Ligands for G-Protein Coupled Receptors

Abstract

The invention provides compounds of general formulae I-IV or pharmaceutically acceptable salts thereof: The invention also provides methods of preparing the compounds, pharmaceutical compositions comprising the compounds and use of the compounds for the preparation of medicaments intended to modulate the activity of one or more members of the G-protein coupled receptor (GPCR) class. Compounds of the invention may be used to create a compound library for use in screening for agents which modulate signalling through GPCRs.

1 . A compound of general formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 X is —CO—(Y) k -(Z) n  or SO 2 —(Y) k -(Z) n ; 
 k is 0 or 1 
 Y is a cycloalkyl or polycyloalkyl group; 
 or Y is a cycloalkenyl or polycycloalkenyl group; 
 each Z is independently selected from hydrogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, charged alkylaminotrialkyl or charged alkylcarboxylate radical of 1 to 20 carbon atoms; 
 or each Z is independently selected from fluoro, chloro, bromo, iodo, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, charged aminotrialkyl, or carboxylate radical; and 
 n is any integer from 1 to m, where m is the maximum number of substitutions permissible on the cyclo-group Y; or 
 alternatively Z may be selected from a peptido radical; and 
 R 3  and R 4  independently represent any variable substituent. 
 
     
     
         2 . A compound of general formula (II) 
       
         
           
           
               
               
           
         
       
       wherein
 X is —CO—(Y) k -(Z) n  or SO 2 —(Y) k -(Z) n ; 
 k is 0 or 1 
 Y is a cycloalkyl or polycyloalkyl group; 
 or Y is a cycloalkenyl or polycycloalkenyl group; 
 each Z is independently selected from hydrogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, charged alkylaminotrialkyl or charged alkylcarboxylate radical of 1 to 20 carbon atoms; 
 or each Z is independently selected from fluoro, chloro, bromo, iodo, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, charged aminotrialkyl, or carboxylate radical; and 
 n is any integer from 1 to m, where m is the maximum number of substitutions permissible on the cyclo-group Y; or 
 alternatively Z may be selected from a peptido radical; and 
 R 3  and R 4  independently represent any variable substituent. 
 
     
     
         3 . A compound of general formula (III) 
       
         
           
           
               
               
           
         
       
       wherein
 X is —CO—(Y) k -(Z) n  or SO 2 —(Y) k -(Z) n ; 
 k is 0 or 1 
 Y is a cycloalkyl or polycyloalkyl group; 
 or Y is a cycloalkenyl or polycycloalkenyl group; 
 each Z is independently selected from hydrogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, charged alkylaminotrialkyl or charged alkylcarboxylate radical of 1 to 20 carbon atoms; 
 or each Z is independently selected from fluoro, chloro, bromo, iodo, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, charged aminotrialkyl, or carboxylate radical; and 
 n is any integer from 1 to m, where m is the maximum number of substitutions permissible on the cyclo-group Y; or 
 alternatively Z may be selected from a peptido radical; and 
 R 2 , R 3  and R 4  independently represent any variable substituent. 
 
     
     
         4 . A compound of general formula (IV) 
       
         
           
           
               
               
           
         
       
       wherein
 X is —CO—(Y) k -(Z) n  or SO 2 —(Y) k -(Z) n ; 
 k is 0 or 1 
 Y is a cycloalkyl or polycyloalkyl group; 
 or Y is a cycloalkenyl or polycycloalkenyl group; 
 each Z is independently selected from hydrogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, charged alkylaminotrialkyl or charged alkylcarboxylate radical of 1 to 20 carbon atoms; 
 or each Z is independently selected from fluoro, chloro, bromo, iodo, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, charged aminotrialkyl, or carboxylate radical; and 
 n is any integer from 1 to m, where m is the maximum number of substitutions permissible on the cyclo-group Y; or 
 alternatively Z may be selected from a peptido radical; and 
 R 2  and R 3  independently represent any variable substituent. 
 
     
     
         5 . A pharmaceutical composition comprising, as active ingredient, a compound of general formula (I), as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and/or carrier. 
     
