Cucurbituril compounds

Abstract

The disclosures herein relate to cucurbituril compounds and methods and compositions for reducing the amount of a toxin in a patient by administering to the patient an effective amount of the cucurbituril compound. Also provided are methods and compositions for preventing or treating an overdose from a toxin that has been ingested by a patient.

Description

CUCURBITURIL COMPOUNDS

[0001] This invention was made with government support under grant no. U01DA053054 awarded by the National Institute of Health. The government has certain rights in the invention.FIELD

[0002] The disclosures herein relate to cucurbituril compounds and methods and compositions for reducing the amount of a toxin in a patient by administering to the patient an effective amount of the cucurbituril compound. Also provided are methods and compositions for preventing or treating an overdose from a toxin that has been ingested by a patient.BACKGROUND

[0003] Cucurbiturils are a class of macrocyclic compounds based on oligomers of glycoluril, its analogues and derivatives. Cucurbiturils can be used to form complexes with other molecules and are useful as sequestering agents. This property makes cucurbiturils an attractive candidate for the entrapment and removal of chemical agents, such as toxins and pollutants.

[0004] There is a significant unmet medical need to sequester and remove ingested toxins, including prescription and illicit drugs, from the bloodstream and / or gastrointestinal tract of a patient. The availability, use, misuse, and abuse of prescription and illicit drugs has increased dramatically over the past decade across all ages ranging from children to adults.

[0005] Drug overdose, intoxication and addiction are major social issues that affects all aspects of society. An epidemic of opioid use disorders and of fatal overdose due to the illicit use of heroin and fentanyl are a growing concern worldwide. Over 100,000 overdose deaths were reported in the 12-month period ending in April 2021, with the large majority of the overdose deaths due to synthetic opioids, mostly fentanyl and its analogs.(http: / / www.cdc.gov / nchs / nvss / vsrr / drug-overdose-data.htm). Alarmingly, potent fentanyl analogs such as carfentanil, cyclopropyl fentanyl, (±)-cis-3 -methyl fentanyl, and furanyl fentanyl have been used as adulterants in illicit drugs, which have resulted in many fatal overdose cases.

[0006] There is also an urgent need for a safe and rapidly acting reversal agent for methamphetamine. Methamphetamine (meth) is the fastest growing drug of abuse in theU.S., representing over 200,000 annual emergency room (ER) visits, with deaths quadrupling since 2015 (9356 deaths in 2017 alone), yet no current therapeutics are available for treating meth intoxication. Meth induces excessive, rapid, and sustained (serum half-life tU ~10hr) stimulation of the sympathetic nervous system, responsible for a recognizable adrenergic toxi drome consisting of both behavioral (psychomotor agitation) and physiological (tachycardia, hypertension, mydriasis, and diaphoresis) components. Meth intoxication can cause cardiovascular and other complications; 20% of ER visits require hospital admission. The current standard of care for meth intoxication is to treat the symptoms only. A reversal agent for meth that normalizes both the behavioral and physiological components would minimize complications, improve patient outcomes, and reduce mortality.

[0007] There remains a need for methods and compositions for the treatment of patients suffering from drug overdose or drug intoxication.SUMMARY

[0008] The present disclosure provides cucurbituril compounds, compositions and methods for addressing these and other circumstances wherein it is desirable to reverse the effect of one or more toxic agents, including but not necessarily limited to drugs of abuse.

[0009] In one aspect, the disclosure provides a cucurbituril compound having the structure of formula I:or a pharmaceutically acceptable salt thereof, wherein: each R1Aand R1Dis independently selected from -O-L-CO2X1; each L is independently selected from Ci to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6;c is 2 to 8; d is 0 to 6; e is 1 to 6;Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or Ci-3 alkyl; each R1Band R1Cis independently selected from hydrogen, halogen, -OH, -CN, CO2H, SO3H, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl; or additionally or alternatively, R1Band R1Cattached on the same phenyl ring, together with the atoms to which they are attached, are joined to form a fused C6-C12 aryl, 5 to 12 membered heteroaryl, or 5 to 7 membered heterocycle, which are optionally substituted with 1 to 3 substituents independently selected halogen, -OH, -NH2, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl; each R3Aand R3Bis independently selected from hydrogen, halogen, -OH, CO2H, CO2R', CONH2, CONHR', C0N(R')2, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; additionally or alternatively, R3Aand R3Battached to adjacent carbon atoms, together with the carbons to which they are attached, are joined to form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring; each R4Aand R4Bis independently selected from hydrogen, halogen, -OH, CO2H, CO2R', CONH2, CONHR', C0N(R')2, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; each R' is independently selected from C1-6 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation; wherein when each of R1Band R1Care H, then L is not -CH2-.

[0010] In another aspect, the disclosure provides a method of reducing the concentration of a toxic agent in the body of a patient by administering to the patient a therapeutically effective amount of a composition comprising a cucurbituril compound. The toxic agent may be a drug of abuse, such as methamphetamine, cocaine, fentanyl or a fentanyl analog, such as carfentanil, or combinations thereof.

[0011] In one embodiment, the dosage form is an aqueous solution that is suitable for injection into a patient comprising (i) a cucurbituril compound disclosed herein, (ii) optionally, a buffering agent, and (iii) optionally a tonicity agent. In another embodiment, the dosage form is a solid for reconstitution comprising (i) a cucurbituril compound as disclosed herein, (iii) optionally, a buffering agent, and (iii) optionally a tonicity agent.

[0012] In another embodiment, the dosage form is an oral dosage form comprising a cucurbituril compound as disclosed herein, and one or more pharmaceutically acceptable carriers.DETAILED DESCRIPTION

[0013] There is an urgent need for therapeutics that facilitate the removal of toxic agents from a patient’s body, particularly in the context of drug abuse and overdose. A new class of drugs, acyclic cucurbiturils, represent a promising technology for lowering the concentration of toxic agents, including drugs of abuse, in a patient suffering from high exposure to the toxic agent, such as drug overdose.

[0014] In an aspect, the cucurbituril compound has a structure of formula I:or a pharmaceutically acceptable salt thereof, wherein: each R1Aand R1Dis independently selected from -O-L-CO2X1; each L is independently selected from Ci to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6; e is 1 to 6;Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or Ci-3 alkyl; each R1Band R1Cis independently selected from hydrogen, halogen, -OH, -CN, CO2H, SO3H, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl; or additionally or alternatively, R1Band R1Cattached on the same phenyl ring, together with the atoms to which they are attached, are joined to form a fused C6-C12 aryl, 5 to 12 membered heteroaryl, or 5 to 7 membered heterocycle, which are optionally substituted with 1 to 3 substituents independently selected halogen, -OH, -NH2, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl; each R3Aand R3Bis independently selected from hydrogen, halogen, -OH, CO2H, CO2R', CONH2, CONHR', C0N(R')2, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; additionally or alternatively, R3Aand R3Battached to adjacent carbon atoms, together with the carbons to which they are attached, are joined to form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring; each R4Aand R4Bis independently selected from hydrogen, halogen, -OH, CO2H, CO2R', CONH2, CONHR', C0N(R')2, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; each R' is independently selected from C1-6 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation; wherein when each of R1Band R1Care H, then L is not -CH2-.

[0015] In embodiments, L is Ci to C10 alkylene, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl / , and O-C1-3 alkyl. In embodiments, L is Ci to C10 alkylene, C2 to C10 alkylene, Ci to Ce alkylene, or C2 to Ce alkylene, each of which may be unsubstituted or substituted. L may be -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, and the like.

[0016] In other embodiments, L is a C2 to C10 alkenylene chain, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl, and which comprises 1 to 3 carbon-carbon double bonds. In embodiments, L is C2 to Ce 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 the like.

[0017] In other embodiments, L is -(CH2)a-(OCH2CH2)e-(Y) / -, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl. L may comprise a polyethylene glycol oligomer, i.e., -(CH2CH2O)x-, in which x is 2 to 6.

[0018] In embodiments, R1Bis hydrogen, halogen, -OH, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl. In embodiments, R1Bis hydrogen, halogen, -OH, or Ci-Ce alkyl, and particularly R1Bis hydrogen or halogen.

[0019] In embodiments, R1Cis hydrogen, halogen, -OH, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl. In embodiments, R1Cis hydrogen, halogen, -OH or Ci-Ce alkyl, and particularly, R1Cis hydrogen or halogen.

[0020] In embodiments, R1Band R1Care hydrogen.

[0021] In embodiments, R1Band R1C, attached on the same phenyl ring, together with atoms attached thereto, join to form C6-C12 aryl, or 5 to 12 membered heteroaryl. In embodiments, R1Band R1C, attached on the same phenyl ring, together with atoms attached thereto, join to form phenyl. In embodiments, R1BandRlc, attached on the same phenyl ring, together with atoms attached thereto, join to form naphthyl or anthracenyl. In embodiments, R1BandRlc, attached on the same phenyl ring, together with atoms attached thereto, join to form pyridyl.

[0022] In embodiments, the C6-C12 aryl or 5 to 12 membered heteroaryl, which are formed by R1Band R1Cattached on the same phenyl ring, may be substituted with one or more substituents, e.g., halogen, -OH, -NH2, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0023] In embodiments, R3Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R3Ais C1-C3 alkyl, and particularly methyl.

[0024] In embodiments, R3Bis hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R3Bis C1-C3 alkyl, and particularly methyl.

[0025] In embodiments, R3Aand R3Bare both hydrogen. Alternatively, R3Aand R3Bare both methyl. In embodiments, one of R3Aand R3Bis hydrogen and the other is methyl.

[0026] In embodiments, R4Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R4Ais C1-C3 alkyl, and particularly methyl. In embodiments, R4Ais H.

[0027] In embodiments, R4Bis hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R4Bis C1-C3 alkyl, and particularly methyl. In embodiments, R4Bis hydrogen.

