BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
The present invention relates to new benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), pharmaceutical compositions thereof, and methods of use thereof.
1 . A compound that is
wherein each position indicated as D has deuterium enrichment of at least 50%.
2 . The compound of claim 1 , wherein each position indicated as D has deuterium enrichment of no less than about 90%.
3 . The compound of claim 1 , wherein each position indicated as D has deuterium enrichment of no less than about 98%.
4 . The compound of claim 1 that is:
5 . The compound of claim 1 that is:
6 . A pharmaceutical composition comprising a compound as recited in claim 4 together with a pharmaceutically acceptable carrier.
7 . A pharmaceutical composition comprising a compound as recited in claim 5 together with a pharmaceutically acceptable carrier.
8 . A method of treating a VMAT2-mediated disorder in a subject comprising administering to the subject a compound of claim 1 .
9 . The method of claim 8 , wherein the VMAT2-mediated disorder is a chronic hyperkinetic movement disorder.
10 . The method of claim 9 , wherein the chronic hyperkinetic movement disorder is Huntington's disease.
11 . The method of claim 9 , wherein the chronic hyperkinetic movement disorder is chorea related to Huntington's disease.
12 . The method of claim 9 , wherein the chronic hyperkinetic movement disorder is Tardive dyskinesia.
13 . The method of claim 9 , wherein the chronic hyperkinetic movement disorder is Tourette's syndrome.
14 . The method of claim 8 , wherein the subject is human.
15 . The method of claim 8 , further resulting in at least one effect selected from the group consisting of:
a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;
b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;
c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;
d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and
e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.
16 . The method of claim 8 , wherein the treatment effects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P450 isoform selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6 in the subject, as compared to the corresponding non-isotopically enriched compound.
17 . The method of claim 8 , resulting in decreased inhibition of at least one cytochrome P450 or monoamine oxidase isoform selected from the group consisting of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO A , and MAO B in the subject per dosage unity, as compared to the non-isotopically enriched compound.
18 . The method of claim 8 , resulting in a reduced deleterious change in a diagnostic hepatobiliary function endpoint selected from the group consisting of alanine aminotransferase (“ALT”), serum glutamic-pyruvic transaminase (“SGPT”), aspartate aminotransferase (“AST” or “SGOT”), ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,” “γ-GTP,” or “GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasonography, liver nuclear scan, 5′-nucleotidase, and blood protein, as compared to the corresponding non-isotopically enriched compound.
19 . The method of claim 8 , wherein the compound is administered with an additional therapeutic agent.
20 . The method of claim 19 , wherein said additional therapeutic agent olanzapine, pimozide, a benzodiazepine, or an antipsychotic.