Tryptamine prodrugs
The present invention provides a tryptamine prodrug compound. A compound represented by the formula (I) where each symbol is as described in the specification, or a salt or zwitterion thereof, is converted to an active which has 5HT2A receptor agonist activity, and is useful as an agent for the treatment of depression.
1. A compound of Formula (I) (II), (III) or (IV) or a pharmaceutically acceptable salt or zwitterion thereof:
wherein:
(1) R1, R2, and R6 are each independently selected from hydrogen, linear or branched alkyl, or arylalkyl;
(2) R4 is
a. —X—CO2H, where X is a linear, cyclic or branched, saturated or unsaturated carbon chain, optionally substituted with —OH or —CO2H; or an aromatic ring, optionally substituted with alkyl or CO 2 H; or
b.
wherein R9 is X—CO2H, where X is as defined in (2)(a) above and R10 is linear or branched alkyl or arylalkyl, optionally substituted by —OH or —CO2H;
(3) R5 is hydrogen, linear or branched alkyl, arylalkyl, or O—R5′, where R5′ is hydrogen, linear or branched alkyl; and
(4) R7 and R8:
c. are each independently selected from hydrogen, linear or branched alkyl, or arylalkyl, with the proviso that each of R7 and R8 is not hydrogen, or
d. together form a non-aromatic N-containing heterocycle, optionally substituted with alkyl.
2. The compound of claim 1 , selected from the group consisting of:
3. The compound of claim 1 wherein:
(1) R1, R2, and R6 are each independently selected from H or linear C 1-5 alkyl;
(2) R4 is —X—CO2H, where X is a linear or branched C 1-5 carbon chain, optionally substituted with OH or CO2H;
(3) R5 is hydrogen, linear or branched C 1-5 alkyl, arylalkyl, or O-R5′, where R5′ is hydrogen, linear or branched C 1-5 alkyl; and/or
(4) R7 and R8 are each independently selected from H or linear or branched C 1-5 alkyl, with the proviso that each of R7 and R8 is not hydrogen.
4. The compound of claim 3 wherein R7 and R8 are the same or different, and are linear or branched C 1-4 alkyl.
5. The compound of claim 4 wherein R7 and R8 are each methyl or isopropyl.
6. The compound of claim 3 wherein X is a linear C1-C3 chain, optionally substituted with OH or CO2H.
7. The compound of claim 5 wherein X is a linear C3 chain.
8. The compound of claim 7 wherein R7 and R8 are both methyl, or R7 and R8 are both isopropyl, or one of R7 and R8 is methyl and the other is isopropyl.
9. A composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
10. The composition of claim 9 comprising an oral dosage formulation or an injectable formulation.
11. The composition of claim 10 which is a solution for injection.
12. The composition of claim 11 wherein the solution has a pH of between about 3.0 and 7.0, preferably 4.0 to 6.0, and more preferably 4.5 to 5.5.
13. A method of treating a mental disorder, comprising the step of administering an effective amount of a compound of claim 1 .
14. The method of claim 13 wherein the mental disorder is depression.
15. A method of making a compound of formula (I), (II), (III) or (IV) in claim 1 comprising reacting a tryptamine with a cyclic anhydride in a suitable anhydrous solvent, wherein the tryptamine is hydroxytryptamine or hydroxyisotryptamine.
16. The method of claim 15 , wherein the solvent contains a base with pKa greater than 4 and less than about 9 , and the resulting compound is isolated as a zwitterion.
17. The method of claim 16 wherein the solvent is pyridine.
18. The method of claim 17 wherein the compound is a compound of claim 2 .
19. The method of claim 15 wherein the tryptamine is 4-OH diisopropyltryptamine or psilocin and the cyclic anhydride is succinic anhydride or glutaric anhydride.
20. N,N diisopropyltryptamine-4-glutarate or a pharmaceutically acceptable salt or zwitterion thereof.
21. A method of treating a mental disorder, comprising the step of administering an effective amount of a compound of claim 20 .
22. The method of claim 21 wherein the mental disorder is depression.
23. A compound of Formula (I) or (III) or a pharmaceutically acceptable salt or zwitterion thereof:
wherein:
(1) R 1 , R 2 , and R 6 are each independently selected from hydrogen, linear or branched alkyl, or arylalkyl;
(2) R4 is
a. (—X—CO2H, where X is a linear, cyclic or branched, saturated or unsaturated carbon chain, optionally substituted with —OH or —CO2H; or
an aromatic ring, optionally substituted with alkyl or CO2H; or
b.
wherein R9 is X 13 CO2H, where X is as defined in (2)(a) above and R10 is linear or branched alkyl or arylalkyl, optionally substituted by —OH or —CO2H;
(3) R5 is hydrogen, linear or branched alkyl, arylalkyl, or O—R5′, where R5′- is hydrogen, linear or branched alkyl; and
(4) R7 and R8:
c. are each independently selected from hydrogen, linear or branched alkyl, or arylalkyl, or
d. together form a non-aromatic N-containing heterocycle, optionally substituted with alkyl.