Cyclodextrin dimers and their use

Abstract

This paper discloses CD dimers, CD compositions, and their uses.CD dimers and their compositions can be useful for various purposes, including targeting 7KC.This paper describes the design and testing of CD dimers.Exemplary CD dimers include heterodimers, homodimers, or asymmetric dimers.

Claims

1. The following general formula structure A-X: CD-[A-B-A']-CD' (Structure AX) A cyclodextrin (CD) dimer having, in the formula, CD is a βCD having structure A-Xa: 【Chemistry 1】 In the formula, CD' is a βCD having structure A-Xb: 【Chemistry 2】 During the ceremony, L1, L2, L3, L1', L2', and L3' may be the same or different, and each may be independently selected from the group consisting of a bond, -O-, -NH-, -NR4-, or -S-, or at least one L1, L2, L3, L1', L2', and L3' is a bond, and the corresponding R1, R2, R3, R1', R2', or R3' group is N ３ , SH, F, Cl, Br, or I, [A-B-A'] is defined as a linking group that together contains the linker length of 2 to 8 atoms. A and A' are independently selected from the group consisting of a bond, -O-, -NH-, -NR4-, -S-, a heteroatom, an alkylene, or an alkylene in which at least one carbon atom is substituted by a heteroatom selected from the list consisting of O, N, S, Si, or P. B is selected from the group consisting of bonds, -O-, -NH-, -NR4-, -S-, heteroatoms, alkylenes, alkylenes in which at least one carbon atom is substituted by a heteroatom selected from the list consisting of O, N, S, Si, or P, saturated or unsaturated cycloalkylenes, saturated or unsaturated heterocycloalkylenes, arylenes, and heteroarylenes. CD and CD' are linked via a secondary surface by at least one linking group. Each linking group A is connected to at least one L1 or L2, with the corresponding R1 or R2 omitted and thus replaced by A, and each linking group A' is connected to at least one L1' or L2', with the corresponding R1' or R2' omitted and thus replaced by A'. At least one of A, B, and A' of each linking group is not a bond, R1, R2, R3, R4, R1', R2', and R3', which are not linked to a linking group, may be the same or different, and each may be independent of: Group (I) consisting of hydrogen, methyl, 2-hydroxypropyl, 3-hydroxypropyl, -CH₂CH(OH)CH₂N(CH₃)₃+, sulfobutyl, succinyl, carboxymethyl, maltosyl, glucosyl, acetyl, amino, ammonium, azide, 1,2-ethylenediamine, carboxy, carbamoyl, carboxamide, cyano, fluoro, hydroxy, sulfuric acid, sulfonamide, trimethylammoniumpropyl, and ureido; or Contains 1 to 6 carbon atoms, including alkyl, hydroxyalkyl, sulfoalkyl, trialkylammoniumalkyl, hydroxytrialkylammoniumalkyl, carboxyalkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxyalkoxyalkyl, alkylcarbonyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxy, hydroxyalkoxy, hydroxyalkoxyalkyl, hydroxycarbonylalkyl, alkylamino, dialkylamino, trialkylammonium, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoalkoxy, hydroxyalkylamino, hydroxyalkylaminoalkyl, aminocarbonyl Group (II) consisting of oxyalkyl, alkoxyamino, alkoxycarbonylamino, alkylaminocarbonyl, alkylaminocarbonylalkyl, alkylsulfonylamide, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfanyl, thioalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonamide, cyanoalkyl, alkylureido, cycloalkyl, heterocyclyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkoxy, heterocycloalkoxy, heterocycloamino, heterocyclylalkyl, heterocyclyloxy, and hydroxycycloalkyl; Selected from, At least one of the R1, R2, R3, R1', R2', and R3' that are not linked to a linking group contains one of the substituents selected from group (I) or group (II), and The CD dimer wherein at least one of the corresponding L1, L2, L3, L1', L2', and / or L3' is not O or contains a bond.

