5-HT
The present invention relates to agonists of the 5-HT 2A serotonin receptors and their medical uses. In one aspect the invention relates to 5-HT 2A agonists of formula (I). In second aspect, the invention relates to selective 5-HT 2A agonists of formula (II). In another aspect, the invention relates to mixed 5-HT 2A /5-HT 2C agonists of formula (III). In yet another aspect, the invention relates to 5-HT 2A agonists for use in the treatment of a depressive disorder, more particular a 5-HT 2A agonist for the use in the treatment of treatment-resistant depression.
1. A method of treating a depressive disorder selected from the group consisting of major depressive disorder (MDD) (also known as clinical depression, unipolar depression), melancholia, psychotic depression, antenatal depression, postnatal depression, bipolar disorder, bipolar type I disorder, bipolar type II disorder, cyclothymic disorder, dysthymic disorder or seasonal affective disorder, treatment-resistant depression disorder (TRD) and severe treatment-resistant depression disorder comprising:
administering an effective amount of a pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof to a subject in need thereof;
wherein formula (III) has the structure,
wherein:
X is selected from the group consisting of F, Cl, Br, I, CN, S—(C 1 -C 5 alkyl), S—(C 1 -C 5 fluoroalkyl), S—(C 2 -C 5 alkenyl), S—(C 2 -C 5 fluoroalkenyl), S—(C 2 -C 5 alkynyl), S—(C 2 -C 5 fluoroalkynyl), C 1 -C 5 alkyl, C 1 -C 5 fluoroalkyl, C 2 -C 5 alkenyl, C 2 -C 5 fluoroalkenyl, C 2 -C 5 alkynyl, and C 2 -C 5 fluoroalkynyl;
Y 1 and Y 2 are independently selected from the group consisting of H, O, S, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, and halogen;
R 1 is not present when Y 1 is H, C 1 -C 3 , alkyl, C 1 -C 3 fluoroalkyl or halogen;
R 2 is not present when Y 2 is H, C 1 -C 3 , alkyl, C 1 -C 3 fluoroalkyl or halogen;
when present, R 1 and R 2 are independently selected from the group consisting of C 1 -C 5 alkyl, C 1 -C 5 fluoroalkyl, C 2 -C 5 alkenyl, C 2 -C 5 fluoroalkenyl, C 2 -C 5 alkynyl, C 2 -C 5 fluoroalkynyl, C 3 -C 5 cycloalkyl, and C 3 -C 5 fluorocycloalkyl;
* denotes the (R) or (S) stereoisomer or any mixture thereof if a chiral center is present;
n is an integer with a value of 1 or 2 to form an azetidine or pyrrolidine ring system;
z denotes the number of R 3 groups and is an integer with a value of 0, 1, 2, 3 or 4
each R 3 is independently selected from the group consisting of F, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 2 -C 3 alkenyl, and C 2 -C 3 alkynyl;
R 4 is H or CH 3 ;
with the proviso that at least one of Y 1 or Y 2 is selected as O or S.
2. A method according to claim 1 , wherein X is selected from F, Cl, Br, I, CN, S—(C 1 -C 3 alkyl), S—(C 1 -C 3 fluoroalkyl), C 1 -C 3 alkyl or C 1 -C 3 fluoroalkyl; Y 1 and Y 2 are independently selected from O, CH 3 , or S; R 1 and R 2 are independently selected from not present (R 1 not present if Y 1 is CH 3 , R 2 not present if Y 2 is CH 3 ), C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 5 cycloalkyl; z is 0, 1, 2 or 3; and R 3 is/are independently selected from F, C 1 -C 2 alkyl or C 1 -C 2 fluoroalkyl.
3. A method according to claim 1 , wherein X is selected from the group consisting of F, Cl, Br, I, CN, S—CH 3 , S—CF 3 , C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, ethynyl, fluoroethynyl, and cyclopropyl; le and R 2 are independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, and C 3 -C 5 cycloalkyl; z is 0, 1 or 2; and each R 3 is independently selected from the group consisting of F, C 1 -C 2 alkyl, and C 1 -C 2 fluoroalkyl.
4. A method according to claim 1 , wherein X is selected from the group consisting of F, Cl, Br, I, CN, S—(C 1 -C 3 alkyl), S—(C 1 -C 3 fluoroalkyl), C 1 -C 5 alkyl and C 1 -C 5 fluoroalkyl.
5. A method according to claim 1 , wherein X is selected from the group consisting of F, Cl, Br, I, CN, S—CH 3 , S—CF 3 , C 1 -C 3 alkyl, and C 1 -C 3 fluoroalkyl.
6. A method according to claim 1 , wherein X is CF 3 .
7. A method according to claim 1 , wherein Y 1 and Y 2 are independently selected from the group consisting of O, S, C 1 -C 2 alkyl, and C 1 -C 2 fluoroalkyl.
8. A method according to claim 1 , wherein Y 1 and Y 2 are independently selected from the group consisting of O, S, CH 3 , and CF 3 .
9. A method according to claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of C 1 -C 3 alkyl, and C 1 -C 3 fluoroalkyl and cyclopropyl.
10. A method according to claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of C 1 -C 3 alkyl, and C 1 -C 3 fluoroalkyl; and wherein Y 1 and Y 2 are O.
11. A method according to claim 1 , wherein n is an integer with a value of 1 to form an azetidine.
12. A method according to claim 1 , wherein Y 1 and Y 2 are independently selected from the group consisting of O and S.
13. A method according to claim 9 , wherein R 1 and R 2 are both CH 3 .