PRODRUGS OF MDMA, MDA, AND DERIVATIVES THEREOF
The present disclosure provides prodrug compounds of MDMA, MDA, and derivatives thereof having an improved pharmacokinetic profile suitable for the treatment of various neurological diseases.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein,
R 1 is H or alkyl;
R 2 and R 2 ′ are each independently H, halogen, alkyl, —OH, or —O-alkyl, or R 2 and R 2 ′ together with the atom to which they are attached form a cycloalkyl ring;
R 3 and R 3 ′ are each independently hydrogen, alkyl, —OH, —O-alkyl, or —O-cycloalkyl, or R 3 and R 3 ′ together with the atom to which they are attached form an oxo;
R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O-cycloalkyl, alkylene—OR 8 , —SH, —S alkyl, —S cycloalkyl, or alkylene—SR 8 , or R 5 and R 6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring;
R 8 is H, alkyl, cycloalkyl, or alkylenecycloalkyl;
X is a cleavable promoiety having the structure
wherein:
R 9 and R 10 are each independently alkyl.
2 . The compound of claim 1 , wherein at least one of R 4 , R 5 , R 6 and R 7 is not H.
3 . The compound of claim 1 , wherein R 1 is H or C 1 -C 6 alkyl.
4 . The compound of claim 1 , wherein RI is H.
5 . The compound of claim 1 , wherein R 1 is CH 3 .
6 . The compound of claim 1 , wherein R 2 and R 2 are each independently H, alkyl, or —OH.
7 . The compound of claim 1 , wherein R 2 is alkyl and R 2 ′ is H.
8 . The compound of claim 1 , wherein R 2 and R 2 ′ are each alkyl.
9 . The compound of claim 6 , wherein the alkyl is methyl or isopropyl.
10 . The compound of claim 1 , wherein R 3 and R 3 ′ are each independently H, —OH, or —O-alkyl, or R 3 and R 3 together with the atom to which they are attached form an oxo.
11 . The compound of claims 1 , wherein R 4 is H.
12 . The compound of claim 1 , wherein R 7 is H.
13 . The compound of claim 1 , wherein R 5 and R 6 are each independently halogen, —OH, —O-alkyl, —O-cycloalkyl, alkylene—OR 8 , —SH, —S-alkyl, —S-cycloalkyl, or alkylene—SR 8 .
14 . The compound of claims 1 , wherein R 5 and R 6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring.
15 . The compound of claim 1 , wherein R 8 is alkyl.
16 . The compound of claim 1 , wherein R 9 is C 1-5 alkyl.
17 . The compound of claim 1 , wherein R 9 is methyl or isopropyl.
18 . The compound of claim 1 , wherein R 10 is C 1-5 alkyl.
19 . The compound of claim 18 , wherein R 10 is methyl or isopropyl.
20 . The compound of claim 1 , having the structure of Formula (Ib):
wherein n is 1 or 2.
21 . The compound of claim 1 , wherein the compound is:
22 . The compound of claim 1 , wherein X is cleavable at a pH of from about 1 to about 5.
23 . The compound of claim 1 , wherein X is cleavable at a pH of from about 2 to about 4.
24 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
25 . The pharmaceutical composition of claim 24 , capable of providing an in vivo plasma level characterized by a Cmax of free amine of about 100 ng/ml to about 500 ng/ml, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (I) and release of promoiety X.
26 . The pharmaceutical composition of claim 24 , capable of providing an in vivo plasma level characterized by an AUC (0-24) of free amine of about 1000 h*ng/ml to about 6000 h*ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (I) and release of promoiety X.
27 . The pharmaceutical composition of claim 24 , capable of providing an in vivo T 1/2 of free amine of about 5 h to about 15 h, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (I) and release of promoiety X.
28 . The pharmaceutical composition of claim 24 , wherein when R 1 is H, the composition is capable of providing a Cmax of free amine within a range of about 60-90% of about 12 ng/mL to about 15 ng/mL achieved following oral administration of a 125 mg dose of MDA to a human subject.
29 . The pharmaceutical composition of claim 24 , wherein when R 1 is H, the composition is capable of providing a Cmax of free amine within a range of about 60-90% of about 7 ng/mL to about 8.5 ng/mL achieved following oral administration of a 75 mg dose of MDA to a human subject.
30 . The pharmaceutical composition of claim 24 , wherein when R 1 is methyl, the composition is capable of providing a Cmax of free amine within a range of about 60-90% of about 220 ng/mL to about 250 ng/mL achieved following oral administration of a 125 mg dose of MDMA to a human subject.
31 . The pharmaceutical composition of claim 24 , wherein RI is methyl, the composition is capable of providing a T 1/2 of free amine within a range of about 105-150% of about 8 h to about 9 h achieved following oral administration of a 125 mg dose of MDMA to a human subject.
32 . The pharmaceutical composition of claim 24 , wherein when RI is methyl, the composition is capable of providing a Cmax of free amine within a range of about 60-90% of about 120 ng/ml to about 140 ng/ml achieved following oral administration of a 75 mg dose of MDMA to a human subject.
33 . The pharmaceutical composition of claim 24 , wherein when RI is methyl, the composition is capable of providing a T 1/2 of free amine within a range of 105-150% of about 7 h to about 9 h achieved following oral administration of a 75 mg dose of MDMA to a human subject.
34 . A method of treating social anxiety, the method comprising administering a therapeutically effective amount of a compound of claim 1 .