Sulfated pillararenes, methods of making same, and uses thereof

Abstract

Sulfated pillararenes and methods of making and using the same are provided. The pillararene has a macrocyclic core having a plurality of aryl groups attached (e.g., covalently bonded) to adjacent methylene groups with para-substitutions. The pillararene is provided with a hydrophobic cavity. The hydrophobic cavities may be used to sequester various materials or to deliver materials sequestered therein.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511152882.8 (22) Application Date 2021.03.01 (30) Priority Data 62 / 982,460 2020.02.27 US 63 / 013,336 2020.04.21 US (62) Divisional Application Data 202180031334.3 2021.03.01 (71) Applicant University of Maryland, Park Campus Address Maryland, USA (72) Inventor Lyle David Isaacs Xue Weijian (74) Patent Agency Beijing Qingyihua Intellectual Property Agency (General Partnership) 11201 Patent Attorney Song Rongbing (51) Int.Cl. C07C 305 / 22(2006.01) A61K 47 / 54(2017.01) A61P 23 / 00(2006.01) A61P 25 / 20(2006.01) A61P 25 / 00(2006.01) A61P 21 / 00(2006.01) A62D 3 / 33(2007.01) A62D 101 / 20(2007.01) (54) Invention Title: Sulfated Columnar Aromatic Hydrocarbons, Methods for Preparing Them and Their Uses (57) Abstract: Sulfated columnar aromatic hydrocarbons, methods for preparing them and using them are provided. The columnar aromatic hydrocarbons have a macrocyclic core having a plurality of aryl groups connected (e.g., covalently bonded) to adjacent methylene groups by para-substitution. The columnar aromatic hydrocarbons have hydrophobic cavities. The hydrophobic cavity can be used to chelate various materials or deliver chelated materials therein. Claims 4 pages, Description 46 pages, Drawings 87 pages, CN 121064070 A 2025.12.05 CN 1 21 06 40 70 A 1. A compound having the following structure: wherein Ar is an aryl group, wherein the aryl group is para-substituted and connected to an adjacent methylene group; each R is independently selected from: -OS(O)2O –M+, -OS(O)2OH, non-sulfate anionic groups, carboxylic acid / carboxylate groups, Phosphonic acid / phosphonate groups, phosphate groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted aliphatic groups, O-alkyl groups, -H, substituted or unsubstituted alkyl groups, halogens, amide groups, cyano groups, substituted or unsubstituted sulfur-containing aliphatic groups, nitro groups, amino groups, substituted or unsubstituted nitrogen-containing aliphatic groups, substituted or unsubstituted polyethylene glycol groups, polyether groups, O-aryl groups, ester groups, urethane groups,The group consists of an imine group, an aldehyde group, a -SO3H group, a -SO3Na group, an -OSO2F group, an -OSO2CF3 group, or an -OSO2OR″′ group, wherein R″′ is a substituted or unsubstituted aryl group or a substituted or unsubstituted alkyl group, or a combination thereof, wherein M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS), x is 0, 1, 2, or 3; and y is independently 0, 1, 2, 3, or 4 each time it appears, provided that at least one y is 1 and at least one R group is -OS(O)2O –M+, wherein M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+ 1. The compound according to claim 1, wherein the aryl group is independently selected from phenyl groups, fused ring groups, biaryl groups, and terphenyl groups each time it appears. 2. The compound according to claim 1, wherein the cyclic core of the compound comprises at least two of the phenyl groups of one or more of the aryl groups having at least one R group independently selected from -OS(O)2O-M+ and -OS(O)2OH. 4. The compound according to claim 3, wherein the compound has the following structure: Claims 1 / 4 page 2 CN 121064070 A 5. The compound according to claim 1, wherein all of the aryl groups comprise an R group that is independently -OS(O)2O-M+ or -OS(O)2OH. 6. The compound of claim 1, wherein at least one aryl group does not contain an R group that is -OS(O)₂O-M+ or -OS(O)₂OH. 7. The compound of claim 1, wherein the compound has the following structure: 8. The compound of claim 7, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 of the R groups are independently -OS(O)₂O-M+ groups or -OS(O)₂OH groups. 9. The compound of claim 7, wherein each phenyl group included in the cyclic core of the compound has at least one R group independently selected from -OS(O)₂O.10. The compound of claim 7, wherein at least one phenyl group does not contain an R group that is -OS(O)2O-M+ or -OS(O)2OH. 11. The compound of claim 1, wherein M+ is Na+, K+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+. 12. The compound of claim 11, wherein M+ is Na+. 13. A composition comprising one or more compounds according to claim 1. 14. The composition of claim 13, further comprising a drug carrier. 15. The composition of claim 13, wherein the one or more compounds are disposed on at least a portion of a solid substrate. 16. The composition of claim 15, wherein the solid substrate comprises silica, polymer beads, polymer resin, metal nanoparticles, metal, or combinations thereof. 17. The composition of claim 13, wherein at least a portion or all of the one or more compounds have one or more pharmaceutically active agents disposed in cavities of the one or more compounds. 18. A method for chelating one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceuticals, one or more insecticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof, comprising: contacting the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceuticals, the one or more insecticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof with one or more compounds of claim 1, wherein the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceuticals, the one or more insecticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof are chelated by the one or more compounds. 19. The method of claim 18, wherein the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceuticals, the one or more insecticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, the one or more hallucinogens, the one or more toxins, or a20. The method of claim 19, wherein the aqueous sample is a wastewater sample, industrial water sample, or municipal water sample. 21. The method of claim 18, wherein the one or more compounds form a complex with the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceuticals, the one or more pesticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, the one or more hallucinogens, the one or more toxins, the one or more metabolites, or a combination thereof. 22. The method of claim 18, wherein the complex is removed from the aqueous sample, the solid sample, or the gaseous sample. 23. The method of claim 18, wherein the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceuticals, the one or more pesticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, the one or more hallucinogens, the one or more toxins, the one or more metabolites, or a combination thereof are present in and / or on an individual, and the contact includes the application of the one or more compounds. Claims 3 / 4 Page 4 CN 121064070 A 24. The method of claim 23, wherein the individual is a human or a non-human mammal. 25. A method for reversing drug-induced neuromuscular blockade and / or anesthesia and / or the effects of one or more agents in an individual, comprising administering one or more compounds according to claim 1 to an individual who requires reversal of neuromuscular blockade and / or reversal of anesthesia and / or reversal of the effects of one or more agents. 26. The method of claim 25, wherein the individual requires reversal of drug-induced neuromuscular blockade. 27. The method of claim 25, wherein the individual requires reversal of anesthesia. 28. The method of claim 25, wherein the individual requires reversal of drug-induced neuromuscular blockade and anesthesia. 29. The method of claim 25, wherein the individual requires reversal of the effects of one or more agents. 30. The method of claim 29, wherein the one or more agents are selected from one or more abuse drugs, one or more pesticides, one or more chemical warfare agents, one or more nerve agents, one or more hallucinogens, one or more toxins, one or more metabolites, and combinations thereof. 31. The method of claim 25, wherein the individual requiring reversal is a human. 32. The method of claim 25, wherein the desired individual is a non-human mammal.33. A method for preventing and / or treating a condition in an individual, comprising administering to an individual requiring the prevention and / or treatment one or more compounds and one or more pharmaceutical agents according to claim 1, wherein the one or more compounds and the one or more pharmaceutical agents are present as a complex, wherein, after the administration, the treatment and / or prevention of the condition in the individual is performed. 34. The method according to claim 33, wherein one or more of the one or more pharmaceutical agents have a solubility of less than 100 μM in an aqueous solvent. Claims 4 / 4 Page 5 CN 121064070 A Sulfated Columnar Aromatic Hydrocarbons, Methods for Preparing Them and Use Thereof

[0001] Cross-Reference to Related Applications

[0002] This application is a divisional application filed on March 1, 2021, with application number 202180031334.3 (PCT / US2021 / 020333), entitled "Sulfated Columnar Aromatic Hydrocarbons, Methods for Preparing Them and Use Thereof".

[0003] This application claims priority to U.S. Provisional Application No. 62 / 982,460, filed February 27, 2020, and U.S. Provisional Application No. 63 / 013,336, filed April 21, 2020, the disclosures of which are incorporated herein by reference.

[0004] Statement Regarding Federally Funded Research

[0005] This invention was made with government support under Contract No. CHE-1404911 granted by the National Science Foundation. The government holds certain rights to this invention. Background Art

[0006] Several classes of molecular container compounds are known, including cyclodextrins, calixarnes, cyclophanes, columnar aromatics, and cucurbiturils. These molecular container compounds bind to their target molecules in solution and thereby modulate the properties of the target, including optical properties, solubility, odor, and even biological activity. Previous workers in the field of column[n]aromatics have synthesized container molecules characterized by hydrophobic cavities and carboxylic acid solubilizing groups, and have shown that they bind with good affinity to cationic targets in water. The challenge in this field is how to generate new molecular containers or modify existing ones to maintain good solubility in water while simultaneously enhancing their binding affinity to their targets. Summary of the Invention

[0007] This disclosure provides sulfated columnar aromatics. This disclosure also provides methods for preparing sulfated columnar aromatics and their uses.

[0008] In this disclosure, it is demonstrated, for example, that positioning anionic solubilizing groups (e.g., sulfate groups) in the column...The edges of the aromatic cavities significantly enhance their binding affinity for cationic targets in water, and thereby enhance their ability as chelating agents for a variety of applications.

[0009] In one aspect, this disclosure provides compounds. These compounds are sulfated columnar aromatics. Sulfated columnar aromatics comprise a macrocyclic core containing a plurality of aryl groups, wherein adjacent aryl groups are covalently linked (e.g., bonded) via alkyl linking groups (e.g., -CH2- groups). The alkyl linking groups are para-positioned on the aryl groups (e.g., 1,4-phenyl bonds). These bonds may be on different benzene rings of the aryl groups, and if the different benzene rings overlap, they correspond to para-position bonds. In several examples, one or more or all of the adjacent aryl groups are not covalently linked by alkyl linking groups at meta-positions on the aryl groups (e.g., 1,3-phenyl bonds (where these bonds are on different benzene rings or aryl groups, and if the different benzene rings overlap, these bonds do not correspond to meta-position bonds)). Non-limiting examples of sulfated columnar aromatics are provided herein. This document provides non-limiting examples of methods for preparing sulfated columnar aromatics.

[0010] In one aspect, this disclosure provides compositions comprising one or more sulfated columnar aromatics. Non-limiting examples of the compositions are described herein.

[0011] The compositions may comprise one or more sulfated columnar aromatics and one or more reagents. In several examples, the reagents comprise one or more positively charged nitrogen atoms (e.g., ammonium ions, primary ammonium ions, secondary ammonium ions, tertiary ammonium ions, quaternary ammonium ions, or combinations thereof, wherein one or more non-hydrogen groups on the ammonium are selected from aliphatic groups, alkyl groups, aryl groups, and combinations thereof).

[0012] In one aspect, this disclosure provides uses of sulfated columnar aromatics. Non-limiting examples of uses of sulfated columnar aromatics are provided herein.

[0013] Sulfated columnar aromatics can be used to chelate various materials, which may be chemical compounds. In several non-limiting examples, one or more sulfated columnar aromatics are used to chelate one or more neuromuscular blocking agents (such as, for example, rocuronium, tubocurarine, atracurium, atracurium (cis)benzenesulfonate, mivacurium, gallamine, pancuronium, vecuronium, and rapacuronium); one or more anesthetics (such as, for example, N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., ketamine); short-acting anesthetics (e.g., etomidate).(etomidate, etc.); one or more agents (such as, for example, drugs (e.g., anticoagulants, such as, for example, hexadimethrine, etc.), abuse drugs (e.g., methamphetamine, cocaine, fentanyl, carfentanil, etc.); one or more insecticides (such as, for example, paraquat, diquat, organochlorines (e.g., DDT, aldrin, etc.), neonicotinoids (e.g., permethrin, etc.), organophosphates (e.g., malathion, glyphosate, etc.), pyrethroids, triazines (e.g., atrazine, etc.); one or more dyes (such as, for example, methylene blue, nile red, crystal violet, thioflavin T, thiazole orange, proflavin, acridine orange, methylene violet, etc.). Azure A, Neutral Red, Cyanide, Direct Orange 26, disperse dyes (e.g., Disperse Yellow 3, Disperse Blue 27, etc.), coumarin, Congo Red, etc.); one or more malodorous compounds (e.g., low molecular weight thiols (e.g., C1-C4 thiols), low molecular weight amines (e.g., triethylamine, putrescein, cadaverine, etc.); or one or more chemical warfare agents (e.g., nitrogen mustard and sulfur mustard (e.g., bis(2-chloroethyl)ethylamine, bis(2-chloroethyl)methylamine, tri(2-chloroethyl)amine, bis(2-chloroethyl)sulfide, bis(2-chloroethylthioethyl) ether, etc.) (bis(2- chloroethylthioethyl)ether), nerve agents (such as, for example, those from the G, GV and V series nerve agents (e.g., tabun, sarin, soman, cyclosarin, 2-(dimethylamino)ethyl N,N-dimethylphosphatamidofluoroester (GV), novichok agent, VE, VG, VM, VX, etc.); or combinations thereof. Brief Description of the Drawings

[0014] For a more complete understanding of the nature and purpose of this disclosure, reference should be made to the following detailed description taken in conjunction with the accompanying drawings.

[0015] Figure 1 shows an example of a host (sulfated columnar aromatic hydrocarbon).

[0016] Figure 2 shows an example of a cationic guest.

[0017] Figure 3 shows an example of a drug of abuse.

[0018] Figure 4 shows an example of a neuromuscular blocking agent.

[0019] Figure 5 shows the binding constants of an exemplary subject complex with a cationic guest.

[0020] Figure 6 shows the binding constants of an exemplary subject complex with a drug of abuse.

[0021] Figure 7 shows the binding constants of an exemplary subject complex with a neuromuscular blocking agent.

[0022] Figure 8 shows the 1H NMR spectra (500 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[6]AS, b) methamphetamine, c) an equimolar mixture of P[6]AS and methamphetamine (0.5 mM), and d) a 2:1 mixture of methamphetamine (1 mM) and P[6]AS (0.5 mM). Instruction manual 2 / 46 pages 7 CN 121064070 A

[0023] Figure 9 shows the 1H NMR spectra (500MHz, RT, 20mM phosphate buffered D2O) recorded for the following: a) P[6]AS, b) Motor 2, c) Rocuronium bromide, d) equimolar mixture of P[6]AS and rocuronium bromide, e) equimolar mixture of Motor 2 and rocuronium bromide, f) mixture of Motor 2 and rocuronium bromide followed by P[6]AS, g) mixture of P[6]AS and rocuronium bromide followed by Motor 2.

[0024] Figure 10 shows the crystal structure of P[6]AS.

[0025] Figure 11 shows a) the structure of CB[n] and M2. b) the preparation of column[n]MaxQ (P[5]AS–P[7]AS) and P[5]ACS and the structure of WP[n]. Conditions: a) Py·SO3, pyridine, 90℃; b) propanesulfonyl lactone, NaOH, acetone, 8%.

[0026] Figure 12 shows the 1H NMR spectra (600MHz, D2O, 298K) recorded for the following solutions: a) P[6]AS (1mM), b) guest 25 (1mM), c) a mixture of P[6]AS (1mM) and guest 25 (1mM); d) a mixture of P[6]AS (1mM) and guest 25 (2mM).

[0027] Figure 13 shows the X-ray crystal structures of P[6]AS and P[5]ACS. a) Cross-eyed stereoview of a molecule of P[6]AS in a unit cell. View of the packing of P[6]AS in the crystal along the b) z-axis and c) y-axis. d) Cross-eyed stereoview of a molecule of P[5]ACS in a unit cell.

[0028] Figure 14 shows a) a graph of DP versus time from titrating a mixture of P[6]AS (100 μM) and 17 (500 μM) in a pool using 20 (1 mM) in a syringe. b) a graph of ΔH versus the molar ratio of P[6]AS to 20; the solid line representsThe best fit of the data and the competitive combination model implemented in the PEAQ-ITC data analysis software, where Ka = (1.20 ± 0.06) × 10¹¹ M⁻¹ and ΔH = -17.1 ± 0.033 kcal mol⁻¹.

[0029] Figure 15 shows the 1H NMR spectra (600 MHz, D₂O, RT) recorded for the following: a) P[6]AS (1 mM), b) M₂ (0.5 mM), c) Rocuronium bromide (0.5 mM), d) P[6]AS·Rocuronium bromide (0.5 mM), e) M₂·Rocuronium bromide (0.5 mM), and f) the solution from the eth part after treatment with 1 equivalent of P[6]AS. The proton labels for M₂, P[6]AS and Rocuronium bromide are given in Figures 11 and 4.

[0030] Figure 16 shows the 1H NMR spectrum (400 MHz, D2O, RT) recorded for P[5]ACS.

[0031] Figure 17 shows the 13C NMR spectrum (150 MHz, D2O, EtOH as internal reference, RT) recorded for P[5]ACS.

[0032] Figure 18 shows the 1H NMR spectrum (600 MHz, D2O, RT) recorded for P[5]AS.

[0033] Figure 19 shows the 13C NMR spectrum (150 MHz, D2O, EtOH as internal reference, RT) recorded for P[5]AS.

[0034] Figure 20 shows the 1H NMR spectrum (600 MHz, D2O, RT) recorded for P[6]AS.

[0035] Figure 21 shows the 13C NMR spectrum (150 MHz, D2O and CD3OD 10:1, RT) recorded for P[6]AS.

[0036] Figure 22 shows the 1H NMR spectrum (600 MHz, D2O, RT) recorded for P[7]AS.

[0037] Figure 23 shows the 13C NMR spectrum (150 MHz, D2O, dioxane as external reference, RT) recorded for P[7]AS.

[0038] Figure 24 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[5]ACS, b) 17, c) an equimolar mixture of P[5]ACS and 17 (1 mM), and d) a 2:1 mixture of 17 (2 mM) and P[5]ACS (1 mM).

[0039] Figure 25 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[5]ACS, b) 21, c) an equimolar mixture of P[5]ACS and 21 (1 mM), and d) 21 (2 mM) and P[5]ACS.A 2:1 mixture of (1mM).

[0040] Figure 26 shows the 1H NMR spectra (600MHz, RT, 20mM phosphate buffered D2O) recorded for the following: a) P[5]AS, b) 23, c) an equimolar mixture of P[5]AS and 23 (1mM), and d) a 2:1 mixture of 23 (2mM) and P[5]AS (1mM). Specification 3 / 46 pages 8 CN 121064070 A

[0041] Figure 27 shows the 1H NMR spectra (600MHz, RT, 20mM phosphate buffered D2O) recorded for the following: a) P[5]AS, b) 21, c) an equimolar mixture of P[5]AS and 21 (1mM), and d) a 2:1 mixture of 21 (2mM) and P[5]AS (1mM).

