ALPHA2 Adrenaline Agonist: A Cephalic Agent Compound

Abstract

This disclosure provides a method for reducing the concentration of α2-adrenergic receptor agonists in a patient's body. It also provides a method for preventing or treating an overdose of α2-adrenergic receptor agonists in a patient, either alone or in combination with another drug of abuse.

Description

[Technical Field]

[0001] This invention was made with the assistance of the United States Government under grant number R44DA052957, granted by the National Institutes of Health. The Government has certain rights in this invention.

[0002] This disclosure provides methods and compositions for reducing α2-adrenergic receptor agonists in a patient's body. It also provides methods and compositions for preventing or treating overdoses of α2-adrenergic receptor agonists, or overdoses of α2-adrenergic receptor agonists in combination with other abused drugs, by administering a therapeutically effective amount of a chelating agent to a patient. [Background technology]

[0003] Drug overdose, addiction, and dependence are major social problems affecting all aspects of society. There is a significant unmet medical need for prescription drugs and antidotes for illegal drugs to treat or prevent abuse and overdose.

[0004] Xylazine is increasingly being found in the U.S. illegal drug supply chain and is linked to deaths from overdoses. A growing number of reports, warnings, and recommendations from public health agencies indicate that xylazine is being abused in combination with other abused drugs such as fentanyl, cocaine, and heroin, causing significant harm. People using illegal drugs may be unaware of the presence of xylazine. The DEA has seized xylazine and fentanyl mixtures in 48 of the 50 states, and the DEA reported that in 2022, approximately 23% of fentanyl powder and approximately 7% of fentanyl pills seized by the DEA contained xylazine.

[0005] Methods and compositions for the treatment of patients suffering from xylazine overdose or poisoning, both for xylazine alone and when xylazine is combined with other abused drugs, are still needed. [Overview of the Initiative]

[0006] This disclosure provides methods and compositions for addressing these and other situations in which it is desirable to reverse the effects of one or more abused drugs, including α2 adrenergic receptor agonists.

[0007] In embodiments, the chelating agent may be administered orally and / or intravenously to the patient. The composition containing the chelating agent is administered to the patient to isolate the abuse of the α2 adrenergic receptor agonist and other drugs, and to remove the drugs from the patient's body, if present. In embodiments, the α2 adrenergic receptor agonist is xylazine.

[0008] Additional drugs may be pharmaceuticals and / or drugs of abuse. In particular, additional drugs of abuse may include one or more amphetamines, barbiturates, opioids, benzodiazepines, and psychedelics. Additional drugs of abuse may include one or more of methamphetamine (and, for example, hydroxymethamphetamine, 3,4-methylenedioxymethamphetamine), fentanyl, and cocaine. Additional drugs of abuse may include fentanyl or fentanyl analogs such as carfentanyl.

[0009] The chelating agent may be cucurbituryl, pyralarene, cyclodextrin, or calixsalen.

[0010] In one embodiment, the disclosure provides a method for rapidly reducing the concentration of an α2-adrenergic receptor agonist in a patient's body by administering a sequestering agent to the patient in an amount sufficient to reduce the concentration of the drug in the patient's body. The administration of the sequestering agent results in a faster drug detoxification in the patient than would occur under metabolic detoxification.

[0011] In some embodiments, the present disclosure provides a method for treating intoxication, overdose, or symptoms thereof caused by an α2 - adrenergic receptor agonist, or a combination of an α2 - adrenergic receptor agonist and another drug of abuse, the method comprising administering a therapeutically effective amount of a blocker or a pharmaceutically acceptable salt thereof, wherein the administration is effective to reduce the concentration of the α2 - adrenergic receptor agonist in the patient. The therapeutically effective amount of the blocker may be simultaneously effective to further reduce the concentration of additional drugs of abuse present in the patient.

[0012] In some embodiments, the present disclosure provides a method for treating suspected overdose or symptoms thereof in a patient, the method comprising administering a therapeutically effective amount of a blocker or a pharmaceutically acceptable salt thereof, wherein the subject is suspected of overdose caused by an α2 - adrenergic receptor agonist, or a combination of an α2 - adrenergic receptor agonist and one or more additional drugs of abuse. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] [Figure 1] Shows the recovery rate of xylazine in urine from rats administered compound A following an IV bolus of xylazine. [Figure 2] Shows the recovery rates of fentanyl (a) and xylazine (b) in urine from rats administered compound A following an IV bolus of fentanyl and xylazine. [Figure 3] Shows the recovery rate of rats by the walking score improved over time after administration of compound A following an IV bolus of xylazine. DETAILED DESCRIPTION OF THE INVENTION

[0014] Since there is no current treatment for this public health crisis, a pharmacological approach for treating the abuse and / or overdose of α2 - adrenergic receptor agonists such as xylazine is urgently needed. Drugs that rapidly detoxify patients from α2 - adrenergic receptor agonists such as xylazine are of great benefit to patients and can save lives.

[0015] This disclosure provides a method for reducing α2-adrenergic receptor agonists from the body of a patient who has been administered an α2-adrenergic receptor agonist, including through self-administration. This disclosure also provides a method for preventing or treating an overdose, or suspected overdose, of an α2-adrenergic receptor agonist administered to a patient. α2-adrenergic receptor agonists may be present in a patient as the sole toxic agent or in combination with another abused agent. This method includes administering a therapeutically effective dose of a chelating agent to the patient at some point after administration of the α2-adrenergic receptor agonist. In embodiments, the administration of the chelating agent may alleviate symptoms associated with α2-adrenergic receptor agonist withdrawal and facilitate transition to a medical assistance therapy (MAT) program.

[0016] The chelating agent strongly binds to α2 adrenergic receptor agonists and other potentially present abused drugs from within the body with high specificity, inactivating and eliminating them. The chelating agent can be administered to the patient intravenously and / or orally.

[0017] When a chelating agent is administered to a patient by injection, it binds to (i.e., occludes) the α2-adrenergic receptor agonist (and, if present, other abused drugs) in the plasma compartment of the blood, removing it from the site of action. The “inactive” drug is then eliminated from the body by filtration in the kidneys. Alternatively or additionally, a composition containing a chelating agent may be administered orally to the patient to occlude the α2-adrenergic receptor agonist (and, if present, other abused drugs) in the gastrointestinal tract, reducing and / or preventing its absorption into the bloodstream, and eliminating it from the patient's body by excretion in the feces. Administration of a chelating agent results in a more rapid drug detoxification in the patient than would occur under metabolic detoxification. Metabolic detoxification refers to the elimination of the α2-adrenergic receptor agonist (and, if present, other abused drugs) from the patient's body via the normal pathways of drug metabolism that would occur in the absence of a chelating agent. Rapid isolation and elimination of α2 adrenergic receptor agonists (and other abused drugs, if present) rapidly reduces drug concentrations in the body and reverses their effects.

[0018] Sequestering agents act by potent, selective molecular binding to α2-adrenergic receptor agonists (and, if present, other abused drugs), resulting in a more potent, rapid-acting, safe, and easily administered antidote. Examples of sequestering agents include cucurbituril, pyrarane, or calixsalen, with cucurbituril compounds being particularly noteworthy.

[0019] In some embodiments, additional abuse drugs are opioid drugs, such as fentanyl, carfentanil, or heroin, which may be present in the patient's body in combination with other abuse drugs, such as stimulants (e.g., methamphetamine or cocaine). In other embodiments, additional abuse drugs are methamphetamine (and, for example, hydroxymethamphetamine, 3,4-methylenedioxymethamphetamine), or stimulants such as cocaine.

[0020] The terms “subject,” “host,” “patient,” and “individual” are used interchangeably herein to refer to any mammalian subject, in particular human, to whom the treatment provided herein is desired.

[0021] α2 adrenaline agonist The methods and compositions provided herein are used to treat patients suffering from alpha-2 adrenergic agonist administration by reducing the concentration of alpha-2 adrenergic agonists in the patient's body by binding to a chelating agent.

[0022] Alpha-adrenergic agonists are a type of sympathetic stimulant that selectively stimulates alpha-adrenergic receptors. Alpha-adrenergic receptors have two subclasses, α1 and α2. α2 receptors are associated with sympathetic blocking effects, which oppose the downstream effects of postganglionic nerve firing in effector organs innervated by the sympathetic nervous system (SNS).

[0023] Alpha-2 adrenergic agonists can mimic the effects of the hormone norepinephrine. Examples of alpha-2 adrenergic agonists include xylazine, guanabenz, guanfacine, and clonidine. The chemical structure of xylazine is shown below. [ka] The IUPAC name is N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiadin-2-amine. After administration, xylazine diffuses widely and crosses the blood-brain barrier.

[0024] Xylazine is often used intentionally or unintentionally in combination with illegal drugs, but it can also be abused alone. Furthermore, published case reports indicate that xylazine has been used in drug-induced crimes. Deaths involving xylazine have been reported. Known doses of xylazine that produce toxicity and lethality in humans range from 40 to 2400 mg. However, most xylazine-related overdose deaths involved additional substances such as fentanyl, heroin, benzodiazepines, alcohol, gabapentin, methadone, prescription opioids, and cocaine. Drug mixtures of xylazine and fentanyl increase the risk of users suffering fatal drug intoxication. Since xylazine is not an opioid, naloxone does not reverse its effects.

[0025] Additional abuse drugs The compositions and methods provided herein are further suitable for treating patients suffering from abuse or overdose of a combination of another abused drug and an α2-adrenergic agonist, such as xylazine.

[0026] As used herein, the term “abuse drug” is intended to mean any drug or substance whose excessive consumption or administration may result in a diagnosis of addiction, overdose, or substance dependence or abuse (e.g., substance use disorder). Abuse drugs include, but are not limited to, opioids, stimulants, barbiturates, benzodiazepines, and psychedelics. Abuse drugs include cocaine, amphetamines, methamphetamine (and e.g., hydroxymethamphetamine, 3,4-methylenedioxymethamphetamine), methylphenidate, heroin, codeine, hydrocodone, oxycodone, marijuana (cannabis), methadone, opioids, fentanyl, carfentenyl, fentanyl analogs, ayahuasca, CNS depressants, N,N-dimethyltryptamine (DMT), gamma-hydroxybutyrate (GHB), hallucinogens, and inhalants. Examples of abused drugs include, but are not limited to, drugs containing, ketamine, crush, kratom, lysergic acid diethylamide (LSD), MDMA (Molly / ecstasy), mescaline (peyoto), dextromethorphan, loperamide, PCP, psilocybin, rohypnol, salvia, synthetic cannabinoids, synthetic cathinone (bath salt), mephedrone, nicotine, dextroamphetamine, dexmethylphenidate, or any combination thereof. Furthermore, abused drugs may include, but are not limited to, those listed by the National Institutes of Health (NIH) and the National Institute on Drug Abuse (NIDA).

[0027] In some embodiments, the drug of abuse may be a stimulant, such as amphetamine, methamphetamine (and, for example, hydroxymethamphetamine, 3,4-methylenedioxymethamphetamine), methylphenidate, cathinone, or methcathinone. In other embodiments, the drug of abuse may be an opioid, such as fentanyl or a fentanyl analog, such as carfentanil. In further embodiments, the drug of abuse may include a combination of one or more stimulants, such as methamphetamine (and, for example, hydroxymethamphetamine, 3,4-methylenedioxymethamphetamine), and one or more opioids, such as fentanyl or a fentanyl analog.

[0028] In this embodiment, the drug of abuse is an opioid, such as heroin, fentanyl, or carfentanil.

[0029] In embodiments, the methods provided in this disclosure may be particularly suitable for the treatment of patients who are abusing, overdosing, or suspected of overdosing on fentanyl and its analogues in combination with α2-adrenergic agonists. Fentanyl (N-(1-phenethylpiperidine-4-yl)-N-phenylpropionamide) is a synthetic lipophilic phenylpiperidine opioid agonist having analgesic and anesthetic properties. Compared to other opioids, fentanyl has a unique pharmacological profile, including high potency (100 times morphine), high lipophilicity, sequestering and sustained release from lipid tissues, and a long elimination half-life. Fentanyl poses a very high risk of overdose in humans, particularly due to its high potency and the unpredictable lethal dose when mixed with other drugs such as xylazine.

[0030] The term "fentanyl analog" refers to a molecule designed to mimic the pharmacological effects of fentanyl. Exemplary fentanyl analogs include 3-allylfentanyl, alfentanil, acrylfentanyl, acetylfentanyl, blifentanil, butyrylfentanyl, 2,2'-difluorofentanyl, carfentanil, crotonylfentanyl, cyclopentylfentanyl, cyclopropylfentanyl, (±)-cis-3-methylfentanyl, furanyl fentanyl, 3-fluorofentanyl, 3-furanyl fentanyl, 3-methylbutyrylfentanyl, 3-methylfentanyl, 3-methylfuranyl fentanyl, 3-methylthiophenfentanyl, 3-phenylpropanoylfentanyl, 4-fluorobutyrylfentanyl, 4-chloroisobutyrylfentanyl, 4-fluoroisobutyrylfentanyl, 4-fluorofentanyl, parafluorofuranyl fentanyl, parachlorofuranyl fentanyl, orthomethylfuranyl fentanyl, 4-phenylfentanyl, lofentanil, 4-methoxybutyrylfentanyl, para-hydroxybutyrylfentanyl, 4-methylphenethylacetylfentanyl, α-methylacetylfentanyl, α-methylbutyrylfentanyl, α-methylbutyrylfentanyl, α-methylthiophenfentanyl, benzodioxolefentanyl, benzoylfentanyl, butyrylfentanyl, isobutyrylfentanyl, isofentanyl, methoxyacetylfentanyl, sufentanil, para-tolylfentanyl, 3-methylfentanyl, α-methylfentanyl, mefentanil, mirfentanil, remifentanil, phenalene, orimifentanil, tre fentanyl, and the like.

[0031] Blocking agent The methods disclosed herein involve the use of chelating agents to reduce the concentrations of α2-adrenergic agonists and other abused drugs in a patient's body. When a chelating agent is administered to a patient, it binds to (i.e., chelates) the α2-adrenergic agonists and other abused drugs in the plasma compartment of the blood and / or the gastrointestinal tract (in the case of oral administration), removing them from the body. The “inactive” drugs are then excreted from the body by filtration in the kidneys or by feces. Administration of a chelating agent results in a more rapid drug detoxification in the patient than would occur under metabolic detoxification. Metabolic detoxification refers to the elimination of abused drugs from the patient's body via the normal pathways of drug metabolism that would occur in the absence of a chelating agent. The rapid isolation and elimination of α2-adrenergic agonists (and other abused drugs, if present) rapidly reduces drug concentrations in the body and reverses their effects.

[0032] In some embodiments, the chelating agent may be cyclodextrin, acyclic cucurbituryl, cyclic cucurbituryl, pyralarene, or calixsalen. In some embodiments, the chelating agent is cucurbituryl. In some embodiments, the chelating agent is acyclic cucurbituryl. In some embodiments, the chelating agent is cyclic cucurbituryl. In some embodiments, the chelating agent is pyralarene. In some embodiments, the chelating agent is calixsalen. In some embodiments, the chelating agent is cyclodextrin.

