Amphiphilic macrocyclic derivatives and their analogues

Abstract

Soluble amphiphilic macrocycle analogues having lipophilic groups attached to one side of the units making up the macrocycle and hydrophilic groups attached to the other side. These amphiphilic macrocyclic derivatives have the ability to self-assemble in aqueous solvent forming micelles or vesicles and can be used as hosts for the solubilisation and/or stabilisation of various compounds. Embodiments of the present invention utilise macrocyclic oligosaccharides and preferably cyclodextrin as the macrocyclic derivatives to be modified.

1 . Soluble amphiphilic macrocyclic derivatives having lipophilic groups attached to one side of the units making up the macrocycle and hydrophilic groups attached to the other side characterised in that; 
 two or more hydrophilic groups are attached to one side of each unit forming the macrocycle; and    one or more lipophilic groups are attached to the opposite side of each unit forming the macrocycle such that the number of hydrophilic groups present is always greater than the number of lipophilic groups and wherein the effective number of the hydrophilic and lipophilic groups allow the self-assembly of the macrocyclic derivatives to form micelles or vesicles in aqueous solution.    
     
     
         2 . A macrocyclic derivative according to  claim 1 , wherein the effective size of the hydrophilic and lipophilic groups allow the self-assembly of the macrocyclic derivatives to form micelles or vesicles in aqueous solution.  
     
     
         3 . A macrocyclic derivative according to  claim 1  wherein the units making up the macrocycle are of the general formula:  
       
         
           
           
               
               
           
         
       
       in which n equals 2-11 or higher, and indicates the number of ring units making up the macrocycle, which may be the same or different, 
 If any one of K, L, M are zero, the remaining are independently one or more of: a simple chemical bond;or an atom or radical having a valency of at least 2 and can be in any position not occupied by a moiety involved in linking adjacent units forming the macrocycle;  
 Y, which may be the same or different, are groups that link the units making up the macrocycle,  
 X 1 , X′ 1 , X 2 , X′ 2 , X 3 , X′ 3 , X 4 , X′ 4 , X 5 , X 6 , independently, are zero or provide linking groups,  
 when one or more but not all of R 1 , R′ 1 , R 4 , R′ 4 , independently is zero, the remaining are groups which are predominantly lipophilic;  
 when one or more but not all of R 2 , R′ 2 , R 3 , R′ 3 , independently is zero, the remaining are groups which are predominantly polar and/or capable of hydrogen-bonding; and  
 R 5 , R 6  are groups which may be polar or lipophilic.  
 
     
     
         4 . A derivative as claimed in  claim 3  wherein the Y group is selected from the group comprising oxygen, sulfur, selenium, nitrogen, phosphorus, carbon, or silicon radicals having a valency of 2-4; or OCH 2 ; or OCH 2 CH(OH); or OCH(CH 2 OH).  
     
     
         5 . A derivative as claimed in  claim 3  wherein X 1 , X′ 1 , X 2 , X′ 2 , X 3 , X′ 3 , X 4 , X′ 4 , X 5 , X 6 , independently may be a simple covalent bond, or an atom or radical with a valency of at least 2.  
     
     
         6 . A derivative as claimed in  claim 5  wherein the radical is, independently, selected from the group comprising: CH 2 , CH 2 O, O, S, Se, N, P, carbonyl, ester, amido, amino, phosphate, sulfonyl, sulfoxide, a polymer, a dendrimer.  
     
     
         7 . A derivative as claimed in  claim 3  wherein R 1 , R′ 1 , R 4 , R′ 4 , independently, are chosen from the group comprising: H, a saturated or unsaturated aliphatic or aromatic carbon or silicon radical or a halogenated version of these.  
     
     
         8 . A derivative as claimed in  claim 7  wherein when R 1  is a straight or branched aliphatic chain the number of carbons in R 1  is 2 to 18.  
     
     
         9 . A derivative as claimed in  claim 7  wherein the cyclic aliphatic system is a hexyl or cholesteryl group.  
     
     
         10 . A derivative as claimed in  claim 7  wherein the aromatic group is a benzyl group.  
     
     
         11 . A derivative as claimed in  claim 3  wherein R 2  R 2 ′ R 3  R 3 ′ independently are selected from the group comprising: H, (CH 2 ) 2-4 OH, CH 2 CH(OH) CH 2 OH, CH 2 CH(OH)CH 2 NH 2 , CH 2 CH 2 NH 2 , a cation, an anion, any pharmaceutically acceptable ion; a predominantly hydrophilic group; a polymer and a dendrimer.  
     
     
         12 . A derivative as claimed in  claim 11  wherein the polymers are selected from the group comprising poly(ethylenimide) polyamides, polyaminoacids, non-immugenic polar groups; antigenic groups; and groups that promote adhesion to specific cells or proteins.  
     
     
         13 . A derivative as claimed in  claim 12  wherein the non-immunogenic group is poly(ethylene glycol).  
     
     
         14 . A derivative as claimed in  claim 12  wherein the non-immunogenic group is sialylGalGlcNAc.  
     