[0028] In embodiments, each R4Aand R4Bis hydrogen. Alternatively, each R4Aand R4Bmay be methyl. In embodiments, one of R4Aand R4Bis hydrogen and the other is methyl.

[0029] In embodiments, each R3Aand R3Bis independently C1-C3 alkyl and R4Aand R4Bare hydrogen, and particularly, each R3Aand R3Bare methyl and each R4Aand R4Bare hydrogen.

[0030] In another aspect, the cucurbituril compound has the structure of formula II:or a pharmaceutically acceptable salt thereof, wherein: each R1Aand R1Dis independently selected from -O-L-CO2X1; each L is independently selected from C2 to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6; e is 1 to 6;Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or Ci-3 alkyl; each R3Aand R3Bis independently selected from hydrogen, halogen, -OH, CO2H, CO2R', CONH2, CONHR', C0N(R')2, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; additionally or alternatively, R3Aand R3Battached to adjacent carbon atoms, together with the carbons to which they are attached, are joined to form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring; each R4Aand R4Bis independently selected from hydrogen, halogen, -OH, CO2H, CO2R', CONH2, CONHR', C0N(R')2, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; each R' is independently selected from C1-6 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation.

[0031] In embodiments, L is C2 to C10 alkylene, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl. In embodiments, L is C2 to Ce alkylene, which may be unsubstituted or substituted. L may be -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, and the like.

[0032] In other embodiments, L is a C2 to C10 alkenylene chain, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl, and which comprises 1 to 3 carbon-carbon double bonds. In embodiments, L is C2 to Ce 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 the like.

[0033] In other embodiments, L is -(CH2)a-(OCH2CH2)e-(Y) / -, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl. L may comprise a polyethylene glycol oligomer, i.e., -(CH2CH2O) -, in which x is 2 to 6.

[0034] In embodiments, R3Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R3Ais C1-C3 alkyl, and particularly methyl.

[0035] In embodiments, R3Bis hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R3Bis C1-C3 alkyl, and particularly methyl.

[0036] In embodiments, R3Aand R3Bare both hydrogen. Alternatively, R3Aand R3Bmay both be methyl. In embodiments, one of R3Aand R3Bis hydrogen and the other is methyl.

[0037] In embodiments, R4Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R4Ais C1-C3 alkyl, and particularly methyl. In embodiments, R4Ais H.

[0038] In embodiments, R4Bis hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R4Bis C1-C3 alkyl, and particularly methyl. In embodiments, R4Bis hydrogen.

[0039] In embodiments, each R4Aand R4Bis hydrogen. Alternatively, each R4Aand R4Bmay be methyl. In embodiments, one of R4Aand R4Bis hydrogen and the other is methyl.

[0040] In embodiments, each R3Aand R3Bis independently C1-C3 alkyl and R4Aand R4Bare hydrogen, and particularly, each R3Aand R3Bare methyl and each R4Aand R4Bare hydrogen.

[0041] In embodiments, R1Aand R1Dattached to the same phenyl ring may be same or different. In embodiments, R1Aand R1Aattached to the different phenyl rings may be same or different. In embodiments, R1Dand R1Dattached to the different phenyl rings may be same or different. In embodiments, each R1Aand R1Dis the same.

[0042] In another aspect, the cucurbituril compound has the structure of formula Ila:or a pharmaceutically acceptable salt thereof, wherein: each R1Aand R1Dis independently selected from -O-L-CO2X1; each L is independently selected from C2 to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8;d is 0 to 6; e is 1 to 6; Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or Ci-3 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation.

[0043] In embodiments, L is C2 to C10 alkylene, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl. In embodiments, L is C2 to Ce alkylene, which may be unsubstituted or substituted. L may be -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, and the like.

[0044] In other embodiments, L is a C2 to C10 alkenylene chain, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl / , and O-C1-3 alkyl, and which comprises 1 to 3 carbon-carbon double bonds. In embodiments, L is C2 to Ce 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 the like.

[0045] In other embodiments, L is -(CH2 -(OCH2CH2 -(Y / -, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl / , and O-C1-3 alkyl. L may comprise a polyethylene glycol oligomer, i.e., -(CH2CH2O / -, in which x is 2 to 6.

[0046] In embodiments, R1Aand R1Dattached to the same phenyl ring may be same or different. In embodiments, R1Aand R1Aattached to the different phenyl rings may be same or different. In embodiments, R1Dand R1Dattached to the different phenyl rings may be same or different. In embodiments, each R1Aand R1Dis the same.

[0047] In another aspect, the cucurbituril compound has the structure of Formula lib :or a pharmaceutically acceptable salt thereof, wherein: each L is independently selected from C2 to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6; e is 1 to 6;Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or C1-3 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation.

[0048] In embodiments, L is C2 to C10 alkylene, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(Ci-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl. In embodiments, L is C2 to Ce alkylene, which may be unsubstituted or substituted. L may be -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, and the like.

[0049] In other embodiments, L is a C2 to C10 alkenylene chain, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(Ci-3 alkyl), N(CI-3 alkyl / , and O-C1-3 alkyl, and which comprises 1 to 3 carbon-carbon double bonds. In embodiments, L is C2 to Ce 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 the like.

[0050] In other embodiments, L is -(CH2)a-(OCH2CH2)e-(Y) / -, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl. L may comprise a polyethylene glycol oligomer, i.e., -(CH2CH2O).-, in which x is 2 to 6.

[0051] In another aspect, the cucurbituril compound has the structure of Formula lie:or a pharmaceutically acceptable salt thereof. Each X is independently H, alkali metal cation (e.g., Li+, Na+, K+, or Cs+), an ammonium cation, or combination thereof. Each n is independently 2, 3 or 4.

[0052] In another aspect, the cucurbituril compound has the structure of Formula lid:or a pharmaceutically acceptable salt thereof. Each X is independently H, alkali metal cation (e.g., Li+, Na+, K+, or Cs+), an ammonium cation, or combination thereof. Each m is independently 1, 2, 3 or 4.

[0053] In another aspect, the cucurbituril compound has the structure of Formula III:or a pharmaceutically acceptable salt thereof, wherein:each R1Aand R1Dis independently selected from -O-L-CO2X1; each L is independently selected from Ci to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6; e is 1 to 6;Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or C1-3 alkyl; each R3Aand R3Bis independently selected from hydrogen, halogen, CO2H, CO2R', CONH2, CONHR', C0N(R')2, -OH, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; additionally or alternatively, R3Aand R3Battached to adjacent carbon atoms, together with the carbons to which they are attached, are joined to form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring; each R4Aand R4Bis independently selected from hydrogen, halogen, -OH, CO2H, CO2R', CONH2, CONHR', C0N(R')2, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; each R' is independently selected from C1-6 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation.

[0054] In embodiments, L is Ci to C10 alkylene, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(Ci-3 alkyl), N(CI-3 alkyl / , and O-C1-3 alkyl. In embodiments, L is Ci to C10 alkylene, C2 to C10 alkylene, Ci to Ce alkylene, or C2 to Ce alkylene, each of which may be unsubstituted or substituted. L may be -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, and the like.

[0055] In other embodiments, L is a C2 to C10 alkenylene chain, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl, and which comprises 1 to 3 carbon-carbon double bonds. In embodiments, L is C2 to Ce 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 the like.

[0056] In other embodiments, L is -(CH2)a-(OCH2CH2)e-(Y) / -, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl. L may comprise a polyethylene glycol oligomer, i.e., -(CH2CH2O)x-, in which x is 2 to 6.

[0057] In embodiments, R3Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R3Ais C1-C3 alkyl, and particularly methyl.

[0058] In embodiments, R3Bis hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R3Bis C1-C3 alkyl, and particularly methyl.

[0059] In embodiments, R3Aand R3Bare both hydrogen. Alternatively, R3Aand R3Bmay both be methyl. In embodiments, one of R3Aand R3Bis hydrogen and the other is methyl.

[0060] In embodiments, R4Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R4Ais C1-C3 alkyl, and particularly methyl. In embodiments, R4Ais H.

[0061] In embodiments, R4Bis hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R4Bis C1-C3 alkyl, and particularly methyl. In embodiments, R4Bis hydrogen.

[0062] In embodiments, each R4Aand R4Bis hydrogen. Alternatively, each R4Aand R4Bmay be methyl. In embodiments, one of R4Aand R4Bis hydrogen and the other is methyl.

[0063] In embodiments, each R3Aand R3Bis independently C1-C3 alkyl and R4Aand R4Bare hydrogen, and particularly, each R3Aand R3Bare methyl and each R4Aand R4Bare hydrogen.

[0064] In another aspect, the cucurbituril compound has the structure of Formula Illa:or a pharmaceutically acceptable salt thereof, wherein: each R1Aand R1Dis independently selected from -O-L-CO2X1; each L is independently selected from Ci to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6; e is 1 to 6; Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or C1-3 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation.

[0065] In embodiments, L is Ci to C10 alkylene, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(Ci-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl. In embodiments, L is Ci to C10 alkylene, C2 to C10 alkylene, Ci to Ce alkylene, or C2 to Ce alkylene, each of which may be unsubstituted or substituted. L may be -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, and the like.

[0066] In other embodiments, L is a C2 to C10 alkenylene chain, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(Ci-3 alkyl), N(CI-3 alkyl / , and O-C1-3 alkyl, and which comprises 1 to 3 carbon-carbon double bonds. In embodiments, L is C2 to Ce 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 the like.

[0067] In other embodiments, L is -(CH2)a-(OCH2CH2)e-(Y) / -, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH,CChH, Ci-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl. L may comprise a polyethylene glycol oligomer, i.e., -(CH2CH2O / -, in which x is 2 to 6.

[0068] In embodiments, R1Aand R1Dattached to the same phenyl ring may be same or different. In embodiments, R1Aand R1Aattached to the different phenyl rings may be same or different. In embodiments, R1Dand R1Dattached to the different phenyl rings may be same or different. In embodiments, each R1Aand R1Dis the same.

