Quinazolines as biogenic amine transport modulators
Inventors
Ananthan, Subramaniam • Rothman, Richard B.
Assignees
Southern Research Institute • National Institutes of Health NIH • Office of Technology Transfer
Publication Number
US-10087148-B2
Publication Date
2018-10-02
Expiration Date
2035-12-04
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The present disclosure relates to certain amine derivatives of fused bicyclic heterocycles that inhibit the amine reuptake function of the biogenic amine transporters, dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine transporter (NET). Compounds of the present disclosure are potent inhibitors of the reuptake of dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) with full or partial maximal efficacy. The compounds with partial maximal efficacy in inhibiting reuptake of all three biogenic amines are herein referred to as partial triple uptake inhibitors (PTRIs). Compounds of the present disclosure are useful for treating depression, pain and substance abuse and relapse to substance abuse and addiction to substances such as cocaine, methamphetamine, nicotine and alcohol. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The invention relates to amine derivatives of fused bicyclic heterocycles that inhibit the amine reuptake function of the biogenic amine transporters dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). These compounds act as potent inhibitors of dopamine, serotonin, and norepinephrine reuptake with either full or partial maximal efficacy. Compounds with partial maximal efficacy in inhibiting reuptake of all three biogenic amines are referred to as partial triple uptake inhibitors (PTRIs).
The compounds are useful for treating CNS disorders including depression, pain, and substance abuse and relapse to addicting substances such as cocaine, methamphetamine, nicotine, and alcohol. The invention includes the synthesis, pharmacological profiles, pharmaceutical compositions, and methods of using these compounds. The methods of treatment involve administering an effective amount of compounds characterized by specific chemical formulae. These compounds selectively inhibit dopamine, serotonin, and norepinephrine transporters, potentially normalizing neurotransmitter levels through partial inhibition mechanisms.
The problem addressed is the need for reuptake inhibitors selective for all three neurotransmitters that balance inhibition potency and efficacy. Existing selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) have drawbacks such as slow onset, side effects, and non-responsiveness in a significant number of patients. Compounds that are multiple reuptake inhibitors with submaximal efficacy could provide therapeutic benefits by adjusting neurotransmitter levels depending on their state, particularly for treating depression, pain, and addiction.
Claims Coverage
The patent contains one independent claim which covers a set of specific compounds represented by detailed chemical structures.
Compounds selectively inhibiting biogenic amine transporters
A specific group of quinazoline-based compounds, including numerous substituted derivatives, that act as inhibitors of dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) with partial or full efficacy.
Pharmaceutical compositions containing the claimed compounds
Pharmaceutical compositions comprising at least one of the claimed compounds or their pharmaceutically acceptable salts, deuterated forms, isomers, solvates, or mixtures thereof, combined with pharmaceutically acceptable carriers.
Methods of treating CNS disorders using the compounds
Methods for treating depression, pain, and addictions to substances such as cocaine, methamphetamine, nicotine, and alcohol by administering effective amounts of the claimed compounds or compositions.
Methods of inhibiting monoamine transporter activity
Methods of inhibiting binding of monoamine transporter ligands and inhibiting activity of dopamine, serotonin, and norepinephrine transporters using the claimed compounds.
Methods of preparing the claimed compounds
Synthetic methods involving reacting 2,4-dichloroquinazolines with an amine followed by coupling with heterocyclic compounds to produce the compounds of formula (I).
The independent claim broadly covers specific quinazoline-based compounds with defined substituents, their pharmaceutical compositions, methods of treating CNS disorders by administration, monoamine transporter inhibition methods, and synthetic processes for their preparation.
Stated Advantages
Compounds provide potent inhibition of dopamine, serotonin, and norepinephrine reuptake with full or partial efficacy.
Partial triple uptake inhibition (PTRIs) potentially offers therapeutic advantages by normalizing neurotransmitter levels depending upon neurotransmitter state.
Useful for treating depression, pain, substance abuse, and addiction relapse, with potentially broader spectrum of pain relief than single or dual acting agents.
Documented Applications
Treatment of depression.
Treatment of pain from various causes including neuropathic, inflammatory, migraine, nerve injury, cancer pain, infections, and bowel disorders like irritable bowel syndrome.
Treatment of addiction and relapse to substances such as cocaine, methamphetamine, nicotine, and alcohol.
Interested in licensing this patent?