NEUROPATHIC PAIN

[0001] This application includes material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent disclosure, as it appears in the Patent and Trademark Office files or records, but otherwise reserves all copyright rights whatsoever.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to United States Patent Application Serial No. 62/928,008, filed on October 30, 2019, entitled “NOVEL SELECTIVE KAPPA OPIOID RECEPTOR ANTAGONISTS AND METHODS RELATED THERETO FOR TREATMENT OF ADDICTION AND NEUROPATHIC PAIN”, which is hereby incorporated herein by reference in its entirety for all purposes.

TECHNICAL FIELD

[0003] The present invention relates in general to the field of therapeutic treatment. In particular, the present invention provides for a novel class of chemical compounds with selective kappa opioid receptor antagonist properties. The disclosed compounds have potential to be used in patients with certain opioid and substance abuse as well as chronic pain.

STATEMENT OF FEDERALLY FUNDED RESEARCH

[0004] None.

BACKGROUND OF THE DISCLOSURE

[0005] Opioid receptors are inhibitory receptors with opioids as ligands. Opioid receptors are widely distributed in the brain and are also found throughout the spinal cord. There are 3 major subtypes of opioid receptors know as delta, kappa, and mu opioid receptors. These receptors are the targets of opium derived drugs known as opioids. Opioids are used for pain relief and anesthesia. Since opioids can produce strong feelings of euphoria, they are commonly used in a recreational setting, and are subject to abuse and addiction. In 2014 almost 2 million Americans abused and were dependent on prescription opioids, and in 2016 64,000 people died of an overdose of opioids. There is a major need for solutions to the increase in opioid usage. [0006] Opioid receptor antagonists are a class of drugs that work by antagonizing or inhibiting the function of opioid receptors. These drugs work by competitively binding to the ligand receptor site of opioid receptors. This competitive inhibition does not allow opioid drugs to bind and thus, they have no effect. Certain opioid antagonists have such a high affinity for opioid receptors that they will displace the opioid drug from the receptor reversing its effect. There are several opioid antagonists currently used in the clinical setting. Naloxone and naltrexone are among the most common and are effective at treating opioid overdose and mitigating the effects of opioids and may be used to treat opioid dependency. However, there is no drug on the market that would efficiently replace existing opioid analgesics, that can have addiction developed over time. Thus, there remains a need in the art to develop superior alternatives to current drugs on the market.

SUMMARY OF THE DISCLOSURE

[0007] The present invention addresses failings in the art by providing class of selective kappa opioid receptor antagonists, particularly, two structurally dissimilar opioid receptors that selectively inhibit the kappa opioid receptor (KOR). Literature has suggested that KOR antagonists may be helpful in the treatment of addiction, withdrawal symptoms and pain, and many psychological disorders. There are currently several different KOR antagonists that are being studied and participating in clinical trials. In addition, the present invention provides for methods for a therapeutic treatment that utilizes such compounds as opioid receptor antagonists.

[0008] The novel compounds of the present invention were unexpectedly found to be selective antagonists of kappa opioid receptors, while exhibiting little or no binding at delta or mu receptors. In one aspect, the present invention provides a pharmaceutical formulation comprising an effective amount of a compound:

Formula I

(see FIG. 1) sufficient as a selective antagonist of the kappa-opioid receptor. [0009] In another aspect, the present invention provides a pharmaceutical formulation comprising an effective amount of a compound:

Formula II

(see FIG. 2) sufficient as a selective antagonist of the kappa-opioid receptor.

[00010] Thus, the present invention also provides a method for blocking kappa opioid receptors in mammalian tissue comprising contacting said receptors in vivo or in vitro with an effective amount of the compound of either Formula I or Formula II, preferably in combination with a pharmaceutically acceptable vehicle. Therefore, the compound of either Formula I or Formula II which exhibit kappa receptor antagonist activity may also be therapeutically useful in conditions where selective blockage of kappa receptors is desired. This includes blockage of the appetite response, blockage of paralysis due to spinal trauma and a variety of other physiological activities that may be mediated through kappa receptors. The novel compounds of the present invention also show the ability to cross the blood-brain-barrier (BBB) where many opioid receptors are present. This novel class of compounds has the potential to be a powerful new treatment to combat conditions such as general opioid abuse, addiction, alcohol dependence, neuropathic pain, and other chronic pain conditions. The novel class of compounds are able to serve as a pain reducer and do not induce addiction. Moreover, when giving in combination with current opioid analgesics, they significantly decrease opioid seeking behavior.

