WO2021087268A1 - Nouveaux antagonistes sélectifs du récepteur opioïde kappa et procédés s'y rapportant pour le traitement de la dépendance et de la douleur neuropathique - Google Patents

Nouveaux antagonistes sélectifs du récepteur opioïde kappa et procédés s'y rapportant pour le traitement de la dépendance et de la douleur neuropathique Download PDF

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Publication number
WO2021087268A1
WO2021087268A1 PCT/US2020/058225 US2020058225W WO2021087268A1 WO 2021087268 A1 WO2021087268 A1 WO 2021087268A1 US 2020058225 W US2020058225 W US 2020058225W WO 2021087268 A1 WO2021087268 A1 WO 2021087268A1
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compound
group
kappa
opioid receptor
formula
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PCT/US2020/058225
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English (en)
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Nadezhda GERMAN
Thomas ABBRUSCATTO
Volker NEUGEBAUER
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Texas Tech University System
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms

Definitions

  • the present invention relates in general to the field of therapeutic treatment.
  • 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.
  • 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.
  • 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.
  • opioid antagonists 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.
  • 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.
  • 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).
  • KOR kappa opioid receptor
  • Literature has suggested that KOR antagonists may be helpful in the treatment of addiction, withdrawal symptoms and pain, and many psychological disorders.
  • KOR antagonists There are currently several different KOR antagonists that are being studied and participating in clinical trials.
  • the present invention provides for methods for a therapeutic treatment that utilizes such compounds as opioid receptor antagonists.
  • 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.
  • the present invention provides a pharmaceutical formulation comprising an effective amount of a compound:
  • the present invention provides a pharmaceutical formulation comprising an effective amount of a compound:
  • 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.
  • BBB blood-brain-barrier
  • 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.
  • 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.
  • 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.
  • BBB blood-brain barrier
  • 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.
  • opioid receptor agonist such as morphine, methadone, codeine, diacetyl morphine, morphine-N-oxide, oxymorphone, oxycodone, hydromorphone, hydrocodone, meperidine, heterocodeine, fentanyl, sufentanil, levo-acetylmethadol, alfentanil
  • a method 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.
  • a method for of treating a mammal 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.
  • the compound comprises an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers or adjuvants.
  • the compound further comprises one or more excipients, carriers, additives, adjuvants, or binders in a tablet or capsule.
  • 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.
  • FIG. 1 depicts the chemical structure for Formula I.
  • FIG. 2 depicts the chemical structure for Formula II.
  • FIG. 3 depicts data relating to rodent-based audible vocalizations for Formula
  • FIG. 4 depicts data relating to rodent-based ultrasonic vocalizations for Formula II.
  • FIG. 5 depicts data relating to rodent-based Electronic von Frey measurements for Formula II.
  • FIG. 6 depicts data relating to rodent-based audible vocalizations for Formula II.
  • FIG. 7 depicts data relating to rodent-based ultrasonic vocalizations for Formula II.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • “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.
  • 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.
  • 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.
  • KOR kappa opioid receptor
  • MOR mu opioid receptor
  • Current literature suggests that includes clinical and basic research reports a strong connection between post-traumatic stress disorder and opioid/alcohol abuse.
  • GPCRs G protein-coupled receptors
  • 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.
  • 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.
  • BBB blood brain barrier
  • KOR kappa opioid receptors
  • 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.
  • 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).
  • SNL spinal nerve ligation
  • Formula I comprises the following:
  • 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.
  • R2 is a chemical group selected from a group consisting of: hydrogen, hydroxy, alkyloxy, alkyl ester, amine, alkylamine, dialkylamine, thio, thioalkyl, and alkyl ethers.
  • R3 is a chemical group selected from a group consisting of: hydrogen, benzyl, substituted benzyl, methyl, alkyl carbamate, alkyl, prenyl, and cycloalkyl.
  • R4 is a chemical group selected from a group consisting of: hydrogen, alkyl, acetyl, cycloalkyl, benzyl, and substituted benzyl.
  • 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.
  • R6 is a chemical group selected from a group consisting of: hydrogen, alkyl ether, halogen, alkyl, amine, monoalkylamine, and dialkyl amine.
  • FIG. 2 presents Formula II of the present invention.
  • Formula II comprises the following:
  • 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.
  • R2 is a chemical group selected from a group consisting of: hydrogen, hydroxy, alkyloxy, alkyl ester, amine, alkylamine, dialkylamine, thio, thioalkyl, and alkyl ethers.
  • R3 is a chemical group selected from a group consisting of: hydrogen, benzyl, substituted benzyl, methyl, alkyl carbamate, alkyl, prenyl, and cycloalkyl.
  • R4 is a chemical group selected from a group consisting of: hydrogen, alkyl, acetyl, cycloalkyl, benzyl, and substituted benzyl.
  • 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.
  • R6 is a chemical group selected from a group consisting of: hydrogen, alkyl ether, halogen, alkyl, amine, monoalkylamine, and dialkyl amine.
  • both Formula I and Formula II are capable of maintaining KOR antagonist properties in the nanomolar range.
  • pharmaceutically acceptable compositions comprising compounds of Formula I and Formula II, and a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Formula I and Formula II were evaluated for selective activity of the KOR.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.

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Abstract

L'invention concerne une composition et une méthode de traitement thérapeutique pouvant lutter contre certains états tels que la dépendance, l'alcoolisme, le traitement d'abus d'opioïdes, les troubles neurologiques, la douleur neuropathique et des combinaisons de ceux-ci. Les composés agissent en tant qu'antagoniste sélectif vis-à-vis du récepteur opioïde kappa (K) qui, lorsqu'il est présent, conduit à l'inhibition d'états, ce qui permet d'obtenir une performance accrue par rapport aux traitements connus. Les composés selon l'invention présentent également une capacité pour franchir la barrière hématoencéphalique d'une manière hautement efficace. Les composés selon l'invention s'avèrent efficaces dans la gamme nanomolaire.
PCT/US2020/058225 2019-10-30 2020-10-30 Nouveaux antagonistes sélectifs du récepteur opioïde kappa et procédés s'y rapportant pour le traitement de la dépendance et de la douleur neuropathique WO2021087268A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
US20060014948A1 (en) * 1998-12-14 2006-01-19 Fujisawa Pharmaceutical Co. Ltd. Piperazine derivatives
US20090156553A1 (en) * 2006-01-02 2009-06-18 Basf Se Piperazine compounds with a herbicidal action
WO2020092996A1 (fr) * 2018-11-02 2020-05-07 Texas Tech University System Nouveaux antagonistes sélectifs du récepteur opioïde kappa et procédés s'y rapportant pour le traitement de la dépendance et de la douleur neuropathique

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US20060014948A1 (en) * 1998-12-14 2006-01-19 Fujisawa Pharmaceutical Co. Ltd. Piperazine derivatives
US20090156553A1 (en) * 2006-01-02 2009-06-18 Basf Se Piperazine compounds with a herbicidal action
WO2020092996A1 (fr) * 2018-11-02 2020-05-07 Texas Tech University System Nouveaux antagonistes sélectifs du récepteur opioïde kappa et procédés s'y rapportant pour le traitement de la dépendance et de la douleur neuropathique

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