[0033] Calixarene In some embodiments, the chelating agent is calixarene. In such embodiments, the present disclosure provides a method for rapidly reducing the concentrations of an α2-adrenergic agonist and another abused drug present in a patient's body by administering to the patient a sufficient amount of a calixarene compound to reduce the concentrations of the α2-adrenergic agonist and the other abused drug if they are present in the patient's body. Administration of a calixarene compound results in a more rapid drug detoxification in the patient than would occur under metabolic detoxification.

[0034] Calixarenes are a family of cyclic macrocyclic compounds having a variable number of phenol units linked by methylene bridges at the ortho position. The number of phenol units can be 4 to 12, with 4, 5, 6, 7, and 8 being preferred.

[0035] Pillar Allen In some embodiments, the chelating agent is pyralerene. In such embodiments, the present disclosure provides a method for rapidly reducing the concentrations of an α2-adrenergic agonist and another abused drug present in a patient's body by administering to the patient a sufficient amount of a pyralerene compound to reduce the concentrations of the α2-adrenergic agonist and the other abused drug if they are present in the patient's body. Administration of a pyralerene compound results in a more rapid drug detoxification in the patient than would occur under metabolic detoxification.

[0036] Pillararenes are macrocyclic molecules composed of aromatic rings linked at the para position by methylene bridges, where the macrocycle consists of 5, 6, 7, or 8 rings. Smaller pillararenes can bond to narrow n-alkane molecules, while larger pillararenes can bond to aromatic, viologen, and alicyclic molecules. Exemplary pillararenes are provided in (Xue et. Al, Angewandte Chemie, 2020), which is incorporated in whole by reference.

[0037] In some embodiments, the chelating agent has the following structure: [ka] Pillaarene, or a pharmaceutically acceptable salt thereof, In the formula, n is selected from 0, 1, 2, or 3, and each R is independently, -(CH2) a S(O) b X 1 ,-(CH2) a CO2X 1 , and -(CH2) a PO b X1 selected from; a is 0, 1, 2, 3 or 4; b is 2 or 3, each X 1 is independently selected from H, -OH, an alkali metal cation, and a quaternary ammonium cation.

[0038] In embodiments, each R is -(CH2) a SO3X 1a -(CH2) a CO2X 1a and -(CH2) a PO3X 1a where a is 0, 1, 2 or 3, and X 1a is H, an alkali metal cation, and a quaternary ammonium cation. In embodiments, R is SO3H or its salt (e.g., SO3Na), or -CH2COOH or its salt (e.g., CH2COONa).

[0039] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n = 1 and R = SO3H or SO3Na, and the compound is referred to herein as compound J.

[0040] Cucurbituryl compounds In some embodiments, the sequestering agent is a cucurbituril compound. In such embodiments, the present disclosure provides a method for rapidly reducing the concentrations of an α2 -adrenergic agonist and another abused drug present in a patient's body by administering to the patient a sufficient amount of a cucurbituril compound to reduce the concentrations of the α2 -adrenergic agonist and the other abused drug present in the patient's body. Administration of the cucurbituril compound results in more rapid drug detoxification in the patient than would occur under metabolic detoxification.

[0041] Cucurbituryl is a class of macrocyclic compounds based on glycoluryl oligomers, analogs, and derivatives. Cucurbituryl can be used to form complexes with other molecules and is useful as a metal ion chelating agent. This property makes cucurbituryl an attractive candidate for the capture and removal of chemical agents.

[0042] Cucurbituryl compounds can be cyclic or acyclic. The molecular structure of cucurbituryl is characterized by a central hydrophobic cavity protected by two symmetrically equivalent ureidylcarbonyl portals with a very negative electrostatic potential. Thus, cucurbituryl may exhibit a preference for cationic (e.g., ammonium) groups to bind to molecules featuring adjacent central hydrophobic domains. Molecular binding is mediated by hydrophobic effects and ionic dipole interactions.

[0043] Acyclic cucurbituryls may exhibit higher water solubility and provide a more flexible bonding cavity capable of accommodating larger molecules. While acyclic cucurbituryls mediate tight bonding through hydrophobic cation interactions, they can also be synthetically modified. These molecules generally feature a central glycol tetramer that confers C-shape and hydrophobic cation bonding properties, presented by two terminal aromatic sidewalls involved in cation-π, CH-π, and π-π interactions with the molecule. In embodiments, four sodium sulfonate arms help increase water solubility and facilitate secondary electrostatic interactions between the cucurbituryl and the bonded molecule.

[0044] In embodiments provided herein, one or more cucurbituril compounds are administered to a patient in an amount sufficient to reduce the concentration of abused drugs, particularly opioids (such as fentanyl and carfentanil), in the patient's body. In some embodiments, cucurbituril compounds can simultaneously reduce the concentration of amphetamine, methamphetamine (and, for example, hydroxymethamphetamine, 3,4-methylenedioxymethamphetamine), or other stimulants in the patient's body.

[0045] The cucurbituryl compounds disclosed herein bind to xylazine. In embodiments, this disclosure provides cucurbituryl compounds that bind to fentanyl or fentanyl analogs. The cucurbituryl compounds disclosed herein bind to fentanyl or fentanyl analogs with high affinity. Cucurbituryl compounds may also bind to amphetamines, methamphetamines (and, for example, hydroxymethamphetamine, 3,4-methylenedioxymethamphetamine), or other stimulants with high affinity.

[0046] In embodiments, cucurbituril compounds can bind to toxic agents having an appropriate molecular size. Cucurbituril may bind with high affinity to opioids (fentanyl, carfentanil, etc.), amphetamines, methamphetamines (and, for example, hydroxymethamphetamine, 3,4-methylenedioxymethamphetamine), or other stimulants, and to xylazine.

[0047] In embodiments of the methods provided in this disclosure, the cucurbituryl compound has the structure of formula I: [ka] or having a pharmaceutically acceptable salt thereof, in the formula, Each R 1A and R 1D However, independently, hydrogen, halogen, -OH, C1-C6 alkyl, 2-6 member heteroalkyl, C3-C6 cycloalkyl, 5-6 member heterocycloalkyl, phenyl, 5-6 member heteroaryl, -O-(CH2) n1 S(O) v1 X 1 -O-(CH2) n1 CO2X 1 , and -O-(CH2) n1 PO v1 X 1 Selected from, Each R 1B and R 1CHowever, independently, hydrogen, halogen, -OH, C1-C6 alkyl, 2-6 member heteroalkyl, C3-C6 cycloalkyl, 5-6 member heterocycloalkyl, phenyl, 5-6 member heteroaryl, -O-(CH2) n1 S(O) v1 X 1 -O-(CH2) n1 CO2X 1 , and -O-(CH2) n1 PO v1 X 1 Selected from, or Additionally or alternatively, two R groups bonded to adjacent positions on the same phenyl ring. 1A 、 R 1B , R 1C and R 1D However, together with the atoms they are bonded to, they form a condensed C6-C 12 They form aryl, 5-12 membered heteroaryl, or 5-7 membered heterocycles, which are independently and optionally substituted with 1-3 substituents on a selected halogen, -OH, -NH2, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2-6 membered heteroalkyl. Each R 3A and R 3B However, they are independently selected from hydrogen, halogens, -OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyl groups. Each R 4A and R 4B However, they are independently selected from hydrogen, halogens, -OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyl groups. Each n1 is independently selected from 0 to 5. Each v1 is independently selected from 2 or 3. each X 1 However, these are independently selected from H, -OH, C1-C6 alkyl, alkali metal cations, and quaternary ammonium cations.

[0048] In this embodiment, R 1Bis hydrogen, halogen, -OH, C1-C6 alkyl, 2-6 member heteroalkyl, C3-C6 cycloalkyl, 5-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl. In embodiments, R 1B is hydrogen, halogen, -OH, or C1-C6 alkyl, especially R 1B It is either hydrogen or a halogen.

[0049] In this embodiment, R 1C is hydrogen, halogen, -OH, C1-C6 alkyl, 2-6 member heteroalkyl, C3-C6 cycloalkyl, 5-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl. In embodiments, R 1C is hydrogen, halogen, -OH, or C1-C6 alkyl, especially R 1C It is either hydrogen or a halogen.

[0050] In this embodiment, R 1B and R 1C It is hydrogen.

[0051] Additionally or alternatively, R bonded to the same phenyl ring 1A and R 1B However, along with the atom bonded to it, C6-C 12 An aryl or a 5-12 membered heteroaryl may be formed. In the embodiment, R bonded to the same phenyl ring 1A and R 1B However, it bonds with the atom bonded to it to form phenyl. In this embodiment, R bonded to the same phenyl ring 1A and R 1B However, it bonds with the atom bonded to it to form naphthyl. In this embodiment, R bonded to the same phenyl ring 1A and R 1B However, it combines with the atom it is bonded to to form a pyridyl.

[0052] In this embodiment, R bonded to the same phenyl ring 1B and R 1CHowever, it bonds together with the atoms that are bonded to them, C6-C 12 It forms an aryl or a 5-12 member heteroaryl. In the embodiment, R bonded to the same phenyl ring 1B and R 1C However, it bonds with the atoms bonded to them to form phenyl. In this embodiment, R bonded to the same phenyl ring 1B and R 1C However, it combines with the atoms bonded to them to form naphthyl. In this embodiment, R bonded to the same phenyl ring 1B and R 1C However, it combines with the atoms bonded to them to form pyridyls.

[0053] In this embodiment, R bonded to the same phenyl ring 1C and R 1D It bonds together with the atoms that are bonded to them, C6-C 12 It forms an aryl or a 5-12 member heteroaryl. In the embodiment, R bonded to the same phenyl ring 1C and R 1D However, it bonds with the atoms bonded to them to form phenyl. In this embodiment, R bonded to the same phenyl ring 1C and R 1D However, it combines with the atoms bonded to them to form naphthyl. In this embodiment, R bonded to the same phenyl ring 1C and R 1D However, it combines with the atoms bonded to them to form pyridyls.

[0054] In this embodiment, R bonded to the same phenyl ring 1A 、 R 1B , R 1C , and R 1D C6-C is formed by two of the two of them. 12 The aryl or 5-12 member heteroaryl may be substituted with one or more substituents, such as halogens, -OH, -NH2, substituted or unsubstituted C1-C6 alkyls, or substituted or unsubstituted 2-6 member heteroalkyls.

[0055] In an embodiment, R 3A is hydrogen or substituted or unsubstituted C1-C3 alkyl. In an embodiment, R 3A is C1-C3 alkyl, particularly methyl.

[0056] In an embodiment, R 3B is hydrogen or substituted or unsubstituted C1-C3 alkyl. In an embodiment, R 3B is C1-C3 alkyl, particularly methyl.

[0057] In an embodiment, R 3A and R 3B are both hydrogen. Alternatively, R 3A and R 3B may both be methyl. In an embodiment, one of R 3A and R 3B is hydrogen and the other is methyl.

[0058] In an embodiment, R 4A is hydrogen or substituted or unsubstituted C1-C3 alkyl. In an embodiment, R 4A is C1-C3 alkyl, particularly methyl. In an embodiment, R 4A is H.

[0059] In an embodiment, R 4B is hydrogen or substituted or unsubstituted C1-C3 alkyl. In an embodiment, R 4B is C1-C3 alkyl, particularly methyl. In an embodiment, R 4B is hydrogen.

[0060] In an embodiment, each R 4A and R 4B is hydrogen. Alternatively, each R 4A and R 4B may be methyl. In an embodiment, one of R 4A and R 4B is hydrogen and the other is methyl.

[0061] Control mechanism, each R 3A and R 3B These are independently C1-C3 alkyl groups, and R 4A and R 4B is hydrogen, and in particular, each R 3A and R 3B is methyl, and each R 4A and R 4B It is hydrogen.

[0062] In another embodiment, the cucurbituryl compound used in the method of the present disclosure has the structure of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof. 1A , R 1D , R 3A , R 3B , R 4A , and R 4B The details of Equation I are as described herein.

[0063] In this embodiment, R 3A is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 3A These are C1-C3 alkyl groups, especially methyl groups.

[0064] In this embodiment, R 3B is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 3B These are C1-C3 alkyl groups, especially methyl groups.

[0065] In this embodiment, R 3A and R 3B Both are hydrogen. Or, R 3A and R 3B Both may be methyl. In this embodiment, R 3A and R 3B One of them is hydrogen, and the other is methyl.

[0066] In this embodiment, R 4Ais hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 4A is a C1-C3 alkyl group, particularly methyl. In the embodiment, R 4A H is H.

[0067] In this embodiment, R 4B is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 4B is a C1-C3 alkyl group, particularly methyl. In the embodiment, R 4B It is hydrogen.

[0068] In the embodiment, each R 4A and R 4B It is hydrogen. Or, each R 4A and R 4B R may be methyl. In this embodiment, R 4A and R 4B One of them is hydrogen, and the other is methyl.

[0069] Control mechanism, each R 3A and R 3B These are independently C1-C3 alkyl groups, and R 4A and R 4B is hydrogen, and in particular, each R 3A and R 3B is methyl, and each R 4A and R 4B It is hydrogen.

[0070] Control mechanism, each R 1A and R 1D It is neutral. In the embodiment, each R 1A and R 1D This is the form of an ionic salt.

[0071] In this embodiment, R 1A is -O-(CH2) n1 S(O) v1 X 1 In this embodiment, R 1A is -O-(CH2) n1 CO2X 1 In this embodiment, R1A is -O-(CH2) n1 PO v1 X 1 In this embodiment, each n1 is 0. In this embodiment, each n1 is 1. In this embodiment, each n1 is 2. In this embodiment, each n1 is 3. In this embodiment, each n1 is 4. In this embodiment, each n1 is 5. In this embodiment, each v1 is 2. In this embodiment, each v1 is 3.

[0072] In this embodiment, R 1D is -O-(CH2) n1 S(O) v1 X 1 In this embodiment, R 1D is -O-(CH2) n1 CO2X 1 In this embodiment, R 1D is -O-(CH2) n1 PO v1 X 1 In this embodiment, each n1 is 0. In this embodiment, each n1 is 1. In this embodiment, each n1 is 2. In this embodiment, each n1 is 3. In this embodiment, each n1 is 4. In this embodiment, each n1 is 5. In this embodiment, each v1 is 2. In this embodiment, each v1 is 3.

[0073] In this embodiment, R bonded to the same phenyl ring 1A and R 1D These may be the same or different. In this embodiment, R bonded to different phenyl rings 1A and R 1A These may be the same or different. In this embodiment, R bonded to different phenyl rings 1D and R 1D They may be the same or different.

[0074] In this embodiment, each R bonded to the same phenyl ring 1A and R 1D It is independently -O-(CH2) n1 S(O) v1 X 1 In this embodiment, each R bonded to a different phenyl ring1A and R 1A It is independently -O-(CH2) n1 S(O) v1 X 1 In this embodiment, each R bonded to a different phenyl ring 1D and R 1D It is independently -O-(CH2) n1 S(O) v1 X 1 That is the case.

[0075] In another embodiment, the cucurbituryl compound used in the method of the present disclosure has the structure of formula (Ib): [ka] or a pharmaceutically acceptable salt thereof. 1A and R 1D This is as described herein for formula I.

[0076] Control mechanism, each R 1A and R 1D It is neutral. In the embodiment, each R 1A and R 1D This is the form of an ionic salt.