[00011] It is therefore and object of the present invention to provide the compound of either Formula I or Formula II. In one aspect of the present invention, said compounds have immunosuppressive capabilities. The KOR antagonist compounds of the present invention offer a new class of selective antagonists that are structurally different from known compounds. In addition, it may offer an increase in the duration of action of the drug since it exhibits a longer half-life.

[00012] In another aspect, said compound is capable of having at least 50% of the administered amount cross the blood-brain barrier (BBB) of a patient. In yet another aspect, said compound is capable of having at least 80% of the administered amount cross the BBB of a patient. The compound of the present invention is effective to treat addiction, alcohol dependence, opioid abuse treatment, neurological disorders, neuropathic pain, and combinations thereof, and is capable of inhibition of the CNS receptor known as the kappa (K) opioid receptor. The compound of the present invention is further effective to block or reduce the tolerance of said mammal to an opioid receptor agonist, such as morphine, methadone, codeine, diacetyl morphine, morphine-N-oxide, oxymorphone, oxycodone, hydromorphone, hydrocodone, meperidine, heterocodeine, fentanyl, sufentanil, levo-acetylmethadol, alfentanil, levorphanol, tilidine, diphenoxylate, hydroxymorphone, noroxymorphone, metopon, propoxyphene, and the pharmaceutically acceptable salts thereof.

[00013] In another aspect of the present invention, a method is provided for treating a disorder selected from the group consisting of addiction, alcohol dependence, opioid abuse treatment, neurological disorders, neuropathic pain, and combinations thereof, comprising administering to a patient a therapeutically effective amount of a compound of either Formula I or Formula II or a pharmaceutically acceptable salt thereof or isotopic variants thereof, stereoisomers or tautomers thereof. In another aspect a method for of treating a mammal is provided comprising the step of: administering to a patient a therapeutically effective amount of a compound of either Formula I or Formula II or a pharmaceutically acceptable salt thereof or isotopic variants thereof, stereoisomers or tautomers thereof, wherein said therapeutically effective amount is effective as an antagonist to one or more opioid receptors.

[00014] In another aspect the compound comprises an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers or adjuvants. In another aspect the compound further comprises one or more excipients, carriers, additives, adjuvants, or binders in a tablet or capsule.

[00015] In another aspect the compound is administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, infusion, implant, aerosol, inhalation, scarification, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, or vaginal route.

BRIEF DESCRIPTION OF THE DRAWINGS

[00016] The foregoing and other objects, features, and advantages of the disclosure will be apparent from the following description of embodiments as illustrated in the accompanying drawings, in which reference characters refer to the same parts throughout the various views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating principles of the disclosure:

[00017] FIG. 1 depicts the chemical structure for Formula I.

[00018] FIG. 2 depicts the chemical structure for Formula II.

[00019] FIG. 3 depicts data relating to rodent-based audible vocalizations for Formula

II.

[00020] FIG. 4 depicts data relating to rodent-based ultrasonic vocalizations for Formula II.

[00021] FIG. 5 depicts data relating to rodent-based Electronic von Frey measurements for Formula II.

[00022] FIG. 6 depicts data relating to rodent-based audible vocalizations for Formula II.

[00023] FIG. 7 depicts data relating to rodent-based ultrasonic vocalizations for Formula II.

DETAILED DESCRIPTION OF THE DISCLOSURE

[00024] While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts, goods, or services. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the disclosure and do not delimit the scope of the disclosure.

[00025] All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[00026] The present invention will now be described more fully hereinafter with reference to the accompanying drawings, which form a part hereof, and which show, by way of illustration, specific example embodiments. Subject matter may, however, be embodied in a variety of different forms and, therefore, covered or claimed subject matter is intended to be construed as not being limited to any example embodiments set forth herein; example embodiments are provided merely to be illustrative. Likewise, a reasonably broad scope for claimed or covered subj ect matter is intended. Among other things, for example, subj ect matter may be embodied as methods, compositions, or systems. Accordingly, embodiments may, for example, take the form of methods, compositions, compounds, materials, or any combination thereof. The following detailed description is, therefore, not intended to be taken in a limiting sense.

[00027] Throughout the specification and claims, terms may have nuanced meanings suggested or implied in context beyond an explicitly stated meaning. Likewise, the phrase “in one embodiment” as used herein does not necessarily refer to the same embodiment and the phrase “in another embodiment” as used herein does not necessarily refer to a different embodiment. It is intended, for example, that claimed subject matter include combinations of example embodiments in whole or in part.