     
         15 . A derivative as claimed in  claim 12  wherein the antigenic group is an antennary oligosaccharide.  
     
     
         16 . A derivative as claimed in  claim 12  wherein the adhesion promoting groups are selected from the group comprising: folic acid, galactose, biotin, lipopolysaccharides, gangliosides, sialo-gangliosides, glycosphingolipids.  
     
     
         17 . An amphiphilic macrocyclic derivative as claimed in  claim 3  wherein the units forming the macrocycle are monosaccharide units forming an oligosaccharide macrocycle with the formula:  
       
         
           
           
               
               
           
         
       
       in which n equals 3-11 or higher, and indicates the number of modified monosaccharide units in the macrocycle which may be the same or different, depending on the X- and R-groups; 
 X 1 , X 2 , X 3  independently, provide linking groups;  
 R 1  independently, provide groups which are predominantly lipophilic;  
 R 2  and R 3 , independently, provide groups which are predominantly polar and/or capable of hydrogen-bonding.  
 
     
     
         18 . A derivative as claimed in  claim 17  wherein the modified units making up the macrocycle are independently aglycone derivatives of D- or L hexoses or dissaccharides.  
     
     
         19 . A derivative as claimed in  claim 18  wherein the hexose units are selected from the group comprising: mannose, galactose, glucose, altrose, idose, rhamnose, arabinose or a dissaccharide unit.  
     
     
         20 . A derivative as claimed in  claim 19  wherein the macrocyclic units are L-glucose.  
     
     
         21 . An amphiphilic macrocyclic derivative, characterised in that the macrocyclic derivative is a cyclodextrin derivative of the following formula:  
       
         
           
           
               
               
           
         
       
       in which n equals 5-11 or higher, and indicates the number of modified glucose units in the macrocycle which may be the same or different, depending on the X- and R-groups, 
 X 1 , X 2 , X 3  independently, provide linking groups;  
 R 1  independently, provide groups which are predominantly lipophilic;  
 R 2  and R 3 , independently, provide groups which are predominantly polar and/or capable of hydrogen-bonding.  
 
     
     
         22 . A derivative as claimed in  claim 21  wherein the lipophilic group is attached at the 6-position and the polar hydrophilic groups are attached at the 2- and 3-positions of the units making up the cyclodextrin macrocycle such that the effective number of the lipophilic groups at the 6-positions and the effective number of the hydrophilic groups at the 2- and 3-position all the self-assembly of the cyclodextrin derivative to form micelles or vesicles in aqueous solution.  
     
     
         23 . A derivative as claimed in  claim 22  wherein the effective size of the lipophilic groups at the 6-positions and the effective size of the hydrophilic groups at the 2- and 3-positions allow self-assembly of the cyclodextrin derivative to form micelles or vesicles in aqueous solution.  
     
     
         24 . A derivative as claimed in  claim 21  wherein X 1 , X 2 , X 3  independently are a simple covalent bond or an atom or radical with a valency of at least two.  
     
     
         25 . A derivative as claimed in  claim 24  wherein the radical is selected from the group comprising:, O, S, Se, N, P, CH 2 , CH 2 O, carbonyl, ester, amido, amino, phosphate, sulfonyl, sulfoxide.  
     
     
         26 . A derivative as claimed in  claim 21  wherein R1 is selected from the group comprising: H, a saturated or unsaturated aliphatic or aromatic carbon or silicon radical or a halogenated version of these.  
     
     
         27 . A derivative as claimed in  claim 21  wherein R 2 , R 3  may be selected from a group comprising: dendrimers; polymers; groups which are employed because of their non-immunogenic as well as polar character; antigenic groups intended to stimulate the production of antibodies; or groups which may be attached for the purpose of promoting adhesion of the amphiphile to specific cells or specific proteins.  
     
     
         28 . A derivative as claimed in  claim 27  wherein the polymers are selected from the group comprising poly(ethylenimide) polyamides, polyaminoacids, non-immunogenic polar groups.  
     
     
         29 . A derivative as claimed in  claim 27  wherein the non-immunogenic group is poly(ethylene glycol).  
     
     
         30 . A derivative as claimed in  claim 27  wherein the non-immunogenic group is sialylGalGlcNAc.  
     
     
         31 . A derivative as claimed in  claim 27  wherein the antigenic group is an antennary oligosaccharide.  
     
     
         32 . A derivative as claimed in  claim 27  wherein the adhesion promoting molecules are selected from the group comprising: polymers, dendrimers, antibodies, folic acid, galactose, biotin, lipopolysaccharides, gangliosides, sialo-gangliosides, glycosphingolipids.  
     
     
         33 . A derivative as claimed in claim  21 wherein the macrocyclic derivatives are in the form bis(cyclodextrin amphiphile) in which two amphiphilic cyclodextrins share common R 1  groups, so as to provide ‘bola amphiphiles’ having two polar groups joined by one or more lipophilic groups, thus: (R 2 , R 3 )-macrocycle-(R 1 )-macrocycle-(R 2 , R 3 ), where linker groups X are understood.  
     