[0077] In this embodiment, R 1A is -O-(CH2) n1 S(O) v1 X 1 In this embodiment, R 1A is -O-(CH2) n1 CO2X 1 In this embodiment, R 1A is -O-(CH2) n1 PO v1 X 1 In this embodiment, each n1 is 0. In this embodiment, each n1 is 1. In this embodiment, each n1 is 2. In this embodiment, each n1 is 3. In this embodiment, each n1 is 4. In this embodiment, each n1 is 5. In this embodiment, each v1 is 2. In this embodiment, each v1 is 3.

[0078] In this embodiment, R1D is -O-(CH2) n1 S(O) v1 X 1 In this embodiment, R 1D is -O-(CH2) n1 CO2X 1 In this embodiment, R 1D is -O-(CH2) n1 PO v1 X 1 In this embodiment, each n1 is 0. In this embodiment, each n1 is 1. In this embodiment, each n1 is 2. In this embodiment, each n1 is 3. In this embodiment, each n1 is 4. In this embodiment, each n1 is 5. In this embodiment, each v1 is 2. In this embodiment, each v1 is 3.

[0079] In this embodiment, R bonded to the same phenyl ring 1A and R 1D These may be the same or different. In this embodiment, R bonded to different phenyl rings 1A and R 1A These may be the same or different. In this embodiment, R bonded to different phenyl rings 1D and R 1D They may be the same or different.

[0080] In this embodiment, each R bonded to the same phenyl ring 1A and R 1D It is independently -O-(CH2) n1 S(O) v1 X 1 In this embodiment, each R bonded to a different phenyl ring 1A and R 1A It is independently -O-(CH2) n1 S(O) v1 X 1 In this embodiment, each R bonded to a different phenyl ring 1D and R 1D It is independently -O-(CH2) n1 S(O) v1 X 1 That is the case.

[0081] In another embodiment, the cucurbituryl compound used in the method of the present disclosure has the structure of formula (Ic): [ka] or a pharmaceutically acceptable salt thereof. 1 And n1 are as described herein for formula I.

[0082] Control device, each X 1 They are the same or different. In this embodiment, each X 1 These are independently H, -OH, C1-C6 alkyl, alkali metal cation, or quaternary ammonium cation. In the embodiment, each n1 is 0 to 5. In the embodiment, each n1 is 1 to 5. In the embodiment, each n1 is 2 to 5. In the embodiment, each n1 is 3 to 5. In the embodiment, each n1 is 4 to 5.

[0083] In another embodiment, the cucurbituryl compound used in the method of the present disclosure has the structure of formula (IA): [ka] or a pharmaceutically acceptable salt thereof. Each X independently contains H, an alkali metal cation (e.g., Li + na + , K + , or Cs + ), or a quaternary ammonium cation.

[0084] In another embodiment, the cucurbituryl compound used in the method of the present disclosure is compound A, which has the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0085] The cucurbituryl compound used in the method of this disclosure has the structure of formula (Id): [ka] or a pharmaceutically acceptable salt thereof. 1A , R 1D , R 3A , R 3B , R 4A , and R 4B The details of Equation I are as described herein.

[0086] In this embodiment, R 3A is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 3A These are C1-C3 alkyl groups, especially methyl groups.

[0087] In this embodiment, R 3B is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 3B These are C1-C3 alkyl groups, especially methyl groups.

[0088] In this embodiment, R 3A and R 3B Both are hydrogen. Or, R 3A and R 3B Both may be methyl. In this embodiment, R 3A and R 3B One of them is hydrogen, and the other is methyl.

[0089] In this embodiment, R 4A is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 4A is a C1-C3 alkyl group, particularly methyl. In the embodiment, R 4A H is H.

[0090] In this embodiment, R 4B is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 4B is a C1-C3 alkyl group, particularly methyl. In the embodiment, R 4B It is hydrogen.

[0091] In the embodiment, each R 4A and R4B It is hydrogen. Or, each R 4A and R 4B R may be methyl. In this embodiment, R 4A and R 4B One of them is hydrogen, and the other is methyl.

[0092] Control mechanism, each R 3A and R 3B These are independently C1-C3 alkyl groups, and R 4A and R 4B is hydrogen, and in particular, each R 3A and R 3B is methyl, and each R 4A and R 4B It is hydrogen.

[0093] Control mechanism, each R 1A and R 1D It is neutral. In the embodiment, each R 1A and R 1D This is the form of an ionic salt.

[0094] In this embodiment, R 1A is -O-(CH2) n1 S(O) v1 X 1 In this embodiment, R 1A is -O-(CH2) n1 CO2X 1 In this embodiment, R 1A is -O-(CH2) n1 PO v1 X 1 In this embodiment, each n1 is 0. In this embodiment, each n1 is 1. In this embodiment, each n1 is 2. In this embodiment, each n1 is 3. In this embodiment, each n1 is 4. In this embodiment, each n1 is 5. In this embodiment, each v1 is 2. In this embodiment, each v1 is 3.

[0095] In this embodiment, R 1D is -O-(CH2) n1 S(O) v1 X 1 In this embodiment, R1D is -O-(CH2) n1 CO2X 1 In this embodiment, R 1D is -O-(CH2) n1 PO v1 X 1 In this embodiment, each n1 is 0. In this embodiment, each n1 is 1. In this embodiment, each n1 is 2. In this embodiment, each n1 is 3. In this embodiment, each n1 is 4. In this embodiment, each n1 is 5. In this embodiment, each v1 is 2. In this embodiment, each v1 is 3.

[0096] In this embodiment, R bonded to the same phenyl ring 1A and R 1D These may be the same or different. In this embodiment, R bonded to different phenyl rings 1A and R 1A These may be the same or different. In this embodiment, R bonded to different phenyl rings 1D and R 1D They may be the same or different.

[0097] In this embodiment, each R bonded to the same phenyl ring 1A and R 1D It is independently -O-(CH2) n1 S(O) v1 X 1 In this embodiment, each R bonded to a different phenyl ring 1A and R 1A It is independently -O-(CH2) n1 S(O) v1 X 1 In this embodiment, each R bonded to a different phenyl ring 1D and R 1D It is independently -O-(CH2) n1 S(O) v1 X 1 That is the case.

[0098] In another embodiment, the cucurbituryl compound used in the method of the present disclosure has the structure of formula (X): [ka] or a pharmaceutically acceptable salt thereof.

[0099] Control mechanism, each R 1A and R 1D It is neutral. In the embodiment, each R 1A and R 1D This is the form of an ionic salt.

[0100] In this embodiment, R 1A is -O-(CH2) n1 S(O) v1 X 1 In this embodiment, R 1A is -O-(CH2) n1 CO2X 1 In this embodiment, R 1A is -O-(CH2) n1 PO v1 X 1 In this embodiment, each n1 is 0. In this embodiment, each n1 is 1. In this embodiment, each n1 is 2. In this embodiment, each n1 is 3. In this embodiment, each n1 is 4. In this embodiment, each n1 is 5. In this embodiment, each v1 is 2. In this embodiment, each v1 is 3.

[0101] In this embodiment, R 1D is -O-(CH2) n1 S(O) v1 X 1 In this embodiment, R 1D is -O-(CH2) n1 CO2X 1 In this embodiment, R 1D is -O-(CH2) n1 PO v1 X 1 In this embodiment, each n1 is 0. In this embodiment, each n1 is 1. In this embodiment, each n1 is 2. In this embodiment, each n1 is 3. In this embodiment, each n1 is 4. In this embodiment, each n1 is 5. In this embodiment, each v1 is 2. In this embodiment, each v1 is 3.

[0102] In this embodiment, R bonded to the same phenyl ring 1A and R 1D These may be the same or different. In this embodiment, R bonded to different phenyl rings 1A and R 1A These may be the same or different. In this embodiment, R bonded to different phenyl rings 1D and R 1D They may be the same or different.

[0103] In this embodiment, each R bonded to the same phenyl ring 1A and R 1D It is independently -O-(CH2) n1 S(O) v1 X 1 In this embodiment, each R bonded to a different phenyl ring 1A and R 1A It is independently -O-(CH2) n1 S(O) v1 X 1 In this embodiment, each R bonded to a different phenyl ring 1D and R 1D It is independently -O-(CH2) n1 S(O) v1 X 1 That is the case.

[0104] In another embodiment, the cucurbituryl compound used in the method of the present disclosure is compound B, which has the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0105] In one aspect, the cucurbituryl compound has the structure of formula XI: [ka] or having a pharmaceutically acceptable salt thereof, in the formula, Each R 1A and R 1D It is independently -OL-CO2X 1 and -OL-SO3X1 Selected from, Each L independently has a chemical bond (single bond), C1~C 10 Alkylene, C2~C 10 Alkenylene, -(CH2) a -O-(CH2) b ,-(CH2) c -N(R)-(CH2) d , and -(CH2) a -(OCH2CH2) e -(Y) f - Selected from, each of these may be unsubstituted or contain halogens, OH, CO2H, C at any carbon. 1-3 Alkyl, NH2, NH(C 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with an alkyl group. a is between 2 and 8. b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C 1-3 Alkyl, or O, f is either 0 or 1, R is H or C 1-3 It is alkyl, Each R 1B and R 1C However, these are independently selected from hydrogen, halogen, -OH, -CN, CO2H, SO3H, C1-C6 alkyl, 2-6 member heteroalkyl, C3-C6 cycloalkyl, 5-6 member heterocycloalkyl, phenyl, 5-6 member heteroaryl, or Additionally or alternatively, R bonded to the same phenyl ring 1B and R 1C However, together with the atoms they are bonded to, they form a condensed C6-C 12They form aryl, 5-12 membered heteroaryl, or 5-7 membered heterocycles, which are independently and optionally substituted with 1-3 substituents on a selected halogen, -OH, -NH2, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2-6 membered heteroalkyl. Each R 3A and R 3B However, these are independently selected from hydrogen, halogens, -OH, CO2H, CO2R', CONH2, CONHR', CON(R')2, C1-C6 alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyls. Additionally or alternatively, R bonded to an adjacent carbon atom 3A and R 3B However, together with the carbon atoms to which they are bonded, they form a 5-membered or 6-membered cycloalkyl ring or heterocycloalkyl ring. Each R 4A and R 4B However, these are independently selected from hydrogen, halogens, -OH, CO2H, CO2R', CONH2, CONHR', CON(R')2, C1-C6 alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyls. Each R' independently 1-6 Selected from alkyl groups, each X 1 However, these are independently selected from H, C1-C6 alkyl groups, alkali metal cations, and quaternary ammonium cations.

[0106] In this embodiment, L is C1~C 10 It is an alkylene, which may be unsubstituted, or a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. In the embodiment, L is C1 to C 10 Alkylene, C2~C 10L is an alkylene, a C1-C6 alkylene, or a C2-C6 alkylene, each of which may be unsubstituted or substituted. L is -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2, etc.

[0107] In another embodiment, L is C2~C 10 The alkenylene chain may be unsubstituted, or it may contain a halogen, OH, CO2H, or C. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups, which include 1 to 3 carbon-carbon double bonds. In embodiments, L is a C2-C6 alkenylene, which may be unsubstituted or substituted. L may be -CH=CH-, -C(CH3)=CH-, -CH2CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, -CH=CHCH=CH-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH=CH-, -CH2CH=CHCH=CH-, -CH2CH2CH=CHCH2-, -CH2CH2CH2CH2CH=CH-, -CH2CH2CH=CHCH=CH-, and so on may occur.

[0108] In other embodiments, L is -(CH2) a -(OCH2CH2) e -(Y) f - and each of these may be unsubstituted, or any carbon may be a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3It may be substituted with 1 to 4 substituents selected from alkyl groups. L is a polyethylene glycol oligomer, i.e., -(CH2CH2O) x - may be included (where x is between 2 and 6).

[0109] In other embodiments, L is a chemical bond.

[0110] In this embodiment, R 1B is hydrogen, halogen, -OH, C1-C6 alkyl, 2-6 member heteroalkyl, C3-C6 cycloalkyl, 5-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl. In embodiments, R 1B is hydrogen, halogen, -OH, or C1-C6 alkyl, especially R 1B It is either hydrogen or a halogen.

[0111] In this embodiment, R 1C is hydrogen, halogen, -OH, C1-C6 alkyl, 2-6 member heteroalkyl, C3-C6 cycloalkyl, 5-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl. In embodiments, R 1C is hydrogen, halogen, -OH, or C1-C6 alkyl, especially R 1C It is either hydrogen or a halogen.

[0112] In this embodiment, R 1B and R 1C It is hydrogen.

[0113] In this embodiment, R bonded to the same phenyl ring 1B and R 1C However, it bonds together with the atoms that are bonded to them, C6-C 12 It forms an aryl or a 5-12 member heteroaryl. In the embodiment, R bonded to the same phenyl ring 1B and R 1C However, it bonds with the atoms bonded to them to form phenyl. In this embodiment, R bonded to the same phenyl ring 1B and R 1CHowever, they bond together with the atoms bonded to them to form naphthyl or anthracenyl. In the embodiment, R bonded to the same phenyl ring 1B and R 1C However, it combines with the atoms bonded to them to form pyridyls.

[0114] In this embodiment, C6-C 12 Aryl or 5-12 member heteroaryls are R groups bonded to the same phenyl ring. 1B and R 1C It is formed by and may be substituted with one or more substituents, such as halogens, -OH, -NH2, substituted or unsubstituted C1-C6 alkyls, or substituted or unsubstituted 2-6 member heteroalkyls.

[0115] In this embodiment, R 3A is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 3A These are C1-C3 alkyl groups, especially methyl groups.

[0116] In this embodiment, R 3B is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 3B These are C1-C3 alkyl groups, especially methyl groups.

[0117] In this embodiment, R 3A and R 3B Both are hydrogen. Or, R 3A and R 3B Both are methyl. In the embodiment, R 3A and R 3B One of them is hydrogen, and the other is methyl.

[0118] In this embodiment, R 4A is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 4A is a C1-C3 alkyl group, particularly methyl. In the embodiment, R 4A H is H.

[0119] In this embodiment, R 4B is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 4B is a C1-C3 alkyl group, particularly methyl. In the embodiment, R 4B It is hydrogen.

[0120] In the embodiment, each R 4A and R 4B It is hydrogen. Or, each R 4A and R 4B R may be methyl. In this embodiment, R 4A and R 4B One of them is hydrogen, and the other is methyl.

[0121] Control mechanism, each R 3A and R 3B These are independently C1-C3 alkyl groups, and R 4A and R 4B is hydrogen, and in particular, each R 3A and R 3B is methyl, and each R 4A and R 4B It is hydrogen.

[0122] In another aspect, the cucurbituryl compound has the structure of formula XII: [ka] or having a pharmaceutically acceptable salt thereof, in the formula, Each R 1A and R 1D It is independently -OL-CO2X 1 , and -OL-SO3X 1 Selected from, Each L is independently a chemical bond, C2~C 10 Alkylene, C2~C 10 Alkenylene, -(CH2) a -O-(CH2) b ,-(CH2) c -N(R)-(CH2) d , and -(CH2) a -(OCH2CH2) e -(Y)f - Selected from, each of these may be unsubstituted or contain halogens, OH, CO2H, C at any carbon. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. a is between 2 and 8. b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C 1-3 Alkyl, or O, f is either 0 or 1, R is H or C 1-3 It is alkyl, Each R 3A and R 3B However, these are independently selected from hydrogen, halogens, -OH, CO2H, CO2R', CONH2, CONHR', CON(R')2, C1-C6 alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyls. Additionally or alternatively, R bonded to an adjacent carbon atom 3A and R 3B However, together with the carbon atoms to which they are bonded, they form a 5-membered or 6-membered cycloalkyl ring or heterocycloalkyl ring. Each R 4A and R 4B However, these are independently selected from hydrogen, halogens, -OH, CO2H, CO2R', CONH2, CONHR', CON(R')2, C1-C6 alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyls. Each R' independently 1-6 Selected from alkyl groups, each X 1 However, these are independently selected from H, C1-C6 alkyl groups, alkali metal cations, and quaternary ammonium cations.