[00028] In general, terminology may be understood at least in part from usage in context. For example, terms, such as “and”, “or”, or “and/or,” as used herein may include a variety of meanings that may depend at least in part upon the context in which such terms are used. Typically, “or” if used to associate a list, such as A, B or C, is intended to mean A, B, and C, here used in the inclusive sense, as well as A, B or C, here used in the exclusive sense. In addition, the term “one or more” as used herein, depending at least in part upon context, may be used to describe any feature, structure, or characteristic in a singular sense or may be used to describe combinations of features, structures or characteristics in a plural sense. Similarly, terms, such as “a,” “an,” or “the,” again, may be understood to convey a singular usage or to convey a plural usage, depending at least in part upon context. In addition, the term “based on” may be understood as not necessarily intended to convey an exclusive set of factors and may, instead, allow for existence of additional factors not necessarily expressly described, again, depending at least in part on context.

[00029] The term "treating" refers to reversing, alleviating, or inhibiting the progress of a disease, or one or more symptoms of such disease, to which such term applies. Depending on the condition of the subject, the term also refers to preventing a disease, and includes preventing the onset of a disease, or preventing the symptoms associated with a disease. A treatment may be either performed in an acute or chronic way. The term also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease. Such prevention or reduction of the severity of a disease prior to affliction refers to administration of a compound or composition of the present invention to a subject that is not at the time of administration afflicted with the disease. "Preventing" also refers to preventing the recurrence of a disease or of one or more symptoms associated with such disease. "Treatment" and "therapeutically," refer to the act of treating, as "treating" is defined above.

[00030] The terms "subject", "individual", or "patient" are used interchangeably herein and refer to an animal preferably a warm-blooded animal such as a mammal. Mammal includes without limitation any members of the Mammalia. In general, the terms refer to a human. The terms also include domestic animals bred for food or as pets, including equines, bovines, sheep, poultry, fish, porcines, canines, felines, and zoo animals, goats, apes (e.g. gorilla or chimpanzee), and rodents such as rats and mice.

[00031] The compounds Formula I and Formula II can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms may be considered equivalent to the unsolvated forms for the purposes of the present invention.

[00032] “Therapeutically effective amount” relates to the amount or dose of an active compound of either Formula I and Formula II, or a composition comprising the same, that will lead to one or more desired effects, in particular, one or more therapeutic effects, more particularly beneficial effects. A therapeutically effective amount of a substance can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the substance to elicit a desired response in the subject. A dosage regimen may be adjusted to provide the optimum therapeutic response (e.g. sustained beneficial effects). For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

[00033] The term “pharmaceutically acceptable” salt, carrier, excipient, or vehicle refers to a medium which does not interfere with the effectiveness or activity of an active ingredient and which is not toxic to the hosts to which it is administered. A carrier, excipient, or vehicle includes diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous materials such as absorbents that may be needed in order to prepare a particular composition. Examples of carriers etc. include but are not limited to a salt formulation, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The use of such media and agents for an active substance is well known in the art.

[00034] In one embodiment of the present invention, the Formulas I and II are compounds with the ability to penetrate the blood brain barrier and inhibit kappa opioid receptors selectively at the level of up to 90% at 10 uM concentration. Active analogs also have no signs of toxicity when administered to animals (rats) and have moderate to excellent enzymatic stability, suggesting its use in oral form, when applicable. In vivo studies have shown that the compounds of the present invention have reduced pain markers by 40-50% and this result is observed starting 30 minutes after administration of compounds.

[00035] Converging evidence from recent research strongly suggests that enhanced kappa opioid receptor (KOR) signaling in brain circuits promotes aversiveness and hypersensitivity in chronic pain, whereas systemically administered kappa-antagonists have analgesic effects. Moreover, kappa antagonists were shown to inhibit the addictive effect of mu opioid receptor (MOR) agonists and alleviate symptoms of opioid-induced addiction; attenuate alcohol seeking and withdrawal anxiety. Current literature suggests that includes clinical and basic research reports a strong connection between post-traumatic stress disorder and opioid/alcohol abuse. Moreover, evidence supports that similar association exists between brain injury and substance abuse. In this case, an overdose often leads to a higher incidence of brain injury, and patients with traumatic brain disorders are more likely to develop a substance abuse disorder. Therefore, KOR antagonists are envisioned to have significant clinical potential as a non-addictive pain management tool and as modulators of drug-seeking behavior.