     
         34 . A derivative as claimed in  claim 21  wherein the macrocyclic derivative is in the bola amphiphile form in which a common set of lipophilic groups (R 1 ) and a common macrocyclic molecule link two sets of polar headgroups (R 2 , R 3 ), thus: (R 2 , R 3 )(R 1 )-macrocycle-(R 2 , R 3 ), where linker groups are understood.  
     
     
         35 . A derivative as claimed in  claim 21  wherein the groups X 1 , or the groups X 2  and X 3 , or the groups R 1 , or the groups R 2  and R 3 , may be linked to each other intramolecularly, as independent sets, by reaction of their chemical precursor groups through catalysis, or by reaction of their chemical precursor groups with a polyfunctional linking agent.  
     
     
         36 . A derivative as claimed in  claim 21  wherein the groups X 1 , or the groups X 2  and X 3 , or the groups R 1 , or the groups R 2  and R 3 , may be linked to each other intermolecularly, as independent sets, by reaction of their chemical precursor groups through catalysis, or by reaction of their chemical precursor groups with a polyfunctional linking reagent, to provide an oligomerised amphiphilic cyclodextrin.  
     
     
         37 . A derivative as claimed in  claim 1  wherein the amphiphilic macrocycles may be mixed with other molecules.  
     
     
         38 . A derivative as claimed in  claim 37  wherein the other molecules are selected to modulate the properties of the macrocycle assemblies.  
     
     
         39 . A derivative as claimed in  claim 38  wherein the modulatory molecules are ceramides or glycerides.  
     
     
         40 . A derivative as claimed in  claim 37  wherein the amphiphilic macrocyclic assembly forms a complex with a guest molecule.  
     
     
         41 . A derivative as claimed in  claim 40  wherein the guest molecule forms a complex with the amphiphilic macrocycle for formulation into pharmaceutical compositions useful for the treatment of human or animal diseases.  
     
     
         42 . A derivative as claimed in  claim 40  wherein the guest molecules that complex with the amphiphilic macrocycle are of a lipophilic nature.  
     
     
         43 . A derivative as claimed in  claim 40  wherein the guest molecules that complex with the amphiphilic macrocycle are of a polar nature.  
     
     
         44 . A derivative as claimed in  claim 40  wherein the guest molecule may bind in the cavity of each unit of the macrocycle, in the lipophilic interior of an assembly, in the aqueous internal compartment(s) of an amphiphile assembly, or may be complexed with the amphiphile.  
     
     
         45 . A derivative as claimed in  claim 37  wherein the amphiphilic assembly is complexed with a molecule or atom used for analysis or diagnosis.  
     
     
         46 . A derivative as claimed in  claim 45  wherein the amphiphilic assembly is complexed to a peptide antigen or an antibody; or a molecule used as a radiation sensitiser.  
     
     
         47 . A derivative as claimed in  claim 45  wherein the amphiphile is complexed with a molecule which functions as a prodrug.  
     
     
         48 . A derivative as claimed in  claim 47  wherein the prodrug is a precursor of nitric oxide.  
     
     
         49 . A derivative as claimed in  claim 40  wherein the amphiphile assembly may be attached to a polymer.  
     
     
         50 . A derivative as claimed in  claim 37  wherein the amphiphilic assembly comprises units in a copolymer.  
     
     
         51 . A derivative as claimed in  claim 50  wherein the amphiphiphile complex is copolymerised within the matrix of a polylactic or polyglycolic acid.  
     
     
         52 . A derivative as claimed in  claim 40  wherein the guest molecule functions as an R-group as specified in  claim 21  so as to provide a precursor of the active form of the guest molecule.  
     
     
         53 . A derivative as claimed in  claim 40  wherein the guest molecule is therapeutic molecule.  
     
     
         54 . A derivative as claimed in  claim 37  wherein the amphiphile or its complex is present as a pharmaceutical formulation with any pharmaceutically acceptable ingredient.  
     
     
         55 . A derivative as claimed in  claim 53  wherein the pharmaceutically acceptable ingredient comprises one or more of a diluent, carrier, preservative (including anti-oxidant), binder, excipient, flavouring agent, thickener, lubricant, dispersing, wetting, surface active or isotonic agent which is compatible with the amphiphile or complex.  
     
     
         56 . A derivative as claimed in  claim 54  wherein the amphiphile or complex is dispersed in a suitable solvent, buffer, isotonic solution, emulsion, gel or lyophilised suspension.  
     
     
         57 . A derivative as claimed in  claim 40  wherein the amphiphile or complex is preferably administered by the following routes of administration comprising parenteral, oral, topical, intranasal, intraocular, vaginal, rectal or by inhalation spray in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.  
     
     
         58 . A derivative as claimed in  claim 37  wherein the amphiphile or amphiphile-therapeutic molecule complexes comprise pharmaceutical formulations exhibiting sustained release of a drug.