[0123] In this embodiment, L is C1~C 10 It is an alkylene, which may be unsubstituted, or a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. In embodiments, L is a C2-C6 alkylene, which may be unsubstituted or substituted. L may be -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, etc. may occur.

[0124] In another embodiment, L is C2~C 10 The alkenylene chain may be unsubstituted, or it may contain a halogen, OH, CO2H, or C. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups, which include 1 to 3 carbon-carbon double bonds. In embodiments, L is a C2-C6 alkenylene, which may be unsubstituted or substituted. L may be -CH=CH-, -C(CH3)=CH-, -CH2CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, -CH=CHCH=CH-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH=CH-, -CH2CH=CHCH=CH-, -CH2CH2CH=CHCH2-, -CH2CH2CH2CH2CH=CH-, -CH2CH2CH=CHCH=CH-, and so on may occur.

[0125] In another embodiment, L is -(CH2) a -(OCH2CH2)e -(Y) f - and each of these may be unsubstituted, or any carbon may be a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. L is a polyethylene glycol oligomer, i.e., -(CH2CH2O) x - may be included (where x is between 2 and 6).

[0126] In another embodiment, L is a single bond.

[0127] In this embodiment, R 3A is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 3A These are C1-C3 alkyl groups, especially methyl groups.

[0128] In this embodiment, R 3B is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 3B These are C1-C3 alkyl groups, especially methyl groups.

[0129] In this embodiment, R 3A and R 3B Both are hydrogen. Or, R 3A and R 3B Both may be methyl. In this embodiment, R 3A and R 3B One of them is hydrogen, and the other is methyl.

[0130] In this embodiment, R 4A is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 4A is a C1-C3 alkyl group, particularly methyl. In the embodiment, R 4A H is H.

[0131] In this embodiment, R 4Bis hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 4B is a C1-C3 alkyl group, particularly methyl. In the embodiment, R 4B It is hydrogen.

[0132] In the embodiment, each R 4A and R 4B It is hydrogen. Or, each R 4A and R 4B R may be methyl. In this embodiment, R 4A and R 4B One of them is hydrogen, and the other is methyl.

[0133] Control mechanism, each R 3A and R 3B These are independently C1-C3 alkyl groups, and R 4A and R 4B is hydrogen, and in particular, each R 3A and R 3B is methyl, and each R 4A and R 4B It is hydrogen.

[0134] In this embodiment, R bonded to the same phenyl ring 1A and R 1D These may be the same or different. In this embodiment, R bonded to different phenyl rings 1A and R 1A These may be the same or different. In this embodiment, R bonded to different phenyl rings 1D and R 1D These may be the same or different. In this embodiment, each R 1A and R 1D They are the same.

[0135] In another embodiment, the cucurbituryl compound has the structure of formula (XIIa): [ka] or having a pharmaceutically acceptable salt thereof, in the formula, Each R 1A and R 1DIt is independently -OL-CO2X 1 and -OL-SO3X 1 Selected from, Each L is independently a chemical bond, C1~C 10 Alkylene, C2~C 10 Alkenylene, -(CH2) a -O-(CH2) b ,-(CH2) c -N(R)-(CH2) d , and -(CH2) a -(OCH2CH2) e -(Y) f - Selected from, each of these may be unsubstituted or contain halogens, OH, CO2H, C at any carbon. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. a is between 2 and 8. b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C 1-3 Alkyl, or O, f is either 0 or 1, R is H or C 1-3 It is alkyl, each X 1 However, these are independently selected from H, C1-C6 alkyl groups, alkali metal cations, and quaternary ammonium cations.

[0136] In this embodiment, L is C1~C 10 It is an alkylene, which may be unsubstituted, or a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3It may be substituted with 1 to 4 substituents selected from alkyl groups. In embodiments, L is a C2 to C6 alkylene, which may be unsubstituted or substituted. L may be -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, etc. may occur.

[0137] In another embodiment, L is C2~C 10 The alkenylene chain may be unsubstituted, or it may contain a halogen, OH, CO2H, or C. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups, which include 1 to 3 carbon-carbon double bonds. In embodiments, L is a C2-C6 alkenylene, which may be unsubstituted or substituted. L may be -CH=CH-, -C(CH3)=CH-, -CH2CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, -CH=CHCH=CH-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH=CH-, -CH2CH=CHCH=CH-, -CH2CH2CH=CHCH2-, -CH2CH2CH2CH2CH=CH-, -CH2CH2CH=CHCH=CH-, and so on may occur.

[0138] In another embodiment, L is -(CH2) a -(OCH2CH2) e -(Y) f - and each of these may be unsubstituted, or any carbon may be a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3It may be substituted with 1 to 4 substituents selected from alkyl groups. L is a polyethylene glycol oligomer, i.e., -(CH2CH2O) x - may be included (where x is between 2 and 6).

[0139] In another embodiment, L is a single bond.

[0140] In this embodiment, R bonded to the same phenyl ring 1A and R 1D These may be the same or different. In this embodiment, R bonded to different phenyl rings 1A and R 1A These may be the same or different. In this embodiment, R bonded to different phenyl rings 1D and R 1D These may be the same or different. In this embodiment, each R 1A and R 1D They are the same.

[0141] In another embodiment, the cucurbituryl compound has the structure of formula (XIIb): [ka] or having a pharmaceutically acceptable salt thereof, in the formula, Each L is independently C1~C 10 Alkylene, C2~C 10 Alkenylene, -(CH2) a -O-(CH2) b ,-(CH2) c -N(R)-(CH2) d , and -(CH2) a -(OCH2CH2) e -(Y) f - Selected from, each of these may be unsubstituted or contain halogens, OH, CO2H, C at any carbon. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. a is between 2 and 8. b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C 1-3 Alkyl, or O, f is either 0 or 1, R is H or C 1-3 It is alkyl, each X 1 However, these are independently selected from H, C1-C6 alkyl groups, alkali metal cations, and quaternary ammonium cations.

[0142] In this embodiment, L is C1~C 10 It is an alkylene, which may be unsubstituted, or a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. In embodiments, L is a C2-C6 alkylene, which may be unsubstituted or substituted. L may be -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, etc.

[0143] In other embodiments, L is C2~C 10 The alkenylene chain may be unsubstituted, or it may contain a halogen, OH, CO2H, or C. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3It may be substituted with 1 to 4 substituents selected from alkyl groups, which include 1 to 3 carbon-carbon double bonds. In embodiments, L is a C2-C6 alkenylene, which may be unsubstituted or substituted. L may be -CH=CH-, -C(CH3)=CH-, -CH2CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, -CH=CHCH=CH-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH=CH-, -CH2CH=CHCH=CH-, -CH2CH2CH=CHCH2-, Possible combinations include -CH2CH2CH2CH2CH=CH-, -CH2CH2CH=CHCH=CH-, and so on.

[0144] In another embodiment, L is -(CH2) a -(OCH2CH2) e -(Y) f - and each of these may be unsubstituted, or any carbon may be a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. L is a polyethylene glycol oligomer, i.e., -(CH2CH2O) x - may be included (where x is between 2 and 6).

[0145] In another embodiment, the cucurbituryl compound has the structure of formula (XIIc): [ka] or a pharmaceutically acceptable salt thereof. Each X independently contains H, an alkali metal cation (e.g., Li + na + , K + , or Cs + ), ammonium cations, or combinations thereof. Each n is independently 1, 2, 3, or 4.

[0146] In another embodiment, the cucurbituryl compound has the structure of formula (XIId): [ka] or a pharmaceutically acceptable salt thereof. Each X independently contains H, an alkali metal cation (e.g., Li + na + , K + , or Cs + ), ammonium cations, or combinations thereof. Each m is independently 1, 2, 3, or 4.

[0147] In another embodiment, the cucurbituryl compound has the structure of formula (XIIe): [ka] or having a pharmaceutically acceptable salt thereof, in the formula, Each L is independently a chemical bond, C1~C 10 Alkylene, C2~C 10 Alkenylene, -(CH2) a -O-(CH2) b ,-(CH2) c -N(R)-(CH2) d , and -(CH2) a -(OCH2CH2) e -(Y) f - Selected from, each of these may be unsubstituted or contain halogens, OH, CO2H, C at any carbon. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. a is between 2 and 8. b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C 1-3Alkyl, or O, f is either 0 or 1, R is H or C 1-3 It is alkyl, each X 1 However, these are independently selected from H, C1-C6 alkyl groups, alkali metal cations, and quaternary ammonium cations.

[0148] In another embodiment, the cucurbituryl compound has the structure of formula (XIII): [ka] or having a pharmaceutically acceptable salt thereof, in the formula, Each R 1A and R 1D However, independently, -OL-CO2X 1 and -OL-SO3X 1 Selected from, Each L is independently a chemical bond, C1~C 10 Alkylene, C2~C 10 Alkenylene, -(CH2) a -O-(CH2) b ,-(CH2) c -N(R)-(CH2) d , and -(CH2) a -(OCH2CH2) e -(Y) f - Selected from, each of these may be unsubstituted or contain halogens, OH, CO2H, C at any carbon. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl) 2, OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. a is between 2 and 8. b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C 1-3 Alkyl, or O, f is either 0 or 1, R is H or C 1-3 It is alkyl, Each R 3A and R 3B However, these are independently selected from hydrogen, halogens, CO2H, CO2R', CONH2, CONHR', CON(R')2, -OH, C1-C6 alkyl, phenyl, substituted phenyl, and 2-6 membered heteroalkyls. Additionally or alternatively, R bonded to an adjacent carbon atom 3A and R 3B However, together with the carbon atoms to which they are bonded, they form a 5-membered or 6-membered cycloalkyl ring or heterocycloalkyl ring. Each R 4A and R 4B However, these are independently selected from hydrogen, halogens, -OH, CO2H, CO2R', CONH2, CONHR', CON(R')2, C1-C6 alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyls. Each R' independently 1-6 Selected from alkyl groups, each X 1 However, these are independently selected from H, C1-C6 alkyl groups, alkali metal cations, and quaternary ammonium cations.

[0149] In this embodiment, L is C1~C 10 It is an alkylene, which may be unsubstituted, or a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. In the embodiment, L is C1 to C 10 Alkylene, C2~C 10 L is an alkylene, a C1-C6 alkylene, or a C2-C6 alkylene, each of which may be unsubstituted or substituted. L is -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, etc. may occur.

[0150] In another embodiment, L is C2~C 10 The alkenylene chain may be unsubstituted, or it may contain a halogen, OH, CO2H, or C. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups, which include 1 to 3 carbon-carbon double bonds. In embodiments, L is a C2-C6 alkenylene, which may be unsubstituted or substituted. L may be -CH=CH-, -C(CH3)=CH-, -CH2CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, -CH=CHCH=CH-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH=CH-, -CH2CH=CHCH=CH-, -CH2CH2CH=CHCH2-, -CH2CH2CH2CH2CH=CH-, -CH2CH2CH=CHCH=CH-, and so on may occur.

[0151] In another embodiment, L is -(CH2) a -(OCH2CH2) e -(Y) f - and each of these may be unsubstituted, or any carbon may be a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. L is a polyethylene glycol oligomer, i.e., -(CH2CH2O) x - may be included (where x is between 2 and 6).

[0152] In other embodiments, L is a chemical bond (i.e., a single bond).

[0153] In this embodiment, R 3A is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 3A These are C1-C3 alkyl groups, especially methyl groups.

[0154] In this embodiment, R 3B is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 3B These are C1-C3 alkyl groups, especially methyl groups.

[0155] In this embodiment, R 3A and R 3B Both are hydrogen. Or, R 3A and R 3B Both may be methyl. In this embodiment, R 3A and R 3B One of them is hydrogen, and the other is methyl.

[0156] In this embodiment, R 4A is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 4A is a C1-C3 alkyl group, particularly methyl. In the embodiment, R 4A H is H.

[0157] In this embodiment, R 4B is hydrogen or a substituted or unsubstituted C1-C3 alkyl group. In the embodiment, R 4B is a C1-C3 alkyl group, particularly methyl. In the embodiment, R 4B It is hydrogen.

[0158] In the embodiment, each R 4A and R 4B It is hydrogen. Or, each R 4A and R 4B R may be methyl. In this embodiment, R 4A and R 4BOne of them is hydrogen, and the other is methyl.

[0159] Control mechanism, each R 3A and R 3B These are independently C1-C3 alkyl groups, and R 4A and R 4B is hydrogen, and in particular, each R 3A and R 3B is methyl, and each R 4A and R 4B It is hydrogen.

[0160] In another embodiment, the cucurbituryl compound has the structure of formula (XIIIa): [ka] or a pharmaceutically acceptable salt thereof, in the formula, Each R 1A and R 1D However, independently, -OL-CO2X 1 and -OL-SO3X 1 Selected from, Each L is independently a chemical bond, C1~C 10 Alkylene, C2~C 10 Alkenylene, -(CH2) a -O-(CH2) b ,-(CH2) c -N(R)-(CH2) d , and -(CH2) a -(OCH2CH2) e -(Y) f - Selected from, each of these may be unsubstituted or contain halogens, OH, CO2H, C at any carbon. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl) 2, OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. a is between 2 and 8. b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C 1-3 Alkyl, or O, f is either 0 or 1, R is H or C 1-3 It is alkyl, each X 1 However, these are independently selected from H, C1-C6 alkyl groups, alkali metal cations, and quaternary ammonium cations.

[0161] In this embodiment, L is C1~C 10 It is an alkylene, which may be unsubstituted, or a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. In the embodiment, L is C1 to C 10 Alkylene, C2~C 10 L is an alkylene, a C1-C6 alkylene, or a C2-C6 alkylene, each of which may be unsubstituted or substituted. L is -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, etc. are often found.

[0162] In another embodiment, L is C2~C 10 The alkenylene chain may be unsubstituted, or it may contain a halogen, OH, CO2H, or C. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3It may be substituted with 1 to 4 substituents selected from alkyl groups, which include 1 to 3 carbon-carbon double bonds. In embodiments, L is a C2-C6 alkenylene, which may be unsubstituted or substituted. L may be -CH=CH-, -C(CH3)=CH-, -CH2CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, -CH=CHCH=CH-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH=CH-, -CH2CH=CHCH=CH-, -CH2CH2CH=CHCH2-, -CH2CH2CH2CH2CH=CH-, -CH2CH2CH=CHCH=CH-, and so on may occur.

[0163] In another embodiment, L is -(CH2) a -(OCH2CH2) e -(Y) f - and each of these may be unsubstituted, or any carbon may be a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. L is a polyethylene glycol oligomer, i.e., -(CH2CH2O) x - may be included (where x is between 2 and 6).

[0164] In this embodiment, L is a chemical bond.