[0042] Figure 28 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[5]AS, b) 22, c) equimolar mixtures of P[5]AS and 22 (1 mM) and d) a 2:1 mixture of 22 (2 mM) and P[5]AS (1 mM), e) a 3:1 mixture of 22 (3 mM) and P[5]AS (1 mM), and f) a 4:1 mixture of 22 (4 mM) and P[5]AS (1 mM).

[0043] Figure 29 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[5]AS, b) 12, c) equimolar mixtures of P[5]AS and 12 (1 mM), d) a 2:1 mixture of 12 (2 mM) and P[5]AS (1 mM), e) a 3:1 mixture of 12 (3 mM) and P[5]AS (1 mM), and f) a 4:1 mixture of 12 (4 mM) and P[5]AS (1 mM).

[0044] Figure 30 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[5]AS, b) 25, c) equimolar mixtures of P[5]AS and 25 (0.5 mM), d) a 2:1 mixture of 25 (1 mM) and P[5]AS (0.5 mM), e) a 3:1 mixture of 25 (1.5 mM) and P[5]AS (0.5 mM), and f) a 4:1 mixture of 25 (2 mM) and P[5]AS (0.5 mM).

[0045] Figure 31 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following:D2O): a) P[5]AS, b) 26, c) equimolar mixtures of P[5]AS and 26 (0.5 mM), d) a 2:1 mixture of 26 (1 mM) and P[5]AS (0.5 mM), and e) a 3:1 mixture of 26 (1.5 mM) and P[5]AS (0.5 mM).

[0046] Figure 32 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[6]AS, b) 23, c) equimolar mixtures of P[6]AS and 23 (1 mM), and d) a 2:1 mixture of 23 (2 mM) and P[6]AS (1 mM).

[0047] Figure 33 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[6]AS, b) 17, c) an equimolar mixture of P[6]AS and 17 (1 mM), and d) a 2:1 mixture of 17 (2 mM) and P[6]AS (1 mM).

[0048] Figure 34 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[6]AS, b) 24, c) an equimolar mixture of P[6]AS and 24 (1 mM), and d) a 2:1 mixture of 24 (2 mM) and P[6]AS (1 mM).

[0049] Figure 35 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[6]AS, b) 11, c) an equimolar mixture of P[6]AS and 11 (1 mM), and d) a 2:1 mixture of 11 (2 mM) and P[6]AS (1 mM).

[0050] Figure 36 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[6]AS, b) 12, c) an equimolar mixture of P[6]AS and 12 (1 mM), and d) a 2:1 mixture of 12 (2 mM) and P[6]AS (1 mM).

[0051] Figure 37 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[6]AS, b) 21, c) an equimolar mixture of P[6]AS and 21 (1 mM), and d) a 2:1 mixture of 21 (2 mM) and P[6]AS (1 mM).

[0052] Figure 38 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following:D2O): a) P[6]AS, b) 22, c) an equimolar mixture of P[6]AS and 22 (1 mM), and d) a 2:1 mixture of 22 (2 mM) and P[6]AS (1 mM). Specification 4 / 46 pages 9 CN 121064070 A

[0053] Figure 39 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[6]AS, b) 26, c) an equimolar mixture of P[6]AS and 26 (0.5 mM), and d) a 2:1 mixture of 26 (1 mM) and P[6]AS (0.5 mM).

[0054] Figure 40 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[7]AS, b) 11, c) an equimolar mixture of P[7]AS and 11 (0.5 mM), and d) a 2:1 mixture of 11 (1 mM) and P[7]AS (0.5 mM).

[0055] Figure 41 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[7]AS, b) 17, c) an equimolar mixture of P[7]AS and 17 (0.5 mM), and d) a 2:1 mixture of 17 (1 mM) and P[7]AS (0.5 mM).

[0056] Figure 42 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[7]AS, b) 23, c) an equimolar mixture of P[7]AS and 23 (0.5 mM), and d) a 2:1 mixture of 23 (1 mM) and P[7]AS (0.5 mM).

[0057] Figure 43 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[7]AS, b) 21, c) an equimolar mixture of P[7]AS and 21 (0.5 mM), and d) a 2:1 mixture of 21 (1 mM) and P[7]AS (0.5 mM).

[0058] Figure 44 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[7]AS, b) 22, c) an equimolar mixture of P[7]AS and 22 (0.5 mM), and d) a 2:1 mixture of 22 (1 mM) and P[7]AS (0.5 mM).

[0059] Figure 45 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following:D2O): a) P[5]AS, b) acetylcholine, c) an equimolar mixture of P[5]AS and acetylcholine (0.5 mM), and d) a 2:1 mixture of acetylcholine (1 mM) and P[5]AS (0.5 mM).

[0060] Figure 46 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[5]AS, b) rocuronium bromide, c) an equimolar mixture of P[5]AS and rocuronium bromide (0.5 mM), d) a 2:1 mixture of rocuronium bromide (1 mM) and P[5]AS (0.5 mM), and e) a 3:1 mixture of rocuronium bromide (1.5 mM) and P[5]AS (0.5 mM).

[0061] Figure 47 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[5]AS, b) vecuronium bromide, c) an equimolar mixture of P[5]AS and vecuronium bromide (0.5 mM), d) a 2:1 mixture of vecuronium bromide (1 mM) and P[5]AS (0.5 mM), and e) a 3:1 mixture of vecuronium bromide (1.5 mM) and P[5]AS (0.5 mM).

[0062] Figure 48 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[5]AS, b) pancuronium bromide, c) an equimolar mixture of P[5]AS and pancuronium bromide (0.5 mM), d) a 2:1 mixture of pancuronium bromide (1 mM) and P[5]AS (0.5 mM), and e) a 3:1 mixture of pancuronium bromide (1.5 mM) and P[5]AS (0.5 mM).

[0063] Figure 49 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[6]AS, b) vecuronium bromide, c) an equimolar mixture of P[6]AS and vecuronium bromide (0.5 mM), and d) a 2:1 mixture of vecuronium bromide (1 mM) and P[6]AS (0.5 mM).

[0064] Figure 50 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[6]AS, b) acetylcholine, c) an equimolar mixture of P[6]AS and acetylcholine (0.5 mM), and d) a 2:1 mixture of acetylcholine (1 mM) and P[6]AS (0.5 mM). Specification 5 / 46 pages 10 CN 121064070 A

[0065] Figure 51 shows the 1H NMR spectra recorded for the following (600MHz, RT, 20mM phosphate buffer).D2O): a) P[6]AS, b) rocuronium bromide, c) an equimolar mixture of P[6]AS and rocuronium bromide (0.5 mM), and d) a 2:1 mixture of rocuronium bromide (1 mM) and P[6]AS (0.5 mM).

[0066] Figure 52 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[6]AS, b) pancuronium bromide, c) an equimolar mixture of P[6]AS and pancuronium bromide (0.5 mM), and d) a 2:1 mixture of pancuronium bromide (1 mM) and P[6]AS (0.5 mM).

[0067] Figure 53 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[7]AS, b) vecuronium bromide, c) an equimolar mixture of P[7]AS and vecuronium bromide (0.5 mM), and d) a 2:1 mixture of vecuronium bromide (1 mM) and P[7]AS (0.5 mM).

[0068] Figure 54 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[7]AS, b) rocuronium bromide, c) an equimolar mixture of P[7]AS and rocuronium bromide (0.5 mM), and d) a 2:1 mixture of rocuronium bromide (1 mM) and P[7]AS (0.5 mM).

[0069] Figure 55 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[7]AS, b) pancuronium bromide, c) an equimolar mixture of P[7]AS and pancuronium bromide (0.5 mM), and d) a 2:1 mixture of pancuronium bromide (1 mM) and P[7]AS (0.5 mM).

[0070] Figure 56 shows the 1H NMR spectra (600 MHz, RT, 20 mM phosphate buffered D2O) recorded for the following: a) P[7]AS, b) cis-atracurium, c) a 1:4 mixture of cis-atracurium (0.125 mM) and P[7]AS (0.5 mM), d) a 1:2 mixture of cis-atracurium (0.25 mM) and P[7]AS (0.5 mM), e) an equimolar mixture of P[7]AS and cis-atracurium (0.5 mM).

[0071] Figure 57 shows the 1H NMR spectra (600 MHz, D2O, 298 K) recorded for a diluted solution (20.0–0.1 mM) of the bulk P[5]AS. The main component P[5]AS is weakly self-associative in water, as confirmed by the high-field chemical shift in the aromatic region at 7.33–7.40 ppm protons.

[0072] Figure 58 shows a plot of the chemical shift of P[5]AS relative to [P[5]AS]. The solid line represents the best nonlinear fit of the data to the 2-fold self-association model, where Ka = 19.7 M⁻¹.

[0073] Figure 59 shows the 1H NMR spectra (600 MHz, D₂O, 298 K) recorded for the diluted solution (20.0–0.1 mM) of the host P[6]AS. The host P[6]AS is weakly self-associated in water, as confirmed by the high-field chemical shift variation in the aromatic region at 7.34–7.38 ppm protons.

[0074] Figure 60 shows a plot of the chemical shift of P[6]AS relative to [P[6]AS]. The solid line represents the best nonlinear fit of the data to the 2-fold self-association model, where Ka = 16.2 M⁻¹.

[0075] Figure 61 shows the 1H NMR spectra (400 MHz, D₂O) recorded for Rim-P[5]AS.

[0076] Figure 62 shows the 13C NMR spectrum recorded for Rim-P[5]AS (150MHz, D2O, EtOH as internal control).

[0077] Figure 63 shows the toxicological assays for HepG2. AK (A, C) and MTS assays (B, D) were performed after the cells had been incubated in the specified containers for 24 h. UT = untreated control; Stx = staurosporine.

[0078] Figure 64 shows the toxicological assays for HEK293. AK (A, C) and MTS assays (B, D) were performed after the cells had been incubated in the specified containers for 24 h. UT = untreated control; Stx = staurosporine.

[0079] Figure 65 shows the MTD study performed for P[6]AS. Female Swiss Webster mice (n=5 per group) were administered different concentrations of P[6]AS or phosphate-buffered saline (PBS) via tail vein on days 0 and 2 (indicated by *). Normalized mean weight changes for each study group are indicated. Error bars represent SEM.

[0080] Figure 66 shows the in vivo reversal of methamphetamine-induced excitatory spontaneous activity via P[6]AS (hyperlocomotion). Mean spontaneous activity counts of male Swiss Webster mice (n=8; mean weight (g) ± SD: 39 ± 2.203) were plotted as a function of treatment. The treatment sequence was counterbalanced over several days, and the mice were treated only once a day. The mice were each treated for six consecutive days.Individual treatments included PBS (PBS; 0.01M; 0.2mL, infusion), P[6]AS only (P[6]AS; 4mM; 0.178mL, infusion), methamphetamine only (METH; 0.5mg / kg; 0.022mL, infusion), a premixed solution of P[6]AS and methamphetamine (premixed; ~7:1 P[6]AS:Meth; 0.178mL P[6]AS + 0.022mL Meth, infusion), P[6]AS followed by methamphetamine administered 30s later (blocking; 0.178mL P[6]AS, 0.022mL Meth, infusion), and methamphetamine followed by P[6]AS administered 30s later (reversing; 0.022mL Meth, 0.178mL P[6]AS, infusion). Bars represent mean spontaneous activity counts. Error bars represent the standard error (SEM) of the mean. Points represent the count per mouse (n=8). The p-values ​​presented are only used for post-hoc comparisons of significance (p<0.05) Tukey-corrected.

[0081] Figure 67 shows the in vivo reversal of methamphetamine-induced excitatory spontaneous activity effects observed after a 5-minute delay between methamphetamine treatment and P[6]AS administration. On days 7 and 8, mice (n=8) received either methamphetamine followed by a 0.01M PBS infusion (REV-C; 0.022mL Meth, 0.2mL PBS, infusion) 5 minutes later, or methamphetamine followed by P[6]AS in an offset manner 5 minutes later (REV-5; 0.022mL Meth, 0.178mL P[6]AS, infusion). Administration of P[6]AS 5 minutes after exposure to methamphetamine reduced excitatory spontaneous activity (paired t-test, t(7) = 2.757, p = 0.0282). Bars represent mean spontaneous activity counts. Error bars represent the standard error (SEM) of the mean. Dots represent the count per mouse (n = 8).

[0082] Figure 68 shows the chemical structures of MDMA, mephedrone, heroin and methamphetamine.

[0083] Figure 69 shows a) a plot of DP versus time from titration of molecular container P[6]AS (100 μM) and 1,3-propane diammonium chloride (150 μM) in a pool using MDMA (1.00 mM) in a syringe in 20 mM NaH2PO4 buffer (pH 7.4); b) a plot of ΔH as a function of molar ratio. The solid line represents the best nonlinear fit of the data and the competitive combination model (Ka = (3.92 ± 0.20) × 10⁷ M⁻¹, ΔH = -13.3 ± 0.1 kcal / mol, -TΔS = 2.95 kcal / mol).

[0084] Figure 70 shows a) a plot of DP versus time from titrating the molecular container P[6]AS (10 μM) in the pool using methoxyephedrine (100 μM) in a syringe in 20 mM NaH2PO4 buffer (pH 7.4); b) a plot of ΔH as a function of molar ratio. The solid line represents the best nonlinear fit of the data to the 1:1 binding model (Ka = (1.91 ± 0.19) × 107 M⁻¹, ΔH = -12.6 ± 0.11 kcal / mol, -TΔS = 2.68 kcal / mol).

[0085] Figure 71 shows a) a plot of DP versus time from titrating the molecular container P[6]AS (10 μM) in the pool using heroin (100 μM) in a syringe in 20 mM NaH2PO4 buffer (pH 7.4); b) a plot of ΔH as a function of molar ratio. The solid line represents the best nonlinear fit of the data to the 1:1 binding model (Ka = (5.78 ± 0.02) × 10⁵ M⁻¹, ΔH = -11.9 ± 0.11 kcal / mol, -TΔS = 4.01 kcal / mol).

[0086] Figure 72 shows a) a plot of DP versus time from molecular containers P[6]AS (100 μM) and 17 (500 μM) titrated with rocuronium bromide (1.00 mM) in 20 mM NaH₂PO₄ buffer (pH 7.4); b) a plot of ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (Ka = (6.33 ± 0.08) × 10¹¹ M⁻¹, ΔH = -24.9 ± 0.177 kcal / mol, -TΔS = 8.79 kcal / mol).

[0087] Figure 73 shows a) a plot of DP versus time from molecular containers P[6]AS (100 μM) and 17 (500 μM) titrated with vecuronium bromide (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) a plot of ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (Ka = (1.00 ± 0.34) × 10¹² M⁻¹, ΔH = -18.5 ± 0.095 kcal / mol, -TΔS = 2.10 kcal / mol).

[0088] Figure 74 shows a) a plot of DP versus time from molecular containers P[6]AS (100 μM) and 17 (150 μM) titrated with pancuronium bromide (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) a plot of ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (Ka = (7.35 ± 1)..23)×1010M-1,ΔH=-16.5±0.216kcal / mol,-TΔS=1.63kcal / mol。

[0089] Figure 75 shows a) a plot of DP from molecular container P[7]AS (10μM) and titrated with cis-atracurium (0.05mM) in 20mM NaH2PO4 buffer (pH 7.4) as a function of time; b) a plot of ΔH as a function of molar ratio. The solid line represents the best nonlinear fit of the data to the 1:1 binding model where n=0.5 (Ka=(1.52±0.12)×107M-1,ΔH=-35.0±0.396kcal / mol,-TΔS=25.2kcal / mol。

[0090] Figure 76 shows a) a plot of DP versus time from the titration of molecular container P[6]AS (100 μM) and propane-1,3-diammonium (150 μM) with methamphetamine (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) a plot of ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (Ka = (9.90 ± 0.39) × 106 M⁻¹, ΔH = -10.4 ± 0.040 kcal / mol, -TΔS = 0.833 kcal / mol).

[0091] Figure 77 shows a) a plot of DP versus time from the titration of molecular container P[6]AS (100 μM) and propane-1,3-diammonium (1.00 mM) with fentanyl (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) a plot of ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (Ka = (1.02 ± 0.03) × 108 M⁻¹, ΔH = -15.0 ± 0.052 kcal / mol, -TΔS = 4.02 kcal / mol).

[0092] Figure 78 shows a) a graph of DP versus time from molecular container P[6]AS (100 μM) titrated with cocaine (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) a graph of ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the 1:1 binding model (Ka = (1.92 ± 0.06) × 106 M⁻¹, ΔH = -15.6 ± 0.047 kcal / mol, -TΔS = 7.07 kcal / mol).

[0093] Figure 79 shows a) a graph of DP versus time from molecular container P[6]AS (100 μM) titrated with ketamine (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔHThe graph shows the variation of H with molar ratio. The solid line represents the best nonlinear fit of the data to the 1:1 combined model (Ka = (1.52 ± 0.25) × 10⁵ M⁻¹, ΔH = -22.0 ± 1.02 kcal / mol, -TΔS = 14.9 kcal / mol).

[0094] Figure 80 shows a) the graph of DP versus time from the titration of molecular container P[6]AS (100 μM) and propane-1,3-diammonium (150 μM) with phenylcyclidine (1.00 mM) in 20 mM NaH₂PO₄ buffer (pH 7.4); b) the graph of ΔH with molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (Ka = (5.85 ± 0.47) × 10⁷ M⁻¹, ΔH = -12.4 ± 0.076 kcal / mol, -TΔS = 1.84 kcal / mol).

[0095] Figure 81 shows a) a plot of DP from molecular container P[6]AS (100 μM) and titrated with morphine (1.00 mM) in 20 mM NaH₂PO₄ buffer (pH 7.4) as a function of time; b) a plot of ΔH as a function of molar ratio. The solid line represents the best nonlinear fit of the data to the 1:1 binding model (Ka = (1.36 ± 0.07) × 10⁶ M⁻¹, ΔH = -12.9 ± 0.073 kcal / mol, -TΔS = 4.49 kcal / mol).

[0096] Figure 82 shows a) a plot of DP versus time from molecular container P[6]AS (100 μM) titrated with hydromorphone (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) a plot of ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the 1:1 binding model (Ka = (1.31 ± 0.04) × 106 M⁻¹, ΔH = -11.9 ± 0.042 kcal / mol, -TΔS = 3.55 kcal / mol).