2. The following general formula structure B-X or structure B-X': CD-[A-B-A']-CD' (Structure B-X) CD'-[A-B-A']-CD (Structure B-X') A CD dimer having, in the formula, The CD is an αCD having the following structure B-Xa, 【Transformation 3】 In the formula, CD' is a βCD having the following structure B-Xb, 【Chemistry 4】 During the ceremony, L1, L2, L3, L1', L2', and L3' may be the same or different, and each may be independently selected from the group consisting of a bond, -O-, -NH-, -NR4-, or -S-, or at least one L1, L2, L3, L1', L2', and L3' is a bond, and the corresponding R1, R2, R3, R1', R2', or R3' group is N ３ , SH, F, Cl, Br, or I, [A-B-A'] is defined as a linking group that together contains the linker length of 2 to 8 atoms. A and A' are independently selected from the group consisting of a bond, -O-, -NH-, -NR4-, -S-, a heteroatom, an alkylene, and an alkylene in which at least one carbon atom is substituted by a heteroatom selected from the list consisting of O, N, S, Si, or P. B is selected from the group consisting of a bond, -O-, -NH-, -NR4-, -S-, heteroatom, alkylene, saturated or unsaturated cycloalkylene, saturated or unsaturated heterocycloalkylene, arylene, and heteroarylene. CD and CD' are linked via a secondary surface by at least one linking group. Each linking group A is connected to at least one L1 or L2, with the corresponding R1 or R2 omitted and thus replaced by A, and each linking group A' is connected to at least one L1' or L2', with the corresponding R1' or R2' omitted and thus replaced by A'. At least one of A, B, and A' of each linking group is not a bond, and R1, R2, R3, R4, R1', R2', and R3', which are not linked to a linking group, may be the same or different, and each may be independent of: Group (I) consisting of hydrogen, methyl, 2-hydroxypropyl, 3-hydroxypropyl, -CH₂CH(OH)CH₂N(CH₃)₃+, sulfobutyl, succinyl, carboxymethyl, maltosyl, glucosyl, acetyl, amino, ammonium, azide, 1,2-ethylenediamine, carboxy, carbamoyl, carboxamide, cyano, fluoro, hydroxy, sulfuric acid, sulfonamide, trimethylammoniumpropyl, and ureido; or Contains 1 to 6 carbon atoms, including alkyl, hydroxyalkyl, sulfoalkyl, trialkylammoniumalkyl, hydroxytrialkylammoniumalkyl, carboxyalkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxyalkoxyalkyl, alkylcarbonyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxy, hydroxyalkoxy, hydroxyalkoxyalkyl, hydroxycarbonylalkyl, alkylamino, dialkylamino, trialkylammonium, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoalkoxy, hydroxyalkylamino, hydroxyalkylaminoalkyl, aminocarbonyl Group (II) consisting of oxyalkyl, alkoxyamino, alkoxycarbonylamino, alkylaminocarbonyl, alkylaminocarbonylalkyl, alkylsulfonylamide, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfanyl, thioalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonamide, cyanoalkyl, alkylureido, cycloalkyl, heterocyclyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkoxy, heterocycloalkoxy, heterocycloamino, heterocyclylalkyl, heterocyclyloxy, and hydroxycycloalkyl; The CD dimer selected from the above.

3. (a) R1, R2, R3, R4, R1', R2', and R3' may be the same or different, and each may be independently selected from group (I) or group (II); and at least two R3 and R3' are not hydrogen; (b) R1, R2, R3, R4, R1', R2', and R3' may be the same or different, and each may be independently selected from group (I) or group (II); and at least two and four or fewer R3 and R3' are not hydrogen; (c) R1, R1', R2, and R2' may be the same or different, and each may be independently selected from group (I) or group (II); (d) R1, R1', R2, and R2' are each hydrogen; R3, R4, and R3' may be the same or different; and each is independently selected from group (I) or group (II); and at least two R3 and R3' are not hydrogen; (e) R1, R1', R2, and R2' are each hydrogen; R3, R4, and R3' may be the same or different; and each is independently selected from group (I) or group (II); and at least two and four or fewer R3 and R3' are not hydrogen; (f) R3 and R3' are each hydrogen; R1, R1', R2, R2', and R4 may be the same or different, each independently selected from group (I) or group (II); or (g) R3 and R3' are identical groups selected from group (I) or group (II); and R1, R1', R2, R2', and R4 may be identical or different, and each is independently selected from group (I); A CD dimer according to any one of claims 1 to 2.