[0069] In another aspect, the cucurbituril compound has the structure of Formula Illb:or a pharmaceutically acceptable salt thereof, wherein: each L is independently selected from Ci to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6; e is 1 to 6;Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or C1-3 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation.

[0070] In embodiments, L is Ci to C10 alkylene, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl. In embodiments, L is Ci to C10 alkylene, C2 to C10 alkylene, Ci to Ce alkylene, or C2 to Ce alkylene, each of which may be unsubstituted or substituted. L may be -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-,-CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, and the like.

[0071] In other embodiments, L is a C2 to C10 alkenylene chain, which may be unsubstituted or substituted with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl, and which comprises 1 to 3 carbon-carbon double bonds. In embodiments, L is C2 to Ce 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 the like.

[0072] In other embodiments, L is -(CH2)a-(OCH2CH2)e-(Y) / -, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl. L may comprise a polyethylene glycol oligomer, i.e., -(CH2CH2O) -, in which x is 2 to 6.

[0073] In another aspect, the cucurbituril compound has the structure of Formula IIIc:or a pharmaceutically acceptable salt thereof. Each X is independently H, alkali metal cation (e.g., Li+, Na+, K+, or Cs+), an ammonium cation, or combination thereof. Each n is independently 1, 2, 3 or 4.

[0074] In another aspect, the cucurbituril compound has the structure of Formula Hid:or a pharmaceutically acceptable salt thereof. Each X is independently H, alkali metal cation (e.g., Li+, Na+, K+, or Cs+), an ammonium cation, or combination thereof. Each m is independently 1, 2, 3 or 4.SYNTHESIS

[0075] Provided herein are methods of preparing the cucurbituril compounds described herein (i.e., compounds of formula I, II, Ila, lib, lie, lid, III, Illa, Illb, IIIc and Illd).

[0076] In embodiments, the methods include the following Scheme 2.Scheme 2II HI wherein R3Aand R3Bare as described herein. In embodiments, R3Aand R3Bare C1-3 alkyl, or R3Aand R3Bare methyl.

[0077] The reaction according to Scheme 2 involves the treatment of a glycoluril compound having the formula II with paraformaldehyde in the presence of an acid to provide the glycoluril bis-ether of formula III. The paraformaldehyde is added in a molar excess relative to the glycoluril compound. The ratio of paraformaldehyde to the glycoluril compound may be from about 3 equivalents to about 8 equivalents, or from about 4 equivalents to about 6 equivalents.

[0078] Paraformaldehyde as used in Scheme 2 is a polyoxymethylene and is the polymerization product of formaldehyde, which may have a typical degree of polymerization of 8-100 units. The paraformaldehyde may be supplied as a solid or as solution, particularly as an aqueous solution.

[0079] The paraformaldehyde may be added to a mixture of the glycoluril compound, the acid and solvent in a reaction vessel. Prior to the addition of the paraformaldehyde to the reaction mixture, the temperature of the mixture may be brought to 35 °C or above. The temperature of the reaction mixture is maintained at 35 °C or above for the duration of the addition, after which the temperature may be maintained, or increased for example to 45 °C or above or to 50 °C or above, which increase may be temporary or maintained for the remainder of the reaction period, or even lowered from the addition temperature so long as the reaction temperature is maintained at or above about 35 °C.

[0080] The acid used in the reaction mixture is a strong acid. In embodiments, the acid in the reaction of Scheme 2 may have a pKa of less than about 2.5, or a pKa of less than about2.0, or a pKa of less than about 1.5, or a pKa of less than about 1, or a pKa of less than about 0.9, or a pKa of less than about 0.8, or a pKa of less than about 0.7, or a pKa of less than about 0.6, or a pKa of less than about 0.5. In embodiments, the acid in the reaction of Scheme 2 may have a pKa of less than about 0.9. The acid in the reaction of Scheme 2 may include, but is not limited to, HF, HC1, HBr, HC1O4, HNO3, H2SO4, H3PO4, sulfonic acids such as methane sulfonic acid, trifluoromethane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid or toluene sulfonic acid, Eaton’s reagent, trifluoroacetic acid, or combinations thereof. In embodiments, the acid in the reaction of Scheme 2 includes HF, HC1 or HBr, and particularly, the acid is HC1. The molar concentration of the acid used in this reaction may range from about 5 to about 10 M, from about 6 to about 9 M, or from about 7 to about 9 M.

[0081] In embodiments, the methods include the following Scheme 3.Scheme 3wherein R4A, and R4Bare as described herein. In embodiments, R4Aand R4Bare hydrogen.

[0082] The reaction according to Scheme 3 involves the treatment of a glycoluril compound having the formula II’ with paraformaldehyde in the presence of an acid to provide the glycoluril dimer of formula IV. The solvent may be selected from water, alcohols such as methanol, ethanol and isopropanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), dioxane, sulfolane, acetone, N,N-dimethylpropyleneurea (DMPU), diglymes, hexamethylphosphoramide (HMPA), or combinations thereof. In embodiments, the solvent is water, or water in combination with another solvent.

[0083] The paraformaldehyde is added in approximately the same or similar amount to the glycoluril compound. The ratio of paraformaldehyde to the glycoluril compound may be from about 0.5 equivalents to about 1.5 equivalents, or from about 0.8 equivalents to about 1.2 equivalents. The paraformaldehyde to the glycoluril compound may be in about 1.0 equivalent.

[0084] According to Scheme 3, the reaction mixture in Scheme 3 does not solidify during the reaction process. For example, the reaction mixture does nor form a gel during the reaction or after the reaction is quenched. Maintaining stoichiometry as the reaction proceeds may be important for selective production of the dimer of formula IV without occurrence of gelling of the reaction mixture. The paraformaldehyde as used in Scheme 3 may be supplied as a solid or as solution, particularly as an aqueous solution. The paraformaldehyde is added to a reaction vessel containing the compound of formula (II’) and acid over an extended period of time, e.g., added by dropwise or by several portions.

[0085] Maintaining careful stoichiometry as the reaction proceeds is important for selectively producing the glycoluril dimer of formula IV. Although the slow addition of the paraformaldehyde to the reaction mixture could be expected to disrupt reaction stoichiometry, the inventors have found that the yield and purity of the glycoluril dimer of formula IV was consistent or improved. Additionally, the slow addition of paraformaldehyde to the reaction mixture reduced or prevented the occurrence of gelling in the reaction mixture. The reaction proceeded more completely and with greatly improved workup, allowing the reaction to be used at a commercial scale.

[0086] Paraformaldehyde may be added to the compound of formula II’ in greater than 4 portions, for example in 4-10 portions, or in 5-8 portions. The paraformaldehyde may be added to the compound of formula II’ in 4 portions, 5 portions, 6 portions, 7 portions, or 8 portions, or more. For example, paraformaldehyde is added in four or more portions separated by at least about 10 minutes, by at least about 15 minutes, by at least about 20 minutes, by at least about 25 minutes, by at least about 30 minutes. In embodiments, the paraformaldehyde is added in six or more portions separated by at least about 30 minutes.

[0087] Alternatively, the paraformaldehyde is added to the compound of formula IF over a period of at least about 45 minutes, or at least about 1 hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours, at least about 3 hours, at least about 3.5 hours, at least about 4 hours, at least about 4.5 hours, or at least about 5 hours, wherein the addition is done continuously over the time period (i.e., from the first addition to the last addition), for example by continuous or dropwise addition, or in multiple portions over the time period.

[0088] The acid used in the reaction mixture of Scheme 3 is a strong acid. In embodiments, the acid in the reaction of Scheme 3 may have a pKa of less than about 2.5, or a pKa of less than about 2.0, or a pKa of less than about 1.5, or a pKa of less than about 1, or a pKa of less than about 0.9, or a pKa of less than about 0.8, or a pKa of less than about 0.7, or a pKa of less than about 0.6, or a pKa of less than about 0.5. In embodiments, the acid inthe reaction of Scheme 3 may have a pKa of less than about 0.9. The acid in the reaction of Scheme 3 may include, but is not limited to, HF, HC1, HBr, HC1O4, HNO3, H2SO4, H3PO4, a sulfonic acid such as methane sulfonic acid, trifluoromethane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid or toluene sulfonic acid, Eaton’s reagent, trifluoroacetic acid, or combinations thereof. In embodiments, the acid in the reaction of Scheme 3 includes HF, HC1 or HBr, and particularly, the acid is HC1. The molar concentration of the acid used in this reaction may range from about 5 to about 10 M, from about 6 to about 9 M, or from about 7 to about 9 M.

[0089] Prior, during and after the addition of paraformaldehyde to the reaction according to Scheme 3, the temperature of the reaction vessel is elevated. The temperature of the reaction vessel after adding the paraformaldehyde is maintained at a temperature above 50 °C, above 51 °C, above 52 °C, above 53 °C, above 54 °C, above 55 °C, above 56 °C, above 57 °C, 58 °C, above 59 °C, above 60 °C, above 61 °C, above 62 °C, above 63 °C, above 64 °C, above 65 °C, above 66 °C, above 67 °C, above 68 °C, above 69 °C, or above 70 °C.

[0090] The method may further include a step of isolation of the glycoluril dimer compound of formula IV. For example, the isolation may include recrystallisation, precipitation, aggregation, centrifugation, filtration or combinations thereof. The isolation process may include contacting the reaction mixture with water, heating to a temperature of at least about 70 °C, cooling to a temperature below about 30 °C, and isolating the solid, for example by filtering or centrifuging the reaction mixture.

[0091] After adding or contacting water to the reaction mixture, the reaction mixture is heated to the temperature of at least about 70 °C, at least about 71 °C, at least about 72 °C, at least about 73 °C, at least 74 °C, at least about 75 °C, at least about 76 °C, at least about 77 °C, at least about 78 °C, at least about 79 °C, or at least about 80 °C. The reaction vessel can be set at the temperature at least about 70 °C, at least about 71 °C, at least about 72 °C, at least about 73 °C, at least 74 °C, at least about 75 °C, at least about 76 °C, at least about 77 °C, at least about 78 °C, at least about 79 °C, or at least about 80 °C while the reaction mixture is stirring for about 1 to 5 days, or for about 2 to 5 days, or for about 3 days.