[00036] Opioid receptors belong to the large superfamily of seven transmembrane- spanning G protein-coupled receptors (GPCRs). As a class, GPCRs are of fundamental physiological importance in mediating the actions of the majority of known neurotransmitters and hormones. They are activated endogenously produced opioid peptides and by exogenously administered opiate compounds. Many of these exogenous compounds are used for pain relief and anesthesia, and these, often, give off strong feelings of euphoria. This strong euphoria makes them a common drug that can be abused in a recreational setting. The effects of this opioid crisis led to more than 115 Americans death per day due to opioid related overdoses, devastating families and communities across the country.

[00037] The present invention presents two analog classes of compounds with the ability to penetrate the blood brain barrier (BBB) and inhibit kappa opioid receptors (KOR) selectively. The active analogs have shown little to no signs of toxicity in laboratory tests that have been performed in rats, and these analogs have shown strong enzymatic stability that suggests its possible use in oral form. These compounds are shown to work as pain reducers that do not induce addiction. They could replace existing opioid analgesics or could be given in combination with current opioid analgesics to significantly decrease opioid-seeking behavior. These active compounds could also work to solve depression, alcohol seeking behavior and opioid withdrawal symptoms.

[00038] The present invention thus presents two structurally novel KOR antagonists with non-opioid pharmacophores. These compounds were confirmed to inhibit kappa opioid receptors selectively, with Ki values of 274 nM and 924 nM, with up to 90% of KOR being inhibited. In addition, BBB permeability of these chemical ligands is confirmed in vitro, and lack of toxicity in rat neurons and bEnd3 cells. Additional experimentation presents pharmacological activity using the well-established spinal nerve ligation (SNL) model of neuropathic pain in rats, where inhibitory effects of KOR antagonism were found on emotional-affective pain responses (audible and ultrasonic vocalization) and hypersensitivity (electronic von Frey test).

[00039] Turning to FIG. 1, Formula I of the present invention is provided. Formula I comprises the following:

[00040] In one embodiment, R1 is a chemical group selected from a group consisting of: hydrogen, halogen, nitro, alkyl, aliphatic, cycloalkyl, trifluoroalkyl, substituted phenyl, carboxylic acid, alkyl ester of carboxylic acid, and acetyl.

[00041] In one embodiment, R2 is a chemical group selected from a group consisting of: hydrogen, hydroxy, alkyloxy, alkyl ester, amine, alkylamine, dialkylamine, thio, thioalkyl, and alkyl ethers.

[00042] In one embodiment, R3 is a chemical group selected from a group consisting of: hydrogen, benzyl, substituted benzyl, methyl, alkyl carbamate, alkyl, prenyl, and cycloalkyl. [00043] In one embodiment, R4 is a chemical group selected from a group consisting of: hydrogen, alkyl, acetyl, cycloalkyl, benzyl, and substituted benzyl. [00044] In one embodiment, R5 is a chemical group selected from a group consisting of: alkyl ester of carboxylic acid, alkyl ether, alkylamide, amine, monoalkylamine, dialkyl amine, and cycloalkyl.

[00045] In one embodiment, R6 is a chemical group selected from a group consisting of: hydrogen, alkyl ether, halogen, alkyl, amine, monoalkylamine, and dialkyl amine.

[00046] FIG. 2 presents Formula II of the present invention. Formula II comprises the following:

Formula II

[00047] In one embodiment, R1 is a chemical group selected from a group consisting of: hydrogen, halogen, nitro, alkyl, aliphatic, cycloalkyl, trifluoroalkyl, substituted phenyl, carboxylic acid, alkyl ester of carboxylic acid, and acetyl.

[00048] In one embodiment, R2 is a chemical group selected from a group consisting of: hydrogen, hydroxy, alkyloxy, alkyl ester, amine, alkylamine, dialkylamine, thio, thioalkyl, and alkyl ethers. [00049] In one embodiment, R3 is a chemical group selected from a group consisting of: hydrogen, benzyl, substituted benzyl, methyl, alkyl carbamate, alkyl, prenyl, and cycloalkyl.

[00050] In one embodiment, R4 is a chemical group selected from a group consisting of: hydrogen, alkyl, acetyl, cycloalkyl, benzyl, and substituted benzyl. [00051] In one embodiment, R5 is a chemical group selected from a group consisting of: alkyl ester of carboxylic acid, alkyl ether, alkylamide, amine, monoalkylamine, dialkyl amine, and cycloalkyl.

