Analogs of cyclobenzaprine and amitryptilene
Inventors
Lederman, Seth • Rideout, Darryl • Sullivan, Greg
Assignees
Tonix Pharmaceuticals Holding Corp
Publication Number
US-12156864-B2
Publication Date
2024-12-03
Expiration Date
2038-07-13
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Abstract
The present invention relates to cyclobenzaprine analogs and amitriptyline analogs, including deuterated forms useful for treatment or prevention of symptoms associated with post-traumatic stress disorder.
Core Innovation
The invention relates to new analogs of cyclobenzaprine and amitriptyline, including deuterated forms, with modifications intended to alter their metabolic properties and pharmacodynamic profiles. These analogs retain the therapeutic utility of cyclobenzaprine, such as treating muscle spasms, fibromyalgia, sleep issues, and symptoms of post-traumatic stress disorder (PTSD), including associated sleep disturbances.
The patent addresses the continuing unmet medical need for effective pharmacological treatments for PTSD, particularly among military populations, where existing approved therapies (SSRIs and SNRIs) have shown inadequate efficacy in clinical trials. Cyclobenzaprine’s efficacy in sleep improvement and symptom alleviation forms the basis for developing novel analogs with enhanced characteristics and minimized side effects, such as reduced next-day drowsiness linked to the build-up of nor-cyclobenzaprine.
The disclosed cyclobenzaprine and amitriptyline analogs (including specific compounds such as (2,2-Difluoro-ethyl)-[3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-methyl-amine; hydrochloride, and 1-(3-Dibenzo[a,d]cyclohepten-5-ylidene-propyl)-3-fluoro-azetidine, oxalate salt) are presented as pharmaceutical compositions suitable for a variety of administration routes and formulations (such as orally dissolving tablets and thin films). The invention also encompasses deuterated versions to further improve pharmacokinetic profiles and addresses methods for treating or preventing PTSD or its symptoms by administering these analogs, either alone or in combination with other drugs.
Claims Coverage
The patent presents coverage that includes one main inventive feature based on the independent claims for amitriptyline analog compounds of Formula B.
Amitriptyline analog compounds of Formula B
An amitriptyline analog compound having Formula B, where: - R1 is selected from H, C1-4-alkyl, and C1-4-alkoxy; - R2 is selected from H, Br, (CH2)nCO2R (where n=0 to 3 and R is C1-4-alkyl, C1-4-alkoxy, or halogen); - R3 is selected from H, C1-4-alkoxy, OH, and OCOR (where R is C1-4-alkyl); - R4 is C1-4-alkyl, which, if ethyl, may have the terminal carbon optionally substituted by fluorine one to three times; and - R5 is C1-4-alkyl; or - R4 and R5 taken together can form a 4-membered saturated ring optionally substituted with methyl, methoxy, CF3, or CHF2. The claims specify various structural possibilities, including deuterated derivatives and additional specific substituent combinations as outlined in dependent claims.
In summary, the claims cover a range of amitriptyline analogs with particular structural definitions to improve therapeutic properties and metabolic profiles.
Stated Advantages
The analogs are designed to decrease the rates of metabolism alpha to nitrogen, reducing the rate at which undesirable nor-cyclobenzaprine-like metabolites are formed.
The compounds aim to cause little or no drowsiness by altering the metabolic properties of cyclobenzaprine.
Deuterated analogs may have a longer half-life due to lower rates of metabolism.
The analogs are intended to provide improved sleep quality and alleviate PTSD symptoms with minimal side effects.
Documented Applications
Treatment or prevention of symptoms associated with post-traumatic stress disorder (PTSD), including sleep disturbances and non-sleep symptoms.
Treatment of muscle spasms, fibromyalgia syndrome, traumatic brain injury, and sleep issues.
Use in pharmaceutical compositions administered orally, sublingually, intranasally, buccally, rectally, parenterally, transdermally, subcutaneously, intramuscularly, intrathecally, and other suitable routes.
Combination therapy with alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors to further alleviate PTSD symptoms.
Prevention or treatment of PTSD symptom initiation, consolidation, or perpetuation phases after a traumatic event.
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