[0092] After heating the reaction mixture and the water, the temperature of the reaction mixture is cooled below about 30 °C, below about 29 °C, below about 28 °C, below about 27 °C, below about 26 °C, below about 25 °C, below about 24 °C, below about 23 °C, below about 22 °C, below about 21 °C, or below about 20 °C.

[0093] In certain embodiments, the compounds of formula IV in a solid form (e.g., precipitate, particles, or powders) may be collected by centrifuging the reaction mixture.Alternatively, the compounds of formula IV in a solid form (e.g., precipitate, particles, or powders) may be collected by filtering. In large scale synthesis, precipitation conditions after the reaction may be important to improve the production yield and purity of the reaction in Scheme 3. The precipitation may include adding various solvents (e.g., water or aqueous solution, or a mixture of polar solvent) and followed by removing the solid, for example by filtering.

[0094] In embodiments, the methods include the following Scheme 4.Scheme 4v wherein R4A, and R4Bare as described herein.

[0095] The reaction according to Scheme 4 involves the condensation of the glycoluril bis-ether of formula III and the glycoluril dimer of formula IV to obtain a glycoluril tetramer of Formula V. The reaction in Scheme 4 is performed in the presence of (a) one or more acids having a pKa of less than about 1, and optionally (b) one or more polar aprotic solvents and / or an additional acid solvents.

[0096] In particular, the reaction solvent includes TFA, which may be present as a sole solvent or may be combined with one or more polar aprotic solvents, in combination with one or more strong acids (e.g., Eaton’s reagent). Using TFA without MeSChH or Eaton’s reagent typically results in very slow and ineffective reaction. Most non-acidic solvents fail to fully dissolve the reagents and product or is incompatible with the strong acidic components.

[0097] In certain embodiments, a solid form of the glycoluril bis-ether of formula III may be dispersed in a solvent component and added to the reaction vessel containing the glycoluril dimer. Moreover, the reaction as described in Scheme 4 may require less amount of catalyticacid by using TFA. In certain embodiments, Eaton’s reagent as one or more acids may still be added in about 10 equiv. or greater to promote an increase in reaction rate.

[0098] One or more of the acids used in the reaction mixture of Scheme 3 is a strong acid. In embodiments, the strong acid in the reaction of Scheme 4 may have a pKa of less than about 1, or less than about 0.5, or less than about 0, or less than about -1. The reaction mixture may comprise an additional acidic solvent. The additional acidic solvent in the reaction of Scheme 4 may have a pKa between about 3 to about 0, or may have a pKa of less than about 2.5, less than about 2.0, less than about 1.5, less than about 1, less than about 0.5.

[0099] The one or more strong acids in the reaction of Scheme 4 may include, but is not limited to, Eaton's reagent, MeSChH, toluene sulfonic acid, H2SO4, triflic acid, phosphoric acid, sulfuric acid, CSA, EtSChH, HC1, HBr, HCIO4, HNO3, or combinations thereof. In embodiments, the acid includes methanesulfonic acid. In embodiments, the acid in the reaction includes Eaton's reagent, which is a combination of methanesulfonic acid and phosphorus pentoxide, for example including about 10 wt% phosphorus pentoxide in methanesulfonic acid. In embodiments, at least about 8 equivalents of the strong acid are used, and particularly, at least about 10 equivalents of the strong acid is used.

[0100] The solvents in the reaction of Scheme 4 may include an additional acid including, but is not limited to, trifluoroacetic acid (TFA), acetic acid, phosphoric acid, polyphosphoric acid (PPA), or combinations thereof. In certain embodiments, the additional acid is TFA.

[0101] The reaction of scheme 4 optionally includes one or more polar aprotic solvents in the reaction of Scheme 4 including, but not limited to, DMF, DMSO, acetonitrile, DMA, NMP, THF, dioxane, sulfolane, acetone, DMPU, diglymes, HMPA, or combinations thereof.

[0102] In embodiments, TFA is used as a solvent and about 10 equivalent of the strong acid (one or more acids having pKa less than 1, e.g., Eaton’s reagent) in the reaction of Scheme 4.

[0103] During the reaction of Scheme 4, the temperature of the reaction vessel may be elevated due to less use of reactive solvent and acid mix by using TFA as solvents. The reaction temperature is maintained at a temperature above 55 °C, above 56 °C, above 57 °C, above 58 °C, above 59 °C, above 60 °C, above 61 °C, above 62 °C, above 63 °C, above 64 °C, above 65 °C, above 66 °C, above 67 °C, above 68 °C. In embodiments, the temperature of the reaction vessel is maintained at a temperature above 69 °C, or above 70 °C. In certain embodiments, the reaction temperature is maintained at a temperature at about 55 °C.

[0104] After the reaction is completed, remaining acids (e.g., MeSChH, etc.) may be removed by filtration and washing for quenching and before drying the crude solid. A singlefiltration / recrystallization step may not be sufficient for removing impurities including excess glycoluril bis-ether.

[0105] Further, as the reaction is completed, additional acid, such as TFA, may be added to the reaction, which can improve the precipitation and improve purification and / or yield in a large scale reaction. At the end of the reaction of Scheme 4, the compound of formula V may be isolated by the steps of adding additional acid, such as TFA, to the reaction mixture after completion of the reaction; precipitating the compound of formula V, for example by the addition of a countersolvent such as water; and collecting a mixture comprising the compound of formula V, for example by filtration.

[0106] The precipitation of the compound of formula V includes a step of adding a countersolvent for the compound of formula V. In certain embodiments, the countersolvent includes, but not limited to, water, methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, THF, dioxane, and combinations thereof.

[0107] In embodiments, the compounds of formula V in a solid form (e.g., precipitate, particles, or powders) may be collected by centrifuging the mixture. Alternatively, the compounds of formula V in a solid form (e.g., precipitate, particles, or powders) may be collected by filtering. In embodiments, the compounds obtained may be washed with water and / or acetone.

[0108] A synthesis of glycoluril tetramer compound 5 is reported by Isaacs and coworkers (Nature Chem 4, 503-510 (2012)) where the investigators found a lower yield (36%). Additionally, the reported purification process of direct recrystallization of the crude product with TFA following a water wash was found to provide lower purity product. Other methods for formation of this compound have been published (see, e.g., Org. Chem. Front., 2019, 1555), however we have found that the procedures were not feasible at large scale due to the small particle size of the product penetrating through the filter centrifuge.Furthermore, we saw improved purity when reducing the concentration of Eaton’s reagent along with waste disposal benefits and cost benefits associated with using less strong acid.

[0109] In one aspect, the methods of preparing the compounds of formula I include the following Scheme 1.Scheme 1wherein R1A, R1B, R1C, R1D, R3A, R3B, R4A, and R4Bare as described herein.

[0110] The reaction according to Scheme 1 involves the condensation of the glycoluril tetramer of Formula V with the compound of Formula VI. The reaction in Scheme 1 is performed in the presence of a solvent system including (i) one or more acids having a pKa of less than about 1 and (ii) anhydride.

[0111] In embodiments, the one or more acids having a pKa of less than about 1 includes trifluoroacetic acid, Eaton’s reagent, methane sulfonic acid (MeSChH), toluene sulfonic acid (TsOH), triflic acid, phosphoric acid, sulfuric acid, camphorsulfonic acid (CSA), ethane sulfonic acid (EtSChH), or combinations thereof. In embodiments, the one or more acids having a pKa of less than about 1 comprises trifluoroacetic acid.

[0112] Using the anhydride as a co-solvent greatly increases the reaction rate and overall yield of the reaction, e.g., overall yield (66%). The anhydride may be an organic acid anhydride in which the acyl groups of the acid anhydride are derived from carboxylic acids, sulfonic acids, phosphonic acids, or combinations. The anhydride may be selected from compounds having the general structure R'-C(=O)-O-C(=O)-R" wherein R' and R" may me the same or different and are independently selected from alkyl, aryl, heteroalkyl, or may be taken together to form a heterocyclic ring, each of which may be substituted by halo, alkyl, trihaloalkyl, or the like. In certain embodiments, the anhydride may be selected from, but is not limited to, acetic anhydride, trifluoroacetic acid anhydride, butyric anhydride, propionic anhydride, triflic anhydride, succinic anhydride, maleic anhydride, or combinations thereof. The anhydride may be acetic anhydride, trifluoroacetic anhydride, or a combination thereof.

[0113] The amount of anhydride in the reaction may be from about 0.01 % by volume of solvent (i.e., vol. anhydride / vol. total solvent x 100) up to the concentration at which the anhydride is no longer soluble in the reaction solvent. The anhydride may be present from about 0.01 % to about 60 % by volume of solvent, or from about 0.3 % to about 55 % by volume of solvent, or from about 1 % to about 55 % by volume of solvent, or from about 2 % to about 50 % by volume of solvent; or from about 1 % to about 45 % by volume of solvent, or from about 2 % to about 40 % by volume of solvent.

[0114] The reaction in Scheme 1 can benefit by avoiding using an undue excess of compound VI such that overall synthesis is more efficient and economical. The reaction of Scheme 1 may use about 4 equivalents or less of compound of Formula VI, or about 3 equivalents or less of compound of Formula VI. In embodiments, the reaction of Scheme 1 uses from about 2 equivalents to about 5 equivalents of compound of Formula VI, or from about 2.5 equivalents to about 4.5 equivalents of compound of Formula VI, or from about 2.5 equivalents to about 4 equivalents of compound of Formula VI.