4. (a) The DS at position C2 of CD (corresponding to L1 / R1) is not equal to the degree of substitution (DS) at position C2 of CD' (corresponding to L1' / R1'). (b) The DS at position C3 of CD (corresponding to L2 / R2) is not equal to the DS at position C3 of CD' (corresponding to L2' / R2'). (c) The DS at position C6 of CD (corresponding to L3 / R3) is not equal to the DS at position C6 of CD' (corresponding to L3' / R3'). (d) At least one L1 / R1, L2 / R2, or L3 / R3 pair is different from the respective L1' / R1', L2' / R2', and L3' / R3' pairs. (e) at least one L1' / R1', L2' / R2', or L3' / R3' pair is different from each of the L1 / R1, L2 / R2, and L3 / R3 pairs, or (f) Any combination of (a) to (e) A CD dimer according to any one of claims 1 to 3, comprising at least one of the above.

5. For each of R1, R2, R3, R1', R2, or R3' which is alkoxyamino, alkoxycarbonylamino, alkoxycarbonyloxy, alkylaminocarbonyl, alkylaminocarbonylalkyl, alkylsulfanyl, alkylsulfonamide, alkylureido, amino, aminosulfonyl, ammonium, arylamino, arylsulfonamide, arylsulfonyl, arylureido, carbamoyl, carboxamide, cyano, heterocyclylcycloalkyl, heteroarylsulfonyl, heterocycloalkoxy, hydroxycarbonyl, hydroxyalkoxyalkyl, hydroxycarbonylalkyl, hydroxyl, nitrite, nitro, phosphoric acid, sulfonamide, thioalkyl, or trialkylammonium, the corresponding L1, L2, L3, L1', L2', or L3' is either not O or contains a bond, the CD dimer according to any one of claims 1 to 4.

6. In the linking group [A-B-A'], B is structure Y: 【Transformation 5】 A and A', or structure Y', as shown: 【Transformation 6】 A CD dimer according to any one of claims 1 to 5, comprising a triazole having connectivity between A' and A as shown in [reference].

7. The CD dimer according to claim 6, wherein A and A' are each independently alkylenes having a length of 1 to 8 carbon atoms; or A is methyl and A' is propyl.

8. The following general formula structure A-X: CD-[A-B-A']-CD' (Structure AX) A cyclodextrin (CD) dimer having, in the formula, CD is a βCD having structure A-Xa: 【Transformation 7】 In the formula, CD' is a βCD having structure A-Xb: 【Transformation 8】 During the ceremony, L1, L2, L3, L1', L2', and L3' may be the same or different, and each is independently selected from the group consisting of bond, -O-, -NH-, -NR4-, or -S-. R1, R2, R3, R4, R1', R2', and R3' are each hydrogen. [A-B-A'] together is defined as a linking group, and is linked to the secondary surfaces of CD and CD'. A and A' are each independently alkylenes having a length of 1 to 8 carbon atoms; or A is methyl and A' is propyl. B is structure Y: 【Chemistry 9】 A and A', or structure Y', as shown: 【Chemistry 10】 It contains a triazole having connectivity from A' to A as shown in, CD and CD' are linked by at least one linking group, Each linking group A is connected to at least one L1 or L2, with the corresponding R1 or R2 omitted and thus replaced by A, and each linking group A' is connected to at least one L1' or L2', with the corresponding R1' or R2' omitted and thus replaced by A'. The CD dimer wherein at least one of L1, L2, L3, L1', L2', and / or L3' is not O.