[0097] Figure 83 shows a) a plot of DP versus time from molecular container P[6]AS (100 μM) titrated with oxycodone (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) a plot of ΔH versus molar ratio. The solid line represents the best nonlinear fit between the data and the 1:1 combined model (Ka = (9.52 ± 0.36) × 10⁴ M⁻¹, ΔH = -8.62 ± 0.097 kcal / mol, -TΔS = 1.83 kcal / mol). See specification page 8 / 46, document number 13, CN 121064070 A for detailed implementation details

[0098] .Although the claimed subject matter will be described with reference to certain examples, other examples, including those that do not provide all the benefits and features set forth herein, are also within the scope of this disclosure. Various structural, logical, and process steps may be changed without departing from the scope of this disclosure.

[0099] Ranges of values ​​are disclosed herein. These ranges specify lower and upper limits. Unless otherwise stated, these ranges include lower limits, upper limits, and all values ​​between the lower and upper limits, including but not limited to all values ​​up to a minimum value (whether lower or upper limit).

[0100] As used herein, unless otherwise stated, the term “group” refers to a monovalent (i.e., having one end that can covalently bond to other chemical species), divalent, or polyvalent (i.e., having two or more ends that can covalently bond to other chemical species) chemical entity. The term “group” also includes free radicals (e.g., monovalent and polyvalent, such as, for example, divalent, trivalent, etc.). Exemplary examples of groups include:

[0101]

[0102] As used herein, unless otherwise specified, the term "aryl group" refers to a C5 to C18 (inclusive of all integer carbon numbers and the range thereof) aromatic or partially aromatic carbocyclic group (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, and C18). Aryl groups may also be referred to as aromatic groups. Aryl groups may include polyaryl groups, such as, for example, fused rings or biaryl groups. Aryl groups may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, various substituents such as, for example, halogens (-F, -Cl, -Br, and -I), azide groups, aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, etc.), aryl groups, hydroxyl groups, alkoxide groups, carboxylic acid ester groups, carboxylic acid groups, ether groups, ester groups, amide groups, thioether groups, thioester groups, etc., and combinations thereof. Substituents may be or further include sulfonate groups or sulfate groups. Examples of aryl groups include, but are not limited to, phenyl groups, biaryl groups (e.g., biphenyl groups), and fused-ring groups (e.g., naphthyl groups, anthracene groups, pyrene groups, etc.), which may be unsubstituted or substituted.

[0103] As used herein, unless otherwise specified, the term "heteroaryl group" refers to a C1 to C18 monocyclic, polycyclic, or bicyclic group (e.g., an aryl group) comprising one or two aromatic rings, wherein the one or two aromatic rings contain at least one heteroatom (e.g., nitrogen, oxygen, sulfur, etc.), which includes all integer carbon numbers and the range of carbon numbers therebetween (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9 ...(C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, and C18). The heteroaryl group can be substituted or unsubstituted. Examples of heteroaryl groups include, but are not limited to, benzofuranyl, thienyl, furanyl, pyridyl, pyrimidinyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazole, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl groups. Examples of substituents include, but are not limited to, halogens (-F, -Cl, -Br, and -I), aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, etc.), aryl groups, alkoxide groups, amine groups, carboxylic acid ester groups, carboxylic acid groups, ether groups, alcohol groups, alkynyl groups (e.g., ethynyl groups, etc.), and combinations thereof.

[0104] As used herein, unless otherwise specified, the term "aliphatic" means a branched or unbranched hydrocarbon group optionally containing one or more unsaturations. Unsaturation can come from, but is not limited to, cyclic aliphatic groups. For example, the aliphatic group / part is a C1 to C40 aliphatic group, including all integer carbon numbers and the range of carbon numbers in between (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, and C40). The aliphatic group includes, but is not limited to, alkyl groups, alkenyl groups, and alkynyl groups. The aliphatic group may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, various substituents such as, for example, halogens (-F, -Cl, -Br and -I), azide groups, aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, etc.), aryl groups, hydroxyl groups, alkoxide groups, carboxylic acid ester groups, carboxylic acid groups, ether groups, ester groups, amide groups, thioether groups, thioester groups, etc., and combinations thereof.

[0105] As used herein, unless otherwise specified, the term "alkyl group" refers to a branched or unbranched saturated hydrocarbon group. Examples of alkyl groups include, but are not limited to, methyl groups, ethyl groups, n-propyl groups and isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups and tert-butyl groups, etc. For example, alkyl groups can be C1 to C12, which includes...All integer carbon numbers and ranges thereof (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12). Alkyl groups may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, various substituents such as, for example, halogens (-F, -Cl, -Br, and -I), azide groups, aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, etc.), aryl groups, hydroxyl groups, alkoxide groups (-OR, where R is an alkyl group), carboxylic acid ester groups, carboxylic acid groups, ether groups, ester groups, amide groups, thioether groups, thioester groups, etc., and combinations thereof.

[0106] This disclosure provides sulfated columnar aromatics. This disclosure also provides methods for preparing sulfated columnar aromatics and their uses.

[0107] In this disclosure, it has been shown, for example, that positioning anionic solubilizing groups at the edge of the columnar aromatic hydrocarbon cavity significantly enhances their binding affinity for cationic targets in water, and thereby enhances their ability as chelating agents for a wide variety of applications.

[0108] In one aspect, this disclosure provides compounds. The compounds are sulfated columnar aromatic hydrocarbons. Sulfated columnar aromatic hydrocarbons comprise a macrocyclic core containing a plurality of aryl groups, wherein adjacent aryl groups are covalently linked (e.g., bonded) via alkyl linking groups (e.g., -CH2- groups). The alkyl linking group is para-positioned on the aryl group (e.g., 1,4-phenyl bond). The bond may be on different benzene rings of the aryl group, and if different benzene rings overlap, it corresponds to a para-position bond. In several examples, one or more or all of the adjacent aryl groups are not covalently linked by alkyl linking groups at the meta position on the aryl group (e.g., 1,3-phenyl bond (where the bond is on different benzene rings or aryl groups, these bonds do not correspond to meta-position bonds if different benzene rings overlap)). This document provides non-limiting examples of sulfated columnar aromatics. This document provides non-limiting examples of methods for preparing sulfated columnar aromatics.

[0109] In several examples, the sulfated columnar aromatics have the following structure:

[0110]

[0111] wherein Ar is an aryl group attached (e.g., covalently bonded) to an adjacent methylene group (e.g., 1,4-phenyl group bond) in the para-substitution position, which may be part of a larger aryl group; each R is independently selected from -OS(O)2O-M+ (wherein M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or the cationic form of ethylenediamine, piperazine or tris(hydroxymethyl)aminomethane (TRIS), -OS(O)2OH, non-sulfate anionic groups (such as, for example, sulfonates (andThe corresponding acid group (e.g., -O(CH2)mS(O)2O –M+ (where M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) / -O(CH2)mS(O)2OH, where m is 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8), -C6H5S(O)2OH, etc., and such groups in which the terminal O is removed), carbonate (and the corresponding acid group) (e.g., -O(CH2)mC(O)O –M+ (where M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+). Or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) / -O(CH2)mC(O)OH, where n is 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8), such as -OCH2CO2 –M+ / -OCH2CO2H groups and such groups in which the terminal O is removed), phosphonate (and corresponding acid) groups (e.g., -O(CH2)mP(O)(OH)2 –M+ (where M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) / -O(CH2)mP(O)(OH)2, where m is 1 Up to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8), such as -O(CH2)2P(O)(OH)2 and such groups in which the terminal O is removed), phosphate groups -OP(O)(OH)2, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted aliphatic groups, O-alkyl groups (including alkyl groups), azide groups, -H, substituted or unsubstituted alkyl groups, halogens (e.g., -Br, -F, -I, -Cl), amide groups, cyano groups, substituted or unsubstituted sulfur-containing aliphatic groups (e.g., -S-alkyl and polysulfides), nitro groups, amino groups, substituted or unsubstituted nitrogen-containing aliphatic groups (e.g., polyamines, aliphatic groups including secondary and / or tertiary amines), substituted or unsubstituted polyethylene glycol groups, polyether groups, O-aryl groups (e.g., aryloxy groups), ester groups, urethane groups, imine groups, aldehyde groups, -SO3H Groups, -SO3Na group, -OSO2F group, -OSO2CF3 group, -OSO2OR″′ group (where R″′ is a substituted or unsubstituted aromatic group)The aryl group (or substituted or unsubstituted alkyl group), and combinations thereof; x is 0, 1, 2, or 3; and y is independently 0, 1, 2, 3, or 4 each time it appears, provided that at least one y is 1 and at least one R group is -OS(O)₂O-M+ (where M+ is Na+, K+) or -OS(O)₂OH, or its salt, partial salt, hydrate, polymorph, stereoisomer, conformational isomer, or mixture. One or more R groups can be located at any position on the aryl group. In the case of an aryl group having multiple R groups, a single R group can be at any combination of the positions of the aryl group. In several examples, all aryl groups contain an R group, which is independently -OS(O)₂O –M⁺ (where M⁺ is Na⁺, K⁺, Ca²⁺, Mg²⁺, Zn²⁺, H₄N⁺, Et₃NH⁺, Me₄N⁺, (HOCH₂CH₂)₃NH⁺, or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) or -OS(O)₂OH. In several examples, at least one aryl group does not contain an R group, which is -OS(O)₂O –M⁺ (where M⁺ is Na⁺, K⁺, Ca²⁺, Mg²⁺, Zn²⁺, H₄N⁺, Et₃NH⁺, Me₄N⁺, (HOCH₂CH₂)₃NH⁺, or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) or -OS(O)₂OH. In several embodiments, the aryl group may be further substituted with various substituents, such as, for example, -H, alkyl groups, aliphatic groups, polyethylene glycol groups, or combinations thereof.

[0112] In some embodiments, M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS).

[0113] In some embodiments, M+ is Na+, K+, and H4N+. In some embodiments, M+ is Na+.

[0114] The sulfated columnar aromatic hydrocarbon may contain various aryl groups. The aryl groups may be all the same or at least two of the aryl groups may be different. Non-limiting examples of aryl groups are selected independently each time they appear from phenyl groups, fused-ring groups (e.g., naphthyl groups, anthracene groups, phenanthrene groups, tetraphenyl groups, pentaphenyl groups, etc.), biaryl groups (e.g., biphenyl groups, etc.), terphenyl groups, etc., and combinations thereof. For the avoidance of doubt, unless otherwise stated, when a phenyl group is not part of a larger aryl group, it is a C6H4 group. A phenyl group may be referred to as a phenylene group.

[0115] Adjacent aryl groups can be bonded by various bonds. These bonds are para-linked phenyl group bonds. In several specifications...Page 11 / 46, CN 121064070 A. In the example, at least some or all of these bonds are 1,4-phenyl groups. Non-limiting examples of para-linked phenyl groups include:

[0116]

[0117]

[0118] and combinations thereof. These are exemplary examples. Other para-linked phenyl groups are within the scope of this disclosure. In several examples, the bond is not a meta bond.

[0119] The aryl group may contain one or more phenyl groups. In several non-limiting examples, the cyclic core of the compound comprises at least two, at least three, or at least four or all of one or more aryl groups and one or more phenyl groups having at least one or at least two R groups, the R groups being independently selected from -OS(O)2O-M+ (where M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) and -OS(O)2OH. All aryl groups (one or more of which may be phenyl groups) may contain a sulfate group -OS(O)2O-M+ (where M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) or -OS(O)2OH. In several examples, at least one aryl group (which may be a phenyl group) does not contain a sulfate group (e.g., -OS(O)2O-M+ (where M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) or -OS(O)2OH).

[0120] In several examples, the sulfated columnar aromatics have the following structures:

[0121] Specification 12 / 46 pages 17 CN 121064070 A

[0122]

[0123] In several examples, each R is -OS(O)2O -M+ (wherein M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) and -OS(O)2OH.

[0124] In several examples, the sulfated columnar aromatics have the following structures:

[0125]

[0126] In several examples, R groups 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 are independently -OS(O)2O-M+ groups (wherein M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) or -OS(O)2OH groups.

[0127] In one aspect, this disclosure provides compositions comprising one or more sulfated columnar aromatics. Non-limiting examples of the compositions are described herein.

[0128] The compositions may comprise one or more sulfated columnar aromatics and one or more pharmaceutical agents. In several examples, the pharmaceutical agent comprises one or more positively charged nitrogen atoms (e.g., ammonium ions, primary ammonium ions, secondary ammonium ions, tertiary ammonium ions, quaternary ammonium ions, or combinations thereof, wherein one or more non-hydrogen groups on the ammonium are selected from aliphatic groups, alkyl groups, aryl groups, and combinations thereof).

[0129] The composition may comprise one or more sulfated columnar aromatics, one or more pharmaceutical carriers, and optionally one or more pharmaceutical agents. The compositions described herein may have one or more pharmaceutically acceptable carriers. Suitable pharmaceutically acceptable carriers are known in the art. Some non-limiting examples of pharmaceutically acceptable carriers can be found in the following literature: Remington: The Science and Practice of Pharmacy (2005), 21st Edition, Philadelphia, PA. Lippincott Williams & Wilkin. In several example specifications, page 13 / 46, 18 CN 121064070 A, the pharmaceutical carrier is pure water or a buffer, such as PBS buffer, etc.

[0130] A composition comprising one or more sulfated columnar aromatic hydrocarbons (which can form guest-host complexes) in combination with one or more pharmaceutical agents can be prepared at any point in time prior to the use of the composition using any suitable technique. The compound-pharmaceutical complex can be formed, for example, by mixing the compound and the pharmaceutical agent in a suitable solvent. It is desirable that the compound and the pharmaceutical agent be soluble in the solvent such that the compound and the pharmaceutical agent form a non-covalent complex. Any suitable solvent can be used. In some examples, the solvent is an aqueous solution, which includes, but is not limited to, water and various buffers (e.g., PBS buffer, etc.). Non-aqueous solvents (e.g., MeOH, EtOH, and other organic solvents, and combinations thereof) can also be used, which are then removed.And if necessary, the composition can be redissolved in an aqueous solution for administration. Generally, a solution of one or more compounds can be provided at a known concentration, examples of which include, but are not limited to, 0.1 to 90 mM (inclusive of end values ​​and all integers in between to ten decimal places), and an agent to enhance solubility is added to the solution. One or more agents can be provided, for example, in solid form. The combination can be shaken or stirred for a period of time, and the amount of dissolved agent monitored. If all the added agent has entered the solution, more agent can be added until some detectable fraction remains undissolved (e.g., solid). The soluble compound-drug complex can then be separated and analyzed using any suitable technique, such as by recovering the centrifuged fraction and analyzing it by NMR to determine the concentration of the agent in the solution. In several examples, the compound is provided in the drug-containing composition at a ratio of at least 1:1 related to the compound-drug stoichiometry (e.g., the ratio of columnar aromatics to the drug). In several examples, the ratio of columnar aromatics (e.g., columnar aromatic sulfate) to the drug is from 100:1 to 1:5, including all ratio values ​​and ranges therebetween (e.g., 100:1, 5:1, 1:2, 1:3, 1:4, or 1:5).

[0131] The composition may be prepared at the patient's bedside or by the drug manufacturer. In the latter case, the composition may be provided in any suitable container (such as, for example, a sealed sterile vial, ampoule, etc.) and may be further packaged to include instructions for use by pharmacists, physicians, other healthcare providers, etc. (the combination may be referred to as a kit). The composition may be provided in liquid form or in lyophilized or powder form (which may be reconstituted when ready for use if desired). In particular, the composition may be provided in combination with any suitable delivery form or solvent (examples of which include, but are not limited to, liquid dosage forms, capsules, tablets, inhalers, or aerosols, etc.). Delivery devices may include components that promote the release of a drug agent over a specific time period and / or interval, and may include compositions that enhance drug delivery, such as nanoparticles, microspheres, or liposome formulations, a wide variety of which are known in the art and are commercially available. Furthermore, each composition described herein may contain one or more drug agents.

[0132] The compositions of this disclosure may contain more than one drug agent. Similarly, compositions may contain different host-guest complexes. For example, a first composition containing one or more sulfated columnar aromatics and a first drug agent may be prepared separately from a composition containing the same compound and a second drug agent, and such formulations may be mixed to provide a dual (or more) approach to achieving the desired prevention or treatment in an individual. Furthermore, compositions may be prepared using a mixture of any of the sulfated columnar aromatic compounds disclosed herein.

[0133] The solid substrate may contain one or more sulfated columnar aromatics disposed on (e.g., chemically bonded to) at least a portion of the surface of the substrate. At least a portion or all of the sulfated columnar aromatics may be chemically bonded to at least a portion of the surface by covalent bonds, non-covalent bonds, or combinations thereof. Methods for attaching sulfated columnar aromatics to a solid surface are known in the art. In several examples, the sulfated columnar aromatics are attached to the surface by covalent and / or non-covalent bond formation reactions (including, but not limited to, amide bond formation, azide alkyne cycloaddition, gold thiol interaction, silanol condensation, etc., and combinations thereof).

[0134] The solid substrate may contain (or be) various materials. In several non-limiting examples, the solid substrate includes or is composed of silica (such as, for example, silica particles), polymer beads, polymer resins (such as, for example, polystyrene, poly(NIPAM), polyacrylic acid), metal nanoparticles (such as, for example, gold nanoparticles, silver nanoparticles, magnetic nanoparticles), metals (such as, for example, gold), or combinations thereof.

[0135] In one aspect, this disclosure provides for the use of sulfated columnar aromatics. Non-limiting examples of the use of sulfated columnar aromatics are provided herein, for example, non-limiting examples of the use of sulfated columnar aromatics are described in the statements and examples.