[00052] In one embodiment, R6 is a chemical group selected from a group consisting of: hydrogen, alkyl ether, halogen, alkyl, amine, monoalkylamine, and dialkyl amine. [00053] In another embodiment, both Formula I and Formula II are capable of maintaining KOR antagonist properties in the nanomolar range. [00054] It is therefore an embodiment of the present invention to provide novel compounds of Formula I and Formula II, and derivatives thereof, or pharmaceutically acceptable salts thereof, which are presented for treating certain disorders in a patient, such as addiction, alcohol dependence, opioid abuse treatment, neurological disorders, and neuropathic pain. It is another embodiment of the present invention to provide pharmaceutically acceptable compositions comprising compounds of Formula I and Formula II, and a pharmaceutically acceptable carrier.

[00055] Another embodiment of the present invention relates to a method for providing neuroprotection in a mammal in need of such treatment. The method comprises administering to the mammal a therapeutically effective amount of a compound of either Formula I or Formula II or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers. The composition is preferably useful for the treatment of the disease conditions described above.

[00056] Further, the present invention provides the use of a compound of either Formula I or Formula II or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of the disease conditions described above.

[00057] In another embodiment, the compounds, compositions, and methods disclosed herein therefore may be utilized to prevent and/or treat a disease such as alcohol dependence, opioid abuse treatment, neurological disorders, neuropathic pain, and fibromyalgia, among other conditions mediated by one or more opioid receptors.

[00058] In an illustrative embodiment of the present invention, Formula I and Formula II, were evaluated for selective activity of the KOR. In one embodiment, compound of the present invention Either Formula I or Formula II, along with gliotoxin, show inhibition with regard to various receptors, including HI and opioid receptors m (MOR), s (DOR), and k (KOR). These molecules of the present invention are shown to inhibit pain response 20-40% (when different pain markers are assessed). Additionally, PK analysis was performed of the class II parent compound (Formula II) in rats. The observed data are set forth in Table 1, below.

Table 1 : Formula II pK data from in vivo study.

[00059] FIGS. 3-9 provides data related to certain pain indices in rodent studies. FIG. 3 presents data relating to rodent-based audible vocalizations for Formula II. FIG. 4 presents data relating to rodent-based ultrasonic vocalizations for Formula II. FIG. 5 presents data relating to rodent-based Electronic von Frey measurements for Formula II. FIG. 6 presents data relating to rodent-based audible vocalizations for Formula II. FIG. 7 presents data relating to rodent-based ultrasonic vocalizations for Formula II.

[00060] It is another embodiment of the present invention to provide either Formula I or Formula II comprising an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers or adjuvants. Either Formula I or Formula II may further comprise one or more excipients, carriers, additives, adjuvants, or binders in a tablet or capsule. Either Formula I or Formula II may further be administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, infusion, implant, aerosol, inhalation, scarification, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, or vaginal route.

[00061] The compounds of the present invention are capable of treatment in a manner selective to CNS activity and does not manipulate the activity of other CNS receptors, as other CNS drugs have a tendency to do. Therefore, the compounds of the present invention have substantially reduced toxicity profiles (i.e. depression, headache, suicidal thoughts, and the like). The compounds of the present invention are further active as low nanomolar ranges due to its potency. [00062] Those skilled in the art will recognize that the methods and compositions of the present invention may be implemented in many manners and as such are not to be limited by the foregoing exemplary embodiments and examples. In other words, functional elements being performed by single or multiple components, in various combinations of hardware and software or firmware, and individual functions, may be distributed among various software applications at either the client level or server level or both. In this regard, any number of the features of the different embodiments described herein may be combined into single or multiple embodiments, and alternate embodiments having fewer than, or more than, all of the features described herein are possible. [00063] Functionality may also be, in whole or in part, distributed among multiple components, in manners now known or to become known. Thus, myriad combinations are possible in achieving the functions, features, and preferences described herein. Moreover, the scope of the present invention covers conventionally known manners for carrying out the described features as well as those variations and modifications that may be made to the processes, composition, or compounds described herein as would be understood by those skilled in the art now and hereafter.

[00064] While various embodiments have been described for purposes of this disclosure, such embodiments should not be deemed to limit the teaching of this disclosure to those embodiments. Various changes and modifications may be made to the elements and operations described above to obtain a result that remains within the scope of the compositions and methods described in this disclosure.