9. The following general formula structure B-X or structure B-X': CD-[A-B-A']-CD' (Structure B-X) CD'-[A-B-A']-CD (Structure B-X') A CD dimer having, in the formula, The CD is an αCD having the following structure B-Xa, 【Chemistry 11】 In the formula, CD' is a βCD having the following structure B-Xb, 【Chemistry 12】 During the ceremony, L1, L2, L3, L1', L2', and L3' may be the same or different, and each is independently selected from the group consisting of bond, -O-, -NH-, -NR4-, or -S-. R1, R2, R3, R4, R1', R2', and R3' are each hydrogen. [A-B-A'] together is defined as a linking group, and is linked to the secondary surfaces of CD and CD'. A and A' are each independently alkylenes having a length of 1 to 8 carbon atoms; or A is methyl and A' is propyl. B is structure Y: 【Chemistry 13】 A and A', or structure Y', as shown: 【Chemistry 14】 It contains a triazole having connectivity from A' to A as shown in, CD and CD' are linked by at least one linking group, Each linking group A is connected to at least one L1 or L2, with the corresponding R1 or R2 omitted and thus replaced by A, and each linking group A' is connected to at least one L1' or L2', with the corresponding R1' or R2' omitted and thus replaced by A', and The CD dimer wherein at least one of L1, L2, L3, L1', L2', and / or L3' is not O.

10. A CD dimer composition comprising a mixture of two or more CD dimers according to any one of claims 1 to 9, wherein the CD dimer composition optionally substantially contains other CD dimers.

11. αCD having the following structure B-Xa, 【Chemistry 15】 βCD having the following structure B-Xb and 【Chemistry 16】 A CD composition comprising, During the ceremony, L1, L2, L3, L1', L2', and L3' may be the same or different, and each may be independently selected from the group consisting of a bond, -O-, -NH-, -NR4-, or -S-, or at least one L1, L2, L3, L1', L2', and L3' is a bond, and the corresponding R1, R2, R3, R1', R2', or R3' group is N ３ , SH, F, Cl, Br, or I, and R1, R2, R3, R4, R1', R2', and R3', which are not linked to a linking group, may be the same or different, and each may be independent of: Group (I) consisting of hydrogen, methyl, 2-hydroxypropyl, 3-hydroxypropyl, -CH₂CH(OH)CH₂N(CH₃)₃+, sulfobutyl, succinyl, carboxymethyl, maltosyl, glucosyl, acetyl, amino, ammonium, azide, 1,2-ethylenediamine, carboxy, carbamoyl, carboxamide, cyano, fluoro, hydroxy, sulfuric acid, sulfonamide, trimethylammoniumpropyl, and ureido; or Contains 1 to 6 carbon atoms, including alkyl, hydroxyalkyl, sulfoalkyl, trialkylammoniumalkyl, hydroxytrialkylammoniumalkyl, carboxyalkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxyalkoxyalkyl, alkylcarbonyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxy, hydroxyalkoxy, hydroxyalkoxyalkyl, hydroxycarbonylalkyl, alkylamino, dialkylamino, trialkylammonium, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoalkoxy, hydroxyalkylamino, hydroxyalkylaminoalkyl, aminocarbonyl Group (II) consisting of oxyalkyl, alkoxyamino, alkoxycarbonylamino, alkylaminocarbonyl, alkylaminocarbonylalkyl, alkylsulfonylamide, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfanyl, thioalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonamide, cyanoalkyl, alkylureido, cycloalkyl, heterocyclyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkoxy, heterocycloalkoxy, heterocycloamino, heterocyclylalkyl, heterocyclyloxy, and hydroxycycloalkyl; The CD composition selected from the above.

12. (a) R1, R2, R3, R4, R1', R2', and R3' may be the same or different, and each may be independently selected from group (I) or group (II); and at least two R3 and R3' are not hydrogen; (b) R1, R2, R3, R4, R1', R2', and R3' may be the same or different, and each may be independently selected from group (I) or group (II); and at least two and four or fewer R3 and R3' are not hydrogen; (c) R1, R1', R2, and R2' may be the same or different, and each may be independently selected from group (I) or group (II); (d) R1, R1', R2, and R2' are each hydrogen; R3, R4, and R3' may be the same or different; and each is independently selected from group (I) or group (II); and at least two R3 and R3' are not hydrogen; (e) R1, R1', R2, and R2' are each hydrogen; R3, R4, and R3' may be the same or different; and each is independently selected from group (I) or group (II); and at least two and four or fewer R3 and R3' are not hydrogen; (f) R3 and R3' are each hydrogen; R1, R1', R2, R2', and R4 may be the same or different, each independently selected from group (I) or group (II); or (g) R3 and R3' are identical groups selected from group (I) or group (II); and R1, R1', R2, R2', and R4 may be identical or different, and each is independently selected from group (I); The CD composition according to claim 11.