[0136] Sulfated columnar aromatics can be used to chelate a variety of materials, which may be chemical compounds. In several non-limiting examples, one or more sulfated columnar aromatics are used to chelate one or more neuromuscular blocking agents (such as, for example, ... Rocuronium bromide, tubocurarine, atracurium bromide, atracurium (cis)benzenesulfonate, vecuronium, galamine, pancuronium bromide, vecuronium bromide, and lapacuronium, etc.; one or more anesthetics (such as, for example, N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., ketamine), short-acting anesthetics (e.g., etomidate, etc.); one or more agents (such as, for example, drugs (e.g., anticoagulants, such as, for example, hymedioxanone, etc.), abuse drugs (e.g., methamphetamine, cocaine, fentanyl, carfentanil, PCP, MDMA, heroin, etc.); one or more insecticides (such as, for example, paraquat, diquat, organochlorines (e.g., DDT, etc.)). Aldrin, neonicotinoids (e.g., permethrin), organophosphates (e.g., malathion, glyphosate), pyrethroids, triazines (e.g., atrazine), etc.; one or more dyes (e.g., methylene blue, Nile red, crystal violet, thiazole T, thiazole orange, proflavin, acridine orange, methylene violet, azurite A, neutral red, cyanine, direct orange 26, disperse dyes (e.g., disperse yellow 3, disperse blue 27), coumarin, Congo red, etc.); one or more malodorous compounds (e.g., low molecular weight thiols).(e.g., C1-C4 thiols), low molecular weight amines (e.g., triethylamine, putrescine, cadaverine, etc.); or one or more chemical warfare agents (e.g., nitrogen mustard and sulfur mustard (e.g., bis(2-chloroethyl)ethylamine, bis(2-chloroethyl)methylamine, tri(2-chloroethyl)amine, bis(2-chloroethyl)sulfide, bis(2-chloroethylthioethyl)ether, etc.), nerve agents (e.g., those from the G, GV, and V series nerve agents (e.g., tabun, sarin, soman, cyclosarin, 2-(dimethylamino)ethyl N,N-dimethylphosphatamidofluoroester (GV), Novichok, VE, VG, VM, VX, etc.); one or more hallucinogens (e.g., ergolines, lysergic acid diethylamide (LSD)). Diethylamide, psilocybin, tryptamines, dimethyltryptamine (DMT), phenethylamines, mescaline, ayahuasca, dextromethorphan, etc.; one or more toxins (e.g., dioxins, perfluoroalkyl sulfonates (PFAS), perfluorooctanoic acid (PFOA), decabromodiphenyl ether (DECA), heavy metals (e.g., mercury), muscarine, tyramine, strychnine, tetrodotoxin, saxitoxin, etc.), cholesterol, deoxycholic acid, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, phenylalanine, tyrosine, etc. Arginine, histamine); one or more metabolites (e.g., toxic metabolites, such as, for example, N-methyl-4-phenylpyridine, spermine, spermidine, N-nitroso compounds such as 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone); or combinations thereof.

[0137] Materials that may be chemical compounds may contain one or more cationic groups. In several examples, materials that may be chemical compounds may contain one or more positively charged nitrogen atoms (e.g., ammonium ions, primary ammonium ions, secondary ammonium ions, tertiary ammonium ions, quaternary ammonium ions, or combinations thereof, wherein one or more non-hydrogen groups on the ammonium are selected from aliphatic groups, alkyl groups, aryl groups, and combinations thereof).

[0138] In several examples, a method for chelating one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceuticals, one or more insecticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, etc., or combinations thereof, includes causing one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceuticals, one or more...Insecticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof, are contacted with one or more sulfated aromatic hydrocarbons and / or one or more compositions, wherein the one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceuticals, one or more insecticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, or combinations thereof are chelated by the one or more sulfated aromatic hydrocarbons and / or one or more compositions.

[0139] One or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceuticals, one or more insecticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof may be present in aqueous samples, solid samples (such as, for example, soil samples), gaseous samples, etc. Aqueous samples can be obtained (e.g., via extraction or other methods for separating one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceuticals, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof from a solid sample). Aqueous samples can be wastewater samples (e.g., municipal wastewater samples, industrial wastewater samples, etc.), industrial water samples (e.g., water used to manufacture commercial products such as reagents, solvents, etc.), municipal water samples, etc.

[0140] The composition may contain one or more pharmaceutically active agents. In several non-limiting examples, at least a portion (or all) of one or more compounds has one or more pharmaceutically active agents disposed within cavities of one or more compounds. Without intending to be bound by any particular theory, it is considered that a complex (which may be referred to as a guest-subject complex) is formed by one or more interactions (e.g., one or more non-covalent interactions, such as one or more non-covalent bonds, formed therebetween) between a compound (which may be referred to as a subject) and one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceutical agents (which may be one or more pharmaceutical agents with undesirable (e.g., low) water solubility), one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof (which may be referred to as one or more guests). Thus, a guest-subject complex can be viewed as an organized chemical entity produced by the association (e.g., through non-covalent intermolecular forces) of one or more pharmaceutical agents (one or more guests) and a subject held together.

[0141] The composition may comprise a variety of pharmaceutical active agents. Non-limiting examples of agents include drugs. One or more pharmaceutical active agents may have different water solubilities. Pharmaceutical active agents may have hydrophobic, hydrophilic, or amphiphilic properties.

[0142] The complex can be removed from aqueous samples, solid samples, gaseous samples, etc. In several examples, one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof, are removed from aqueous samples, solid samples, gaseous samples, etc., using a solid surface on which one or more sulfated columnar aromatic hydrocarbons are disposed.

[0143] Sulfated columnar aromatic hydrocarbons can be used to chelate various materials in an individual. In several non-limiting examples, one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceuticals, one or more insecticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof, are present in an individual, and exposure includes administering one or more compounds and / or one or more compositions to the individual.

[0144] Sulphated aryl hydrocarbons can be used to reverse drug-induced neuromuscular blockade and / or anesthesia and / or the effects of one or more pharmaceuticals (e.g., one or more abused pharmaceuticals) in or on an individual, comprising administering one or more sulphated aryl hydrocarbons and / or one or more compositions to an individual who requires reversal of neuromuscular blockade and / or reversal of anesthesia and / or reversal of the effects of one or more pharmaceuticals (e.g., one or more abused pharmaceuticals). The individual may require reversal of drug-induced neuromuscular blockade. An individual may need to reverse anesthesia. An individual may need to reverse drug-induced neuromuscular blockade and anesthesia. An individual may need to reverse the effects of one or more agents, such as one or more drugs (which may be one or more abused drugs). An individual may have been exposed to one or more abused drugs (e.g., carfentanil, etc.) in a terrorist attack.

[0146] Sulfated columnar aromatic compounds can be used as containers for dissolving chemical compounds. Improving the solubility of compounds in, for example, aqueous solutions is desirable for studying pharmaceutical compounds and for improving the bioavailability of drugs for purposes such as, for example, treatment and / or prevention. For example, sulfated columnar aromatic compounds are used to enhance the stability of drugs in water, in the solid state, or both (e.g., reducing degradation, increasing shelf life, etc.).

[0147] In some examples, sulfated columnar aromatic compounds can be used to rescue promising drug candidates with undesirable solubility and bioavailability, and thus reduce consumption in the drug development process for anticancer agents and agents intended to treat other diseases. The container can be used to target and deliver drugs to specific cell types, such as, for example, tumor cells, to improve the effectiveness of existing drugs, reduce one or more of their toxic side effects, or both.

[0148] In several examples, the composition comprises one or more sulfated columnar aromatic compounds and one or more pharmaceutical agents. Such compositions can be provided as pharmaceutical formulations as described herein.

[0149] It is important to emphasize that there are no particular limitations on the one or more pharmaceutical agents that may be included in a composition comprising one or more sulfated columnar aromatic compounds and one or more pharmaceutical agents. In some examples, the one or more pharmaceutical agents combined with one or more sulfated columnar aromatic compounds are one or more pharmaceutical agents with poor water solubility. In some other examples, the one or more pharmaceutical agents combined with one or more sulfated columnar aromatic compounds are one or more pharmaceutical agents with water solubility.

[0150] If desired, the solubility of any particular pharmaceutical agent can be determined using any of a wide variety of techniques well known to those skilled in the art. If necessary, solubility can be determined at any pH (such as physiological pH) and / or at any desired temperature. Suitable temperatures include, but are not necessarily limited to, 4°C to 70°C (inclusive), and include all integer °C values ​​in between.

[0151] Regarding poorly soluble or lowly soluble pharmaceutical agents suitable for use in this disclosure, in several examples, such agents are considered to be those with a solubility of less than 100 μM in water or aqueous buffer solutions.

[0152] In several other examples, poorly soluble pharmaceutical agents are considered to include compounds that are Class 2 or Class 4 drugs in the Biopharmaceutics Classification System (BCS). The BCS is well known to those skilled in the art and is based on the water solubility of drugs reported in readily available references, and for drugs administered orally, it includes the correlation of human intestinal membrane permeability (see, for example, Takagi et al., (2006) Molecular Pharmaceutics, Vol. 3, No. 6, pp. 631-643). Therefore, a person skilled in the art can easily identify a drug as a member of BCS Class 2 or Class 4 based on published literature, or can test a drug with unknown BCS or other solubility values ​​to determine whether it has characteristics consistent with any of these classifications, or otherwise is suitable for use in this disclosure. In one example, solubility is determined according to the parameters listed in this matrix:

[0153] Solubility Number of solvent parts required for 1 part of solute Solubility range (mg / mL) Very soluble <1 ≥1000 Soluble 1 to 10 100-1000 Soluble 10 to 30 33-100 Slightly soluble 30 to 100 10-33Page 17 / 46, CN 121064070 A Slightly soluble 100 to 1000 1-10 Very slightly soluble 1000 to 10000 0.1-1 Practically insoluble ≥10000 <0.1

[0154] Therefore, for the purposes of this disclosure, any poorly soluble agent that can be combined with one or more sulfated aromatic hydrocarbons can be any agent falling into the categories of slightly soluble, slightly soluble, very slightly soluble, and practically insoluble as shown in the matrix above.

[0155] Again, it should be emphasized that there are no limitations on the agents that can be combined with one or more sulfated aromatic hydrocarbons except for those characterized as having low solubility in aqueous solutions. In this respect, at least one use of this disclosure is the combination of one or more of a wide variety of different agents with one or more sulfated aromatic hydrocarbons, and as a result of combining these compounds with one or more agents, the solubility of one or more agents increases. In several examples, suitable agent types for solubilization include, but are not limited to, mitotic inhibitors (e.g., taxol, a mitotic inhibitor used in cancer chemotherapy, etc.); nitrogen mustard alkylating agents (e.g., melphalan, traded as Alkeran for chemotherapy, etc.); benzimidazoles (e.g., albendazole, marketed as Albenza, Eskazole, Zentel, and Andazol, used to treat a wide variety of worm infections, etc.); and antagonists of estrogen receptors in breast tissue used to treat breast cancer (e.g., tamoxifen, etc.). Ifen, which, when metabolized to its active form hydroxytamoxifen, is an estrogen receptor antagonist, etc.; antihistamines (e.g., Cinnarizine, marketed as Sturgeon and Stunarone, for controlling symptoms of motion sickness, etc.); thienopyridine antiplatelet agents (e.g., clopidogrel, marketed as Plavix, for inhibiting thrombosis in coronary artery disease and other diseases, etc.); and antiarrhythmic agents (e.g., amiodarone, for treating tachyarrhythmias, etc.). Other agents not explicitly listed herein are also included within the scope of this disclosure. Some examples of such agents include, but are not limited to, adjuvants for enhancing immune responses, analgesics, detectable labeling reagents for diagnostic imaging, etc. Any combination of these exemplary agents may be used. Sulfated columnar aromatics may be combined with agents and improve the solubility of agents that are members of distinctly different classes of compounds characterized by completely different chemical structures and biological activities.

[0156] The compositions of this disclosure can be applied to any person or non-person who needs treatment or prevention of one or more conditions.In humans and animals, the agent is intended to provide preventative or therapeutic benefits for the stated condition. Therefore, an individual may be diagnosed with, suspected of having, or at risk of developing any of a wide variety of conditions (with the aim of reducing their severity). Non-limiting examples of such conditions include cancers, including solid tumors, blood cancers (e.g., leukemia, lymphoma, myeloma, etc.). Specific examples of cancers include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelioma, lymphangiosarcoma, pseudomyxoma peritonei, lymphangioendothelioma, synovial tumor, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, head and neck cancer, and sweat gland cancer. Sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilns' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor (Instruction manual 18 / 46 pages 23 CN 121064070 A)(pinealoma), hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, thymoma, Waldenstrom's macroglobulinemia, heavy chain disease, etc.

[0157] In addition to various malignant tumors, the compounds of this disclosure are also suitable for providing benefits for cardiovascular-related conditions, examples of which include, but are not limited to, angina pectoris, arrhythmia, atherosclerosis, cardiomyopathy, congestive heart failure, coronary artery disease, carotid artery disease, endocarditis, coronary thrombosis, myocardial infarction, hypertension, hypercholesterolemia / hyperlipidemia, mitral valve prolapse, peripheral artery disease, stroke, thrombosis, embolism, and other forms of ischemic injury.

[0158] Furthermore, the compositions of this disclosure can be used with regard to the treatment of a wide variety of infectious diseases. A wide variety of agents intended for the treatment and / or inhibition of infectious diseases caused by, for example, bacteria, protozoa, worms, fungi, viruses, etc., can be aided by the use of the compositions of this disclosure.

[0159] The compounds and / or compositions of this disclosure can be introduced into an individual using various methods known to those skilled in the art. These methods include, but are not limited to, intravenous, intramuscular, intracranial, intrathecal, intradermal, subcutaneous, oral routes, and combinations thereof. The dosage of the composition containing the compound and the agent will necessarily depend on the needs of the individual to whom the composition is to be administered. These factors include, but are not limited to, weight, age, sex, medical history, and the nature and stage of the disease for which a therapeutic or preventative effect is desired. The composition may be used in conjunction with any other conventional treatment modality designed to improve the expected therapeutic or preventative effect of the disease, non-limiting examples of which include surgical intervention and radiation therapy. The composition may be administered once or in a series of administrations at different intervals determined by a person skilled in the art, and provide the benefits of this disclosure.

[0160] The methods of this disclosure can be used on a variety of individuals. In many examples, the individual is a human or a non-human mammal. Examples of non-human mammals include, but are not limited to, farm animals such as, for example, cattle, pigs, sheep, etc., and pet or sporting animals such as, for example, horses, dogs, cats, etc. Other non-limiting examples of individuals include, but are not limited to, rabbits, rats, mice, etc.

[0161] The steps of the methods described in the various examples disclosed herein are sufficient to implement the methods of this disclosure. Thus, in one example, the method is essentially composed of a combination of the steps of the methods disclosed herein. In another example, the method is composed of such steps.

[0162] In one aspect, this disclosure provides articles comprising compounds of this disclosure.

[0163] The articles may be manufactured articles. Non-limiting examples of articles include wipes impregnated with one or more compounds of this disclosure. For example, such wipes are used to clean surfaces from any material capable of being chelated by compounds (e.g., columnar aromatics of this disclosure). For example, wipes are used to clean surfaces that have been or previously exposed to toxins, abused drugs, or combinations thereof.

[0164] The following statements illustrate various embodiments of this disclosure.

[0165] Statement 1. A compound having the following structure: Specification 19 / 46 pages 24 CN 121064070 A

[0166]

[0167] wherein Ar is an aryl group, wherein adjacent aryl groups are bonded by para-linked phenyl groups (e.g., one or more 1,4-phenyl groups) (e.g., the aryl group is para-substituted to be connected to an adjacent methylene group), which may be part of a larger aryl group; each R is independently selected from -OS(O)2O-M+ (where M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or ethylenediamine, piperazine or tris(hydroxymethyl)aminomethane (TRIS) The cationic form), and -OS(O)2OH, non-sulfate anionic groups (such as, for example, sulfonate (and corresponding acid) groups (e.g., -O(CH2)mS(O)2O –M+ (where M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or the cationic form of ethylenediamine, piperazine or tris(hydroxymethyl)aminomethane (TRIS)) / -O(CH2)mS(O)2OH, where n is 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8), -C6H5S(O)2OH, etc., and such groups where the terminal O is removed), carboxylate (and corresponding acid) groups (e.g., -O(CH2)mC(O) ... +, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) / -O(CH2)mC(O)OH, where m is 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8), such as -OCH2CO2 –M+ / -OCH2CO2H groups, and such groups in which the terminal O is removed), phosphate (and corresponding acid) groups (e.g., -O(CH2)mP(O)(OH)2 –M+ (where M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, or the cationic form of ethylenediamine, piperazine or tris(hydroxymethyl)aminomethane (TRIS)) / -O(CH2)mP(O)(OH)2, where m is 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8), such as -O(CH2)2P(O)(OH)2, and such groups in which the terminal O is removed), Phosphate ester groups (e.g., OP(O)(OH)2), substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted aliphatic groups, O-alkyl groups (including alkyl groups), polyether groups (e.g., polyethylene glycol (PEG) groups), azide groups, -H, substituted or unsubstituted alkyl groups, halogens (e.g., -Br, -F, -I, -Cl), amide groups, cyano groups, substituted or unsubstituted sulfur-containing aliphatic groups (e.g., -S-alkyl and polysulfides), nitro groups, amino groups, Substituted or unsubstituted nitrogen-containing aliphatic groups (e.g., polyamines, aliphatic groups containing secondary and / or tertiary amines, etc.), substituted or unsubstituted polyethylene glycol groups, polyether groups, O-aryl groups (e.g., aryloxy groups), ester groups, urethane groups, imine groups, aldehyde groups, -SO3H groups, -SO3Na groups, -OSO2F groups, -OSO2CF3 groups, -OSO2OR″′ groups (where R″′ is a substituted or unsubstituted aryl group or a substituted or unsubstituted alkyl group), etc., and combinations thereof; x is 0, 1, 2, or 3; and y is independently 0, 1, 2, 3, or 4 each time it appears, provided that at least one y is 1 and at least one R group is -OS(O)2O –M+ (where M+ is Na+, K+, Ca2+, Mg2+, Zn2+, H4N+, Et3NH+, Me4N+, (HOCH2CH2)3NH+, Or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS) or -OS(O)₂OH, or its salts, partial salts, hydrates, polymorphs, stereoisomers, conformational isomers, or mixtures. The one or more R groups can be at any one or more positions on the aryl group. In the case of an aryl group with multiple R groups, each R group can be at any combination of positions on the aryl group. In several embodiments, the aryl group can be further substituted with...Various substituents. Specification 20 / 46 pages 25 CN 121064070 A

[0168] Statement 2. The compound according to statement 1, wherein the aryl group is independently selected from phenyl groups, fused ring groups (e.g., naphthyl groups, anthracene groups, phenanthrene groups, tetraphenyl groups, pentaphenyl groups, etc.), biaryl groups (e.g., biphenyl groups, etc.), terphenyl groups, etc., each time it appears.

[0169] Statement 3. The compound according to statement 1 or 2, wherein the cyclic core of the compound contains at least two, at least three, or at least four or all of one or more phenyl groups of one or more aryl groups having at least one or at least two R groups independently selected from -OS(O)2O-M+ and -OS(O)2OH.

[0170] Statement 4. The compound according to statement 3, wherein the compound has the following structure:

[0171]

[0172] In several examples, each R is -OS(O)2O-M+ and -OS(O)2OH.

[0173] Statement 5. A compound according to any of the preceding statements, wherein all aryl groups contain an R group that is independently -OS(O)2O-M+ or -OS(O)2OH.