     
         6 . A pharmaceutical composition comprising, as active ingredient, a compound of general formula (II), as defined in  claim 2 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and/or carrier. 
     
     
         7 . A pharmaceutical composition comprising, as active ingredient, a compound of general formula (III), as defined in  claim 3 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and/or carrier. 
     
     
         8 . A pharmaceutical composition comprising, as active ingredient, a compound of general formula (IV), as defined in  claim 4 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and/or carrier. 
     
     
         9 - 18 . (canceled) 
     
     
         19 . A method of treatment, amelioration or prophylaxis of the symptoms of disease or condition selected from the group consisting of hypertension, atherosclerosis, asthma, obesity, neurodegenerative disorders, autoimmune disorders or psychopathic disorders by the administration to a patient of an effective amount of a compound, as claimed in any of  claims 1  to  4 . 
     
     
         20 . A library composed of, or enriched in, diverse library elements which are compounds according to any of  claims 1  to  4 , where said compounds have diverse substitutions as the variable substituents. 
     
     
         21 . A method which involves the use of a library according to  claim 20  in an assay for the purpose of screening to identify agent(s) which modulate signalling through GPCRs comprising screening the library according to  claim 20  to identify agent(s) which modulate signalling through GPCRs. 
     
     
         22 . A method according to  claim 21 , where the agent(s) identified are antagonists at one or more GPCRs. 
     
     
         23 . A method according to  claim 21  where the agent(s) identified are agonists at one or more GPCRs. 
     
     
         24 . A method according to  claim 21  where the GPCR is selected from the group consisting of adrenalin receptors, endothelin receptors, chemokine receptors, EDG receptors, VIP/PECAP receptors, dopamine receptors, serotonin receptors, purine receptors, metabotropic gluatmate receptors, acetyl choline receptors, C5a receptors, fMLP receptors, glucagon or GLP receptors, NPY receptors, MSH receptors, glycoprotein hormone receptors, protease activated receptors (PARs), somatostatin receptors, angiotensin receptors, cholecystokinin receptors or melatonin receptors. 
     
     
         25 . A method according to  claim 21  further comprising synthesising a carbon analogue of said compound, wherein the heteroatom in the lactam ring which is not part of the “ideal” GPCR substrate motif (at position 1) is replaced by —CH 2 —; and providing said carbon analogue (or a pharmaceutically acceptable salt thereof) in isolated and purified form. 
     
     
         26 . A pharmaceutical composition comprising, as active ingredient, a compound produced according to step (d) of  claim 25 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and/or carrier. 
     
     
         27 . The use of a compound produced according to step (d) of  claim 25 , or a pharmaceutically acceptable salt thereof, for the preparation of a medicament intended to modulate the activity of one or more members of the G-protein coupled receptor (GPCR) class. 
     
     
         28 . Use of a compound according to  claim 27  wherein the GPCR to be modulated is selected from the group consisting of adrenalin receptors, endothelin receptors, chemokine receptors, EDG receptors, VIP/PECAP receptors, dopamine receptors, serotonin receptors, purine receptors, metabotropic gluatmate receptors, acetyl choline receptors, C5a receptors, FMLP receptors, glucagon or GLP receptors, NPY receptors, MSH receptors, glycoprotein hormone receptors, protease activated receptors (PARs), somatostain receptors, angiotensin receptors, cholecystokinin receptors or melatonin receptors. 
     
     
         29 . A method of treatment, amelioration or prophylaxis of the symptoms of disease or condition selected from the group consisting of hypertension, atherosclerosis, asthma, obesity, neurodegenerative disorders, autoimmune disorders or psychopathic disorders by the administration to a patient of an effective amount of a compound produced according to  claim 25 . 
     
     
         30 . A method for preparing a compound of formula (I) as defined in  claim 1 , which method comprises the steps of;
 (a) selective acylation of the N-α-amino group of cysteine, S-alkyl cysteine or a 7-membered lactam ring derived from an S-alkyl cysteine;   (b) S-alkylation of cysteine or N-acyl cysteine; and   (c) cyclisation of S-alkyl-cysteine or S-alkyl-N-acyl-cysteine   
       where the steps are performed in any appropriate order, using selective protecting groups as required. 
     