13. The CD composition according to any one of claims 11 to 12, wherein for each of R1, R2, R3, R1', R2', or R3' which is alkoxyamino, alkoxycarbonylamino, alkoxycarbonyloxy, alkylaminocarbonyl, alkylaminocarbonylalkyl, alkylsulfanyl, alkylsulfonamide, alkylureido, amino, aminosulfonyl, ammonium, arylamino, arylsulfonamide, arylsulfonyl, arylureido, carbamoyl, carboxamide, cyano, heterocyclylcycloalkyl, heteroarylsulfonyl, heterocycloalkoxy, hydroxycarbonyl, hydroxyalkoxyalkyl, hydroxycarbonylalkyl, hydroxyl, nitrite, nitro, phosphoric acid, sulfonamide, thioalkyl, or trialkylammonium, the corresponding L1, L2, L3, L1', L2', or L3' is either not O or contains a bond.

14. The CD composition according to any one of claims 11 to 13, wherein the molar ratio of αCD to βCD is 3:1 to 1:3, 2.5:1 to 1:2.5, 2:1 to 1:2, 1.5:1 to 1:1.5, 1.2:1 to 1:1.2, or about 1:1, preferably about 1:

1.

15. A pharmaceutical composition comprising a CD dimer according to any one of claims 1 to 9, a CD dimer composition according to claim 10, or a CD composition according to any one of claims 11 to 14 and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition according to claim 15, wherein the CD dimer, the CD dimer composition, or the CD composition is the sole active ingredient in the pharmaceutical composition.

17. The pharmaceutical composition according to claim 15, comprising the CD dimer, the CD dimer composition, or the CD composition and the pharmaceutically acceptable carrier, or essentially comprising them.

18. The pharmaceutical composition according to claim 15, further comprising at least one hydrophobic drug comprising estrogen, progesterone, and / or testosterone, and optionally comprising the CD dimer or the CD composition in an amount effective for solubilizing the hydrophobic drug.

19. A pharmaceutical composition according to any one of claims 15 to 18 for reducing the amount of 7-ketocholesterol (7KC) and / or cholesterol in a subject requiring treatment.

20. Atherosclerosis / coronary artery disease, arteriosclerosis, coronary artery atherosclerosis due to calcified coronary artery lesions, heart failure (all stages), Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, vascular dementia, multiple sclerosis, Smith-Lemle-Oppitz syndrome, pediatric neuronal ceroid lipofuscinosis, lysosomal acid lipase deficiency, cerebral tendon xanthomatous dystrophy, X-linked adrenoleukodystrophy, sickle cell disease, Niemann-Pick disease type A, Niemann-Pick disease type B, The pharmaceutical composition according to claim 19, which prevents, treats, or alleviates symptoms of one or more of the following: Niemann-Pick disease type C, Gaucher disease, Stargardt disease, age-related macular degeneration (atrophic type), idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, cystic fibrosis, liver injury, liver failure, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, and / or hypercholesterolemia, and optionally, the treatment is administered in combination with another treatment.

21. A method for improving the solubility of a hydrophobic drug, comprising estrogen, progesterone, and / or testosterone, the method comprising mixing the hydrophobic drug with a CD dimer according to any one of claims 1 to 9, a CD dimer composition according to claim 10, a CD composition according to any one of claims 11 to 14, or a pharmaceutical composition according to claim 15.

22. Use of a CD dimer according to any one of claims 1 to 9, a CD dimer composition according to claim 10, a CD composition according to any one of claims 11 to 14, or a pharmaceutical composition according to claim 15 in the manufacture of a pharmaceutical for reducing the amount of 7KC and / or cholesterol in a subject requiring treatment.