[0174] Statement 6. A compound according to any of statements 1-3, wherein at least one aryl group does not contain an R group that is -OS(O)2O-M+ or -OS(O)2OH.

[0175] Statement 7. The compound according to Statement 1, wherein the compound has the following structure: Specification 21 / 46 pages 26 CN 121064070 A

[0176]

[0177] Statement 8. The compound according to Statement 7, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 of the R groups are independently -OS(O)2O-M+ groups or -OS(O)2OH groups.

[0178] Statement 9. The compound according to Statement 7 or 8, wherein each phenyl group included in the cyclic core of the compound has at least one or at least two R groups independently selected from -OS(O)2O-M+ and -OS(O)2OH.

[0179] Statement 10. A compound according to any one of statements 7-9, wherein at least one phenyl group does not contain an R group that is -OS(O)₂O-M+ or -OS(O)₂OH.

[0180] Statement 11. A composition comprising one or more compounds according to any one of the preceding statements.

[0181] Statement 12. The composition according to statement 11, further comprising a drug carrier.

[0182] Statement 13. The composition according to statement 11, wherein one or more compounds are arranged (e.g., chemically bonded) to a solid state.At least a portion of the solid substrate.

[0183] Statement 14. The composition of statement 13, wherein the solid substrate comprises (or) silica (such as, for example, silica particles), polymer beads, polymer resins (such as, for example, polystyrene, polyNIPAM, polyacrylic acid), metal nanoparticles (such as gold nanoparticles, silver nanoparticles, magnetic nanoparticles), metals (such as, for example, gold), or combinations thereof.

[0184] Statement 15. The composition of any one of statements 11-14, wherein at least a portion (or all) of one or more compounds has one or more pharmaceutically active agents disposed in cavities of one or more compounds (e.g., non-covalently coordinated with one or more compounds).

[0185] Statement 16. A method for chelating the following substances: one or more neuromuscular blocking agents (such as, for example, rocuronium bromide, tubocurarine, atracurium, atracurium (cis)benzenesulfonate, mevecurium, galamine, pancuronium bromide, vecuronium bromide, and lapacurium, etc.); one or more anesthetics (such as, for example, N-methyl D-aspartate (NMDA) receptor antagonists (e.g., ketamine, etc.), short-acting anesthetics (e.g., etomidate, etc.); one or more agents (such as, for example, drugs (e.g., anticoagulants, such as, for example, hymedioxanone, etc.), abuse drugs (e.g., methamphetamine, cocaine, fentanyl, carfentanil, PCP, MDMA, heroin, etc.); one or more insecticides (such as, for example, paraquat, diquat, organochlorines (e.g., DDT, etc.)). Aldrin, neonicotinoids (e.g., permethrin), organophosphates (e.g., malathion, glyphosate), pyrethroids, triazines (e.g., atrazine), etc.; one or more dyes (e.g., methylene blue, Nile red, crystal violet, thiazole T, thiazole orange, proflavin, acridine orange, methylene violet, azure A, neutral red, cyanine, direct orange 26, disperse dyes (e.g., disperse yellow 3, disperse blue 27), coumarin, Congo red, etc.); one or more odorants Compounds (such as, for example, low molecular weight thiols (e.g., C1-C4 thiols), low molecular weight amines (e.g., triethylamine, putrescine, cadaverine, etc.)); or one or more chemical warfare agents (such as, for example, nitrogen mustard and sulfur mustard (e.g., bis(2-chloroethyl)ethylamine, bis(2-chloroethyl)methylamine, tri(2-chloroethyl)amine, bis(2-chloroethyl)sulfide, bis(2-chloroethylthioethyl)ether, etc.), nerve agents (such as, for example, those from the G, GV and V series nerve agents, page 22 / 46, 27 CN 121064070 A, such as tabun, sarin, soman, cyclosarrin, 2-(dimethylamino)ethyl N,N-dimethylphosphatamidofluoroester (GV), Novichok, VE, VG, VM, VX, etc.); one or more hallucinogens (e.g., ergot alkaloids, diethyl lysergic acid).LSD, seroceramide, tryptamine, dimethyltryptamine (DMT), phenethylamine, mescaline, ayahuasca, dextromethorphan, etc.; one or more toxins (e.g., dioxins, perfluoroalkyl sulfonates (PFAS), perfluorooctanoic acid (PFOA), decabromodiphenyl ether (DECA), heavy metals (e.g., mercury), muscarinic acid, tyramine, strychnine, tetrodotoxin, salicylic acid, cholesterol, deoxycholic acid, N-methyl-4-phenyl-1,2,3,6-tetrahydro- Pyridine, phenylalanine, tyrosine, arginine, histamine); one or more metabolites (e.g., toxic metabolites, such as, for example, N-methyl-4-phenylpyridine, spermine, spermidine, N-nitroso compounds such as 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone); etc., or combinations thereof, which are chelated by one or more compounds according to any one of statements 1-10 and / or one or more compositions according to any one of statements 11-14.

[0186] Statement 17. The method of statement 16, wherein one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceuticals, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof are present in an aqueous sample, a solid sample (such as, for example, a soil sample), a gaseous sample, a solid surface, etc.

[0187] Statement 18. The method of Statement 17, wherein the aqueous sample is a wastewater sample (e.g., municipal wastewater sample, industrial wastewater sample, etc.), an industrial water sample (e.g., water used to manufacture commercial products such as, for example, reagents, solvents, etc.), a municipal water sample, etc.

[0188] Statement 19. The method of any one of Statements 16-18, wherein a complex is formed by one or more compounds and one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceuticals, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof (e.g., one or more interactions therebetween (e.g., the formation of one or more non-covalent bonds therebetween)).

[0189] Statement 20. The method of any one of Statements 16-19, wherein the complex is removed from the aqueous sample, solid sample, gaseous sample, etc.

[0190] Statement 21. The method of Statement 16, wherein one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceuticals, one or more insecticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof are present in and / or on an individual, and contact includes administering one or more compounds and / or combinations thereof to the individual.

[0191] Statement 22. The method of statement 21, wherein the individual is a human or a non-human mammal.

[0192] Statement 23. A method for reversing drug-induced neuromuscular blockade and / or anesthesia and / or the effects of one or more agents (e.g., one or more abused drugs) in an individual, comprising administering to an individual who requires reversal of neuromuscular blockade and / or reversal of anesthesia and / or reversal of the effects of one or more agents (e.g., one or more abused drugs) one or more compounds according to any one of statements 1-10 and / or one or more compositions according to any one of statements 11-14.

[0193] Statement 24. The method of statement 23, wherein the individual requires reversal of drug-induced neuromuscular blockade.

[0194] Statement 25. The method of statement 23, wherein the individual requires reversal of anesthesia.

[0195] Statement 26. The method of statement 23, wherein the individual requires reversal of drug-induced neuromuscular blockade and anesthesia.

[0196] Statement 27. The method of Statement 23, wherein an individual needs to reverse the effects of one or more agents selected from one or more abused drugs, one or more pesticides, one or more chemical warfare agents, one or more neurotoxins, one or more hallucinogens, one or more toxins and / or one or more metabolites. In one example, an individual is exposed to one or more abused drugs (e.g., carfentanil, etc.), one or more pesticides, one or more chemical warfare agents, one or more nerve agents, one or more hallucinogens, one or more toxins, one or more metabolites (in a terrorist attack), and combinations thereof.

[0197] Statement 28. The method of any one of Statements 23-27, wherein the individual in need is a human.

[0198] Statement 29. The method of any one of Statements 23-27, wherein the individual in need is a non-human mammal.

[0199] Statement 30. A method for preventing and / or treating a condition in an individual, comprising administering to an individual requiring prevention and / or treatment one or more compounds and one or more pharmaceutical agents according to any one of statements 1-10, wherein the one or more compounds and one or more pharmaceutical agents are present as a complex (or a composition comprising one or more of said complexes, which may be a pharmaceutical composition), wherein, after administration, treatment and / or prevention of the condition in the individual are performed.

[0200] Statement 31. The method of statement 30, wherein one or more of the one or more pharmaceutical agents have a solubility of less than 100 μM in an aqueous solvent.

[0201] Statement 32. A compound according to any one of statements 1-10, a composition according to any one of statements 11-15, or a method according to any one of statements 16-31, wherein M+ is Na+, K+, H4N+, Et3NH+, Me4N+.+、(HOCH2CH2)3NH +。

[0202] Statement 33. A compound according to any one of statements 1-10, a composition according to any one of statements 11-15, or a method according to any one of statements 16-31, wherein M+ is Na+.

[0203] The following examples are provided to illustrate the present disclosure. They are not intended to be limiting in any way.

[0204] Example 1

[0205] This example provides a description of the compounds of the present disclosure, methods for preparing the compounds, characterization of the compounds, and use of the compositions.

[0206] General experimental details. Starting materials were purchased from commercial suppliers and used without further purification or prepared by literature procedures. Melting points were measured in an open capillary on a Meltemp instrument and were not calibrated. IR spectra were recorded on a JASCO FT / IR 4100 spectrometer and reported in cm⁻¹. 1H NMR spectra were measured on a Bruker instrument operating at 400 or 600 MHz for 1H and 100 MHz for 13C. Mass spectrometry was performed using a JEOL AccuTOF electrospray ionization (ESI) instrument. ITC data were collected on a Malvern Microcal PEAQ-ITC instrument.

[0207] Synthesis procedure and characterization data.

[0208] Body P[5]AS. Specification 24 / 46 pages 29 CN 121064070 A

[0209]

[0210] The first two compounds (2 and 3) were synthesized by means of a method adapted from those known in the art. The procedure for the last step was as follows: anhydrous pyridine (10 mL) was added to a mixture of compound 3 (0.200 g, 0.328 mmol) and the pyridine sulfur trioxide complex (1.050 g, 6.56 mmol). The resulting mixture was stirred at 90 °C for 24 hours under N2. The reaction mixture was cooled to room temperature. The product precipitated from the solution and was collected by filtration. The solid was made into a slurry in water (5 mL) and the pH was adjusted to 8.4 by slowly adding a saturated NaHCO3 aqueous solution. After adding EtOH (35 mL), the crude product was collected by centrifugation at 7000 rpm for 7 min. The precipitate was suspended in ethanol (20 mL × 2), sonicated for 30 min, and the solid was collected by centrifugation. The crude solid was redissolved in a minimal amount of water (2 mL) and purified by size exclusion chromatography using G25 resin (30 mm × 200 mm) and eluted with water. The pure product was collected as front fractions. After drying under high vacuum, compound P[5]AS was obtained as a white solid (0.374 g,0.229 mmol (70% yield). Mp > 310℃ (decomposed). IR (ATR, cm⁻¹): 3490 w, 1630 m, 1497 m, 1399 m, 1234 s, 1116 s, 1042 s, 995 m, 941 m, 858 m, 806 m. ¹H NMR (600 MHz, D₂O): 7.31 (s, 10H), 4.00 (s, 10H). ¹³C NMR (150 MHz, D₂O, EtOH as internal reference): 147.4, 134.1, 125.6, 30.8. MS (ESI): m / z 791.78179 ([M⁻²Na]²⁻), theoretical value 791.79597.

[0211] Main body P[5]ACS.

[0212]

[0213] A solution of P[5]A (0.200 g, 0.28 mmol) in NaOH (10 wt%, 2 mL) was treated dropwise with a solution of propane sulcolone (0.687 g, 5.63 mmol) in acetone (4 mL). This solution was stirred at room temperature for 5 days (d), and then EtOH (25 mL) was added to the mixture to obtain a crude product, which was a precipitate. The precipitate was obtained by filtration, and the solid was dissolved in H2O (0.5 mL), and then redeprecipitated by adding EtOH (5 mL) to obtain P[5]ACS, which was a light yellow solid (45 mg, 0.022 mmol, 8%). Mp>300℃ (decomposed). IR (ATR, cm-1): 3452w, 2936w, 1725m, 1625m, 1479m, 1471m, 1406m, 1181s, 1035s, 951w, 798m, 756m. 1H NMR (400MHz, D2O): 6.76 (s, 10H), 3.90 (m, 10H), 3.86 (s, 10H), 3.68 (m, 10H), 3.05 (m, 20H), 2.08 (m, 20H). 13C NMR (150 MHz, D2O, EtOH as internal reference): δ 150.9, 129.8, 116.7, 68.5, 49.1, 31.1, 25.5. HR-MS (ESI): m / z 1002.03215 ([M- 2Na]2-), theoretical value 1002.03072.

[0214] Main body P[6]AS.

[0215]

[0216] The first two compounds (7 and 8) were synthesized using methods adapted from those known in the art. The procedure for the last step was: to mix compound 8 (0.200 g, 0.27 mmol) and pyridine sulfur trioxide complex (1.090 g, 6.83 mmol)Anhydrous pyridine (10 mL) was added to the mixture. The resulting mixture was stirred at 70 °C for 24 hours under N2. The reaction mixture was cooled to room temperature. The product precipitated from the solution and was collected by filtration. The solid was slurried in water (5 mL) and the pH was adjusted to 8.4 by slowly adding a saturated aqueous solution of NaHCO3. After adding EtOH (35 mL), the crude product was collected by centrifugation at 7000 rpm for 7 min. The precipitate was suspended in ethanol (20 mL × 2), sonicated for 30 min, and the solid was collected by centrifugation. The crude solid was redissolved in a minimal amount of water (2 mL) and purified by size exclusion chromatography using G25 resin (30 mm × 200 mm) and eluted with water. The purified product was collected as a pre-fraction. After drying under high vacuum, compound P[6]AS was obtained as a white solid (0.352 g, 0.18 mmol, 66% yield). Mp > 290 °C (decomposed). IR (ATR, cm-1): 3509 w, 1712 m, 1630 m, 1498 m, 1364 m, 1237 m, 1113 s, 1045 s, 995 m, 942 m, 861 m, 813 m. 1H NMR (600 MHz, D2O): 7.35 (s, 12H), 4.11 (s, 12H). 13C NMR (150 MHz, D2O and CD3OD 10:1): δ 148.1, 133.6, 125.6, 31.5. MS (ESI): m / z 954.7593 ([M-2Na]2-), theoretical value 954.7537.

[0217] Main body P[6]A8S. Specification 26 / 46 pages 31 CN 121064070 A

[0218]

[0219] The first three compounds were synthesized using methods adapted from those known in the art. The procedure for the final step was as follows: anhydrous pyridine (5 mL) was added to a mixture of compound octahydroxy columnar[6]arene (0.100 g, 0.15 mmol) and pyridine sulfur trioxide complex (0.479 g, 3 mmol). The resulting mixture was stirred at 70 °C for 24 hours under N2. The reaction mixture was cooled to room temperature. The product precipitated from the solution and was collected by filtration. The solid was slurried in water (4 mL) and the pH was adjusted to 8.4 by slowly adding a saturated aqueous solution of Na2CO3. After adding EtOH (10 mL), the crude product was collected by centrifugation at 7000 rpm × 7 min. The precipitate was suspended in ethanol (10 mL × 2), sonicated for 30 min, and the solid was collected by centrifugation. The crude solid was redissolved in a minimal amount of water (0.5 ml) and G25 resin (30 mm) was used.The sample was purified by size exclusion chromatography (×200 mm) and eluted with water. The pure product was collected as a pre-fraction. After drying under high vacuum, compound P[6]A8S(10) was obtained as a white solid (0.075 g, 0.051 mmol, 33% yield). Mp > 285 °C (decomposed). IR (ATR, cm-1): 3491 w, 1630 m, 1440 s, 1234 s, 1078 m, 1043 s, 941 m, 878 m, 800 m, 667 m. 1H NMR (600 MHz, D2O): 7.39 (s, 4H), 7.25 (s, 4H), 7.04 (s, 8H), 4.07 (s, 4H), 3.99 (s, 8H). 13C NMR (150MHz, D2O, EtOH as internal reference): δ 147.7, 147.6, 138.7, 134.2, 133.2, 129.2, 125.3, 125.1, 35.7, 31.1. MS (ESI): m / z 718.88334 ([M-2Na]2-), theoretical value 718.88632.

[0220] Main body P[7]AS. Specification 27 / 46 pages 32 CN 121064070 A

[0221]

[0222] The first two compounds were synthesized by means of methods adapted from those known in the art. The procedure for the final step was as follows: Anhydrous pyridine (3 mL) was added to a mixture of compound (HO)14[7] aromatics (0.020 g, 0.023 mmol) and pyridine sulfur trioxide complex (0.375 g, 2.34 mmol). The resulting mixture was stirred at 70 °C for 24 hours under N2. The reaction mixture was cooled to room temperature. The product precipitated from the solution and was collected by filtration. The solid was slurried in water (1 mL) and the pH was adjusted to 8.4 by slowly adding a saturated aqueous solution of Na2CO3. After adding EtOH (10 mL), the crude product was collected by centrifugation at 7000 rpm for 7 min. The precipitate was suspended in ethanol (10 mL × 2), sonicated for 30 min, and the solid was collected by centrifugation. The crude solid was redissolved in a minimal amount of water (0.5 mL) and purified by size exclusion chromatography using G25 resin (30 mm × 200 mm) and eluted with water. The pure product was collected as a pre-fraction. After drying under high vacuum, compound P[7]AS was obtained as a white solid (0.025 g, 0.011 mmol, 46% yield). Mp > 290 °C (decomposed). IR (ATR, cm⁻¹): 3494 w, 1624 m, 1444 s, 1244 m, 1102 s, 1049 s, 995 m, 875 m, 807 m, 614 s. 1HNMR (600MHz, D2O): 7.29 (s, 14H), 4.14 (s, 14H). 13C NMR (150MHz, D2O, dioxane as external reference): δ 147.6, 132.8, 124.7, 30.8. MS (ESI): m / z 547.36023 ([M-4Na]4-), theoretical value 547.36080.