     
         31 . A method for preparing a compound of formula (II) as defined in  claim 2 , which method comprises the steps of;
 (a) selective acylation of the N-α-amino group of penicillamine, S-alkyl penicillamine or a 7-membered lactam ring derived from an S-alkyl penicillamine;   (b) S-alkylation of penicillamine or N-acyl penicillamine; and   (c) cyclisation of S-alkyl penicillamine or S-alkyl-N-acyl penicillamine   
       where the steps are performed in any appropriate order, using selective protecting groups as required. 
     
     
         32 . A method for preparing a compound of formula (III) as defined in  claim 3 , which method comprises the steps of;
 (a) selective acylation of the N-α-amino group of 3-aminoalanine, N-β-alkyl 3-aminoalanine, N-β-aryl 3-aminoalanine, N-β-dialkyl 3-aminoalanine or a 7-membered lactam ring derived from an N-β-alkyl 3-aminoalanine, N-β-aryl-N-β-alkyl 3-amoinoalanine, N-β-dialkyl 3-aminoalanine;   (b) N-β-alkylation or N-β-arylation or N-β-sulfonation of 3-aminoalanine, N-β-alkyl 3-aminoalanine or a 7-membered lactam ring derived from an N-β-alkyl 3-aminoalanine, all with or without prior N-α-acyl modification;   (c) N-β-alkylation using a protected β-amino alcohol of 3-aminoalanine, N-β-alkyl 3-aminoalanine or N-β-aryl 3-aminoalanine, all with or without prior N-α-acyl modification; and   (d) cyclisation of N-β-alkyl 3-aminoalanine, N-β-dialkyl 3-aminoalanine or N-β-aryl-N-β-alkyl 3-aminoalanine, all with or without prior N-α-acyl modification   
       where the steps are performed in any appropriate order, using selective protecting groups as required. 
     
     
         33 . A method for preparing a compound of formula (IV) as defined in  claim 4 , which method comprises the steps of;
 (a) selective acylation of the N-α-amino group of 3-aminoalanine, N-β-alkyl 3-aminoalanine, N-β-aryl 3-aminoalanine, N-β-alkyl-N-β-acyl 3-aminoalanine, N-β-aryl-N-β-acyl 3-aminoalanine or a 7-membered lactam ring derived from an N-β-acyl 3-aminoalanine, N-β-aryl-N-β-acyl 3-amoinoalanine, N-β-alkyl-N-β-acyl 3-aminoalanine;   (b) N-β-alkylation or N-β-arylation of 3-aminoalanine, N-β-acyl 3-aminoalanine or a 7-membered lactam ring derived from an N-β-acyl 3-aminoalanine, all with or without prior N-α-acyl modification;   (c) N-β-acylation using a protected α-amino acid of 3-aminoalanine, N-β-alkyl 3-aminoalanine or N-β-aryl 3-aminoalanine, all with or without prior N-α-acyl modification; and   (d) cyclisation of N-β-acyl 3-aminoalanine, N-β-acyl-N-β-aryl 3-aminoalanine or N-β-acyl-N-β-alkyl 3-aminoalanine, all with or without prior N-α-acyl modification   
       where the steps are performed in any appropriate order, using selective protecting groups as required. 
     
     
         34 . A method according to  claim 30 , for preparing a compound of formula (I), which method uses a synthetic route selected from the group consisting of
 (i) Scheme 1A;   (ii) Scheme 1B; and   (iii) Scheme 1C.   
     
     
         35 . A method according to  claim 31 , for preparing a compound of formula (II), which method uses a synthetic route selected from the group consisting of
 (i) Scheme 2A;   (ii) Scheme 2B; and   (iii) Scheme 2C.   
     
     
         36 . A method according to  claim 32 , for preparing a compound of formula (III), which method uses a synthetic route selected from the group consisting of
 (i) Scheme 3A;   (ii) Scheme 3B;   (iii) Scheme 3C;   (iv) Scheme 3D;   (v) Scheme 3E; and   (vi) Scheme 3F.   
     