[0165] In this embodiment, R bonded to the same phenyl ring 1A and R 1D These may be the same or different. In this embodiment, R bonded to different phenyl rings 1A and R 1A These may be the same or different. In this embodiment, R bonded to different phenyl rings 1D and R 1D These may be the same or different. In this embodiment, each R1A and R 1D They are the same.

[0166] In another embodiment, the cucurbituryl compound has the structure of formula (XIIIb): [ka] or having a pharmaceutically acceptable salt thereof, in the formula, Each L is independently C1~C 10 Alkylene, C2~C 10 Alkenylene, -(CH2) a -O-(CH2) b ,-(CH2) c -N(R)-(CH2) d , and -(CH2) a -(OCH2CH2) e -(Y) f - Selected from, each of these may be unsubstituted or contain halogens, OH, CO2H, C at any carbon. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. a is between 2 and 8. b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C 1-3 Alkyl, or O, f is either 0 or 1, R is H or C 1-3 It is alkyl, each X 1 However, these are independently selected from H, C1-C6 alkyl groups, alkali metal cations, and quaternary ammonium cations.

[0167] In this embodiment, L is C1~C 10It is an alkylene, which may be unsubstituted, or a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. In the embodiment, L is C1 to C 10 Alkylene, C2~C 10 L is an alkylene, a C1-C6 alkylene, or a C2-C6 alkylene, each of which may be unsubstituted or substituted. L is -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, etc. are often found.

[0168] In another embodiment, L is C2~C 10 The alkenylene chain may be unsubstituted, or it may contain a halogen, OH, CO2H, or C. 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups, which include 1 to 3 carbon-carbon double bonds. In embodiments, L is a C2-C6 alkenylene, which may be unsubstituted or substituted. L may be -CH=CH-, -C(CH3)=CH-, -CH2CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, -CH=CHCH=CH-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH=CH-, -CH2CH=CHCH=CH-, -CH2CH2CH=CHCH2-, -CH2CH2CH2CH2CH=CH-, -CH2CH2CH=CHCH=CH-, and so on may occur.

[0169] In another embodiment, L is -(CH2) a -(OCH2CH2) e -(Y) f - and each of these may be unsubstituted, or any carbon may be a halogen, OH, CO2H, C 1-3 Alkyl, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, and OC 1-3 It may be substituted with 1 to 4 substituents selected from alkyl groups. L is a polyethylene glycol oligomer, i.e., -(CH2CH2O) x - may be included (where x is between 2 and 6).

[0170] In another embodiment, the cucurbituryl compound has the structure of formula (XIIIc): [ka] or a pharmaceutically acceptable salt thereof. Each X independently contains H, an alkali metal cation (e.g., Li + na + , K + , or Cs + ), ammonium cations, or combinations thereof. Each n is independently 1, 2, 3, or 4.

[0171] In another embodiment, the cucurbituryl compound has the structure of formula (XIIId): [ka] or a pharmaceutically acceptable salt thereof. Each X independently contains H, an alkali metal cation (e.g., Li + na + , K + , or Cs + ), ammonium cations, or combinations thereof. Each m is independently 1, 2, 3, or 4.

[0172] Cucurbituryl compounds may have the following chemical structures: Compound A: [ka] Compound B: [ka] Compound C [ka] Compound D [ka] Compound E [ka] Compound F [ka]

[0173] Cucurbituril compounds may be prepared according to the method of U.S. Patent Application No. 15 / 417,785 (US2017 / 0137431). U.S. Provisional Application No. 63 / 380,318, filed on October 20, 2022, entitled "Methods of Synthesis For Cucurbituril Compounds," each of which is incorporated herein by reference in whole.

[0174] The abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed according to the rules of the standard chemical valence known in the field of chemistry.

[0175] The term "alkyl" refers to the radical of a saturated aliphatic group, including linear and branched alkyl groups. Alkyl groups may contain a specified number of carbon atoms (e.g., C1-C1). 10(where n- is 1 to 10 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl.

[0176] The term "alkenyl" refers to a linear or branched hydrocarbyl group having at least one carbon-carbon double bond, and includes linear and branched alkenyl groups. Examples of alkenyl groups (e.g., "C2-C6 alkenyls") include vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. If a compound of this disclosure contains an alkenyl group, the compound may exist as an E-type, a Z-type, or any mixture thereof.

[0177] The term "alkynyl" refers to a linear or branched hydrocarbyl group that has at least one carbon-carbon triple bond and includes both linear and branched alkynyl groups. Examples of alkenyl groups (e.g., "C2-C6 alkynyl") include ethynyl and propynyl.

[0178] The term "cycloalkyl" refers to a saturated carbocyclic group having 3-9 carbon atoms in the ring, including monocyclic, bicyclic, or polycyclic cycloalkyl ring systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are either bridged monocyclic rings or fused bicyclic rings. In embodiments, the bridged monocyclic ring contains a monocyclic cycloalkyl ring, where two non-adjacent carbon atoms of the monocyclic ring are cross-linked with 1-3 additional carbon atoms of alkylene (i.e., (CH2) in the form of w = 1, 2, or 3). wThey are linked by a bridging group. Typical examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.

[0179] The term "heteroalkyl," either by itself or in combination with another term, means, unless otherwise specified, a stable linear or branched chain, or a combination thereof, comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be stationed at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to: -O-C1-C6 alkyl, -O-C2-C6 alkenyl, -O-C2-C6 alkynyl, -S-C1-C6 alkyl, -S-C2-C6 alkenyl, -S-C2-C6 alkynyl, -NH-C1-C6 alkyl, -NH-C2-C6 alkenyl, -NH-C2-C6 alkynyl, -N-(C1-C6 alkyl)2, -S(O)-C1-C6 alkyl, -S(O)-C2-C6 alkenyl, -S(O)-C2-C6 alkynyl, -S(O)2-C1 -C6 alkyl, -S(O)2-C2-C6 alkenyl, -S(O)2-C2-C6 alkynyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-S-C1-C6 alkyl, -C1-C6 alkyl-NH-C1-C6 alkyl, -C1-C6 alkyl-N-(C1-C6 alkyl)2, -C1-C6 alkyl-S(O)-C1-C6 alkyl, -C1-C6 alkyl-S(O)2-C1-C6 alkyl, and more specifically, ―CH2―O―CH3, ―CH2―NH―CH3, ―CH2―CH2―N(CH3)―CH3, ―CH2―S―CH3, This includes, but is not limited to, —S(O)—CH3, —CH2—S(O)2—CH3, —Si(CH3)3, —O—CH3, or —O—CH2—CH3. Up to two or three heteroatoms may be consecutive, for example, —CH2—NH—OCH3 and —CH2—O—Si(CH3)3. The term “heteroalkenyl” means a heteroalkyl group containing at least one carbon-carbon double bond, either by itself or in combination with another term, unless otherwise specified. The term “heteroalkynyl” means a heteroalkyl group containing at least one carbon-carbon triple bond, either by itself or in combination with another term, unless otherwise specified.

[0180] As used herein, the term "cycloalkenyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In embodiments, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3–9 carbon atoms, such a group is unsaturated (i.e., contains at least one cyclic carbon-carbon double bond) but is not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, a bicyclic cycloalkenyl ring is a bridged or fused bicyclic ring.

[0181] As used herein, the terms “heterocyclic,” “heterocyclic,” or “heterocyclic formula” mean monocyclic, bicyclic, or polycyclic heterocyclic rings. A monocyclic heterocyclic ring is a 3, 4, 5, 6, 7, or 8-membered ring in which the ring is saturated or unsaturated but contains at least one heteroatom independently selected from the group consisting of O, N, S, Si, and P, which are not aromatic. Typical examples of monocyclic heterocyclic rings include azetidinyl, azepanyl, azilidinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolidinyl, oxazoli Examples of bicyclic heterocycles include, but are not limited to, dinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholin sulfone), thiopyranyl, and trithianil. Representative examples of bicyclic heterocycles include, but are not limited to, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothienyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. Heterocyclic rings are bonded to the parent molecule via any carbon or nitrogen atom contained within a monocyclic or bicyclic ring system.

[0182] As used herein, the term “aryl” includes five- and six-membered monocyclic aromatic groups that may contain 0 to 4 heteroatoms, such as benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl groups having heteroatoms in their ring structure may also be referred to as “aryl heterocyclic,” “heteroaromatic,” or “heteroaryl.” The term “aryl” also includes polycyclic ring systems of 7 to 14 members having two or more cyclic rings (rings that are “fused rings”) in which two or more carbons are shared by two adjacent rings, wherein at least one of the rings is aromatic (including heteroaryl), and the other cyclic rings may be, for example, fused cycloalkyl, cycloalkenyl, aryl, heteroaryl, and / or heterocyclic groups. A monocyclic heteroaryl group may have 1 to 3 ring heteroatoms, and a condensed polycyclic heteroaryl group may have 1 to 5 ring heteroatoms, with the ring heteroatoms being selected from N, O, and S.

[0183] The term “alkylene” means a divalent radical derived from an alkyl group, either by itself or as part of another substituent, unless otherwise specified, including, but not limited to, -CH2CH2CH2CH2. Typically, alkyl (or alkylene) groups have 1 to 24 carbon atoms, and those having 10 or fewer carbon atoms are preferred herein. “Lower alkyl” or “lower alkylene” refers to a shorter-chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term “alkenylene” means a divalent radical derived from an alkene, either by itself or as part of another substituent, unless otherwise specified.

[0184] It will be understood that the terms "substituted," "substituted," or "substituted with" implicitly include the condition that such substitution conforms to the allowable valencies of the substituted atom and substituent, and that the substitution results in a stable compound, such as one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc. Exemplary substituents used herein include oxo, halogen, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-8 member heteroalkyl, 2-6 member heteroalkyl, or 2-4 member heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 member heterocycloalkyl, 3-6 member heterocycloalkyl, or 5-6 member heterocycloalkyl), aryl (e.g., C6-C 10 Ariel, C 10 This refers to a group selected from aryl, phenyl, or heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and these alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups can optionally be substituted with at least one substituent. For example, in the cucurbituryl compounds disclosed herein, each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and heterocycle can optionally be substituted with 1 to 4 substituents selected from the aforementioned substituents.

[0185] The quaternary ammonium cations used herein have a structure + The formula has N(R)4, where each R is independently selected from alkyl, cycloalkyl, aryl, aralkyl, and heteroaryl, and each of these can be optionally substituted. Quaternary ammonium cations are, for example, structure + N(C 1-6 It may have alkyl)4, where C is bonded to nitrogen in the formula. 1-6 Each alkyl group is selected independently.

[0186] The terms "a" or "an" as used herein mean one or more. In addition, the phrase "[n] substituted" as used herein means that a particular group may be substituted with one or more of any or all of the specified substituents. For example, a group such as an alkyl or heteroaryl group may be "unsubstituted C1-C 20 If it is "substituted with an alkyl or an unsubstituted 2-20 member heteroalkyl," then the group is one or more unsubstituted C1-C 20 It may contain alkyl groups and / or one or more unsubstituted 2- to 20-membered heteroalkyl groups.

[0187] Certain compounds provided in this disclosure may exist in specific geometric or stereoisomeric forms. This disclosure intends to include all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, racemic mixtures thereof, and other mixtures thereof, within the scope of the invention. Further chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included in the invention.

[0188] The term "pharmaceutically acceptable salt" refers to inorganic and organic acid addition salts and inorganic and organic base addition salts of the compounds disclosed herein that are relatively nontoxic. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either in its original form or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either in its original form or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, and methanesulfonic acid.

[0189] Administration of a chelating agent Administration refers to the method by which an α2-adrenergic receptor agonist, abuse drug, or chelating agent is taken into a patient's body. The route of administration can be classified according to the site of application of the substance. Common examples include oral and intravenous administration. Routes can also be classified based on where the target of action is, such as topical, enteral (administered through the gastrointestinal tract but affecting the whole body), or parenteral (administered via a route other than the gastrointestinal tract and affecting the whole body). Administration includes self-administration by the patient and administration by a healthcare professional or another person. Administration may be intentional or accidental, especially when applied to α2-adrenergic receptor agonists or abuse drugs.

[0190] The chelating agent pharmaceutical compositions described herein may be formulated for parenteral administration to patients. In particular, the chelating agent pharmaceutical compositions may be suitable for administration by injection to patients, including intravenous, intramuscular, subcutaneous, and intraperitoneal administration, and preferably for intravenous administration.

[0191] In one embodiment, the dosage form containing a chelating agent is an oral dosage form comprising (i) a chelating agent and (ii) one or more pharmaceutically acceptable carriers. The oral formulation may be a capsule or a tablet. Alternatively, the oral dosage form may be an orally administered solution, suspension, or syrup.

[0192] In another embodiment, the dosage form is an aqueous solution suitable for injection into a patient, comprising (i) a chelating agent, (ii) optionally a buffering agent, and (iv) optionally an isotonic agent. In another embodiment, the dosage form is a solid for reconstitution, comprising (i) a chelating agent, (ii) optionally a buffering agent, and (iv) optionally an isotonic agent.

[0193] For parenteral administration in aqueous solutions, for example, the liquid dosage form may need to be appropriately buffered as needed, and the liquid diluent may need to be isotonic with sufficient saline or glucose. In this regard, sterile aqueous media that can be employed are known to those skilled in the art in light of this disclosure. For example, one dose may be dissolved in 1 mL to 20 mL of isotonic NaCl solution and added to 100 mL to 1000 mL of fluid (e.g., sodium bicarbonate-buffered saline) or injected into the intended injection site.

[0194] The chelating agent pharmaceutical compositions described herein may be formulated for parenteral administration to patients. Oral dosage forms for chelating agent administration include buccal films, tablets, capsules, oral liquids, and syrups.

[0195] Compositions containing chelating agents may be included in pharmaceutical compositions for oral administration to patients. The pharmaceutical compositions of this disclosure may further include pharmaceutically acceptable carriers, excipients, or diluents.

[0196] In one embodiment, the disclosure provides an oral dosage form. The chelating agent can be administered to a patient as one or more tablets or capsules. The chelating agent can be administered to a patient as an aqueous solution or aqueous suspension. The chelating agent can be administered to a patient in amounts ranging from about 5 mg / kg to about 500 mg / kg.

[0197] The oral dosage form may contain the cucurbituryl compound as an aqueous solution or aqueous suspension containing 5 mg to 500 mg of the cucurbituryl compound.

[0198] In embodiments, the present disclosure provides a rapidly disintegrating oral tablet containing a cucurbituryl compound.

[0199] The term "pharmaceutical composition," as used herein, refers to a composition containing a chelating agent, formulated on a pharmaceutically acceptable carrier, and manufactured or marketed with the approval of a government regulatory authority as part of a treatment plan for the treatment of a patient's disability. Pharmaceutical compositions may be formulated, for example, in unit dosage forms (e.g., tablets, capsules, caplets, gel caps, syrups, or solutions) for oral administration.

[0200] As used herein, the term “pharmaceutically acceptable carrier” refers to a carrier that is physiologically acceptable to the treated mammal (e.g., human) while retaining the therapeutic properties of the cucurbituril compound to which it is administered. One exemplary pharmaceutically acceptable carrier is saline. Other physiologically acceptable carriers and their formulations are known to those skilled in the art, e.g., Remington's Pharmaceutical Sciences (18 th This is described in edition, A. Gennaro, 1990, Mack Publishing Company, Easton, Pa., and is incorporated herein by reference.