[0223] Rim-P[5]AS. Specification 28 / 46 pages 33 CN 121064070 A

[0224]

[0225] The starting material 2-(benzyloxy)-5-methoxybenzyl alcohol was synthesized based on methods known in the art. Pentahydroxy column[5] aromatic compounds were synthesized using methods known in the art. Anhydrous pyridine (10 mL) was added to a mixture of pentahydroxy[5] aromatic hydrocarbon (0.200 g, 0.328 mmol) and pyridine sulfur trioxide complex (1.050 g, 6.56 mmol). The resulting mixture was stirred at 70 °C for 24 hours under N2. The reaction mixture was cooled to room temperature. The product precipitated from the solution and was collected by filtration. The solid was slurried in water (5 mL) and the pH was adjusted to 9 by slowly adding a saturated aqueous solution of NaHCO3. EtOH (EtOH / H2O v / v = 2:1) was added to produce a precipitate, which was removed by centrifugation (7000 rpm × 10 min). The filtrate was collected as crude product and redissolved in a minimal amount of water (2 mL), and purified by size exclusion chromatography using G25 resin (5 cm × 50 cm) with water as the eluent. The first fraction eluted from the column contained the pure product. After drying under high vacuum, Rim-P[5]AS was obtained as a white solid (0.374 g, 0.229 mmol, 67% yield, purity: ~92%, determined by using sodium 2-bromoethanesulfonate as an internal standard for 1H NMR). Mp > 300 °C (decomposed). 1H NMR (400 MHz, D2O): 7.21 (s, 5H), 6.56 (s, 5H), 3.90 (s, 10H), 3.24 (s, 15H). 13C NMR (150 MHz, D2O, EtOH as internal reference): 155.3, 143.2, 134.5, 129.6, 124.7, 114.9, 56.7, 30.6.

[0226] Solubility determination.

[0227] Determination of the solubility of P[5]AS in water. Compound P[5]AS was added in excess to 0.5 mL of deuterium oxide. The suspension was magnetically stirred overnight at room temperature, and then centrifuged twice (4500 rpm), each time for 10 minutes. The supernatant (50 mL) was collected.The concentration of P[5]AS was determined by 1H NMR and 3-(trimethylsilyl)propionate sodium-2,2,3,3-d4 (TMSP) (10 mM, 50 μL, in D2O) was added to 0.4 mL of deuterium solvent.

[0228] Determination of the solubility of P[6]AS in water. Compound P[6]AS was added in excess to 0.5 mL of deuterium oxide. The suspension was magnetically stirred overnight at room temperature and then centrifuged (4500 rpm) twice for 10 minutes each time. The supernatant (50 μL) and 3-(trimethylsilyl)propionate sodium-2,2,3,3-d4 (TMSP) (10 mM, 50 μL, in D2O) were added to 0.4 mL of deuterium solvent. The concentration of P[6]AS was measured by 1H NMR and calculated using sodium 3-(trimethylsilyl)propionate-2,2,3,3-d4 (TMSP) as an internal reference.

[0229] Ka between various host and cationic guest or abused drugs or neuromuscular blocking agents was determined by isothermal titration calorimetry (ITC). All ITC experiments were performed in a 200 μL working volume in the sample cell of the PEAQ ITC instrument. We used a 40 μL syringe. In each case, both the host and guest solutions were prepared in 20 mM NaH2PO4 buffer (pH 7.4). The sample cell was filled to capacity (200 μL) with the host solution and the guest solution was titrated (first injection = 0.4 μL, subsequent 18 injections = 2 μL). The combined data were fitted using a 1:1 combination model in the MicroCal PEAQ-ITC analysis software. In cases where Ka is too large to be determined by direct titration, competitive ITC titration is performed. The competing guest with known Ka and ΔH, as described on pages 29 / 46 of CN 121064070 A, is included in the ITC cell along with the host, and then the host is titrated with the guest whose Ka is to be determined.

[0230] WP5, WP6, and the following compounds are compounds used in the comparative examples:

[0231]

[0232]

[0233] 1H NMR spectra of the selected drug and host. Figure 8 shows an example of the 1H NMR spectra of the drug (methamphetamine) and the host (P[6]AS).

[0234] 1H NMR spectra of competitive binding. Figure 9 shows the binding of P[6]AS with rocuronium bromide, stronger than that of the previously known compound (Motor 2, also known as Calabadion 2).

[0235] (Pages 30 / 46 of CN 121064070 A)The crystal structure P[6]AS was also determined. Figures 10 and 13 show the crystal structure of P[6]AS.

[0236] Table 1. Crystal data and structure refinement of P[6]AS.

[0237] Empirical formula of crystal C45.44H24Na12O65.65S12

[0238]

[0239]

[0240] Table 2. Fractional atomic coordinates and equivalent isotropic displacement parameter Ueq of P[6]AS are defined as 1 / 3 of the trace of the UIJ tensor in the orthogonalization specification 31 / 46 page 36 CN 121064070 A

[0241]

[0242] Specification 32 / 46 pages 37 CN 121064070 A

[0243] Table 3. Anisotropic displacement parameters of P[6]AS The anisotropic displacement factor exponent takes the following form: -2π2[h2a*2U11+2hka*b*U12+…].

[0244]

[0245]

[0246] Table 4. Bond lengths of P[6]AS. Instructions 33 / 46 Page 38 CN 121064070 A

[0247]

[0248]

[0249] 11+Y‑X, 1‑X, +Z; 21‑Y, +X‑Y, +Z; 31‑Y+X, 1‑Y, 1 / 2‑Z; 4+X, +X‑Y, 1 / 2+Z; 52‑X, 1‑Y, 1‑Y Z; 61‑X, 1‑Y, 1‑Z; 72‑X, 1‑X+Y, 1 / 2‑Z; 81+Y‑X, +Y, 1 / 2+Z; 91‑Y, 1+X‑Y, +Z; 10+Y, +X, 1 / 2‑Z; 11‑X,‑Y, 1‑Z; 12‑Y+X, +X, 1‑Z; 13+Y,‑X+Y, 1‑Z Table 5. Bond angles of P[6]AS. Instructions 34 / 46 Page 39 CN 121064070 A

[0251] Instructions 35 / 46 Page 40 CN 121064070 A

[0252]

[0253] 11+Y‑X, 1‑X, +Z; 21‑Y, +X‑Y, +Z; 31‑Y+X, 1‑Y, 1 / 2‑Z; 4+X, +X‑Y, 1 / 2+Z; 52‑X, 1‑Y, 1‑Z 13 -Y+X, 1-Y, 1 / 2-Z; 14 -X, -Y, 1-Z; 15 -Y+X, +X, 1-Z; 16 +Y, -X+Y, 1-Z; 17 +Y-X, 1-X, +Z Table 6.P[6] AS torsion angle. Instruction manual 36 / 46 pages 41CN 121064070 A

[0254] Instructions 37 / 46 Page 42 CN 121064070 A

[0255]

[0256] 11-Y, + ‑Y+X, 1‑Y, 1 / 2‑Z; 81‑X, 1‑Y, 1‑Z; 91+Y‑X, 1‑X, +Z; 101+Y‑X, +Y, 1 / 2+Z; 111-Y, 1+X-Y, +Z; 121+X, 1+Y, +Z; 13-Y+X, +X, 1-Z; 14-X, -Y, 1-Z; 15+Y, -X+Y, 1-Z; 16+Y-X, 1-X, +Z; 17+Y-X, -X, +Z; 18-Y, +X-Y, +Z

[0257] Table 7. Hydrogen atom coordinates and isotropic displacement parameters of P[6]AS

[0258] Atom Z yz U(eq) H3 1.002(2) 0.569(2) 0.2874(14) 0.039(9) H4 0.937(2) 0.703(2) 0.1741(14) 0.026(7) H6 0.691(2) 0.532(2) 0.3338(14) 0.032(8) H7 0.590(2) 0.588(2) 0.2112(14) 0.035(8)

[0259] Table 8. Atom occupancy rate of P[6]AS.

[0260] Atom Occupancy Rate Atom Occupancy Rate Atom Occupancy Rate Na3 0.6667 O1 0.887(5) O2 0.887(5) O3 0.887(5) S1 0.887(5) O4 0.887(5) O1A 0.113(5) O2A 0.113(5) O3A 0.113(5) S1A 0.113(5) O4A 0.113(5) O5 0.58(3) S2 0.58(3) O6 0.58(3) O7 0.58(3) O8 0.58(3) O5A 0.42(3) S2A 0.42(3) O6A 0.42(3) O7A 0.42(3) O8A 0.42(3) O1B 0.85 C2B 0.285(13) O3B 0.308(7) C4B 0.15 O1C 0.808(11) O2C 0.317(10) O3C 0.306(10) O1D 0.353(9) C2D 0.412(17)

[0261] Experiment. Select a suitable P[6]AS single crystal and in BrukerMeasurements were performed on a Smart Apex2 diffractometer. The crystal corresponds to C45.44H24Na12O65.65S12. The crystal was held at 150(2) K during data collection. Using a multi-scan method with SADABS software, the integrated intensity was correct for absorption. The minimum and maximum transmittances obtained were 0.634 and 0.959, respectively. The structure was solved using the ShelXT-2014 (Sheldrick, 2015a) program and refined using the ShelXL-2015 (Sheldrick, 2015c) program and least-squares minimization using the ShelX software package. The number of constraints used = 387. Specification 38 / 46 pages 43 CN 121064070 A

[0262] Crystal structure determination. Crystal data for C45.44H24Na12O65.65S12 (M = 2280.86 g / mol): Trigonal system, space group P-3c1 (no. 165), Z = 2, T = 150(2) K, μ(MoKα) = 0.519 mm-1, Dcalc = 1.881 g / cm3, 23483 reflections measured (4° ≤ 2Θ ≤ 53.178°), 2810 unique (Rint = 0.0602, Rsig = 0.0410) (for all calculations). The final R1 is 0.0448 (I > 2σ(I)) and wR2 is 0.1097 (for all data).

[0263] Refinement details. H atoms (except those in disordered solvents) are located from the differential Fourier map and freely refined (including Uiso). Water and ethanol solvents are severely disordered and modeled using partially occupied O and C atoms.

[0264] Example 2

[0265] This example provides the synthesis, X-ray crystal structure, and molecular recognition properties of the column[n]arene derivative P[6]AS (which is occasionally referred to herein as column[6]MaxQ) and analogs P[5]AS and P[7]AS for guests 11–28. This example confirms the ultra-tight binding affinity of P[5]AS and P[6]AS for quaternary (di)ammonium ions, which supports their use in imaging and delivery applications in in vitro and in vivo non-covalent bioconjugations and as in vivo chelating agents.

[0266] In more detail, those skilled in the art will recognize that advances in the construction of supramolecular systems for biological applications (e.g., imaging and drug delivery) and chemical applications (e.g., sensing, catalysis, separation) heavily depend on the availability of libraries of structural units that can be readily integrated into more complex and more functional systems. Molecular containers—whether prepared through covalent bonding reactions or self-assembly processes—occupy the central position in this field. Some of the most popular molecular containers...This group includes cyclodextrins, calix[n]arenes, crown ethers, cycloarenes, coordination cages, molecular clips and tweezers, cucurbit[n]urea (CB[n]), and H-bonded capsules. Within this group, the CB[n] family (Fig. 11a) has proven particularly useful because they form tight CB[n]·guest complexes in a selective and stimulus-responsive manner, allowing them to be used to create sensing ensembles, supramolecular polymers, molecular machines for bioconjugation, as non-covalent locking systems, and for drug solubilization and delivery. Given the high binding affinity of acyclic CB[n] for their preferred guests, acyclic CB[n] (e.g., M2, Fig. 11a) have been developed as in vivo chelators for neuromuscular blocking agents and drugs of abuse. Recently, the synthesis and molecular recognition properties of column[n]arenes (Fig. 11b, e.g., WP[5] and WP[6]) in both organic and aqueous solutions have been extensively studied, and their chemical and biological applications have been well reviewed. Column[n]aromatics represent the best point of interest for the study of molecular recognition in water because they typically exhibit Kd values ​​in the μM range and are more easily functionalized than CB[n]. Therefore, this embodiment provides a description of the preparation of column[n]aromatic sulfates (aka column[n]MaxQ) which have extremely high binding affinity for quaternary diammonium ions in aqueous solution (Kd in the pM range), making them particularly well-suited as in vivo chelating agents.

[0267] Considering the creation of new ultra-tightly bound hosts based on column[n]aromatics leads us to consider the relevant structural features of CB[n] (Fig. 11a). The ultra-tightly bound features of CB[n] have been traced back to their highly electrostatically negative urea C=O inlets and the number and energy of water molecules released within the host cavity upon binding (e.g., non-classical hydrophobic effects). Due to their double CH2- joints, CB[n] do not have free rotors, cannot self-complex, and are therefore highly pre-organized hosts. This disclosure relates to the replication of these structural features in the column[n]arene family through rational molecular design. Although anionic water-soluble columnarenes (e.g., WP[5] and WP[6]) are known, they contain a CH2- linker between the aromatic ring and the anionic functional group (e.g., carboxylates, sulfonates, phosphonates). This disclosure includes the removal of the CH2- linker and the conversion to a highly acidic sulfate functional group to provide a higher negative charge density around the opening of the cavity. At the same time, it is envisioned that two sulfate groups be added to each phenyl group to electrostatically minimize the possibility of known phenyl groups tilting into their own cavities.

[0268] Figure 11 shows the synthesis of P[5]AS–P[7]AS. The parent hydroxylated columnarenes (P[5]A–P[7]A) were prepared according to a literature procedure. Subsequently, P[5]A–P[7]A were reacted with pyridine·SO3 in pyridine at 90°C to achieve 70% and 46% concentrations, respectively.44 CN 121064070 A P[5]AS–P[7]AS were obtained in yields of 66% and 46%. To gain a deeper understanding of the role of the CH2-linker, P[5]ACS was prepared as a control compound in low yield (8%) by reacting P[5]A with propanesulfonyl lactone and NaOH in acetone. Finally, known host compounds WP[5] and WP[6] were prepared as additional comparisons by methods known in the art. All new compounds were fully characterized by 1H and 13C NMR, IR and high-resolution electrospray ionization mass spectrometry. It is known that column[6]arenes can exist in five different conformations due to rotation around the phenylene unit. Figure 12a shows the 1H NMR recorded for P[6]AS in D2O at room temperature, which consists of two relatively sharp singlets. This indicates that P[6]AS is either locked in the depicted C6-symmetric structure or the phenylene unit rotates rapidly on the chemical shift chronograph. Based on the host-guest experiment, it can be inferred that the rotation of the OSO3- group through the ring of the P[6]AS columnar aromatic hydrocarbon is rapid.

[0269] The inherent water solubility of the two most effective hosts (P[5]AS: 100 mM; P[6]AS: 20 mM; see below) was measured by integrating the 1H NMR resonance of the host solution relative to the methyl resonance of sodium 3-(trimethylsilyl)propionate-2,2,3,3-d4 as an internal standard at a known concentration. Before proceeding to investigate the host-guest properties of the new hosts, we conducted dilution experiments monitored by 1H NMR spectroscopy to quantify their intermolecular self-association. Using the standard 2-fold self-association model, the spectra of P[5]AS and P[6]AS were recorded as a function of concentrations (P[5]AS: 20–0.1 mM; P[6]AS: 20–0.1 mM) used to calculate Ks values. These Ks values ​​ensure that the body remains monomeric at the mM concentration used in the NMR and ITC experiments described below in this embodiment. Crystals of both P[6]AS and P[5]ACS were obtained, as well as their structures as resolved by X-ray diffraction measurements (Fig. 13, CCDC 1996177 and CCDC 1996179). Fig. 13d shows the structure of a molecule of P[5]ACS in crystal. As is commonly seen in columnar aromatic crystal structures, the orientation of the phenylene ring is generally perpendicular to the average plane of the macrocycle, and the substituents are used to deepen the cavity. The S···S distance between the sulfonates attached to the single phenylene ring is in the range of . Fig. 13a shows the structure of a single molecule of P[6]AS in crystal. Unlike P[5]ACS, P[6]AS adopts an uncommon conformation, in which the structure is reminiscent of cycloaspartene.In the geometry of (cyclotriveratrylene), alternating phenylene units are slightly tilted into cavities on opposite faces of the macroring. The tilt of the phenylene is measured to be 35–38 degrees from the vertical direction. Interestingly, the OSO3- groups are not located on the average plane of the phenylene units, but are alternately displayed above and below this plane. This tilt and alternation results in 12 OSO3- groups being roughly positioned at the corners and edges of a triangular antiprism with sides of length and height . Thus, P[6]AS has a fairly high charge density of -12 within a small volume (the CPK molecular volume of P[6]AS). The effect of the Na+ counterion on the observed conformation of P[6]AS is unclear. The P[6]AS molecule is stacked in a hexagonal array on the xy-plane, as shown in Figure 13b; the OSO3- subunits are extensively bridged by coordinating Na+ ions. These hexagonally stacked P[6]AS sheets are aligned and stacked together along the z-axis, such that the P[6]AS unit defines a tube (Fig. 13c). The stacking of P[5]ACS also shows stacked sheets held together by a network bridging Na+ ions.

[0270] Fig. 12a shows two singlets of individual P[6]AS and a single set of sharp resonances of the P[6]AS·25 complex (Fig. 12c). The significant high-field shift observed for the resonance of guest 25 confirms that it is contained within the cavity of P[6]AS. At a 1:2 P[6]AS:25 ratio, the resonance of guest 25 shifts back toward the free 25, indicating that guest exchange occurs rapidly on the chemical shift timescale. Similar studies were conducted for different combinations of host and guest from Figs. 2–4, and in many cases the situation is more complex. For example, in many cases, the resonance of the aryl H-atom (Ha) broadens or splits into many different sharp resonances after mixing with an equivalent of the guest. Of course, it is well known that column [n]arenes have several different lower symmetry conformations (n ​​= 5: 4 conformational isomers; n = 6: 5 conformational isomers), which would be expected to produce broadened or additional resonances, as observed in a guest-dependent manner. For the host P[6]AS and P[7]AS, a high-field shift of the guest resonance was observed after binding, indicating cavity binding of the hydrophobic portion of the guest. For P[5]AS, the narrower guests (e.g., 21 and 23) bind within the cavity, as indicated by the high-field change in chemical shift, but the wider guests (e.g., 12 and 25) show a high-field shift of the NMe3+ group rather than their hydrophobic portion, indicating +NMe3 binding near the inlet. ITC measurements (see below) indicate that 12 and 25 bind to P[5]AS in a 1:2 host:guest stoichiometry.

