PRODRUGS OF FUSED HETEROCYCLIC INHIBITORS OF D-AMINO ACID OXIDASE
The invention relates to prodrugs of fused heterocyclic inhibitors of D-amino oxidase (DAAO) and methods of treating diseases and conditions, wherein modulation of D-amino acid oxidase activity, D-serine levels, D-serine oxidative products and NMDA receptor activity in the nervous system of a mammalian subject is effective.
1 . A compound having the formula:
wherein
R x1 is a member selected from H and
wherein
L x is a member selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; and
R x3 is a member selected from substituted or unsubstituted alkyl and substituted or unsubstituted aryl;
n1 is selected from the integers from 0 to 10; and
R x2 is a member selected from H, unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl,
halogen and
wherein
R x4 and R x5 are independently selected substituted or unsubstituted C 2 -C 10 alkyl; and
R x4 and R x5 , together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted 3- to 8-membered heterocycloalkyl ring,
wherein
said heterocycloalkyl ring comprises up to one additional non-oxygen heteroatom; and
said heterocycloalkyl ring is other than unsubstituted azetidine or substituted pyrrolidine;
R x6 and R x7 are independently selected substituted or unsubstituted C 1 -C 10 alkyl
m1 is selected from the integers from 0 to 3;
R x8 is a member selected from substituted or unsubstituted piperazinyl and 4H-furo[3,2-b]pyrrol-5-yl;
R x9 is a member selected from H, methyl, ethyl, and iso-propyl; and
R x10 is a member selected from unsubstituted C 1 -C 4 alkyl and 4H-furo[3,2-b]pyrrol-5-yl,
wherein
when R x1 and R x9 are H, R x10 is other than methyl;
when R x1 is H and R x9 is methyl, R x10 is other than methyl, ethyl or iso-propyl; and
when R x1 is H and R x9 is iso-propyl, R x10 is other than methyl;
with the proviso that:
when R x1 is H, R x2 is other than H or unsubstituted alkyl;
when R x1 is H and n1 is 1, R x2 is other than phenyl or imidazol-1-yl;
when R x1 is H and n1 is 2, R x2 is other than imidazol-1-yl;
when n1 is other than 0, R x2 is other than
and
when R x2 is H, n1 is 0 and R x1 is
2 . The compound according to claim 1 , wherein
R x1 is
and
R x2 is a member selected from H, methyl, ethyl and —CH 2 O(CO)CH 3 .
3 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4 . A method for treating or preventing a condition which is a member selected from a neurological disorder, pain, ataxia, convulsion, loss of memory, loss of cognition and a combination thereof, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .
5 . The method according to claim 4 , wherein said condition is pain, wherein said pain is neuropathic pain.
6 . The method according to claim 4 , wherein said condition is selected from loss of memory, loss of cognition and a combination thereof
7 . The method according to claim 6 , wherein said condition is associated with Alzheimer's disease.
8 . The method according to claim 6 , wherein said condition is associated with schizophrenia.
9 . The method according to claim 4 , wherein said compound is administered as a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a dosage of from about 1 mg to about 7000 mg of said compound.
10 . A compound having a formula selected from:
11 . A pharmaceutical composition comprising a compound according to claim 10 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12 . A method for treating or preventing a condition which is a member selected from a neurological disorder, pain, ataxia, convulsion, loss of memory, loss of cognition and a combination thereof, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 10 .
13 . The method according to claim 12 , wherein said condition is pain, wherein said pain is neuropathic pain.
14 . The method according to claim 12 , wherein said condition is selected from loss of memory, loss of cognition and a combination thereof
15 . The method according to claim 14 , wherein said condition is associated with Alzheimer's disease.
16 . The method according to claim 14 , wherein said condition is associated with schizophrenia.
17 . The method according to claim 12 , wherein said compound is administered as a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a dosage of from about 1 mg to about 7000 mg of said compound.