[0115] The resulting product after this reaction may be precipitated using antisolvents (e.g., a polar solvent), particularly in large scale synthesis. Exemplary antisolvents may include acetone, salt water, ethanol, methanol, brine, or combinations thereof.DEFINITIONS

[0116] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0117] The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups and branched-chain alkyl groups. The alkyl may include a designated number of carbons (e.g., Ci-Cio means one to ten carbons). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0118] The term “alkenyl” refers to a linear or branched hydrocarbyl having at least one carbon-carbon double bond and including straight-chain and branched-chain alkenyl groups. Examples of alkenyl groups (e.g., “C2-C6 alkenyl”) includes 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, 4-methyl-3 -pentenyl, and the like. When the compound of the present disclosure contains an alkenyl group, the compound may exist as the E-form, the Z- form, or any mixture thereof.

[0119] The term “alkynyl” refers to a linear or branched hydrocarbyl having at least one carbon-carbon triple bond and including straight-chain and branched-chain alkynyl groups. Examples of alkenyl groups (e.g., “C2-C6 alkynyl”) includes ethynyl, propynyl, and the like.

[0120] The term “cycloalkyl” refers to saturated, carbocyclic groups having from 3 to 9 carbons in the ring and including a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)w, where w is 1, 2, or 3).Representative 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.

[0121] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and 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 placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -O-C1-C6 alkyl, -O-C2-C6 alkenyl, -O-C2-C6 alkynyl, -S-Ci-C6alkyl, -S-C2-C6 alkenyl, -S-C2- Ce alkynyl, -NH-Ci-Ce alkyl, -NH-C2-C6 alkenyl, -NH-C2-C6 alkynyl, -N-(Ci-Ce alkyl)2, - S(O)-C1-C6alkyl, -S(O)-C2-C6alkenyl, -S(O)-C2-C6alkynyl, -S(O)2-Ci-C6alkyl, -S(O)2-C2- C6alkenyl, -S(O)2-C2-C6alkynyl, -Ci-C6alkyl-O-Ci-C6alkyl, -Ci-C6alkyl-S-Ci-C6alkyl, - C1-C6 alkyl-NH-Ci-Ce alkyl, -Ci-C6alkyl-N-(Ci-C6alkyl)2, -Ci-C6alkyl-S(O)-Ci-C6alkyl, - Ci-Ce alkyl-S(O)2-Ci-Ce alkyl, and more particularly include, but are not limited to: — CH2— O— CH3, — CH2— NH— CH3, — CH2— CH2— N(CH3)— CH3, — CH2— S— CH3, — 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, such as, for example, — CH2 — NH — OCH3and — CH2 — O — Si(CH3)3. The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one carbon-carbon double bond. The term “heteroalkynyl,” by itself or in combination with another term,means, unless otherwise stated, a heteroalkyl including at least one carbon-carbon triple bond. The term “heterocycloalkyl” refers to a saturated ring structure comprising at least one heteroatom as a member in the ring system.

[0122] The term “cycloalkenyl” as used herein is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. In embodiments, monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 9 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon-carbon double bond), but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged or fused bicyclic rings.

[0123] The term “heterocycle,” “heterocyclyl” or “heterocyclic” as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6, 7 or 8 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, S, Si, and P where the ring is saturated or unsaturated, but not aromatic. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. Representative examples of bicyclic heterocycles include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-l-yl, indolin- 2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro- IH-indolyl, and octahydrobenzofuranyl. The heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic or bicyclic ring system.

[0124] The term "aryl" as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heteroaromatics" or "heteroaryl". The term “aryl” also includes 7- to 14-membered polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic (including heteroaryl), e.g., theother cyclic rings can be fused cycloalkyls, cycloalkenyls, aryls, heteroaryl and / or heterocyclic groups. Single-ring heteroaryl groups may have from 1 to 3 ring heteroatoms and fused polycyclic heteroaryl groups may have from 1 to 5 ring heteroatoms, wherein the ring heteroatoms are selected from N, O and S.

[0125] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, — CH2CH2CH2CH2 — . Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0126] It will be understood that "substituted", "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Exemplary substituents as used herein means a group selected from oxo, halogen, CN, OH, NH2, COOH, CONH2, NO2, SH, — SCH3, — SOsH, SO U L — SO2NH2, — NHNH2, — ONH2, — NHC(O)NHNH2, — NHC(O)NH2, — NHSO2H, — NHC(O)H, — NHC(O)OH, — NHOH, — OCF3, — OCCI3, — OCBr3, — OCI3, — OCHF2, — OCHCh, — OCHBr2, — OCHI2, — OCH2F, — OCH2CI, — OC EBr, — OCH2I, alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., Ce-Cio aryl, Cio aryl, or phenyl), or heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and these alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be optionally substituted with at least one substituents. For example, in the cucurbituril compounds disclosed herein, each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl and heterocycle may be optionally substituted with 1 to 4 substituents selected from the foregoing substituents.

[0127] A quaternary ammonium cation as used herein is has the structure+N(R)4, wherein each R is independently selected from alkyl, cycloalkyl, aryl, aralkyl and heteroaryl, each of which may be optionally substituted. The quaternary ammonium cations, for example, mayhave the structure+N(CI-6 alkyl)4, wherein each of the Ci-6 alkyl group boned to the nitrogen is independently selected.

[0128] Eaton’s reagent is a phosphorus pentoxide solution in methanesulfonic acid. The wt% of the phosphorus pentoxide in the methane sulfonic acid may be from about 7% to about 15%, for example 7.5% or 10%.

[0129] The terms “a” or “an” as used in herein means one or more. In addition, the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C1-C20 alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0130] Certain compounds provided in this disclosure may exist in particular geometric or stereoisomeric forms. The disclosure contemplates all such compounds, including cis- and / ra / z.s-i somers, R- and 5-enantiomers, diastereomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in this invention.

[0131] The term "pharmaceutically-acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds disclosed herein and inorganic and organic basic addition salts of the compounds disclosed herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.Treatments

[0132] The compositions and methods provided in this disclosure use a cucurbituril compound to facilitate and accelerate the clearance of one or more toxic agents from the body of a patient. The composition comprising the cucurbituril compound is administered to the patient, particularly by injection, and sequesters the toxic agent in the plasma compartment of blood and removes it from the patient’s body. The now ‘inactive’ toxic agent is eliminated from the body by filtration in the kidney. Rapid sequestration and clearance of the toxic agent may rapidly reverse its effects, with the reversal effect starting immediately after administration, to lower the level of toxic agent in the body and render the patient. Alternatively or additionally, the composition comprising the cucurbituril compound is administered orally to the patient, and sequesters the toxic agent in the gastrointestinal tract, reducing, slowing and / or preventing absorption into the blood, and removes it from the patient’s body.

[0133] The terms “subject,” “host,” “patient,” and “individual” are used interchangeably herein to refer to any mammalian subject for whom the therapy provided herein is desired, particularly humans.

[0134] As used herein, the term “soluble” refers to the ability of the cucurbituril compound to form a homogenous aqueous solution.

[0135] As used herein, the term “stable” refers to the ability of the cucurbituril compound to be maintained as a homogenous aqueous solution.

[0136] The compositions and methods provided in this disclosure are particularly suitable for the treatment of patients suffering from exposure to, ingestion of, or administration of (including self-administration) a toxic agent, by lowering the amount of the toxic agent by sequestration by the cucurbituril compound.

[0137] A toxic agent refers to any agent which may be present in the body of a patient that is capable of causing the illness or death of the patient when present at sufficient levels. Toxic agents may include some medicines that are helpful in low doses, but are harmful or poisonous in larger amounts. In some embodiments, the toxic agent is a pharmaceutical drug or is a drug of abuse.

[0138] As used herein, the term “drug of abuse” is intended to mean any substance the excessive consumption or administration of which can result in intoxication, overdose, or a diagnosis of substance dependence or substance abuse (e.g., substance use disorder). Drugsof abuse include, without limitation, psychoactive drugs such as amphetamine-type stimulants, barbiturates, opioids, benzodiazepines, and psychedelics. Drug of abuse include, but are not limited to, cocaine, amphetamines, methamphetamine, methylphenidate, heroin, codeine, hydrocodone, oxycodone, marijuana(cannabis), methadone, opioids, fentanyl, carfentenil, fentanyl analogs, ayahuasca, CNS depressants, N,N-dimethyltryptamine (DMT), gamma-hydroxybutyrate (GHB), hallucinogens, inhalants, ketamine, khat, kratom, lysergic acid diethylamide (LSD), MDMA (molly / ecstasy), mescaline (peyote), dextromethorphan, loperamide, PCP, psilocybin, rohypnol, salvia, synthetic cannabinoids, synthetic cathinones (bath salts), mephedrone, nicotine, extroamphetamine, dexmethylphenidate, or any combination thereof. Furthermore, drugs of abuse can include, but are not necessarily limited to those drugs listed by the National Institute of Health (NIH) and the National Institute of Drug Abuse (NIDA).

[0139] In embodiments, the drug of abuse may be a stimulant phenethylamine, including amphetamine, methamphetamine, methylphenidate, cathinone, methcathinone, and the like. In other embodiments, the drug of abuse may be an opioid, including fentanyl or a fentanyl analog such as carfentanil. In further embodiments, the drug of abuse comprises a combination of a stimulant phenethylamine, such as methamphetamine, and fentanyl or a fentanyl analog.

