Organic compounds
The invention relates to particular prodrugs of substituted heterocycle fused gamma-carbolines, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving the 5-HT 2A receptor, the serotonin transporter (SERT), pathways involving the dopamine D 1 and D 2 receptor signaling system, and/or the μ-opioid receptor.
1. A compound of a Formula I:
wherein:
R is —C(O)—O—C(R a )(R b )(R c ), —C(O)—O—CH 2 —O—C(R a )(R b )(R c ) or —C(R 6 )(R 7 )—O—C(O)—R 8 ;
Z is O, or —C(O)—;
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 each independently selected from H and C 1-24 alkyl;
R d and R e are each independently selected from H and C 1-24 alkyl;
R 6 and R 7 are each independently selected from H, C 1-6 alkyl, carboxy and C 1-6 alkoxycarbonyl;
in free or salt form;
or
a compound of a Formula II:
wherein:
Z is O, or —C(O)—:
R 1 , R 2 , R 3 and R 4 are each independently selected from H and C 1-6 alkyl;
n is an integer from 1 to 23;
in free or salt form.
2. A compound of Formula I according to claim 1 , wherein Z is O.
3. A compound of Formula I according to claim 1 , wherein Z is —C(O).
4. A compound of Formula I according to claim 1 , wherein R 5 is —C(O)—O—C(R a )(R b )(R c ).
5. A compound of Formula I according to claim 1 , wherein R 5 is —C(O)—O—CH 2 —O—C(R a )(R b )(R c ).
6. A compound of Formula I according to claim 1 , wherein R 5 is —C(R 6 )(R 7 )—O—C(O)—R 8 , and R 8 is —C(R a )(R b )(R c ).
7. A compound of Formula I according to claim 1 , wherein R 5 is —C(R 6 )(R 7 )—O—C(O)—R 8 , and R 8 is —O—C(R a )(R b )(R c ).
8. A compound of Formula I according to claim 1 , wherein R 5 is —C(R 6 )(R 7 )—O—C(O)—R 8 , and R 8 is —N(R d )(R e ).
9. A compound of a Formula II according to claim 1 :
wherein:
Z is O, or —C(O)—;
R 1 , R 2 , R 3 and R 4 are each independently selected from H and C 1-6 alkyl;
n is an integer from 1 to 23;
in free or salt form.
10. A compound according to claim 1 in the form of a salt.
11. A pharmaceutical composition comprising a compound according to claim 1 , in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.
12. The pharmaceutical composition of claim 11 , wherein the composition is formulated as a long acting injectable.
13. The pharmaceutical composition according to claim 12 , wherein the composition comprises the compound in free or pharmaceutically acceptable salt form or in crystal form, wherein said compound is formed into particles or crystals having a volume-based particle size of 0.5-100 microns; and optionally, wherein the particles have a surface area of 0.1 to 5 m 2 /g.