[0271] Initially, via 1HNMR spectroscopy was used to investigate the molecular recognition properties of the new host to guests 11–28 (Figure 2). Compounds 11–28 were chosen because they have different numbers of charged groups (one or two), lengths of hydrophobic residues, widths of hydrophobic residues, and degrees of ammonium ion substitution (1°, 2°, 3°, 4°) to assess the preference of the new host. Figure 12 shows the 1H NMR spectra recorded for P[6]AS, 25, and 1:1 and 1:2 mixtures of P[6]AS and 25, an example of particularly well resolved data. Next, the strength of the binding interactions between the various host and guest was quantified. Given the complexity of the 1H NMR spectra and the observed tight binding (see below), we used isothermal titration calorimetry (ITC). For most complexes, we performed direct titration of the host in the cell using the guest in a syringe. Figures 5–7 show the thermodynamic parameters determined by these direct ITC titrations, and representative experimental data are shown in Figures 69–83. Direct titration is not suitable for tighter host-guest complexes where the Ka value exceeds 4 × 10⁷ M⁻¹, where the c-value exceeds the recommended range even when working at [host] = 10 μM. In these cases, a competitive ITC experiment is used, in which a mixture of the host and an excess of the weaker bound guest in the cell is titrated with a stronger bound guest in the syringe. In these ITC competitive experiments, the ΔH and Ka values ​​of the weaker host-guest complex are determined independently and used as inputs for competitive ITC titration. Figure 14a shows the titration of a mixture of P[6]AS and the weaker bound guest 17 in the cell with a stronger bound guest 20 in the syringe. Fitting the data (Figure 14b) to a competitive binding model allows the extraction of the thermodynamic parameters of P[6]AS·20 (Ka = (1.20 ± 0.06) × 10¹¹ M⁻¹; ΔH = -17.1 ± 0.033 kcal mol⁻¹). Figures 5-7 report the results of competitive ITC titrations for the tighter host-guest complexes.

[0272] The extensive dataset presented in Figures 5-7 allows for a comprehensive discussion of the binding preference of the new host compared to previously known WP[5] and WP[6]. All complexes are driven by favorable ΔH values, suggesting that these complexes benefit from non-classical hydrophobic effects as expected. First, it is noted that P[5]ACS with its (CH2)3-linker binds to alkyl diammonium ions 16–20 times weaker than that observed for WP[5], which may be a result of these linkers partially blocking the host cavity or a result of the longer linker with the anionic SO3- group reducing electrostatic interactions. Furthermore, P[5]ACS and WP[5] show very little selectivity in binding based on the degree of methylation of the diammonium ion (e.g., 1°: 17, 2°: 18; 3°: 19; 4°: 20).In comparison, P[5]AS is a superior host for diammonium ions compared to WP[5] (e.g., 17: 41 times; 18: 390 times; 19: 7300 times; 20: 88000 times). P[5]AS exhibits increased binding affinity with increasing methylation of the N atom of the guest. Therefore, this type of host is called column[n]MaxQ to predict their generally excellent binding affinity and selectivity for quaternary ammonium ions. A comparison of the binding affinity of P[5]AS for quaternary diammonium ions of different lengths (e.g., 15, 16, 20) shows that the binding of C4-diammonium ions is 317-458 times weaker than that of C5- and C6- analogs, possibly due to a better match of the N···N to -O3S···SO3- distance and the increased hydrophobicity of the C6- hydrophobic residues. Of great interest, the comparison of the affinity of P[5]AS for monoseasonal guest 13 (4.41 × 10⁸ M⁻¹) and biseasonal guest 20 (9.90 × 10¹¹ M⁻¹) reveals the importance of electrostatic interactions in the recognition process. All of these narrow guests form 1:1 P[5]AS·guest complexes. In contrast, ITC results reveal that wider guests (e.g., 12, 25, 27, cis, roc, vec, pan) do not form inclusion complexes with P[5]AS, but instead form 1:2 P[5]AS:guest complexes at the inlet. ITC titration of P[5]AS with guests of this subgroup is well suited to a 1:1 binding model where N = 2, and therefore the Ka values ​​reported in Figures 5–7 have M⁻¹ units and involve each of the two independent binding events. The Ka value of P[5]AS for Me4N+ (P[5]AS·26; Ka = 3.11 × 104 M⁻¹) reveals that each quaternary ammonium ion head group makes a significant contribution to the observed ultra-high affinity of P[5]AS for (bi)quaternary ammonium ions (e.g., 20).

[0273] Figures 5–7 show the binding constants (Ka, M⁻¹) and thermodynamic parameters (ΔH, kcal mol⁻¹) of various host and guest 11–28, with neuromuscular blocking agents shown in Figure 4 and abused drugs shown in Figures 3 and 68. Conditions: H₂O, 20 mM, NaH₂PO₄ buffer, pH 7.4, 298 K. – Not measured. nb = No thermal change detected by ITC. a Measured by direct ITC titration using [host] ≥ 10 μM. b. Measured using a competitive ITC titration method of 13. c. Measured using a competitive ITC titration method of 14. d. Measured using a competitive ITC titration method of 16. e. Measured using a competitive ITC titration method of 17. f. Measured using a competitive ITC titration method of 21. g. Measured using a competitive ITC titration method of 24. h. Measured using a competitive ITC titration method of 24.Measured by competitive ITC titration using 27. i Measured by competitive ITC titration using 28. j 1:2 subject:guest complex. k 2:1 subject:guest complex.

[0274] Relevant comparisons can be made between subjects WP[6] and P[6]AS, which exhibit a 1:1 subject:guest complex for all guests used in this study. For example, except for 1° ammonium ions 24 and 27, P[6]AS is a superior subject for 20 of the 23 guests studied. Similar to P[5]AS, P[6]AS is highly selective based on guest length (e.g., 14 vs. 28 vs. 17; 15 vs. 16 vs. 20) and based on the degree of methylation of diammonium ions (e.g., 17 vs. 20; Ka = 1.43 × 10⁹ vs. 1.20 × 10¹¹ M⁻¹). Interestingly, P[6]AS exhibits a binding affinity for Me4N+ (26, Ka = 2.32 × 106 M⁻¹) that is 75 times stronger than that of P[5]AS, suggesting that P[6]AS should be considered a potent host for quaternary ammonium ions. Indeed, the Kd values ​​of P[6]AS for the guest group range from single digits μM to 1 pM, placing P[6]AS alongside CB[n] as one of the highest affinity host-guest systems in water, although the balance between recombination driving forces (e.g., electrostatics versus hydrophobic effects) differs significantly. Finally, Figures 5–7 show the binding affinity of P[7]AS for a group of guests (11–28). In this case, a comparison with the water-soluble columnar aromatic analogue (WP[7]) is not possible because it is unavailable. Nevertheless, a detailed review of Figures 5–7 reveals that, except for primary ammonium ion 24, P[7]AS is a significantly less efficient acceptor than P[6]AS for the guest group. Although the cause of the relatively poor performance of P[7]AS is not determined, and is not intended to be constrained by any particular theory, it is speculated that the cause may be similar to those of the CB[n] host family, in which the size of the electrostatically negative inlet and the energy and quantity of bound water in the host cavity play an important role.

[0275] Given the proven preference of P[5]AS and P[6]AS for quaternary diammonium ions, the guest group was expanded to include clinically important neuromuscular blocking agents roc, vec, pan, and cis, as well as acetylcholine (ACh). Macrocyclic receptors (e.g., the γ-cyclodextrin derivative sugammadex marketed by Merck under Bridion™, the acyclic CB[n]-type receptor M2, and WP[6]) have previously been used as in vivo chelators for NMBA. Therefore, the binding affinity of P[5]AS–P[7]AS, WP[5], and WP[6] for NMBA was measured (Figure 7). Most notably, it was found that P[6]AS was significantly lower than WP[6] or sugammadextrose compared to roc,The binding affinity of vec to pan is 104–105 times stronger, while maintaining a very good level of discrimination for acetylcholine (103–104 times), which is also present in the neuromuscular junction. In fact, the affinity of P[6]AS for roc, vec, and pan is >100 times higher than that of the previously reported host M2 (Ka: M2·roc = 3.4 × 109 M⁻¹; M2·vec = 1.6 × 109 M⁻¹; M2·pan = 5.3 × 10⁸ M⁻¹), which has been shown to successfully reverse the biological effects of roc, vec, and cis in vivo in rats. To further confirm the superior binding affinity of P[6]AS for roc relative to M2, a head-to-head test was performed by 1H NMR spectroscopy. Figures 15a-e show the 1H NMR spectra recorded for unreconstituted P[6]AS, M2, and roc, as well as for the P[6]AS·roc complex and the M2·roc complex. For the M2·roc complex, for the enantiomeric pure complex, there are Ha* and Hb* splitting into a total of 8 resonances and low-field shifts. For both complexes, there are significant high-field shifts for the axial steroid Me- groups (Hp and Hq), which allows for monitoring the composition of mixtures of these two competing host-guest complexes. Figure 15f shows the 1H NMR spectra recorded when a solution of M2·roc (0.5 mM) was treated with 1 equivalent of P[6]AS. The loss of resonance in M2·roc and the appearance of resonance in P[6]AS·roc further validate the excellent affinity of P[6]AS in the context of neuromuscular blocking agents. Previously, due to the low binding affinity of the M2·cis complex (Ka = 4.8 × 10⁶ M⁻¹), the in vivo reversal of the effects of cis was only achieved in rats at higher doses of M2 (≥ 40 mg kg⁻¹). Experiments revealed that P[7]AS and cis form the (P[7]AS)₂·cis complex, in which each benzyl isoquinoline onion terminal group is complexed with the P[7]AS host. The ITC data for (P[7]AS)₂·cis can be fitted to a 1:1 binding model where N sites = 2 and Ka = 1.52 × 10⁷ M⁻¹. Therefore, P[7]AS has the potential to convert cis into an in vivo reversal agent.

[0276] In summary, this embodiment describes the synthesis of P[5]AS-P[7]AS, the X-ray crystal structures of P[5]ACS and P[6]AS, and their molecular recognition properties for (di)ammonium ions in aqueous solution. P[n]AS packs 2n negative charges into a small volume near the entrance of the acceptor, which increases the electrostatic contribution to the binding free energy. P[5]AS and P[6]AS were discovered.AS has a significantly higher binding affinity for (bis)quaternary (di)ammonium ions than WP[5] and WP[6]. Therefore, the proposed family name is column[n]MaxQ. P[6]AS has a picomolar affinity for roc and vec that is much greater than that for acyclic CB[n]-type receptor M2 and suglucose, which is used in clinical practice under the trade name BRIDION™. The ultratight binding (e.g., picomolar Kd) exhibited by P[5]AS and P[6]AS puts them alongside CB[n] as some of the most efficient synthetic receptors in water. The ultratight binding of P[5]AS and P[6]AS suggests that sulfated columnar aromatics and their functionalized derivatives can be used as non-covalent linkers for bioconjugation, for (bio)chemical separation, for therapeutic diagnostics, and for chelation and repair in chemical and biological systems.

[0277] The Ka between various host and cationic guests was determined using isothermal titration calorimetry (ITC). All ITC experiments were performed in a 200 μL working volume in the sample cell of the PEAQ ITC instrument. A 40 μL injection syringe was used. In each case, both the host and guest solutions were prepared in 20 mM NaH2PO4 buffer (pH 7.4). The sample cell was filled to capacity (200 μL) with the host solution and the guest solution was titrated (first injection = 0.4 μL, subsequent 18 injections = 2 μL). Binding data were fitted using a 1:1 binding model or a competitive binding model in the MicroCal PEAQ-ITC analysis software.

[0278] Example 3

[0279] This example provides the in vivo effects of P[6]AS on reversing methamphetamine-induced hyperlocomotion in a relevant mouse model. This example also provides results from in vivo toxicology studies of P[5]AS and P[6]AS.

[0280] Cytotoxicity data of P[5]AS and P[6]AS. To test the cytotoxicity and cell survival of the above compounds, we used two different assays: the MTS (CellTiter 96AQueous) assay, which measures cell metabolism, and the AK (BioAssay Kit) assay, which measures cell death by releasing the cytoplasmic enzyme adenosine kinase into the supernatant. Both assays were performed using two different cell lines. HEK293 and Hep G2 cells are frequently used in drug toxicity studies. HEK293 (human kidney cell line) was used to evaluate the effects of drugs on the renal system, while Hep G2 (human liver cell line) was used to assess the response of hepatocytes in which drugs are metabolized. The MTS and AK assays for both cell lines were performed after incubation with the compounds at concentrations of 0.01 mM, 0.03 mM, 0.1 mM, 0.3 mM, and 1 mM for 24 h. Eight assays were specified for untreated cells.Repeat, and four technical replicates were specified for cells treated with each compound and staurosporine (apoptosis inducer).

[0281] The collected absorbance and relative luminescence data were normalized to percentage of cell survival (MTS) and percentage of cell death (AK) using Equations 1 and 2:

[0282] 1) Cell survival % = (Abs sample / average Abs UT) × 100

[0283] 2) Cell death % = (RLU sample / average RLU distilled water) × 100

[0284] A toxicity study of the hepatocyte line HepG2 using MTS and AK assays showed that P[5]AS exhibited low cytotoxicity at concentrations up to 1 mM and high cell tolerance at concentrations up to 0.3 mM (Fig. 63A, B). P[6]AS exhibited low cytotoxicity at concentrations up to 1 mM and high cell tolerance at concentrations up to 0.1 mM in human HepG2 cells (Fig. 63C, D).

[0285] Similar toxicity studies on human kidney (HEK293) cells showed that P[5]AS exhibited low cytotoxicity at concentrations up to 1 mM and high cell tolerance at concentrations up to 0.1 mM (Figs. 64A, B). P[6]AS exhibited low cytotoxicity at concentrations up to 1 mM and high cell tolerance at concentrations up to 0.03 mM (Figs. 64C-D).

[0286] Maximum tolerated dose (MTD) study in vivo. Animal studies were conducted (IACUC# R-JAN-17-25) at the University of Maryland, Microbiology Building, under the supervision of Dr. Volker Briken. A total of 20 female Swiss Websters were used in this study. Three different concentrations of P[6]AS (11.31 mM, 7.54 mM, 3.77 mM) were used. A PBS control group was also included. Each concentration group and control group contained 5 mice. Mice were administered the compound in 0.150 ml of PBS via tail vein injection, with an interval of 48 hours between injections. The weight and health status of mice were monitored for 2 weeks after the last injection. Behavioral summary: The 11.31 mM dose group showed dose-dependent side effects in the form of freeze-up and some respiratory distress. The 11.31 mM dose group returned to baseline behavior (behavior observed using the PBS control) approximately 2–3 hours after injection. The lowest dose group of 3.77 mM did not show side effects and behaviors comparable to the PBS control group.

[0287] MTD study of P[6]AS. Female Swiss Webster mice (n=5 per group) were administered the compound via tail vein injection in the 11.31 mM dose group.Different concentrations of P[6]AS or phosphate-buffered saline (PBS) were administered on days 0 and 2 (indicated by *). Standardized mean weight changes for each study group are shown. Error bars represent SEM.

[0288] In vivo reversal of methamphetamine-induced excitatory spontaneous activity by P[6]AS

[0289] Animals. Eight male Swiss Webster (CFW) mice were obtained from Charles River Laboratories, weighing approximately 30 g upon arrival. Mice were housed individually in temperature- and humidity-controlled rooms with a 12-hour light / dark schedule, with lights on at 6:00 a.m. Eastern Time (EST). Mice had free access to food and water throughout both experiments. All behavioral tests were conducted between 6:30 a.m. and 2:00 p.m. EST, and all experimental procedures were approved by the University of Maryland Animal Care and Use Committee and in accordance with guidelines developed by the National Research Council.

[0290] Surgical procedures. Mice were anesthetized by intraperitoneal (IP) injection of ketamine (100 mg / kg) / toluidine (10 mg / kg) (n = 8) and a jugular vein catheter with a head-mounting port was implanted. All procedures were performed aseptically, with body temperature monitored and maintained throughout the operation. The catheter was placed in the right jugular vein, with the port subcutaneously extending to the top of the skull. The port (5 mm Up Pedestal; P1 Technologies) was secured to the skull using a combination of strong adhesive (Loctite) and dental cement. Immediately postoperatively, mice received an injection of Rimadyl (5 mg / kg) and 0.4 mL of warm sterile saline. Mice were treated with Rimadyl (5 mg / kg) for two days postoperatively and for at least five days prior to recovery training. The catheter was flushed daily with 0.1 mL of sterile saline solution containing gentamicin (0.33 mg / mL) and 0.1 mL of sterile saline solution containing heparin (20 IU / mL) to reduce clotting and maintain catheter patency. From the first day post-surgery until the end of the test, duct patency was assessed daily. Any mouse whose duct showed significant reflux for most days was excluded from the analysis.

[0291] Behavioral testing. Mice were trained to self-model tasks according to the criteria described above. All behavioral programs were performed in a Med Associates test chamber equipped with a food cup, a retractable lever, and four floor IR beams. Timestamps were generated when the head entered the food cup, the lever deflected downwards, or the floor beams broke, and were recorded by a behavioral computer.

[0292] Mice were given a one-day food box training consisting of thirty random deliveries at variable intervals of 30 ± 15 minutes.20 mg of sucrose pellets (Bioserv) were given to acclimate mice to the box and pellet delivery. To minimize the effects of novelty-induced feeding inhibition, mice were given five to six 20 mg sucrose pellets in their respective cages for 2–3 days prior to the start of training.

[0293] After box training, mice began a Pavlovian training phase, which consisted of presenting a lever (CS) for 8 seconds, followed by immediate delivery of a sucrose pellet and retraction of the lever. The CS was presented at random intervals of 90 ± 30 s. Each Pavlovian phase consisted of 30 trials. Pavlovian training lasted for 4 days prior to surgery. After surgery and recovery, mice underwent an additional 8 days of Pavlovian training while being exposed to various treatments.

[0294] Experimental design. The efficacy of P[6]AS was evaluated using a semi-offset design in which all mice received each possible experimental treatment. The objectives of the experiment were: (1) to verify that methamphetamine is not impaired in vivo by binding to P[6]AS, (2) to verify that P[6]AS does not alter spontaneous behavior, and (3) to confirm that P[6]AS can chelate methamphetamine in vivo. On the first day, mice received a treatment-free refresher session regardless of the experiment. Over the next six phases, mice received one of six possible treatments: 0.01M PBS (0.2 mL, infusion), P[6]AS only (4 mM; 0.178 mL, infusion), methamphetamine only (0.5 mg / kg; 0.022 mL, infusion), a premix of P[6]AS and methamphetamine (premix; ~7:1 P[6]AS:Meth; 0.178 mL P[6]AS + 0.022 mL Meth, infusion), P[6]AS followed by methamphetamine administered 30 s later (0.178 mL P[6]AS, 0.022 mL Meth, infusion), and methamphetamine followed by P[6]AS administered 30 s later (0.022 mL Meth, 0.178 mL P[6]AS, infusion). Mice received only one infusion per day. The dosage of methamphetamine was selected based on previously disclosed values ​​that showed reliable excitatory voluntary activity in mice. This was to select the minimum dose that reliably induced excitatory voluntary activity.