[0140] The term “fentanyl analog” refers to a molecule that has been designed to mimic the pharmacological effects of fentanyl. Exemplary fentanyl analogs include 3 -allylfentanyl, alfentanil, acrylfentanyl, acetylfentanyl, brifentanil, butyrfentanyl, 2,2'-difluorofentanyl, carfentanil, crotonylfentanyl, cyclopentylfentanyl, cyclopropyl fentanyl, (±)-cis-3 -methyl fentanyl, furanyl fentanyl, 3-fluorofentanyl, 3-furanylfentanyl, 3 -methylbutyrfentanyl, 3- methylfentanyl, 3-methylfuranylfentanyl, 3 -methylthiofentanyl, 3-phenylpropanoylfentanyl, 4-fluorobutyrfentanyl, 4-chloroisobutyrylfentanyl, 4-fluoroisobutyrfentanyl, 4-fluorofentanyl, para-fluorofuranylfentanyl, para-chlorofuranylfentanyl, ortho-methylfuranylfentanyl, 4- phenylfentanyl, lofentanil, 4-methoxybutyrfentanyl, para-hydroxy-butyrylfentanyl, 4- methylphenethylacetylfentanyl, a-methylacetylfentanyl, a-m ethylbutyrfentanyl, a- methylbutyrfentanyl, a-methylthiofentanyl, benzodioxolefentanyl, benzoylfentanyl, butyrfentanyl, isobutyrylfentanyl, isofentanyl, methoxyacetylfentanyl, sufentanil, paratolylfentanyl, 3 -methylfentanyl, a-methylfentanyl, mefentanyl, mirfentanil, remifentanil, phenaridine, ohmefentanyl, trefentanil, and the like.

[0141] In one embodiment, the compositions and methods use a cucurbituril compound for reversing methamphetamine intoxication. Since meth intoxication cases often involve a high level of meth inside the patient, therapeutic doses of the cucurbituril compound may be sufficiently high in order for sufficient reversal of intoxication upon the first administration. Although cucurbituril compounds may have a relatively high limit of solubility, the high therapeutic dose means that increasing the solubility is of interest for reducing the burden of administration via a decrease in the volume required to achieve a therapeutic dose. Additionally, the cucurbituril compounds may be used in other cases of drug intoxication outside of meth. In these cases, a potential higher dose may facilitate the cucurbituril compound to sequester drugs with a lower binding affinity. This capability is of particular interest for cases of polysubstance abuse, where it is highly beneficial to remove each of the drugs of abuse from a patient’s system.Administration of the cucurbituril compound

[0142] The composition comprising a cucurbituril compound can be included in pharmaceutical compositions for administration to the patient. The pharmaceutical compositions of the disclosure may further include a pharmaceutically acceptable carrier, excipient, or diluent.

[0143] The term “pharmaceutical composition” as used herein refers to a composition containing a cucurbituril compound formulated with a pharmaceutically acceptable carrier, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disorder in a patient. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gel cap, syrup, or solution); or for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.

[0144] The term “pharmaceutically acceptable carrier” as used herein refers to a carrier which is physiologically acceptable to a treated mammal (e.g., a human) while retaining the therapeutic properties of the cucurbituril compound, with which it is administered. One exemplary pharmaceutically acceptable carrier is physiological saline. Other physiologically acceptable carriers and their formulations are known to one skilled in the art and described, for example, in Remington's Pharmaceutical Sciences (18thedition, A. Gennaro, 1990, Mack Publishing Company, Easton, Pa.), incorporated herein by reference.

[0145] Pharmaceutical compositions containing cucurbituril compound are, in some embodiments, prepared as solutions, dispersions in glycerol, liquid polyethylene glycols, and any combinations thereof in oils, in solid dosage forms, as inhalable dosage forms, as intranasal dosage forms, as liposomal formulations, dosage forms comprising nanoparticles, dosage forms comprising microparticles, polymeric dosage forms, or any combinations thereof.

[0146] A pharmaceutically acceptable excipient is, in some examples, an excipient described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986). Non-limiting examples of suitable excipients include a buffering agent, a preservative, a stabilizer, a binder, a compaction agent, a lubricant, a chelator, a dispersion enhancer, a disintegration agent, a flavoring agent, a sweetener, a coloring agent.

[0147] In some embodiments an excipient is a buffering agent. Non-limiting examples of suitable buffering agents include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate. As a buffering agent, 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 is used, in some embodiments, in a pharmaceutical composition of the present disclosure.

[0148] In some embodiments an excipient comprises a preservative. Non-limiting examples of suitable preservatives include antioxidants, such as alpha-tocopherol and ascorbate, and antimicrobials, such as parabens, chlorobutanol, and phenol. In some examples, antioxidants further include but are not limited to EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), sodium sulfite, p-amino benzoic acid, glutathione, propyl gallate, cysteine, methionine, ethanol and N-acetyl cysteine. In some instances preservatives include validamycin A, TL-3, sodium ortho vanadate, sodium fluoride, N-a-tosyl-Phe-chloromethylketone, N-a-tosyl-Lys-chloromethylketone, aprotinin, phenylmethyl sulfonyl fluoride, diisopropylfluorophosphate, kinase inhibitor, phosphatase inhibitor, caspase inhibitor, granzyme inhibitor, cell adhesion inhibitor, cell divisioninhibitor, cell cycle inhibitor, lipid signaling inhibitor, protease inhibitor, reducing agent, alkylating agent, antimicrobial agent, oxidase inhibitor, or other inhibitor.

[0149] In some embodiments a pharmaceutical composition as described herein comprises a binder as an excipient. Non-limiting examples of suitable binders include starches, pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, and combinations thereof. The binders used in a pharmaceutical formulation are, in some examples, selected from starches such as potato starch, com starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or any combinations thereof.

[0150] In some embodiments a pharmaceutical composition as described herein comprises a lubricant as an excipient. Non-limiting examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. The lubricants that are used in a pharmaceutical formulation, in some embodiments, are be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc or a combination thereof.

[0151] In some embodiments a pharmaceutical formulation comprises a dispersion enhancer as an excipient. Non-limiting examples of suitable dispersants include, in some examples, starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.

[0152] In some embodiments a pharmaceutical composition as described herein comprises a disintegrant as an excipient. In some embodiments a disintegrant is a non-effervescent disintegrant. Non-limiting examples of suitable non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth. In some embodiments a disintegrant is an effervescent disintegrant. Non-limiting examples of suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.

[0153] In some embodiments an excipient comprises a flavoring agent. Flavoring agents incorporated into an outer layer are, in some examples, chosen from synthetic flavor oils and flavoring aromatics; natural oils; extracts from plants, leaves, flowers, and fruits; and combinations thereof. In some embodiments a flavoring agent can be selected from the group consisting of cinnamon oils; oil of wintergreen; peppermint oils; clover oil; hay oil; anise oil; eucalyptus; vanilla; citrus oil such as lemon oil, orange oil, grape and grapefruit oil; and fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0154] In some embodiments an excipient comprises a sweetener. Non-limiting examples of suitable sweeteners include glucose (com syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as a sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; and sugar alcohols such as sorbitol, mannitol, sylitol, and the like.

[0155] In some instances, a pharmaceutical composition as described herein comprises a coloring agent. Non-limiting examples of suitable coloring agents include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), and external drug and cosmetic colors (Ext. D&C). A coloring agents can be used as dyes or their corresponding lakes.

[0156] In some instances, a pharmaceutical composition as described herein comprises a chelator. In some cases, a chelator is a fungicidal chelator. Examples include, but are not limited to: ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA); a disodium, trisodium, tetrasodium, dipotassium, tripotassium, dilithium and diammonium salt of EDTA; a barium, calcium, cobalt, copper, dysprosium, europium, iron, indium, lanthanum, magnesium,manganese, nickel, samarium, strontium, or zinc chelate ofEDTA; trans- 1,2- diaminocyclohexane-N,N,N',N'-tetraaceticacid monohydrate; N,N-bis(2- hydroxyethyl)glycine; l,3-diamino-2-hydroxypropane-N,N,N',N'-tetraacetic acid; 1,3- diaminopropane-N,N,N',N'-tetraacetic acid; ethylenediamine-N,N'-diacetic acid; ethylenediamine-N,N'-dipropionic acid dihydrochloride; ethylenediamine-N,N'- bis(methylenephosphonic acid) hemihydrate; N-(2-hydroxyethyl)ethylenediamine-N,N',N'- triacetic acid; ethylenediamine-N,N,N',N'-tetrakis(methylenephosponic acid); 0,0'-bis(2- aminoethyl)ethyleneglycol-N,N,N',N'-tetraacetic acid; N,N-bis(2- hydroxybenzyl)ethylenediamine-N,N-diacetic acid; 1 ,6-hexamethylenediamine-N,N,N',N'- tetraacetic acid; N-(2-hydroxyethyl)iminodiacetic acid; iminodiacetic acid; 1,2- diaminopropane-N,N,N',N'-tetraacetic acid; nitrilotriacetic acid; nitrilotripropionic acid; the trisodium salt of nitrilotris(methylenephosphoric acid); 7,19,30-trioxa-l,4,10,13,16,22,27,33- octaazabicyclofl 1,11,1 l]pentatriacontane hexahydrobromide; or triethylenetetramine- N,N,N',N",N'",N'"-hexaacetic acid.

[0157] The pharmaceutical compositions of the cucurbituril compound as described herein may be formulated for parenteral administration to the patient. In particular, the pharmaceutical compositions of the cucurbituril compound will be suitable for administration by injection into the patient, including intravenous, intramuscular, subcutaneous, and intraperitoneal administration, and preferably will be suitable for intravenous administration.

[0158] In an embodiment, the dosage form is an oral dosage form comprising a cucurbituril compound, and (one or more pharmaceutically acceptable carriers. The oral dosage form may be a capsule or a tablet. Alternatively, the oral dosage form may be an orally administrable solution, suspension, or syrup.

[0159] In another embodiment, the dosage form is an aqueous solution that is suitable for injection into a patient comprising (i) a cucurbituril compound, (ii) optionally, a buffering agent, and (iii) optionally a tonicity agent. In another embodiment, the dosage form is a solid for reconstitution comprising (i) a cucurbituril compound, (ii) optionally, a buffering agent, and (iii) optionally a tonicity agent.

[0160] For parenteral administration in an aqueous solution, for example, the liquid dosage form may be suitably buffered if necessary and the liquid diluent rendered isotonic with sufficient saline or glucose. In this connection, sterile aqueous media that can be employed will be known to those of skill in the art in light of the present disclosure. Forexample, one dosage is dissolved, in certain cases, in 1 mL to 20 mL of isotonic NaCl solution and either added to 100 mL to 1000 mL of a fluid, e.g., sodium-bicarbonate buffered saline, or injected at the proposed site of infusion.

