Substituted pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalines for inhibiting serotonin reuptake transporter activity
The invention relates to substituted pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]-quinoxaline compounds, represented by Formula 1, defined herein, free base or pharmaceutically acceptable salt forms of the compounds, pharmaceutical compositions thereof, and methods of treating conditions of the central nervous system therewith:
1. A compound of Formula I:
in free base or pharmaceutically acceptable salt form,
wherein:
X is —N(H)— or —N(C 1-6 alkyl)-;
Y is —C(O)—, —O— or —C(H)(OR 4 )—;
R 4 is H or —C(O)—C 1-21 alkyl;
R 6 and R 7 are independently H or C 1-6 alkyl;
R 8 is —C(R a )(R b )(R c ), —O—C(R a )(R b )(R c ) or —N(R d )(R e );
R a , R b and R c are independently H or C 1-24 alkyl;
R d and R e are independently H or C 1-24 alkyl; and
W − is a pharmaceutically acceptable anion selected from the group consisting of Cl − , Br − , I − , HC(O)O − , CH 3 C(O)O − , CF 3 C(O)O − and H 2 PO 4 − .
2. The compound according to claim 1 , in free base or pharmaceutically acceptable salt form, wherein the compound is selected from the group consisting of:
(6bR,10aS)-8-Decanoyloxymethyl-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-ium formate;
(6bR,10aS)-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-8-isopropoxycarbonyloxymethyl-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-ium formate;
(6bR,10aS)-8-(2,2-dimethyl-propionyloxymethyl)-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-ium formate; and
(6bR,1 aS)-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-8-hexylcarbamoyloxymethyl-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-ium formate.
3. A pharmaceutical composition comprising the compound according to claim 1 , in free base or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.
4. The pharmaceutical composition according to claim 3 , wherein the pharmaceutical composition is formulated for controlled-release and/or sustained release of the compound over a period of 7 days, 14 days, 30 days, 60 days or 90 days.
5. The pharmaceutical composition according to claim 3 , wherein the pharmaceutical composition further comprises a viscosity enhancing agent.
6. The pharmaceutical composition according to claim 5 , wherein the viscosity enhancing agent is sodium carboxymethylcellulose.
7. A pharmaceutical composition comprising (i) the compound according to claim 1 , or a pharmaceutically acceptable salt thereof; and (ii) a polymeric matrix.
8. The pharmaceutical composition according to claim 7 , wherein the polymeric matrix is a biodegradable poly(D,L-lactide-co-glycolide) microsphere.
9. A pharmaceutical composition or device comprising (a) a gelatin capsule containing the pharmaceutical composition according to claim 3 ; (b) a multilayer wall superposed on the gelatin capsule comprising, in outward order from the capsule: (i) a barrier layer, (ii) an expandable layer, and (iii) a semipermeable layer; and (c) and orifice formed or formable through the wall.
10. A pharmaceutical composition or device comprising (a) a first layer containing the pharmaceutical composition according to claim 3 ; (b) a second layer containing a polymer; (c) an outer wall surrounding the first layer and the second layer; and (d) an orifice in the outer wall.
11. A method for inhibiting serotonin reuptake transport activity in a patient, comprising administering to a patient in need thereof an effective amount of the compound according to claim 1 .
12. The method according to claim 11 , wherein the patient has a disorder involving the serotonin (5-hydroxytryptamine) 2A , dopamine D2 and/or serotonin reuptake transporter pathway.
13. The method according to claim 12 , wherein the patient has a disorder selected from the group consisting of schizophrenia in a patient suffering from depression; depression in a patient suffering from schizophrenia; a mood disorder associated with schizophrenia or Parkinson's disease; and a sleep disorder associated with schizophrenia or Parkinson's disease.
14. The method according to claim 11 , wherein the patient has a disorder selected from the group consisting of obesity, anxiety, psychosis, schizophrenia, a sleep disorder, a sexual disorder, migraine, a condition associated with cephalic pain, a social phobia, agitation in dementia, agitation in autism and related autistic disorders, and dysfunction of the gastrointestinal tract motility.
15. The method according to claim 11 , wherein the patient has schizophrenia.
16. The method according to claim 11 , wherein the patient has depression.