[0295] After completing the first six phases, the mice completed two more days of behavioral testing. On day 7, half of the mice (n = 4) received P[6]AS, followed by methamphetamine (0.178 mL P[6]AS, 0.022 mL Meth, infusion) administered 5 minutes later.The mice were administered methamphetamine infusion on day 8 of the test, followed by P[6]AS (0.022 mL Meth, 0.178 mL P[6]AS, infusion) 5 minutes later. The other half of the mice (n=4) received the exact same treatment but in reverse order on days 7 and 8.

[0296] For each experiment, total spontaneous activity counts (i.e., total number of beam interruptions) were obtained for each mouse throughout each training period. For each experiment, spontaneous activity counts were then analyzed during treatment using one-way repeated measures ANOVA (with paired post-hoc t-tests corrected for Tukey) in Graphpad Prism (version 9.0.0).

[0297] In vivo reversal of the methamphetamine-induced excitatory spontaneous activity effect was observed after a 5-minute delay between treatments administered with methamphetamine and P[6]AS. On days 7 and 8, mice (n=8) received methamphetamine followed by an infusion of 0.01M PBS (REV-C; 0.022mL Meth, 0.2mL PBS infusion) 5 minutes later, or received methamphetamine followed by an inverse administration of P[6]AS (REV-5; 0.022mL Meth, 0.178mL P[6]AS infusion) 5 minutes after exposure to methamphetamine. Administration of P[6]AS 5 minutes after exposure to methamphetamine reduced excitatory spontaneous activity (paired t-test, t(7) = 2.757, p = 0.0282). Bars represent mean spontaneous activity counts. Error bars represent the standard error (SEM) of the mean. Dots represent the count for each mouse (n=8).

[0298] As will be appreciated from the foregoing, this example provides an analysis of the efficacy of P[6]AS in chelating methamphetamine in vivo. Eight male Swiss Webster (CFW) mice were trained according to the previously described Pavlovian automorphism task, and spontaneous activity values ​​were obtained and analyzed accordingly. To establish methamphetamine-induced excitatory spontaneous activity and examine the efficacy of P[6]AS, mice were first treated with a single infusion of PBS (0.01M), P[6]AS only, methamphetamine only, a premixed solution of P[6]AS and methamphetamine, P[6]AS followed by methamphetamine administration 30 s later, or methamphetamine followed by P[6]AS administration 30 s later (in a counteracting manner). Figure 66 depicts the results of this experiment by plotting spontaneous activity counts as a function of treatment. Mixed-effects analysis revealed a significant main effect of treatment (F(5,35)=7.116, p=0.0001), where Tukey-corrected post-hoc comparisons showed a significant increase in spontaneous activity counts with methamphetamine treatment relative to all other treatments (p's<0.001)..05). Crucially, there was no difference in voluntary activity compared between the reversals (i.e., first meth, then P[6]AS 30 seconds later), suggesting that P[6]AS itself had no negative impact on voluntary behavior, and that successive administration of P[6]AS reduced methamphetamine-induced excitatory voluntary activity to control levels.

[0299] Although the results of this first analysis suggest the potential efficacy of P[6]AS in chelating methamphetamine and inducing behavioral changes, it is possible that the 30-second interval between methamphetamine administration and P[6]AS administration in the reversal conditions was too short to be behaviorally relevant. To address this issue, a follow-up experiment was conducted in which, on days 7 and 8 of the test, mice (n=8) were administered methamphetamine in a counteracting manner before completing the self-molding task, followed by administration of 0.01M PBS (REV-C) 5 minutes later, or methamphetamine was administered followed by administration of P[6]AS 5 minutes later (REV-5). Figure 67 plots the changes in spontaneous activity counts with REV-C or REV-5 treatment. A significant reduction in spontaneous activity was observed under REV-5 conditions relative to REV-C (paired t-test, t(7) = 2.757, p = 0.0282). Although not directly equivalent from an experimental design perspective, it is important that on days 1–6, the level of spontaneous activity under REV-5 conditions was very close to that observed under control conditions, while the spontaneous activity count under REV-C conditions appeared to be close to that observed when methamphetamine was used alone. In summary, these findings suggest that P[6]AS can chelate methamphetamine in vivo and reverse methamphetamine-induced excitatory voluntary activity with little to no effect on the animal's own voluntary behavior.

[0300] Example 4

[0301] The following examples illustrate ITC data for the binding of various drugs to the subject of this disclosure.

[0302] Table 10. Ka for MDMA, methoxyephedrine and heroin.

[0303]

[0304]

[0305] a. ITC measured by competitive titration of the subject (0.1 mM) and 1,3-propanediamine chloride (0.15 mM) in a pool using the subject (1 mM) in a syringe. b. ITC measured directly by titration of the subject (10 μM) in a pool using the subject (10 μM) in a syringe. c. ITC measured directly by titration of the subject (0.1 mM) in a pool using the subject (1 mM) in a syringe.

[0306] Figures 69-71 show ITC data for P[6]AS and MDMA, methoxyephedrine and heroin.

[0307] Although this disclosure has been described with respect to one or more specific embodiments, it should be understood thatOther embodiments of this disclosure may be formed without departing from the scope of this disclosure. Instruction manual page 46 / 46, 51 CN 121064070 A, Figure 1; Instruction manual figure 1 / 87 page, 52 CN 121064070 A, Figure 2; Instruction manual figure 2 / 87 page, 53 CN 121064070 A, Figure 3; Instruction manual figure 3 / 87 page, 54 CN 121064070 A, Figure 4; Instruction manual figure 4 / 87 page, 55 CN 121064070 A, Figure 5; Instruction manual figure 5 / 87 page, 56 CN 121064070 A, Figure 5 (continued); Instruction manual figure 6 / 87 page, 57 CN 121064070 A, Figure 5 (continued); Instruction manual figure 7 / 87 page, 58 CN 121064070 A, Figure 6; Instruction manual figure 8 / 87 page, 59 CN 121064070 A, Figure 6 (continued); Instruction manual figure 9 / 87 page, 60 CN 121064070 Figure 7. Instruction Manual Appendix 10 / 87, Page 61, CN 121064070 Figure 8. Instruction Manual Appendix 11 / 87, Page 62, CN 121064070 Figure 9. Instruction Manual Appendix 12 / 87, Page 63, CN 121064070 Figure 10. Instruction Manual Appendix 13 / 87, Page 64, CN 121064070 Figure 11. Instruction Manual Appendix 14 / 87, Page 65, CN 121064070 Figure 12. Instruction Manual Appendix 15 / 87, Page 66, CN 121064070 Figure 13. Instruction Manual Appendix 16 / 87, Page 67, CN 121064070 Figure 13 (continued), Instruction Manual Appendix 17 / 87, Page 68, CN 121064070 Figure 14. Instruction Manual Appendix 18 / 87, Page 69, CN 121064070 Figure 15. Instruction Manual Appendix 19 / 87 Page 70 CN 121064070 A Figure 16 Description Drawing 20 / 87 Page 71 CN 121064070 A Figure 17 Description Drawing 21 / 87 Page 72 CN 121064070 A Figure 18 Description Drawing 22 / 87 Page 73 CN 121064070 A Figure 19 Description Drawing 23 / 87 Page 74 CN 121064070 A Figure 20 Description Drawing 24 / 8775 CN 121064070 A Figure 21 Appendix to the Instruction Manual 25 / 87 pages 76 CN 121064070 A Figure 22 Appendix to the Instruction Manual 26 / 87 pages 77 CN 121064070 A Figure 23 Appendix to the Instruction Manual 27 / 87 pages 78 CN 121064070 A Figure 24 Appendix to the Instruction Manual 28 / 87 pages 79 CN 121064070 A Figure 25 Appendix to the Instruction Manual 29 / 87 pages 80 CN 121064070 A Figure 26 Appendix to the Instruction Manual 30 / 87 pages 81 CN 121064070 A Figure 27 Appendix to the Instruction Manual 31 / 87 pages 82 CN 121064070 A Figure 28 Appendix to the Instruction Manual 32 / 87 pages 83 CN 121064070 A Figure 29 Appendix to the Instruction Manual 33 / 87 pages 84 CN Figure 30 of the instruction manual, attached drawing 34 / 87, page 85; Figure 31 of the instruction manual, attached drawing 35 / 87, page 86; Figure 32 of the instruction manual, attached drawing 36 / 87, page 87; Figure 33 of the instruction manual, attached drawing 37 / 87, page 88; Figure 34 of the instruction manual, attached drawing 38 / 87, page 89; Figure 35 of the instruction manual, attached drawing 39 / 87, page 90; Figure 36 of the instruction manual, attached drawing 40 / 87, page 91; Figure 37 of the instruction manual, attached drawing 41 / 87, page 92; Figure 38 of the instruction manual, attached drawing 42 / 87, page 93; Figure 38 of the instruction manual, attached drawing 42 / 87, page 93. Figure 39 Appendix to the Instruction Manual, Page 43 / 87, 94 CN 121064070 A Figure 40 Appendix to the Instruction Manual, Page 44 / 87, 95 CN 121064070 A Figure 41 Appendix to the Instruction Manual, Page 45 / 87, 96 CN 121064070 A Figure 42 Appendix to the Instruction Manual, Page 46 / 87, 97 CN 121064070 A Figure 43 Appendix to the Instruction Manual, Page 47 / 87, 98 CN 121064070 A Figure 44 Appendix to the Instruction Manual, Page 48 / 87, 99 CN 121064070 A Figure 45 Appendix to the Instruction Manual, Page 49 / 87100 CN 121064070 A Figure 46 Appendix to the Specification, page 50 / 87 101 CN 121064070 A Figure 47 Appendix to the Specification, page 51 / 87 102 CN 121064070 A Figure 48 Appendix to the Specification, page 52 / 87 103 CN 121064070 A Figure 49 Appendix to the Specification, page 53 / 87 104 CN 121064070 A Figure 50 Appendix to the Specification, page 54 / 87 105 CN 121064070 A Figure 51 Appendix to the Specification, page 55 / 87 106 CN 121064070 A Figure 52 Appendix to the Specification, page 56 / 87 107 CN 121064070 A Figure 53 Appendix to the Specification, page 57 / 87 108 CN 121064070 A Figure 54 Appendix to the Specification, page 58 / 87 Page 109 CN 121064070 A Figure 55 Description drawing 59 / 87 Page 110 CN 121064070 A Figure 56 Description drawing 60 / 87 Page 111 CN 121064070 A Figure 57 Description drawing 61 / 87 Page 112 CN 121064070 A Figure 58 Description drawing 62 / 87 Page 113 CN 121064070 A Figure 59 Description drawing 63 / 87 Page 114 CN 121064070 A Figure 60 Description drawing 64 / 87 Page 115 CN 121064070 A Figure 61 Description drawing 65 / 87 Page 116 CN 121064070 A Figure 62 Description drawing 66 / 87 Page 117 CN 121064070 A Figure 63 Description drawing 67 / 87 Page 118 CN 121064070 A Figure 63 (continued) Instruction Manual Figures 68 / 87 Page 119 CN 121064070 A Figure 64 Instruction Manual Figures 69 / 87 Page 120 CN 121064070 A Figure 64 (continued) Instruction Manual Figures 70 / 87 Page 121 CN 121064070 A Figure 65 Figure 66 Instruction Manual Figures 71 / 87 Page 122 CN 121064070 A Figure 67 Figure 68 Instruction Manual Figures 72 / 87 Page 123 CN 121064070 A Figure 69 Instruction Manual Figures 73 / 87124 CN 121064070 A Figure 70 Appendix to the Specification, page 74 / 87 125 CN 121064070 A Figure 71 Appendix to the Specification, page 75 / 87 126 CN 121064070 A Figure 72 Appendix to the Specification, page 76 / 87 127 CN 121064070 A Figure 73 Appendix to the Specification, page 77 / 87 128 CN 121064070 A Figure 74 Appendix to the Specification, page 78 / 87 129 CN 121064070 A Figure 75 Appendix to the Specification, page 79 / 87 130 CN 121064070 A Figure 76 Appendix to the Specification, page 80 / 87 131 CN 121064070 A Figure 77 Appendix to the Specification, page 81 / 87 132 CN 121064070 A Figure 78 Appendix to the Specification, page 82 / 87 Page 133 CN 121064070 A Figure 79 Appendix 83 / 87 Page 134 CN 121064070 A Figure 80 Appendix 84 / 87 Page 135 CN 121064070 A Figure 81 Appendix 85 / 87 Page 136 CN 121064070 A Figure 82 Appendix 86 / 87 Page 137 CN 121064070 A Figure 83 Appendix 87 / 87 Page 138 CN 121064070 A Abstract Provided are sulfated pillarerenes and methods of making and using the same. The pillarerenes have a macrocycle core having a plurality of aryl groups, attached (e.g., covalently bonded) in a para orientation to the adjacent methylene groups. The pillarerenes have a hydrophobic cavity. The hydrophobic cavity may be used to sequester various materials or to deliver materials sequestered therein.

Claims

1. A compound having the structure: wherein Ar is an aryl group, wherein the aryl group is substituted at the para position with the adjacent methylene group; or a salt, partial salt, hydrate, polymorph, stereoisomer, conformer, or mixture thereof. each R is independently selected from the group consisting of: -OS(O)2O – M + , -OS(O)2OH, a non-sulfate anionic group, a carboxylic acid / carboxylate group, a phosphonic acid / phosphonate group, a phosphate group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aliphatic group, an O-alkyl group, -H, a substituted or unsubstituted alkyl group, a halogen, an amide group, a cyano group, a substituted or unsubstituted sulfur-containing aliphatic group, a nitro group, an amino group, a substituted or unsubstituted nitrogen-containing aliphatic group, a substituted or unsubstituted polyethylene glycol group, a polyether group, an O-aryl group, an ester group, a carbamate group, an imine group, an aldehyde group, a -SO3H group, a -SO3Na group, a -OSO2F group, a -OSO2CF3 group, a -OSO2OR'" group, where R'" is a substituted or unsubstituted aryl group or a substituted or unsubstituted alkyl group, and combinations thereof, where M + is Na + , K + , Ca 2+ , Mg 2+ , Zn 2+ , H4N + , Et3NH + , Me4N + , (HOCH2CH2)3NH + , or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS), x is 0, 1, 2, or 3; and y is independently at each occurrence 0, 1, 2, 3, or 4, with the proviso that at least one y is 1 and at least one R group is -OS(O)2O – M + , wherein M + is Na + , K + , Ca 2+ , Mg 2+ , Zn 2+ , H4N + , Et3NH + , Me4N + , (HOCH2CH2)3NH + , or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS), or -OS(O)2OH, 2. The compound of claim 1, wherein the aryl group is, at each occurrence, independently selected from a phenyl group, a fused ring group, a biaryl group, and a terphenyl group.

4. The compound of claim 3, wherein the compound has the structure:

3. The compound of claim 1, wherein at least two of one or more phenyl groups in one or more of the aryl groups comprised by the cyclic core of the compound have at least one R group selected from -OS(O)2O – M + and -OS(O)2OH.

7. The compound of claim 1, wherein the compound has the structure:

5. The compound of claim 1, wherein the aryl groups all comprise R groups that are independently -OS(O)2O – M + or -OS(O)2OH.

6. The compound of claim 1, wherein at least one aryl group does not contain an R group that is -OS(O)2O – M + or -OS(O)2OH.

13. A composition comprising one or more compounds of claim 1.

8. The compound of claim 7, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 of the R groups are independently -OS(O)2O – M + groups, or -OS(O)2OH groups.

9. The compound of claim 7, wherein the cyclic core of the compound comprises each phenyl group having at least one R group independently selected from -OS(O)2O – M + and -OS(O)2OH.

10. The compound of claim 7, wherein at least one phenyl group does not comprise an R group that is -OS(O)2O – M + or -OS(O)2OH.

11. The compound of claim 1, wherein M + is Na + , K + , H4N + , Et3NH + , Me4N + , (HOCH2CH2)3NH + .

12. The compound of claim 11, wherein M + is Na + .

14. The composition of claim 13, further comprising a pharmaceutical carrier.

15. The composition of claim 13, wherein the one or more compounds are disposed on at least a portion of a solid substrate.

16. The composition of claim 15, wherein the solid substrate comprises silica, polymeric beads, polymeric resin, metal nanoparticles, metal, or a combination thereof.

17. The composition of claim 13, wherein at least a portion or all of the one or more compounds have one or more pharmaceutically active agents disposed in a cavity of the one or more compounds.

18. A method for sequestering one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof, comprising: contacting the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceutical agents, the one or more pesticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof with one or more compounds of claim 1, wherein the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceutical agents, the one or more pesticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are sequestered by the one or more compounds.

19. The method of claim 18, wherein the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceutical agents, the one or more pesticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are present in an aqueous sample, a solid sample, a gaseous sample, or on a solid surface. ​ 20. The method of claim 19, wherein the aqueous sample is a wastewater sample, an industrial water sample, or a municipal water sample.

21. The method of claim 18, wherein a complex is formed from the one or more compounds and the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceutical agents, the one or more pesticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof.

22. The method of claim 18, wherein the complex is removed from the aqueous sample, the solid sample, or the gaseous sample.

23. The method of claim 18, wherein the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceutical agents, the one or more pesticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are present in and / or on an individual, and the contacting comprises administering the one or more compounds.

24. The method of claim 23, wherein the individual is a human or a non-human mammal.

25. A method for reversing drug-induced neuromuscular blockade and / or anesthesia and / or the effects of one or more pharmaceutical agents in an individual, comprising administering one or more compounds according to claim 1 to an individual in need of reversing neuromuscular blockade and / or reversing anesthesia and / or reversing the effects of one or more pharmaceutical agents.

26. The method of claim 25, wherein the individual is in need of reversing drug-induced neuromuscular blockade.

27. The method of claim 25, wherein the individual is in need of reversing anesthesia.

28. The method of claim 25, wherein the individual is in need of reversing drug-induced neuromuscular blockade and anesthesia.

29. The method of claim 25, wherein the individual is in need of reversing the effects of one or more pharmaceutical agents.

30. The method of claim 29, wherein the one or more pharmaceutical agents are selected from the group consisting of one or more drugs of abuse, one or more pesticides, one or more chemical warfare agents, one or more nerve agents, one or more hallucinogens, one or more toxins, one or more metabolites, and a combination thereof.

31. The method of claim 25, wherein the individual in need is a human.

32. The method of claim 25, wherein the individual in need is a non-human mammal.

33. A method for preventing and / or treating a disorder in an individual, comprising administering one or more compounds according to claim 1 and one or more pharmaceutical agents to an individual in need of the prevention and / or the treatment, wherein the one or more compounds and the one or more pharmaceutical agents are present as a complex, wherein after the administration, the treatment and / or the prevention of a disorder in the individual is carried out.

34. The method of claim 33, wherein one or more of the one or more agents has a solubility in aqueous solvent of less than 100 mM.

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