[0161] The compositions may comprise a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The pharmaceutical compositions comprise a carrier which is a solvent or a dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and / or vegetable oils, or any combinations thereof. Proper fluidity may be maintained, for example, by the use of an agent, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms is brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, isotonic agents are included, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0162] In certain embodiments, sterile injectable solutions are prepared by incorporating a cucurbituril compound, in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. The compositions disclosed herein are, in some instances, formulated in a neutral or salt form. Upon formulation, the pharmaceutical compositions are administered, in some embodiments, in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.

[0163] In some embodiments, the cucurbituril compound or a pharmaceutically acceptable salt thereof is administered at about 0.05 mg / kg to 500 mg / kg. In some embodiments, sequestering agent is administered at about 0.05 mg / kg - 50 mg / kg, 50 - 60 mg / kg, 50 - 70 mg / kg, 50 - 80 mg / kg, 50 - 90 mg / kg, 50 - 100 mg / kg, 50 - 120 mg / kg, 50 - 140 mg / kg, 50 - 160 mg / kg, 50 - 180 mg / kg, 50 - 200 mg / kg, 50 - 220 mg / kg, 50 - 240 mg / kg, 50 - 260 mg / kg, 50 - 280 mg / kg, 50 - 300 mg / kg, 50 - 350 mg / kg, 50 - 400 mg / kg, 50 - 450 mg / kg, 50 - 500 mg / kg, 60 - 70 mg / kg, 60 - 80 mg / kg, 60 - 90 mg / kg, 60 - 100 mg / kg, 60- 120 mg / kg,60- 140 mg / kg, 60 - 160 mg / kg, 60 - 180 mg / kg, 60 - 200 mg / kg, 60 - 220 mg / kg, 60 - 240 mg / kg, 60- 260 mg / kg, 60 - 280 mg / kg, 60 - 300 mg / kg, 60 - 350 mg / kg, 60 - 400 mg / kg, 60 - 450 mg / kg, 60- 500 mg / kg, 80 - 90 mg / kg, 80 - 100 mg / kg, 80 - 120 mg / kg, 80 - 140 mg / kg, 80 - 160 mg / kg, 80 - 180 mg / kg, 80 - 200 mg / kg, 80 - 220 mg / kg, 80 - 240 mg / kg, 80 - 260 mg / kg, 80 - 280 mg / kg, 80 - 300 mg / kg, 80 - 350 mg / kg, 80 - 400 mg / kg, 80 - 450 mg / kg, 80 - 500 mg / kg, 100 - 120 mg / kg, 100 - 130 mg / kg, 100 - 140 mg / kg, 100 - 150 mg / kg, 100 - 160 mg / kg, 100 - 180 mg / kg, 100 - 200 mg / kg, 100 -220 mg / kg, 100 - 240 mg / kg, 100 - 260 mg / kg, 100 - 280 mg / kg, 100 - 300 mg / kg, 100 - 350 mg / kg, 100 - 400 mg / kg, 100 - 450 mg / kg, 100 - 500 mg / kg, 140 - 160 mg / kg, 140 - 180 mg / kg, 140 - 200 mg / kg, 140 - 220 mg / kg, 140 - 240 mg / kg, 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.

[0164] In some embodiments, cucurbituril compound or a pharmaceutically acceptable salt thereof is administered at about at least 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, 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 500 mg / kg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered at about less than 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 500 mg / kg.

[0165] In some embodiments, the cucurbituril compound or a pharmaceutically acceptable salt thereof can be administered at about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg.EXAMPLESExample 1: Synthesis of glycoluril tetramer 5.

[0166] Step 1 : Synthesis of [2], Dimethyl glycoluril

[0167] A solution of urea (1510 g, 25.1 mol) in HCI (0.3 M, 3.7 L) was treated with 2,3- butanedione (660 g, 7.7 mol). The solution was stirred at RT for 12 h. The reaction mixture was filtered and the solid was washed with water (3.5 L x 2) and then ethanol (2.0 L) to yield 2 as a white solid (1168 g, 86%).

[0168] Step 2: Synthesis of [4], dimethyl glycoluril bis-ether

[0169] 7.5 kg water and 66.86 kg 31.5% HCI were charged to the reactor and the reactor temperature was set to 35 °C. A wet cake of dimethyl glycoluril (19.54 kg, 114.8 mol) was added to the reactor and paraformaldehyde (15.67 kg, 522.3 mol, 4.5 equiv.) was subsequently added and rinsed with water. The reaction mixture was set to a temperature of 50 °C and then cooled to a temperature of 35 °C. The reaction mixture was stirred for 24 hours and then cooled to a temperature of 25 °C. Water (120.5 L) was added for quenching and the resulting mixture was stirred at a temperature of 25 °C for 6h, and filtered. The filtered mixture was washed with water (4 x 46.0 L), filtered and washed with acetone (0-2 x 27.6 L). The mixture was dried and 19.5 kg of glycoluril bis-ether was recovered at yield 72%.

[0170] Step 4: Synthesis of [3], glycoluril dimer

[0171] Water (8.8 kg), 31.5% HCI (35.8 kg), and 29.29 kg glycoluril (206.1 mol) were charged to a reaction vessel, and the reaction vessel was set to a temperature of 50 °C.Paraformaldehyde (6.08 kg, 202.7 mol, 1.0 equiv.) was added into the reaction vessel in 6parts and the reaction temperature was set to 70 °C and the reaction mixture was stirred for 3 days. The reaction mixture was diluted with 29.4 kg water and transferred to another vessel containing 119.4 kg water, and the vessel was set to a temperature of 80 °C and the reaction mixture was stirred for 2 hours. The reaction was cooled to a temperature of 25 °C and the reaction mixture is centrifuged, washed with water (2 x 115 L) and acetone 1 x (73 L), dried under vacuum at a temperature of 50 °C. 16.5 kg of the glycoluril dimer 3 was recovered (52%).

[0172] Step 5: Synthesis of [5], Glycoluril tetramer

[0173] 5.21 (20.5 mol) kg of dimer 3, 15.04 kg bis-ether 4 (59.2 mol, 2.8 equiv.), 41.78 kgTFA were charged into the reaction vessel and the reaction temperature was set to a temperature of 55 °C, and stirred for 90 minutes until all solids were dissolved and the temperature was set to a temperature of 40 °C. Eaton’s reagent (19.31 kg) was added to the reaction vessel and the temperature was set to 55 °C for 4 hours, and then to 40 °C. The reaction mixture was transferred to a vessel containing 148.4 kg water, set at a temperature of 25 °C, and stirred for 30 minutes. The reaction mixture was centrifuged, washed with water (2 x 26.1 L) then acetone (2 x 25.5 L), transferred to vacuum oven, and then dried at a temperature of 50 °C.

[0174] The dried material was dissolved in TFA (117.6 kg), and stirred at a temperature of 35 °C until dissolved, then water 83.66 kg was added. The mixture was centrifuged, washed with water (1 x 87.5 L) then acetone (1 x 88.2 L). Water (43 kg) was added to the mixture to create a slurry and it was centrifuged, washed with water (116 kg), then acetone (117 L). A slurry was created by adding 88 L acetone and the slurry was stirred, centrifuged, washed with acetone (117L), and dried under vacuum at a temperature of 50 °C. The reaction product 5 (15.0 kg) was recovered (51%).Example 2

[0175] To a mixture of hydroquinone (2.2 g, 20.0 mmol) and methyl butanoate bromide (9.6mL, 80.33mmol) was added butanone (40 mL). While stirring, potassium carbonate (11.0 g, 79.6 mmol) was added slowly into the flask. The suspended reaction was refluxed at 75 °C overnight. Ethyl acetate (125 mL) and DI water (125 mL) were added to the reaction mixture. The layers were separated using a separatory funnel. The aqueous layer was extracted with ethyl acetate (3 x 125mL) and the combined organic extracts were washed with DI water (2 x 125 mL) and brine (1 x 125 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting yellow solid was dried on hi-vac and purified by flash column chromatography using a gradient method (100% hexanes / 0% ethyl acetate to 0% hexanes / 100% ethyl acetate). Concentration of eluted fractions using rotary evaporation gave 4.53 g (74%) of diester 6 as an off-white solid.

[0176] To a mixture of sidewall 6 (2.1 g, 7.0 mmol) and tetramer (2.2 g, 2.8 mmol) in TFA (40 mL) was added AC2O (8 mL, 84.6 mmol). The mixture was heated at ~70 °C and stirred for 2h. The solvent was removed by rotary evaporation. The resulting solid was suspended in diethyl ether (60 mL) and stirred for ~10 mins. Filtration and washing with diethyl ether (2 x 60 mL) resulted in isolation of a white solid. The solid was suspended in a solution containing 1 : 1 FLO / MeOH solution (100 mL) containing NaOH (s, 2.5 g, 62.8 mmol). The mixture was refluxed at 80 °C for 15 h with stirring. The solvent was removed by rotary evaporation. The crude solid was dissolved in water (60 mL) and treated with con. HC1(4.0 mL). The resulting suspension was filtered and dried on high vacuum. The resulting crude solid was filtered, washed with MeOH (2 x 65mL), water (60 mL), and dried. The resulting solid was suspended in H2O and IM NaOH was added until the bulk of the solids dissolved (2 mL). The solution was filtered through 0.45um filter then TFA was added to adjust the pH (1 mL) until precipitation was observed (pH ~5). The suspension was filtered and washed with acetone (2 x 75mL) resulting in the isolation of a white solid (Comp. 2) which was dried on high vacuum until a stable mass was achieved (3.66 g, 96% yield).Example 3

[0177] To an oven dried round bottom flask containing 1,4-dihydroxy naphthalene (10 g, 62.0 mmol) and methyl bromoacetate (38.2 g, 0.250 mol) was added butanone (25 mL). While stirring, potassium carbonate (34.5, 25.0 mmol) was added slowly into the flask. The reaction mixture was refluxed at 80 °C overnight. The reaction mixture was added to a mixture of ethyl acetate (250 mL) and water (250 mL) in a separation funnel. The aqueous layer was extracted three times with ethyl acetate (3 x 125 mL). The combined organic layers were washed twice with water (2 x 125 mL) and once with saturated brine solution (125 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The solid was suspended in hexanes (150 mL) in an 80 °C bath and ethyl acetate was slowly added until the solids were completely dissolved. The solution was allowed to cool to room temperature then kept at 4° C fridge overnight. The resulting reddish crystals were filtered and dried providing 7 in good yield (12.1 g, 64% yield).

