Deuterated compounds
Described herein are compounds of formula (I) as defined herein, which comprise a greater proportion of deuterium to protium than naturally found in hydrogen; and compositions, including pharmaceutical compositions, comprising these compounds and optionally analogous compounds of formula (I), which are not deuterium-enriched. These compounds and compositions are of use in therapy, in particular in the treatment of psychiatric or neurological disorders. Varying the amounts of the different compounds within the compositions of the invention allows tailoring of the compositions' therapeutic effects. A particularly efficient synthetic method which enables compounds of formula (I) and related compounds of formula (I′) is also provided.
1. A method of synthesising a compound of formula (I′):
or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (II):
with LiAlH 4 and/or LiAlD 4 , wherein the compound of formula (II) is made by:
reacting a compound of formula (III)
with two or more coupling agents to produce an activated compound; and
(ii) reacting the activated compound with an amine having the formula R 2 R 3 NH or R 2 R 3 ND, wherein:
R 1′ is independently selected from —R 4 , —OPR, —OR 4 , —F, —Cl, —Br and —I;
PR is a protecting group,
n is selected from 0, 1, 2, 3 or 4;
R 2 is C( x H) 3 ;
R 3 is C( x H) 3 or H;
each R 4 is independently selected from C 1 -C 4 alkyl; and
each x H and y H is independently protium or deuterium,
wherein a ratio of deuterium:protium in a C( x H) 3 moiety in the compound of formula (I′) is greater than that found naturally in hydrogen,
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 wherein a ratio of LiAlH 4 and/or LiAlD 4 :compound of formula (II) of 0.8:1 to 1:1 is used.
3. The method of claim 1 wherein the two or more coupling agents comprise an additive coupling agent.
4. The method of claim 3 , wherein the two or more coupling agents comprise a carbodiimide.
5. The method of claim 3 , wherein the additive coupling agent is selected from the group consisting of 1-hydroxybenzotriazole, hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine, N-hydroxysuccinimide, 1-hydroxy-7-aza-1H -benzotriazole, ethyl 2-cyano-2-(hydroximino)acetate and 4-(N,N-Dimethylamino)pyridine.
6. A method of psychedelic-assisted psychotherapy for treating a psychiatric or neurological disorder, comprising:
administering to a patient in need thereof the compound
or a pharmaceutically acceptable salt thereof.
7. A method of psychedelic-assisted psychotherapy for treating a psychiatric or neurological disorder, comprising:
administering to a patient in need thereof a compound of formula:
or a pharmaceutically acceptable salt thereof,
wherein the patient in need thereof is subjected to a psychedelic experience induced by administration of the compound, or a pharmaceutically acceptable salt thereof.