Potent and selective inhibitors of monoamine transporters; method of making; and use thereof
Inventors
Newman, Amy Hauck • OKUNOLA-BAKARE, OLUYOMI M • Cao, Jianjing
Assignees
US Department of Health and Human Services • Office of Technology Transfer
Publication Number
US-9862679-B2
Publication Date
2018-01-09
Expiration Date
2034-03-07
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Abstract
Disclosed herein are bisarylmethylthioacetamides and bisarylmethylthioethylamines useful as inhibitors of monoamine transporters. The compounds are potent and/or selective inhibitors of dopamine (DA), serotonin (5-HT), and/or norepinephrine (NE) reuptake via their respective transporters, DAT, SERT and NET. Also disclosed are methods for eliciting a wake-promoting or cognitive or attention enhancing effect and for treating substance use disorders, attention deficit (hyperactivity) disorder, depressive disorders, bipolar disorder or other neuropsychiatric disorders sleep disorders or cognitive impairment using the compounds.
Core Innovation
Disclosed herein are bisarylmethylthioacetamides and bisarylmethylthioethylamines useful as inhibitors of monoamine transporters. The compounds are potent and/or selective inhibitors of dopamine (DA), serotonin (5-HT), and/or norepinephrine (NE) reuptake via their respective transporters, DAT, SERT and NET. The invention includes pharmaceutical compositions containing these compounds and methods for eliciting a wake-promoting, cognition-enhancing or mood-enhancing effect, and for treating substance use disorders, attention deficit (hyperactivity) disorder, depressive disorders, bipolar disorder or other neuropsychiatric disorders, sleep disorders or cognitive impairment.
The problem being solved is the need for compounds with improved monoamine transporter affinity(ies) and enhanced solubility properties compared to modafinil. Modafinil is limited by its non-aminergic nature and limited water solubility, requiring high concentrations for in vitro and in vivo studies. Modafinil binds DAT uniquely in comparison to cocaine, suggesting potential for efficacious therapeutics without abuse liability. However, existing compounds like modafinil lack optimal affinity and solubility, complicating investigation and therapeutic use.
Claims Coverage
The patent contains one independent claim directed to compounds of formula V and related pharmaceutical compositions and methods of use. The main inventive features focus on the specific chemical structure, substituents, stereochemistry, and pharmaceutical formulations.
Compound or salt of formula V with specific substituents and configurations
A compound or salt of formula V comprising a bisarylmethylthio core with R5 selected from 3-phenylpropyl, —CH2CH(OH)CH3, or —CH2CH(OH)CH2Ph; substituents X located at para or meta positions being fluoro, methyl, or CF3; Y being S or S(O); and Z being O or 2H. The sulfoxide fragment may have an (R)- or (S)-configuration.
Pharmaceutical composition containing compound of formula V
A pharmaceutical composition comprising a compound or salt of formula V with at least one pharmaceutically acceptable carrier. The compositions may be formulated as injectable fluids, aerosols, creams, gels, tablets, pills, capsules, syrups, ophthalmic solutions, or transdermal patches.
Packaging and instructions for therapeutic use
Packages comprising the pharmaceutical composition of formula V in a container with instructions for eliciting wake-promoting, cognition-enhancing or mood-enhancing effects, or for treating substance use disorders, attention deficit (hyperactivity) disorder, depressive disorders, sleep disorders, or cognitive impairment.
The independent claims cover compounds of formula V with specific substituents and stereochemistry, their pharmaceutical compositions in various dosage forms, and packaging including therapeutic instructions. These features define novel chemical entities with specified pharmacological applications.
Stated Advantages
The compounds have higher affinity for monoamine transporters compared to modafinil, which may translate into lower effective doses and better bioavailability in vivo.
Several compounds exhibit improved water solubility over modafinil, facilitating improved investigation and potential therapeutic application.
Compound 4g showed no locomotor stimulation up to 30 mg/kg dose unlike cocaine, suggesting reduced abuse potential.
Compound 4g demonstrated excellent brain penetrability following oral and intravenous dosing, with brain-to-plasma ratios ranging from 4 to 60 fold.
Documented Applications
Eliciting wake-promoting, cognition-enhancing, or mood-enhancing effects in patients.
Treatment of substance use disorders including cocaine, methamphetamine, opioids, and nicotine abuse.
Treatment of attention deficit (hyperactivity) disorder (ADHD).
Treatment of depressive disorders and bipolar disorder.
Treatment of sleep disorders.
Treatment of cognitive impairment including that associated with psychostimulant abuse, schizophrenia, NeuroAIDS, Alzheimer’s disease, cancer-associated fatigue, and multiple sclerosis-associated fatigue.
Treatment of jet-lag, post-operative grogginess, age-related memory decline, obesity, anxiety, and obsessive-compulsive disorders.
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