[0178] Compound 7 (3.0 g, 9.9 mmol) was suspended in 0.5M NaOH (60 mL) and stirred at 70 °C for 5h. The reaction mixture was concentrated to dryness and 0.5g of the resultingsolid was added to 0.3 g (0.4 mmol) compound 5 in an oven-dried round bottom flask.Eaton’s reagent (25 mL) was added, and the reaction was stirred at 25 °C for 4h. The reaction mixture was poured onto 60 g of DI ice and stirred for 10 minutes. The resulting solid was collected by vacuum filtration. The solid was slurried in approximately 5 mL of water and adjusted to a stable pH between 7-8 using IM NaOH. The solution was concentrated in vacuo. The solid was recrystallized in water and Ethanol (1 :3, v / v, 600 mL) filtered and dried to provide Comp. 3 as a tan powder (203 mg, 38% yield).Example 4

[0179] Compound 4, shown below, was prepared according to the protocols of Examples 1 to 3.Comp. 4Example 5

[0180] Preparation of host solutions:

[0181] Isothermal Titration Calorimetry - A 1 mM solution of host was prepared volumetrically using 20 mM pH 7.4 phosphate buffer. This solution was diluted to 0.1 mM using the same 20 mM pH 7.4 phosphate buffer.

[0182] Fluorescence - A 1 mM solution of host was prepared volumetrically using 20 mM pH 7.4 phosphate buffer. The solution was diluted to 0.2 mM and 0.02 mM using the same 20 mM pH 7.4 phosphate buffer.

[0183] Preparation of guest solutions:

[0184] Isothermal Titration Calorimetry - A 1 mM solution of each guest molecule was prepared non-volumetrically using 20 mM pH 7.4 phosphate buffer.

[0185] Fluorescence - A 25 mM solution of each guest molecule was prepared non- volumetrically with methanol and diluted to the appropriate concentrations. Studies were conducted with various target molecules to confirm the small amount of residual methanol (<1%) did not interfere with binding.

[0186] Preparation of Rhodamine 6G solutions:

[0187] Fluorescence - A 1 mM solution of Rhodamine 6G was prepared volumetrically using 20 mM pH 7.4 phosphate buffer. That solution was diluted to 0.2 mM using the same 20 mM pH 7.4 phosphate buffer.

[0188] Determination of binding constants

[0189] For each host-guest binding constant determination, the average binding affinity from three measurements was recorded.

[0190] Isothermal Titration Calorimetry - A Malvern Panalytical MicroCai PEAQ-ITC was used to perform isothermal calorimetry titrations. The concentration of each guest was 1 mM and the concentration of host was 0.1 mM. The sample cell was filled with 290 pL of host solution and the syringe was loaded from a vial containing 80 pL of the guest. A 19- inj ection method was run with the first injection being 0.4 pL followed by 18x 2 pL injections. In the case of weak binding guests, two 19-inj ection titrations were run. After the first titration was completed, excess liquid from the sample cup was removed and the syringe reloaded with guest solution. The temperature was set to 25 °C, reference power was set to 10 pcal / s, the feedback was set to high, the stir speed set to 750 rpm, the initial delay was set to 60 s, the injection spacing was set to 150 s, and the injection duration was set to 4 s. The data was processed using Malvern software.n.d. = not determined

Claims

We Claim:or a pharmaceutically acceptable salt thereof, wherein: each R1Aand R1Dis independently selected from -O-L-CO2X1; each L is independently selected from Ci to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6; e is 1 to 6;Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or C1-3 alkyl; each R1Band R1Cis independently selected from hydrogen, halogen, -OH, -CN, CO2H, SO3H, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl; or additionally or alternatively, R1Band R1Cattached on the same phenyl ring, together with the atoms to which they are attached, are joined to form a fused C6-C12 aryl, 5 to 12 membered heteroaryl, or 5 to 7 membered heterocycle, which are optionally substituted with 1 to 3 substituents independently selected halogen, -OH, -NH2, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl;each R3Aand R3Bis independently selected from hydrogen, halogen, -OH, CO2H, CO2R', CONH2, CONHR', CON(R')2, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; additionally or alternatively, R3Aand R3Battached to adjacent carbon atoms, together with the carbons to which they are attached, are joined to form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring; each R4Aand R4Bis independently selected from hydrogen, halogen, -OH, CO2H, CO2R', CONH2, CONHR', C0N(R')2, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; each R' is independently selected from C1-6 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation; wherein when both R1Band R1Care H, then L is not -CH2-.

2. The compound of claim 1, having the structure of formula II:or a pharmaceutically acceptable salt thereof, wherein: each R1Aand R1Dis independently selected from -O-L-CO2X1; each L is independently selected from Ci to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl / , and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6; e is 1 to 6;Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or Ci-3 alkyl; each R3Aand R3Bis independently selected from hydrogen, halogen, -OH, CO2H, CO2R', CONH2, CONHR', C0N(R')2, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; additionally or alternatively, R3Aand R3Battached to adjacent carbon atoms, together with the carbons to which they are attached, are joined to form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring; each R4Aand R4Bis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; each R' is independently selected from C1-6 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation.

3. The compound of claim 1, having the structure of formula Ila:or a pharmaceutically acceptable salt thereof, wherein each R1Aand R1Dis independently selected from -O-L-CO2X1; each L is independently selected from Ci to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl / , and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6; e is 1 to 6;Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or C1-3 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation.

4. The compound of claim 1, having the structure of formula Hb:or a pharmaceutically acceptable salt thereof, wherein each L is independently selected from Ci to Cio alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6; e is 1 to 6;Y is NH, N(CI-3alkyl), or O; / is 0 or 1;R is H or C1-3 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation.

5. The compound of claim 1, having the structure of formula lie:or a pharmaceutically acceptable salt thereof, wherein:each X is independently H, alkali metal cation, an ammonium cation, or combination thereof; and each n is independently 2, 3 or 4.

6. The compound of claim 1, having structure of formula lid:or a pharmaceutically acceptable salt thereof, wherein each X is independently H, alkali metal cation, an ammonium cation, or combination thereof; and each m is independently 1, 2, 3 or 4.

7. The compound of claim 1, having the structure of formula III:or a pharmaceutically acceptable salt thereof, wherein: each R1Aand R1Dis independently selected from -O-L-CO2X1; each L is independently selected from Ci to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6; e is 1 to 6;Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or C1-3 alkyl; each R3Aand R3Bis independently selected from hydrogen, halogen, -OH, CO2H, CO2R', CONH2, CONHR', C0N(R')2, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; additionally or alternatively, R3Aand R3Battached to adjacent carbon atoms, together with the carbons to which they are attached, are joined to form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring; each R4Aand R4Bis independently selected from hydrogen, halogen, -OH, CO2H, CO2R', CONH2, CONHR', C0N(R')2, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl; each R' is independently selected from C1-6 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation.

8. In another aspect, the cucurbituril compound has the structure of formula Illa:or a pharmaceutically acceptable salt thereof, wherein: each R1Aand R1Dis independently selected from -O-L-CO2X1; each L is independently selected from Ci to C10 alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6;e is 1 to 6;Y is NH, N(C 1-3 alkyl), or O; / is 0 or 1;R is H or Ci-3 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation.

9. The compound of claim 1, having the structure of formula Illb :or a pharmaceutically acceptable salt thereof, wherein: each L is independently selected from Ci to Cio alkylene, C2 to C10 alkenylene, -(CH2)a-O-(CH2 , -(CH2)c-N(R)-(CH2)d, and -(CH2)a-(OCH2CH2)e-(Yy, each of which may be unsubstituted or substituted at any carbon with 1 to 4 substituents selected from halogen, OH, CO2H, C1-3 alkyl, NH2, NH(CI-3 alkyl), N(CI-3 alkyl)2, and O-C1-3 alkyl; a is 2 to 8; b is 0 to 6; c is 2 to 8; d is 0 to 6; e is 1 to 6;Y is NH, N(C 1-3 alkyl), or O; is 0 or 1;R is H or C1-3 alkyl; and each X1is independently selected from selected from H, Ci-Ce alkyl, alkali metal cation, and quaternary ammonium cation.

10. The compound of claim 1, having the structure of formula IIIc:or a pharmaceutically acceptable salt thereof, wherein: each X is independently H, alkali metal cation, an ammonium cation, or combination thereof; each n is independently 1, 2, 3 or 4.

11. The compound of claim 1, having the structure of formula Illd:or a pharmaceutically acceptable salt thereof, wherein: each X is independently H, alkali metal cation, an ammonium cation, or combination thereof; and each m is independently 1, 2, 3 or 4.

12. The compound of claim 1, having the structure:Comp.

413. A method of reducing the concentration of a toxic agent in the body of a patient by administering to the patient a therapeutically effective amount of a composition comprising a cucurbituril compound according to any one of claims 1 to 12.

14. The method of claim 13, wherein the toxic agent is a drug of abuse.

15. The method of claim 14, wherein the drug of abuse is such methamphetamine, cocaine, fentanyl or a fentanyl analog, or combinations thereof.