[0201] Pharmaceutical compositions containing cucurbituryl compounds and amino acids or amino acid derivatives are prepared in some embodiments as solutions, dispersions in glycerol, liquid polyethylene glycol, and any combination thereof, in oil, in solid dosage forms, as inhalable dosage forms, as intranasal dosage forms, as liposome formulations, dosage forms containing nanoparticles, dosage forms containing microparticles, polymer dosage forms, or any combination thereof.

[0202] Pharmaceutically acceptable excipients, in some examples, are those listed in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986). Non-limiting examples of suitable excipients include buffers, preservatives, stabilizers, binders, compressors, lubricants, chelating agents, dispersion enhancers, disintegrants, flavoring agents, sweeteners, and colorants.

[0203] In some embodiments, the excipient is a buffer. Non-limiting examples of suitable buffers include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate. Sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, and other calcium salts or combinations thereof are used as buffers in some embodiments of the pharmaceutical compositions of this disclosure.

[0204] In some embodiments, the excipients include preservatives. Non-limiting examples of suitable preservatives include antioxidants, such as α-tocopherol and ascorbates, and antimicrobial agents, such as parabens, chlorobutanol, and phenols. In some embodiments, antioxidants further include, but are not limited to, EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium sulfite, p-aminobenzoic acid, glutathione, propyl gallate, cysteine, methionine, ethanol, and N-acetylcysteine. In some cases, preservatives include validamycin A, TL-3, sodium orthovanadate, sodium fluoride, sodium tosyl-Phe-chloromethyl ketone, sodium tosyl-Lys-chloromethyl ketone, aprotinin, phenylmethylsulfonyl fluoride, diisopropyl fluorophosphate, kinase inhibitors, phosphatase inhibitors, caspase inhibitors, granzyme inhibitors, cell adhesion inhibitors, cell division inhibitors, cell cycle inhibitors, lipid signaling inhibitors, protease inhibitors, reducing agents, alkylating agents, antibacterial agents, oxidase inhibitors, or other inhibitors.

[0205] In some embodiments, the pharmaceutical compositions described herein include a binder as an excipient. Non-limiting examples of suitable binders include starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxoazolidone, polyvinyl alcohol, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, sugars, oligosaccharides, and combinations thereof. Binders used in pharmaceutical formulations are selected from, in some examples, starches such as potato starch, corn starch, and wheat starch; sugars such as sucrose, glucose, dextrose, lactose, and maltodextrin; natural and synthetic rubbers; gelatin; cellulose derivatives, such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methyl cellulose, and ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; alcohols such as calcium carbonate, calcium phosphate, sorbitol, xylitol, and mannitol; and water, or any combination thereof.

[0206] In some embodiments, the pharmaceutical compositions described herein include a lubricant as an excipient. Non-limiting examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oils. Lubricants used in pharmaceutical formulations are selected in some embodiments from metal stearates (such as magnesium stearate, calcium stearate, and aluminum stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), aliphatic alcohols, glyceryl behenate, mineral oil, paraffin, hydrogenated vegetable oil, leucine, polyethylene glycol (PEG), metal lauryl sulfates (such as sodium lauryl sulfate and magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate, and talc or combinations thereof.

[0207] In some embodiments, the pharmaceutical composition includes a dispersion enhancer as an excipient. Non-limiting examples of suitable dispersants include, in some cases, starch, alginic acid, polyvinylpyrrolidone, guar gum, kaolin, bentonite, refined woody cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as a high-HLB emulsifying surfactant.

[0208] In some embodiments, the pharmaceutical compositions described herein include a disintegrant as an excipient. In some embodiments, the disintegrant is a non-foaming disintegrant. Non-limiting examples of suitable non-foaming disintegrants include starches, e.g., corn starch, potato starch, their pregelatinized and modified starches, sweeteners, clays, e.g., bentonite, microcrystalline cellulose, alginate, sodium starch glycolate, gums, e.g., agar, guar, locust bean, karaya, pectin, and tragacanth. In some embodiments, the disintegrant is a foaming disintegrant. Non-limiting examples of suitable foaming disintegrants include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.

[0209] In some embodiments, the excipients include flavoring agents. The flavoring agents incorporated into the outer layer are selected, in some examples, from synthetic flavoring oils and flavoring agents; natural oils; extracts from plants, leaves, flowers, and fruits; and combinations thereof. In some embodiments, the flavoring agents can be selected from cinnamon oil, wintergreen oil, peppermint oil, clover oil, hay oil, anise oil, eucalyptus oil, vanilla oil, citrus oils, such as lemon oil, orange oil, grape oil, and grapefruit oil, as well as fruit essences, such as apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0210] In some embodiments, the excipients include sweeteners. Non-limiting examples of suitable sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and various salts thereof, e.g., sodium salts; dipeptide sweeteners, e.g., aspartame; dihydrochalcone compounds, glycyrlysine; stevia rebaudiana (stevioside); chloro derivatives of sucrose, e.g., sucralose; and sugar alcohols, e.g., sorbitol, mannitol, silitol.

[0211] In some cases, the pharmaceutical compositions described herein include colorants. Non-limiting examples of suitable colorants include colorants for food, pharmaceuticals, and cosmetics (FD&C), colorants for pharmaceuticals and cosmetics (D&C), and colorants for topical medicines and cosmetics (topical medicine D&C). Colorants can be used as pigments or their corresponding lakes.

[0212] In some embodiments, the chelating agent or a pharmaceutically acceptable salt thereof is administered at approximately 0.05 mg / kg to 500 mg / kg. In some embodiments, the chelating agent is administered at approximately 0.05 mg / kg to 50 mg / kg, 50 to 60 mg / kg, 50 to 70 mg / kg, 50 to 80 mg / kg, 50 to 90 mg / kg, 50 to 100 mg / kg, 50 to 120 mg / kg, 50 to 140 mg / kg, 50 to 160 mg / kg, 50 to 180 mg / kg, 50 to 200 mg / kg, 50 to 220 mg / kg, 50 to 240 mg / kg, 50 to 260 mg / kg, 50 to 280 mg / kg, 50 to 300 mg / kg, 50 to 350 mg / kg, 50 to 400 mg / kg. g, 50~450mg / kg, 50~500mg / kg, 60~70mg / kg, 60~80mg / kg, 60~90mg / kg, 60~100mg / kg, 60~120mg / kg, 60~140mg / kg, 60~160mg / kg, 60~180mg / k g, 60~200mg / kg, 60~220mg / kg, 60~240mg / kg, 60~260mg / kg, 60~280mg / kg, 60~300mg / kg, 60~350mg / kg, 60~400mg / kg, 60~450mg / kg, 60~500m g / kg, 80~90mg / kg, 80~100mg / kg, 80~120mg / kg, 80~140mg / kg, 80~160mg / kg, 80~180mg / kg, 80~200mg / kg, 80~220mg / kg, 80~240mg / kg, 80~26 0mg / kg, 80-280mg / kg, 80-300mg / kg, 80-350mg / kg, 80-400mg / kg, 80-450mg / kg, 80-500mg / kg, 100-120mg / kg, 100-130mg / kg, 100-140mg / kg , 100~150mg / kg, 100~160mg / kg, 100~180mg / kg, 100~200mg / kg, 100~220mg / kg, 100~240mg / kg, 100~260mg / kg, 100~280mg / kg, 100~300mg / kg , 100~350mg / kg, 100~400mg / kg, 100~450mg / kg, 100~500mg / kg, 140~160mg / kg, 140~180mg / kg, 140~200mg / kg, 140~220mg / kg, 140~240mg / kg,administered at 140 - 260 mg / kg, 140 - 280 mg / kg, 140 - 300 mg / kg, 140 - 350 mg / kg, 140 - 400 mg / kg, 140 - 450 mg / kg, 140 - 500 mg / kg, 160 - 200 mg / kg, 160 - 220 mg / kg, 160 - 240 mg / kg, 160 - 260 mg / kg, 160 - 280 mg / kg, 160 - 300 mg / kg, 160 - 350 mg / kg, 160 - 400 mg / kg, 160 - 450 mg / kg, 160 - 500 mg / kg, 180 - 200 mg / kg, 180 - 220 mg / kg, 180 - 240 mg / kg, 180 - 260 mg / kg, 180 - 280 mg / kg, 180 - 300 mg / kg, 180 - 350 mg / kg, 180 - 400 mg / kg, 180 - 450 mg / kg, 180 - 500 mg / kg, 200 - 220 mg / kg, 200 - 240 mg / kg, 200 - 260 mg / kg, 200 - 280 mg / kg, 200 - 300 mg / kg, 200 - 350 mg / kg, 200 - 400 mg / kg, 200 - 450 mg / kg, 200 - 500 mg / kg, 220 - 240 mg / kg, 220 - 260 mg / kg, 220 - 280 mg / kg, 220 - 300 mg / kg, 240 - 260 mg / kg, 240 - 280 mg / kg, 240 - 300 mg / kg, 240 - 350 mg / kg, 240 - 400 mg / kg, 240 - 450 mg / kg, 240 - 500 mg / kg, 260 - 280 mg / kg, 260 - 300 mg / kg, 280 - 300 mg / kg, 260 - 350 mg / kg, 260 - 400 mg / kg, 260 - 450 mg / kg, 260 - 500 mg / kg, 280 - 350 mg / kg, 280 - 400 mg / kg, 280 - 450 mg / kg, or 280 - 500 mg / kg.

[0213] In some embodiments, the chelating agent or a pharmaceutically acceptable salt thereof is present in amounts of at least about 0.05 mg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, and 150 mg It is administered at doses of 160 mg / kg, 170 mg / kg, 180 mg / kg, 190 mg / kg, 200 mg / kg, 210 mg / kg, 220 mg / kg, 230 mg / kg, 240 mg / kg, 250 mg / kg, 260 mg / kg, 270 mg / kg, 280 mg / kg, 290 mg / kg, 300 mg / kg, 350 mg / kg, 400 mg / kg, 450 mg / kg, or 500 mg / kg. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered at approximately 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 mg / kg, 180 mg / kg, 190 mg / kg, 200 mg / kg, 210 mg / kg, 220 mg / kg, 230 mg / kg, 240 mg / kg, 250 mg / kg, 260 mg / kg, 270 mg / kg, 280 mg / kg, 290 mg / kg, 300 mg / kg, 350 mg / kg, 400 mg / kg, 450 mg / kg, or less than 500 mg / kg.

[0214] In some embodiments, the chelating agent or a pharmaceutically acceptable salt thereof is approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, 450 mg, approximately 50 It can be administered in doses of 0 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, approximately 1400 mg, approximately 1450 mg, approximately 1500 mg, approximately 1550 mg, approximately 1600 mg, approximately 1650 mg, 1700 mg, approximately 1750 mg, approximately 1800 mg, approximately 1850 mg, approximately 1900 mg, approximately 1950 mg, or approximately 2000 mg. [Examples]

[0215] Example 1. In vitro binding test In vitro binding studies were conducted under simulated physiological conditions using chelating agents against abused drugs, and are summarized in Table 1. [Table 1]

[0216] Compound J contains 8.4 × 10⁻⁶ units of methamphetamine. 6 They bind due to their binding affinity.

[0217] Preparation of the host solution:

[0218] Isothermal titration calorimetry - A 1 mM solution of the host was prepared volumetrically using 20 mM pH 7.4 phosphate buffer. This solution was then diluted to 0.1 mM using the same 20 mM pH 7.4 phosphate buffer.

[0219] A 1 mM solution of the fluorescent host was prepared by volume using 20 mM pH 7.4 phosphate buffer. This solution was then diluted to 0.2 mM and 0.02 mM using the same 20 mM pH 7.4 phosphate buffer.

[0220] Preparation of guest solution:

[0221] Isothermal titration calorimetry - 1 mM solutions of each guest molecule were prepared non-volume using 20 mM pH 7.4 phosphate buffer.

[0222] Fluorescence: 25 mM solutions of each guest molecule were prepared non-volume with methanol and diluted to appropriate concentrations. Tests were conducted with various target molecules to confirm that small amounts of residual methanol (<1%) did not interfere with binding.

[0223] Preparation of rhodamine 6G solution:

[0224] A 1 mM solution of fluorescent rhodamine 6G was prepared by volume using 20 mM pH 7.4 phosphate buffer. This solution was then diluted to 0.2 mM using the same 20 mM pH 7.4 phosphate buffer.

[0225] Determination of coupling constants

[0226] For determining each host-guest binding constant, the average binding affinity from three measurements was recorded.

[0227] Isothermal calorimetry was performed using the Malvern Panalytical MicroCal PEAQ-ITC. Each guest was concentrated at 1 mM, and the host at 0.1 mM. A sample cell was filled with 290 μL of host solution, and a syringe was loaded from a vial containing 80 μL of guest. A 19-injection method was performed, with the first injection being 0.4 μL, followed by 18 injections of 2 μL each. For guests with weak binding, two 19-injection titrations were performed. After the first titration was complete, excess liquid was removed from the sample cup, and the guest solution was reloaded into the syringe. The temperature was set to 25°C, the baseline power to 10 μcal / s, the feedback to fast, the stirring speed to 750 rpm, the initial delay to 60 seconds, the injection interval to 150 seconds, and the injection duration to 4 seconds. Data were processed using Malvern software. [Table 2]

[0228] Example 3. Capture and excretion of unmetabolized xylazine in urine. Rats (Sprague Dawley, N=4) were administered a single IV bolus (1 mL / kg) of 3 mg / kg xylazine hydrochloride via jugular venous catheter (JVC). Five minutes later, the rats were administered a single IV bolus of 150 mg / kg of compound A (1 mL / kg) via JVC, and were immediately placed in a metabolic cage for up to 24 hours. Total urine volume was collected at 2, 8, and 24 hours, and the total amount of xylazine in each volume was measured using LC-MS / MS. The recovery rate of xylazine is shown in Figure 1.

[0229] The amount of xylazine captured in the urine was statistically equivalent to the amount captured in the xylazine / fentanyl combination experiment described later.

[0230] Example 4. Capture and excretion of unmetabolized xylazine / fentanyl in urine. Rats (Sprague Dawley; N=4) were administered a single IV bolus (1 mL / kg) of 3 mg / kg xylazine hydrochloride via jugular venous catheter (JVC), followed immediately by a single IV bolus (1 mL / kg) of fentanyl citrate 100 μg / kg. Five minutes later, the rats were administered a single IV bolus of either physiological saline (1 mL / kg) or a 150 mg / kg compound. Compound A (1 mL / kg) was administered via JVC, and the rats were immediately placed in metabolic cages for up to 24 hours to collect urine.

[0231] Total urine volume was collected at 2, 8, and 24 hours, and the total amounts of xylazine and fentanyl in each volume were measured using LC-MS / MS. The recovery rates of fentanyl and xylazine are shown in Figures 2a and 2b, respectively. Rats given compound A were observed to recover to normal behavior faster than rats given placebo.