23. A method for producing a CD dimer according to any one of claims 1 to 9, (a) A primary-protected CD molecule is reacted with a dialkylating agent to produce a primary-protected CD dimer linked via a secondary surface, and the primary-protected CD dimer is optionally purified. (b) Deprotecting the primary surface protected CD dimer to produce a deprotected CD dimer, and optionally purifying the deprotected CD dimer. (c) The method comprising optionally functionalizing the deprotected CD dimer with the R1, R2, R3, R1', R2', and / or R3' groups to produce the CD dimer, and optionally purifying the CD dimer.

24. (i) The CD protected on the primary surface comprises one or more protecting groups selected from the group consisting of trityl, benzoyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS), or comprises heptakis(6-O-tert-butyldimethylsilyl)cyclodextrin; (ii) The dialkylating agent comprises a dihaloalkane or 1,4-dibromobutane; (iii) Step (a) is carried out under anhydrous conditions and / or using sodium hydride as the base; (iv) The purification in step (a) comprises normal-phase or reverse-phase chromatography using isocratic elution and / or crystallization; (v) Step (b) is carried out using tetrabutylammonium fluoride in tetrahydrofuran (THF); (vi) The purification in step (b) includes normal-phase or reverse-phase chromatography using isocratic elution and / or crystallization; or (vii) Any combination of (i) to (vi); The method according to claim 23, including the method described in claim 23.

25. (i) Step (c) comprises reacting the deprotected CD dimer with a hydroxypropylating agent comprising propylene oxide, a methylating agent comprising methyl iodide, a succinylating agent comprising succinic anhydride, a sulfobutylating agent comprising 1,4-butanesultone, and / or a quaternary ammonium reagent comprising glycidyltrimethylammonium chloride; (ii) Step (c) is carried out in an aqueous solvent with a base comprising sodium hydroxide or lithium hydroxide; and / or (iii) The purification in step (c) comprises one or more of the following: ion exchange resin treatment, activated carbon clarification, and dialysis; The method according to claim 23 or 24.

26. A method for producing a CD dimer according to any one of claims 1 to 9, comprising (a) reacting 2-O-(n-azidoalkyl)-CD or 3-O-(n-azidoalkyl)-CD or a mixture thereof with 2-O-(n-alkyne)-CD or 3-O-(n-alkyne)-CD or a mixture thereof to form a CD-triazole-CD dimer, and optionally comprising (b) purifying the CD-triazole-CD dimer.

27. (i) Step (a) is carried out using a copper(I) catalyst, a silver(I) catalyst, a ruthenium catalyst, copper(I) bromide, or copper bromide tris(triphenylphosphine) [(PPh3)3CuBr]; (ii) Step (a) is carried out in an aqueous solution or in a solution containing water and 50% dimethylformamide; (iii) The purification in step (b) comprises silica gel chromatography and / or crystallization; or (iv) The method further comprises, prior to step (a), reacting an n-azido-1-bromoalkane with a base comprising cyclodextrin and lithium hydride, sodium hydride, and n-butyllithium, and optionally with a catalytic amount of lithium iodide in DMSO to produce the 2-O-(n-azidoalkyl)-CD; (v) The method further comprises purifying the 2-O-(n-azidoalkyl)-CD by silica gel chromatography; (vi) The method further comprises, prior to step (a), reacting the n-bromo-1-alkyne with a base comprising cyclodextrin and lithium hydride, sodium hydride, and n-butyllithium, and optionally with a catalytic amount of lithium iodide in DMSO to produce the 2-O-(n-alkyne)-CD; (vii) The method further comprises purifying the 2-O-(n-alkyne)-CD by silica gel chromatography; (viiii) The method further comprises, after step (b), reacting the CD-triazole-CD dimer with a base comprising lithium hydroxide or sodium hydroxide and one or more of the following: a hydroxypropylating agent comprising propylene oxide, a methylating agent comprising methyl iodide, a succinylating agent comprising succinic anhydride, a sulfobutylating agent comprising 1,4-butanesultone, and / or a quaternary ammonium reagent comprising glycidyltrimethylammonium chloride; (ix) Purifying the CD-triazole-CD dimer by one or more of the following: ion exchange resin treatment, activated carbon clarification, membrane filtration, and dialysis; or Any combination of (x)(i) to (ix); The method according to claim 26, including the method described in claim 26.

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