF 3 , arylsulfonyl, arylsulfonamide, o-OCH 3 , 2,3-dichloro, pyridinyl, bipyridinyl, or p-NHSO 2 CH 3 .
7. A compound selected from the group consisting of:
and
pharmaceutically acceptable salts thereof,
wherein:
R 8 is hydrogen (H), hydroxyl, ═O, C 1-8 alkyl, C 1-8 alkoxyl, C 2-8 alkenyl, C 2-10 alkynyl, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, halo, C 1-4 aldehyde, or —NR 4 q where R 4 is H, C 1-8 alkyl, C 2-8 alkenyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, or C 6-10 aryl; and
n is 1, 2, 3, 4, 5, or 6.
8. The compound of claim 7 wherein R 8 is hydrogen (H), hydroxyl, C 1-8 alkyl, C 1-8 alkoxyl, C 2-8 alkenyl, C 2-10 alkynyl, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, halo, C 1-4 aldehyde, or —NR 4 q where R 4 is H or organyl groups and q is 2 or 3.
9. The compound of claim 8 wherein R 4 is H, C 1-8 alkyl, C 2-8 alkenyl, C 2-10 alkynyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, or C 6-10 aryl.
10. A compound selected from the group consisting of:
and
pharmaceutically acceptable salts thereof,
wherein:
X is NR 2 , O, or S;
R 2 is H or C 1-10 alkyl;
R 7 , R 8 are each independently, hydrogen (H), hydroxyl, ═O, C 1-8 alkyl, C 1-8 alkoxyl, C 2-8 alkenyl, C 2-10 alkynyl, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, halo, C 1-4 aldehyde, or —NR 4 q where R 4 is H, C 1-8 alkyl, C 2-8 alkenyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, or C 6-10 aryl;
q is 2 or 3; and
n is 1, 2, 3, 4, 5, or 6.
11. A compound selected from the group consisting of:
and
pharmaceutically acceptable salts thereof,
wherein:
X is NR 2 , O, or S;
R is H or C 1-10 alkyl;
R 2 is H or C 1-10 alkyl;
R 7 , R 8 are each independently, hydrogen (H), hydroxyl, ═O, C 1-8 alkyl, C 1-8 alkoxyl, C 2-8 alkenyl, C 2-10 alkynyl, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, halo, C 1-4 aldehyde, or —NR 4 q where R 4 is H, C 1-8 alkyl, C 2-8 alkenyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, or C 6-10 aryl;
q is 2 or 3;
R 9 is H or C 1-10 alkyl; and
n is 1, 2, 3, 4, 5, or 6.
12. A compound having formula IA or IB for treating neurodegenerative and other related CNS diseases:
or a pharmaceutically acceptable salt or ester thereof,
wherein
R 1 is an optionally substituted C 1-8 alkyl, C 1-8 alkoxyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, or C 6-10 aryl;
R 2 are hydroxyl, C 1-4 alkoxyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, C 6-10 aryl, —NR 3 q or C 1-10 hydrocarbon groups containing one or more O, N, S, or Se heteroatoms where R 3 individually are H or organyl groups and q is 2 or 3, with the proviso that when q is 3, the group bears a positive formal charge;
A is
R 7 is hydroxyl, C 1-8 alkyl, C 1-8 alkoxyl, C 2-8 alkenyl, C 2-10 alkynyl, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, halo, C 1-4 aldehyde, or —NR 4 q where R 4 is H, C 1-8 alkyl, C 2-8 alkenyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, or C 6-10 aryl;
p is an integer from 1 to 6;
Z m is absent; and
o is 0, 1, 2, 3, or 4 for formula IA and 0 for formula IB.
13. A compound selected from the group consisting of:
and
pharmaceutically acceptable salts thereof,
wherein:
X is NH, O, or S; and
R 7 is hydrogen (H), hydroxyl, ═O, C 1-8 alkyl, C 1-8 alkoxyl, C 2-8 alkenyl, C 2-10 alkynyl, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, halo, C 1-4 aldehyde, or —NR 4 q where R 4 is H, C 1-8 alkyl, C 2-8 alkenyl, C 4-8 cycloalkyl, C 4-8 cycloalkenyl, or C 6-10 aryl;
q is 2 or 3; and
n is 1, 2, 3, 4, 5, or 6.
14. A compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
15. A compound selected from the group consisting of:
and pharmaceutically acceptable salts and esters thereof.
16. A compound selected from the group consisting of:
and pharmaceutically acceptable salts and esters thereof.