[0232] Example 5. Observation / behavioral experiment of xylazine in rats Rats (Sprague Dawley, N=4) were administered a single IV bolus (1 mL / kg) of xylazine hydrochloride at 3 mg / kg via the tail vein. Five minutes later, the rats were administered a single IV bolus of physiological saline or 400 or 200 mg / kg of compound A via the tail vein. Fifteen minutes after the loading test (10 minutes after the initial dose), some rats were given an additional dose of compound A (either 400 or 200 mg / kg). The test groups were as follows: Control group = 3 mg / kg xylazine HCl and 5-minute doses of physiological saline. Test group 1 = 3 mg / kg xylazine HCl, compound A at a 5-minute dose of 400 mg / kg, and compound A at a 15-minute dose of 400 mg / kg. Test group 2 = 3 mg / kg xylazine HCl, compound A at a 5-minute dose of 200 mg / kg, and compound A at a 15-minute dose of 200 mg / kg. Test group 3 = 3 mg / kg xylazine HCl and compound A at a 5-minute dose of 400 mg / kg.

[0233] At specific time intervals following the drug administration in the stress test (2-3 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 60 minutes, 90 minutes, and 120 minutes), the rats were removed from the housing and placed in a plastic bottle test chamber, and the patient's gait was quantified by at least two observers according to the following criteria: 0 - Normal gait / mobility. 1. Slight impairment (may be evident in any or all of the following): mild ataxia, swaying or spasms while walking; hunched or hunched posture; walking on tiptoes. 2. Moderate impairment (one or all of the following may be present): marked ataxia; legs turned outward from the body, and hind limbs exhibiting exaggerated or excessive movement, resistance, or spread. 3. Severe disability (may be evident in any or all of the following): Forelimbs resist or are unable to support weight; body is dragged or flattened against a surface.

[0234] In all groups, when compound A was administered, rats showed significantly faster improvement in walking scores (decrease in score number) compared to the control group. The walking scores over time for each group are shown in Figure 3. Test group 1 (compound A at 400 mg / kg in two doses, one at 5 minutes and the other at 15 minutes) showed a change in the walking recovery curve by approximately 30 minutes compared to the control (similar walking ability at 30 minutes post-administration compared to the same score observed at 60 minutes in the control).

Claims

1. A method for reducing the concentration of an α2-adrenergic receptor agonist in the body of a patient who has been administered the α2-adrenergic receptor agonist, The method comprising administering a therapeutically effective dose of a chelating agent to the patient at some point after the administration of the α2-adrenergic receptor agonist.

2. The method according to claim 1, wherein the α2 adrenergic receptor agonist is xylazine.

3. The method according to claim 1 or 2, wherein the patient is also administered pharmaceuticals and / or additional drugs of abuse.

4. The method according to claim 3, wherein the patient is also administered additional abuse drugs.

5. The method according to claim 4, wherein the additional abusive drugs include one or more of amphetamine stimulants, barbiturate hypnotics, opioids, benzodiazepines, and psychedelics.

6. The method according to claim 4, wherein the additional drug of abuse comprises one or more of methamphetamine, fentanyl, and cocaine.

7. The method according to claim 4, wherein the additional drug of abuse comprises fentanyl or a fentanyl analog.

8. The method according to claim 7, wherein the fentanyl analog is carfentanyl.

9. The method according to any one of claims 1 to 8, wherein the chelating agent is administered orally to the patient.

10. The method according to any one of claims 1 to 9, wherein the suffocating agent is administered by injection to the patient.

11. The method according to any one of claims 1 to 10, wherein the chelating agent comprises cucurbituryl, pyralarene, or calyxsalen.

12. The method according to any one of claims 1 to 10, wherein the chelating agent comprises a cucurbituryl compound.

13. The cucurbituryl compound has the structure of formula (I): 【Chemistry 1】 or having a pharmaceutically acceptable salt thereof, During the ceremony, Each R １Ａ and R １Ｄ is independently hydrogen, halogen, -OH, C １ -C ６ alkyl, 2- to 6-membered heteroalkyl, C ３ -C ６ cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -O-(CH ２ ) ｎ１ S(O) ｖ１ X １ -O-(CH ２ ) ｎ１ CO ２ X １ and -O-(CH ２ ) ｎ１ PO ｖ１ X １ Selected from, Each R １Ｂ and R １Ｃ However, independently, hydrogen, halogen, -OH, C １ -C ６ Alkyl, 2-6 member heteroalkyl, C ３ -C ６ Cycloalkyl, 5-6 member heterocycloalkyl, phenyl, 5-6 member heteroaryl, -O-(CH ２ ) ｎ１ S(O) ｖ１ X １ , -O-(CH ２ ) ｎ１ CO ２ X １ , and -O-(CH ２ ) ｎ１ PO ｖ１ X １ Selected from, or Additionally or alternatively, two R groups bonded to adjacent positions on the same phenyl ring may be added. １Ａ 、 R １Ｂ , R １Ｃ and R １Ｄ However, together with the atoms to which they are bonded, condensation C ６ -C １２ They form aryl, 5- to 12-membered heteroaryl, or 5- to 7-membered heterocycles, which are independently selected halogens, -OH, and -NH ２ , substitution or non-substitution C １ -C ６ Alkyl, or optionally substituted with 1 to 3 substituents on a substituted or unsubstituted 2- to 6-membered heteroalkyl group, Each R ３Ａ and R ３Ｂ However, independently, hydrogen, halogen, -OH, C １ -C ６ Selected from alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyl groups, Each R ４Ａ and R ４Ｂ However, independently, hydrogen, halogen, -OH, C １ -C ６ Selected from alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyl groups, Each n1 is independently selected from 0 to 5. Each v1 is independently selected from 2 or 3. each X １ However, independently, H, -OH, C １ -C ６ The method according to claim 12, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

14. The cucurbituryl compound has the structure of formula (I-a): 【Chemistry 2】 or having a pharmaceutically acceptable salt thereof, in the formula R １Ａ , R １Ｄ , R ３Ａ , R ３Ｂ , R ４Ａ , and R ４Ｂ The method according to claim 12, defined for formula I.

15. The cucurbituryl compound has the structure of formula (I-b): 【Transformation 3】 or having a pharmaceutically acceptable salt thereof, in the formula R １Ａ and R １Ｄ The method according to claim 12, wherein the formula is as described for formula I.

16. The cucurbituryl compound has the structure of formula (I-c): 【Chemistry 4】 or having a pharmaceutically acceptable salt thereof, wherein X １ The method according to claim 12, wherein n1 is as described for formula I.

17. The cucurbituryl compound has the structure of formula (I-A). 【Transformation 5】 The method according to claim 12, wherein the method comprises a pharmaceutically acceptable salt thereof, where each X is independently H, an alkali metal cation, or a quaternary ammonium cation.

18. The cucurbituryl compound is compound A, and has the following structure: 【Transformation 6】 The method according to claim 12, comprising a pharmaceutically acceptable salt thereof.

19. The cucurbituryl compound has the structure of formula (I-D). 【Transformation 7】 or having a pharmaceutically acceptable salt thereof, in the formula R １Ａ , R １Ｄ , R ３Ａ , R ３Ｂ , R ４Ａ , and R ４Ｂ The method according to claim 12, wherein formula I is as described.

20. The cucurbituryl compound has the structure of formula (X): 【Transformation 8】 or having a pharmaceutically acceptable salt thereof, in the formula R １Ａ and R １Ｄ The method according to claim 12, wherein the formula I is as described.

21. The cucurbituryl compound is compound B, and has the following structure: 【Chemistry 9】 The method according to claim 12, comprising a pharmaceutically acceptable salt thereof.

22. The cucurbituryl compound has the structure of formula XI: 【Chemistry 10】 or having a pharmaceutically acceptable salt thereof, in the formula, Each R １Ａ and R １Ｄ However, independently, -O-L-CO ２ X １ and -O-L-SO ３ X １ Selected from, Each L is independently a chemical bond (single bond), C １ to C １０ alkylene, C ２ to C １０ alkenylene, -(CH ２ ) ａ -O-(CH ２ ) ｂ 、-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ 、and -(CH ２ ) ａ -(OCH ２ CH ２ ) ｅ -(Y) ｆ - and is selected from, each of which may be unsubstituted or at any carbon, halogen, OH, CO ２ H, C １－３ alkyl, NH ２ , NH(C １－３ alkyl), N(C) １－３ Alkyl) ２ , and O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, Each R １Ｂ and R １Ｃ However, independently, hydrogen, halogen, -OH, -CN, CO ２ H, SO ３ H, C １ -C ６ Alkyl, 2-6 member heteroalkyl, C ３ -C ６ Selected from cycloalkyl, 5-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl, Additionally or alternatively, R bonded to the same phenyl ring １Ｂ and R １Ｃ However, together with the aforementioned atoms to which they are bonded, condensation C ６ -C １２ They form aryl, 5- to 12-membered heteroaryl, or 5- to 7-membered heterocycles, which are independently selected halogens, -OH, and -NH ２ , substitution or non-substitution C １ -C ６ Alkyl, or optionally substituted with 1 to 3 substituents on a substituted or unsubstituted 2- to 6-membered heteroalkyl group, Each R ３Ａ and R ３Ｂ However, independently, hydrogen, halogen, -OH, CO ２ H, CO ２ R', CONH ２ , CONHR', CON(R') ２ , C １ -C ６ Selected from alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyl groups, Additionally or alternatively, R bonded to an adjacent carbon atom ３Ａ and R ３Ｂ However, together with the carbon atoms to which they are bonded, they form a five-membered or six-membered cycloalkyl ring or a heterocycloalkyl ring. Each R ４Ａ and R ４Ｂ However, independently, hydrogen, halogen, -OH, CO ２ H, CO ２ R', CONH ２ ,CONHR',CON(R') ２ , C １ -C ６ Selected from alkyl, phenyl, substituted phenyl and 2-6 member heteroalkyl groups, Each R' independently １－６ Selected from alkyl groups, each X １ However, independently, H and C １ -C ６ The method according to claim 12, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

23. The cucurbituryl compound has the structure of formula XII: 【Chemistry 11】 or having a pharmaceutically acceptable salt thereof, in the formula, Each R １Ａ and R １Ｄ It is independently -O-L-CO ２ X １ , and -O-L-SO ３ X １ Selected from, Each L is independently a chemical bond, C ２ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, -(CH ２ ) ａ -O-(CH ２ ) ｂ ,-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N(C) １－３ Alkyl) ２ , and O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, Each R ３Ａ and R ３Ｂ However, independently, hydrogen, halogen, -OH, CO ２ H, CO ２ R', CONH ２ , CONHR', CON(R') ２ , C １ -C ６ Selected from alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyl groups, Additionally or alternatively, R bonded to an adjacent carbon atom ３Ａ and R ３Ｂ However, together with the carbon atoms to which they are bonded, they form a five-membered or six-membered cycloalkyl ring or a heterocycloalkyl ring. Each R ４Ａ and R ４Ｂ However, independently, hydrogen, halogen, -OH, CO ２ H, CO ２ R', CONH ２ ,CONHR',CON(R') ２ , C １ -C ６ Selected from alkyl, phenyl, substituted phenyl and 2-6 member heteroalkyl groups, Each R' independently １－６ Selected from alkyl groups, each X １ However, independently, H and C １ -C ６ The method according to claim 13, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

24. The cucurbituryl compound has the structure of formula XIIa: 【Chemistry 12】 or having a pharmaceutically acceptable salt thereof, in the formula, Each R １Ａ and R １Ｄ However, independently, -O-L-CO ２ X １ and -O-L-SO ３ X １ Selected from, Each L is independently a chemical bond, C １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, -(CH ２ ) ａ -O-(CH ２ ) ｂ ,-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N(C) １－３ Alkyl) ２ , and O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, each X １ However, independently, H and C １ -C ６ The method according to claim 13, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

25. The cucurbituryl compound has the structure of formula XIIb: 【Chemistry 13】 or having a pharmaceutically acceptable salt thereof, in the formula, Each L independently １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, - (CH ２ ) ａ -O-(CH ２ ) ｂ ,-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N (C １－３ Alkyl) ２ , and O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, each X １ However, independently, H and C １ -C ６ The method according to claim 13, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

26. The cucurbituryl compound has the structure of formula XIIc: 【Chemistry 14】 or a pharmaceutically acceptable salt thereof, wherein each X is independently H, an alkali metal cation, (e.g., Li ＋ Na ＋ _K ＋ , or Cs ＋ The method according to claim 13, wherein n is independently 1, 2, 3 or 4; ) ammonium cations or combinations thereof; and each n is independently 1, 2, 3 or 4.

27. The cucurbituryl compound has the structure of formula (XIId): 【Chemistry 15】 The method according to claim 13, wherein the formula comprises a pharmaceutically acceptable salt thereof, where each X independently is H, an alkali metal cation, an ammonium cation, or a combination thereof, and each m independently is 1, 2, 3, or 4.

28. The cucurbituryl compound has the structure of formula (XIIe): 【Chemistry 16】 or having a pharmaceutically acceptable salt thereof, in the formula, Each L is independently a chemical bond, C １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, -(CH ２ ) ａ -O-(CH ２ ) ｂ ,-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N(C) １－３ Alkyl) ２ , and O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, each X １ However, independently, H and C １ -C ６ The method according to claim 13, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

29. The cucurbituryl compound has the structure of formula XIII: 【Chemistry 17】 or having a pharmaceutically acceptable salt thereof, in the formula, Each R １Ａ and R １Ｄ However, independently, -O-L-CO ２ X １ and -O-L-SO ３ X １ Selected from, Each L is independently a chemical bond, C １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, -(CH ２ ) ａ -O-(CH ２ ) ｂ ,-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N(C) １－３ Alkyl) ２ , O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, Each R ３Ａ and R ３Ｂ However, independently, hydrogen, halogen, CO ２ H, CO ２ R', CONH ２ ,CONHR',CON(R') ２ , -OH, C １ -C ６ Selected from alkyl, phenyl, substituted phenyl and 2-6 member heteroalkyl groups, Additionally or alternatively, R bonded to an adjacent carbon atom ３Ａ and R ３Ｂ However, together with the carbon atoms to which they are bonded, they form a five-membered or six-membered cycloalkyl ring or a heterocycloalkyl ring. Each R ４Ａ and R ４Ｂ However, independently, hydrogen, halogen, -OH, CO ２ H, CO ２ R', CONH ２ ,CONHR',CON(R') ２ , C １ -C ６ Selected from alkyl, phenyl, substituted phenyl and 2-6 member heteroalkyl groups, Each R' independently １－６ Selected from alkyl groups, each X １ However, independently, H and C １ -C ６ The method according to claim 13, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

30. The cucurbituryl compound has the structure of formula XIIIa: [Chemistry 18] or having a pharmaceutically acceptable salt thereof, in the formula, Each R １Ａ and R １Ｄ However, independently, -O-L-CO ２ X １ and -O-L-SO ３ X １ Selected from, Each L is independently a chemical bond, C １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, -(CH ２ ) ａ -O-(CH ２ ) ｂ ,-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N(C) １－３ Alkyl) ２ , O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, each X １ However, independently, H and C １ -C ６ The method according to claim 13, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

31. The cucurbituryl compound described above has the following structure: 【Chemistry 19】 The method according to claim 13, having the following characteristics.

32. The method according to any one of claims 1 to 10, wherein the sequestering agent is pillararene.

33. The septic agent is a pillararene having the structure: 【Chemistry 20】 or having a pharmaceutically acceptable salt thereof, in the formula, n is selected from 0, 1, 2, or 3. Each R independently, -(CH ２ ) ａ S(O) ｂ X １ ,-(CH ２ ) ａ CO ２ X １ , and - (CH ２ ) ａ PO ｂ X １ Selected from; a is 0, 1, 2, 3, or 4; b is 2 or 3, each X １ The method according to claim 32, wherein the cation is independently selected from H, -OH, alkali metal cations, and quaternary ammonium cations.

