Inhibitor(s) of transporters or uptake of monoaminergic neurotransmitters
The present disclosure concerns a compound, or a pharmaceutically acceptable salt thereof, having a formula: where at least one of R 1 -R 4 is a heterocycle, at least one of R 1 -R 4 is an aryl group coupled to the ring by a linker atom, functional group, or other moiety, or where none of R 1 -R 4 is an amide, and any and all combinations thereof. Remaining R 1 -R 4 substituents independently are aliphatic, substituted aliphatic, amine, substituted amine, aryl, substituted aryl, cyclic, substituted cyclic, halide, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, hydrogen or hydroxyl. A method for treating a subject also is provided comprising administering a disclosed compound or compounds, or a prodrug that is converted into the disclosed compound or compounds, or a composition comprising the compound, compounds, or prodrugs thereof, to a subject. A method for making disclosed compounds also is provided.
1. A compound having a formula
or a pharmaceutically acceptable salt thereof, where n is from 1 to 10, R groups independently are aliphatic, substituted aliphatic, aryl, substituted aryl,-cyclic, substituted cyclic, halide, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, hydrogen or hydroxyl, R 1 substituents independently are aliphatic, substituted aliphatic, cyclic, substituted cyclic, heterocyclic, substituted heterocyclic, or hydrogen, X 1 is carbon, oxygen, nitrogen or sulfur, and X 2 is a bond to the 3-membered ring, or is selected from a carbon, oxygen, nitrogen or sulfur atom.
2. The compound according to claim 1 where X 2 is selected from a carbon atom, nitrogen atom, oxygen atom or sulfur atom.
3. The compound according to claim 1 having a formula
or a pharmaceutically acceptable salt thereof, where n is from 1 to 10, R independently are aliphatic, substituted aliphatic, amine, cyclic, substituted cyclic, halide, heterocyclic, substituted heterocyclic, hydrogen or hydroxyl, and R 1 substituents independently are aliphatic, substituted aliphatic, cyclic, substituted cyclic, heterocyclic, substituted heterocyclic, or hydrogen.
4. A compound, or a biological active salt thereof, having a formula
5. A composition, comprising:
a compound or pharmaceutically acceptable salt thereof, having a formula
where n is from 1 to 10, R groups independently are aliphatic, substituted aliphatic, cyclic, substituted cyclic, halide, heterocyclic, substituted heterocyclic, hydrogen or hydroxyl, R 1 substituents independently are aliphatic, substituted aliphatic, cyclic, substituted cyclic, heterocyclic, substituted heterocyclic, or hydrogen, X 1 is carbon, oxygen, nitrogen or sulfur, and X 2 is a bond to the 3-membered ring, or is selected from a carbon, oxygen, nitrogen or sulfur atom; and
at least one additional material useful for making a pharmaceutically acceptable composition.
6. A method for making a compound having a formula
where n is from 1 to 10, R groups independently are aliphatic, substituted aliphatic, cyclic, substituted cyclic, halide, heterocyclic, substituted heterocyclic, hydrogen or hydroxyl, R 1 substituents independently are aliphatic, substituted aliphatic, cyclic, substituted cyclic, heterocyclic, substituted heterocyclic, or hydrogen, and X 1 is carbon, oxygen, nitrogen or sulfur, the method comprising:
forming an ester by reacting a carboxylic acid with an aryl alcohol, wherein the carboxylic acid has a formula
and the aryl alcohol has a formula
performing a Tebbe or Wittig methylenation reaction on the ester to provide an olefin; and
forming a 3-membered ring from the olefin using a diazo compound.
7. An in vitro method, comprising contacting a neurotransmitter transporter with an amount of a compound effective to inhibit an activity of the neurotransmitter transporter, the compound having a formula
or a pharmaceutically acceptable salt thereof, where n is from 1 to 10, R groups independently are aliphatic, substituted aliphatic, cyclic, substituted cyclic, halide, heterocyclic, substituted heterocyclic, hydrogen or hydroxyl, R 1 substituents independently are aliphatic, substituted aliphatic, cyclic, substituted cyclic, heterocyclic, substituted heterocyclic, or hydrogen, X 1 is carbon, oxygen, nitrogen or sulfur, and X 2 is a bond to the 3-membered ring, or is selected from a carbon, oxygen, nitrogen or sulfur atom.
8. A method of treating a subject, comprising:
administering to the subject a compound having a formula
or a pharmaceutically acceptable salt thereof, where n is from 1 to 10, R groups independently are aliphatic, substituted aliphatic, cyclic, substituted cyclic, halide, heterocyclic, substituted heterocyclic, hydrogen or hydroxyl, R 1 substituents independently are aliphatic, substituted aliphatic, cyclic, substituted cyclic, heterocyclic, substituted heterocyclic, or hydrogen, X 1 is carbon, oxygen, nitrogen or sulfur, and X 2 is a bond to the 3-membered ring, or is selected from a carbon, oxygen, nitrogen, or sulfur atom; and
wherein the subject is suffering from a disease, or a symptom thereof, selected from diabetic peripheral neuropathy, major depressive disorder (MDD), generalized anxiety disorder (GAD), or posttraumatic stress disorder.
9. The method according to claim 7 where the compound has a binding affinity from greater than 0 nM to about 40 nM for the serotonin transporter.
10. The method according to claim 9 where the compound has a binding affinity from about 1 nM to about 10 nM.
11. The method according to claim 7 where the compound has a binding affinity of greater than 0 nM to about 500 nM for the norepinephrine transporter.
12. The method according to claim 11 where the compound has a binding affinity of 1 nM to about 200 nM.