34. Each R is -(CH ２ ) ａ SO ３ X １ａ ,-(CH ２ ) ａ CO ２ X １ａ , and - (CH ２ ) ａ PO ３ X １ａ Selected from; a is 0, 1, 2 or 3, X １ａ The method according to claim 33, wherein is H, an alkali metal cation, and a quaternary ammonium cation.

35. R is SO ３ H or its salts (e.g., SO ３ Na), or -CH ２ COOH or its salt (e.g., CH ２ The method according to claim 33, wherein COONa is used.

36. R is SO ３ H and SO ３ The method according to claim 33, wherein n is selected from Na and n is 1.

37. A method for preventing or treating an overdose of one or more abused drugs in a patient who needs them, The procedure includes administering a therapeutically effective dose of a sequestering agent to the patient at some point after the administration of one or more abused drugs to the patient. The method wherein the one or more abused drugs include an α2 adrenergic receptor agonist.

38. The method according to claim 37, wherein the α2 adrenergic receptor agonist is xylazine.

39. The method according to claim 37 or claim 38, wherein the one or more abused drugs further comprise one or more amphetamine stimulants, barbiturate hypnotics, opioids, benzodiazepines, and psychedelics.

40. The method according to claim 37 or claim 38, wherein the one or more abused drugs include one or more methamphetamine, fentanyl, and cocaine.

41. The method according to claim 37 or claim 38, wherein the one or more abused drugs further comprise fentanyl or a fentanyl analog.

42. The method according to claim 41, wherein the fentanyl analog is carfentanyl.

43. The method according to any one of claims 37 to 42, wherein the chelating agent comprises cucurbituryl, pyralarene, or calixsalen.

44. The method according to any one of claims 37 to 43, wherein the chelating agent comprises a cucurbituryl compound.

45. The cucurbituryl compound has the structure of formula I: 【Chemistry 21】 or having a pharmaceutically acceptable salt thereof, in the formula, Each R １Ａ and R １Ｄ However, independently, hydrogen, halogen, -OH, C １ -C ６ Alkyl, 2-6 member heteroalkyl, C ３ -C ６ Cycloalkyl, 5-6 member heterocycloalkyl, phenyl, 5-6 member heteroaryl, -O-(CH ２ ) ｎ１ S(O) ｖ１ X １ , -O-(CH ２ ) ｎ１ CO ２ X １ , and -O-(CH ２ ) ｎ１ PO ｖ１ X １ Selected from, Each R １Ｂ and R １Ｃ However, independently, hydrogen, halogen, -OH, C １ -C ６ Alkyl, 2-6 member heteroalkyl, C ３ -C ６ Cycloalkyl, 5-6 member heterocycloalkyl, phenyl, 5-6 member heteroaryl, -O-(CH ２ ) ｎ１ S(O) ｖ１ X １ , -O-(CH ２ ) ｎ１ CO ２ X １ , and -O-(CH ２ ) ｎ１ PO ｖ１ X １ Selected from, or Additionally or alternatively, two R groups bonded to adjacent positions on the same phenyl ring may be added. １Ａ 、 R １Ｂ , R １Ｃ and R １Ｄ However, together with the atoms to which they are bonded, condensation C ６ -C １２ They form aryl, 5- to 12-membered heteroaryl, or 5- to 7-membered heterocycles, which are independently selected halogens, -OH, and -NH ２ , substitution or non-substitution C １ -C ６ Alkyl, or optionally substituted with 1 to 3 substituents on a substituted or unsubstituted 2- to 6-membered heteroalkyl group, Each R ３Ａ and R ３Ｂ However, independently, hydrogen, halogen, -OH, C １ -C ６ Selected from alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyl groups, Each R ４Ａ and R ４Ｂ However, independently, hydrogen, halogen, -OH, C １ -C ６ Selected from alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyl groups, Each n1 is independently selected from 0 to 5. Each v1 is independently selected from 2 or 3. each X １ However, independently, H, -OH, C １ -C ６ The method according to claim 44, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

46. The cucurbituryl compound has the structure of formula (I-a): 【Chemistry 22】 or having a pharmaceutically acceptable salt thereof, in the formula R １Ａ , R １Ｄ , R ３Ａ , R ３Ｂ , R ４Ａ , and R ４Ｂ The method according to claim 44, defined for formula I.

47. The cucurbituryl compound has the structure of formula (I-b): 【Chemistry 23】 or having a pharmaceutically acceptable salt thereof, in the formula R １Ａ and R １Ｄ The method according to claim 44, wherein the formula is as described for formula I.

48. The cucurbituryl compound has the structure of formula (I-c): 【Chemistry 24】 or having a pharmaceutically acceptable salt thereof, wherein X １ The method according to claim 44, wherein n1 is as described for formula I.

49. The cucurbituryl compound has the structure of formula (I-A): 【Chemistry 25】 The method according to claim 44, wherein the method comprises a pharmaceutically acceptable salt thereof, where each X is independently H, an alkali metal cation, or a quaternary ammonium cation.

50. The cucurbituryl compound is compound A, and has the following structure: 【Chemistry 26】 The method according to claim 44, comprising a pharmaceutically acceptable salt thereof.

51. The cucurbituryl compound has the structure of formula (I-D): 【Chemistry 27】 or having a pharmaceutically acceptable salt thereof, in the formula R １Ａ , R １Ｄ , R ３Ａ , R ３Ｂ , R ４Ａ , and R ４Ｂ The method according to claim 44, wherein formula I is as described.

52. The cucurbituryl compound has the structure of formula (X): 【Chemistry 28】 or having a pharmaceutically acceptable salt thereof, in the formula R １Ａ and R １Ｄ The method according to claim 44, wherein the formula I is as described.

53. The cucurbituryl compound is compound B, and has the following structure: 【Chemistry 29】 The method according to claim 44, comprising a pharmaceutically acceptable salt thereof.

54. The cucurbituryl compound has the structure of formula XI: 【Transformation 30】 or having a pharmaceutically acceptable salt thereof, in the formula, Each R １Ａ and R １Ｄ However, independently, -O-L-CO ２ X １ and -O-L-SO ３ X １ Selected from, Each L is independently chemically bonded (single bond), C １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, -(CH ２ ) ａ -O-(CH ２ ) ｂ , (CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N (C １－３ Alkyl) ２ , and O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, Each R １Ｂ and R １Ｃ However, independently, hydrogen, halogen, -OH, -CN, CO ２ H, SO ３ H, C １ -C ６ Alkyl, 2-6 member heteroalkyl, C ３ -C ６ Selected from cycloalkyl, 5-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl, Additionally or alternatively, R bonded to the same phenyl ring １Ｂ and R １Ｃ However, together with the aforementioned atoms to which they are bonded, condensation C ６ -C １２ They form aryl, 5- to 12-membered heteroaryl, or 5- to 7-membered heterocycles, which are independently selected halogens, -OH, and -NH ２ , substitution or non-substitution C １ -C ６ Alkyl, or optionally substituted with 1 to 3 substituents on a substituted or unsubstituted 2- to 6-membered heteroalkyl group, Each R ３Ａ and R ３Ｂ However, independently, hydrogen, halogen, -OH, CO ２ H, CO ２ R', CONH ２ , CONHR', CON(R') ２ , C １ -C ６ Selected from alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyl groups, Additionally or alternatively, R bonded to an adjacent carbon atom ３Ａ and R ３Ｂ However, together with the carbon atoms to which they are bonded, they form a five-membered or six-membered cycloalkyl ring or a heterocycloalkyl ring. Each R ４Ａ and R ４Ｂ However, independently, hydrogen, halogen, -OH, CO ２ H, CO ２ R', CONH ２ ,CONHR',CON(R') ２ , C １ -C ６ Selected from alkyl, phenyl, substituted phenyl and 2-6 member heteroalkyl groups, Each R' independently １－６ Selected from alkyl groups, each X １ However, independently, H and C １ -C ６ The method according to claim 44, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

55. The cucurbituryl compound has the structure of formula XII: 【Chemistry 31】 or having a pharmaceutically acceptable salt thereof, in the formula, Each R １Ａ and R １Ｄ It is independently -O-L-CO ２ X １ , and -O-L-SO ３ X １ Selected from, Each L is independently a chemical bond, C ２ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, -(CH ２ ) ａ -O-(CH ２ ) ｂ ,-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N(C) １－３ Alkyl) ２ , and O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, Each R ３Ａ and R ３Ｂ However, independently, hydrogen, halogen, -OH, CO ２ H, CO ２ R', CONH ２ , CONHR', CON(R') ２ , C １ -C ６ Selected from alkyl, phenyl, substituted phenyl, and 2-6 member heteroalkyl groups, Additionally or alternatively, R bonded to an adjacent carbon atom ３Ａ and R ３Ｂ However, together with the carbon atoms to which they are bonded, they form a five-membered or six-membered cycloalkyl ring or a heterocycloalkyl ring. Each R ４Ａ and R ４Ｂ However, independently, hydrogen, halogen, -OH, CO ２ H, CO ２ R', CONH ２ ,CONHR',CON(R') ２ , C １ -C ６ Selected from alkyl, phenyl, substituted phenyl and 2-6 member heteroalkyl groups, Each R' independently １－６ Selected from alkyl groups, each X １ However, independently, H and C １ -C ６ The method according to claim 54, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

56. The cucurbituryl compound has the structure of formula XIIa: 【Chemistry 32】 or having a pharmaceutically acceptable salt thereof, in the formula, Each R １Ａ and R １Ｄ However, independently, -O-L-CO ２ X １ and -O-L-SO ３ X １ Selected from, Each L is independently a chemical bond, C １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, -(CH ２ ) ａ -O-(CH ２ ) ｂ ,-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N(C) １－３ Alkyl) ２ , and O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, each X １ However, independently, H and C １ -C ６ The method according to claim 54, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

57. The cucurbituryl compound has the structure of formula XIIb: 【Transformation 33】 or having a pharmaceutically acceptable salt thereof, in the formula, Each L independently １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, - (CH ２ ) ａ -O-(CH ２ ) ｂ ,-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N (C １－３ Alkyl) ２ , and O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, each X １ However, independently, H and C １ -C ６ The method according to claim 54, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

58. The cucurbituryl compound has the structure of formula XIIc: 【Transformation 34】 The method according to claim 54, wherein the formula comprises a pharmaceutically acceptable salt thereof, where each X independently is H, an alkali metal cation, an ammonium cation, or a combination thereof, and each n independently is 1, 2, 3, or 4.

59. The cucurbituryl compound has the structure of formula XIId: 【Chemistry 35】 The method according to claim 54, wherein the formula comprises a pharmaceutically acceptable salt thereof, where each X independently is H, an alkali metal cation, an ammonium cation, or a combination thereof, and each m independently is 1, 2, 3, or 4.

60. The cucurbituryl compound has the structure of formula XIIe: 【Transformation 36】 or having a pharmaceutically acceptable salt thereof, in the formula, Each L is independently a chemical bond, C １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, -(CH ２ ) ａ -O-(CH ２ ) ｂ ,-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N(C) １－３ Alkyl) ２ , and O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, each X １ However, independently, H and C １ -C ６ The method according to claim 54, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

61. The cucurbituryl compound has the structure of formula XIII: 【Chemistry 37】 or having a pharmaceutically acceptable salt thereof, in the formula, Each R １Ａ and R １Ｄ However, independently, -O-L-CO ２ X １ and -O-L-SO ３ X １ Selected from, Each L is independently a chemical bond, C １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, -(CH ２ ) ａ -O-(CH ２ ) ｂ ,-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N(C) １－３ Alkyl) ２ , O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, Each R ３Ａ and R ３Ｂ However, independently, hydrogen, halogen, CO ２ H, CO ２ R', CONH ２ ,CONHR',CON(R') ２ , -OH, C １ -C ６ Selected from alkyl, phenyl, substituted phenyl and 2-6 member heteroalkyl groups, Additionally or alternatively, R bonded to an adjacent carbon atom ３Ａ and R ３Ｂ However, together with the carbon atoms to which they are bonded, they form a five-membered or six-membered cycloalkyl ring or a heterocycloalkyl ring. Each R ４Ａ and R ４Ｂ However, independently, hydrogen, halogen, -OH, CO ２ H, CO ２ R', CONH ２ ,CONHR',CON(R') ２ , C １ -C ６ Selected from alkyl, phenyl, substituted phenyl and 2-6 member heteroalkyl groups, Each R' independently １－６ Selected from alkyl groups, each X １ However, independently, H and C １ -C ６ The method according to claim 54, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

62. The cucurbituryl compound has the structure of formula XIIIa: 【Transformation 38】 or having a pharmaceutically acceptable salt thereof, in the formula, Each R １Ａ and R １Ｄ However, independently, -O-L-CO ２ X １ and -O-L-SO ３ X １ Selected from, Each L is independently a chemical bond, C １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, -(CH ２ ) ａ -O-(CH ２ ) ｂ ,-(CH ２ ) ｃ -N(R)-(CH ２ ) ｄ , and - (CH ２ ) ａ - (OCH ２ CH ２ ) ｅ - (Y) ｆ - Selected from, each of these may be unsubstituted or contain a halogen, OH, CO at any carbon. ２ H, C １－３ Alkyl, NH ２ NH(C １－３ Alkyl), N(C) １－３ Alkyl) ２ , O-C １－３ It may be substituted with 1 to 4 substituents selected from alkyl groups. a is 2 to 8, b is between 0 and 6. c is between 2 and 8. d is between 0 and 6. e is 1 to 6, Y is NH, N(C １－３ Alkyl), or O, f is either 0 or 1, R is H or C １－３ It is alkyl, each X １ However, independently, H and C １ -C ６ The method according to claim 54, selected from alkyl, alkali metal cations, and quaternary ammonium cations.

63. The cucurbituryl compound described above has the following structure: 【Chemistry 39】 The method according to claim 54, having the following characteristics.

64. The method according to any one of claims 27 to 33, wherein the sequestering agent is pillararene.

65. The septic agent is a pillararene having the structure: 【Chemistry 40】 or having a pharmaceutically acceptable salt thereof, in the formula, n is selected from 0, 1, 2, or 3. Each R independently, -(CH ２ ) ａ S(O) ｂ X １ ,-(CH ２ ) ａ CO ２ X １ , and - (CH ２ ) ａ PO ｂ X １ Selected from; a is 0, 1, 2, 3, or 4; b is 2 or 3, each X １ The method according to claim 64, wherein the cation is independently selected from H, -OH, alkali metal cations, and quaternary ammonium cations.

66. Each R is -(CH ２ ) ａ SO ３ X １ａ ,-(CH ２ ) ａ CO ２ X １ａ , and - (CH ２ ) ａ PO ３ X １ａ Selected from; a is 0, 1, 2 or 3, X １ａ The method according to claim 65, wherein is H, an alkali metal cation, and a quaternary ammonium cation.

67. R is SO ３ H or its salts (e.g., SO ３ Na), or -CH ２ COOH or its salt (e.g., CH ２ The method according to claim 65, wherein COONa is used.

68. R is SO ３ H and SO ３ The method according to claim 65, wherein n is selected from Na and n is 1.

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