     
         37 . A method according to  claim 33 , for preparing a compound of formula (IV), which method uses a synthetic route selected from the group consisting of
 (i) Scheme 4A;   (ii) Scheme 4B; and   (iii) Scheme 4C.   
     
     
         38 . A method for preparing a library of compounds enriched in GPCR antagonists and/or GPCR agonists wherein the library is prepared by reacting a diversity of α-amino acids and/or β-amino alcohols with a “suitable” acylamino acid; a “suitable” acylamino acid being defined as any acylamino acid which generates an acylaminolactam when reacted with an α-amino acid or a β-amino alcohol. 
     
     
         39 . A compound of formula (II) according to  claim 2  where R 3  is not carboxylate; or a carboxylate ester (with the carboxylate attached directly to the acylaminolactam ring); or a carboxylate amide (with the carboxylate attached directly to the acylaminolactam ring); or a carboxylate thioester (with the carboxylate attached directly to the acylaminolactam). 
     
     
         40 . A compound of formula (IV) according to  claim 4  wherein the compound is not R 3 =benzyl or R 3 ═CH 2 CH 2 COR′ where R′ is variable. 
     
     
         41 . The compound according to  claim 1 ,  2 ,  3  or  4  wherein Y is an adamantyl, adamantanemethyl, bicyclooctyl, cyclohexyl, or cyclopropyl group. 
     
     
         42 . The compound according to  claim 1 ,  2 ,  3  or  4  wherein the peptide radical has from 1 to 4 peptidic moieties linked together by peptide bonds. 
     
     
         43 . The compound according to  claim 42  where the peptido radical has 1 to 4 amino acid residues. 
     
     
         44 . The compound according to  claim 1 ,  2 ,  3  or  4  wherein the R 1  radical has a key carbon which is di-substituted with the same or different groups selected from: alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl and alkylamino radicals. 
     
     
         45 . The compound according to  claim 44  wherein the key carbon is chiral. 
     
     
         46 . The compound according to  claim 44  wherein the key carbon has sp3 hybridised bonds. 
     
     
         47 . The compound according to  claim 44  wherein the key carbon has essentially tetrahedral bond angles. 
     
     
         48 . The compound according to  claim 1 ,  2 ,  3  or  4  wherein the ring or rings of Y constrain the bond angles at the key carbon to be essentially tetrahedral. 
     
     
         49 . A method to modulate the activity of one or more members of the G-protein coupled receptor (GPCR) class, comprising: administering to a patient an effective amount of a compound of general formula (I), (II), III) or (IV), or a pharmaceutically acceptable salt thereof, wherein formula (I) is 
       
         
           
           
               
               
           
         
       
       wherein
 X is —CO—(Y) k -(Z) n  or SO 2 —(Y) k -(Z) n ; 
 k is 0 or 1 
 Y is a cycloalkyl or polycyloalkyl group; 
 or Y is a cycloalkenyl or polycycloalkenyl group; 
 each Z is independently selected from hydrogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, charged alkylaminotrialkyl or charged alkylcarboxylate radical of 1 to 20 carbon atoms; 
 or each Z is independently selected from fluoro, chloro, bromo, iodo, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, charged aminotrialkyl, or carboxylate radical; and 
 n is any integer from 1 to m, where m is the maximum number of substitutions permissible on the cyclo-group Y; or 
 alternatively Z may be selected from a peptido radical; and 
 R 3  and R 4  independently represent any variable substituent; 
 formula (II) is 
 
       
         
           
           
               
               
           
         
       
       wherein
 X is —CO—(Y) k -(Z) n  or SO 2 —(Y) k -(Z) n ; 
 k is 0 or 1 
 Y is a cycloalkyl or polycyloalkyl group; 
 or Y is a cycloalkenyl or polycycloalkenyl group; 
 each Z is independently selected from hydrogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, charged alkylaminotrialkyl or charged alkylcarboxylate radical of 1 to 20 carbon atoms; 
 or each Z is independently selected from fluoro, chloro, bromo, iodo, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, charged aminotrialkyl, or carboxylate radical; and 
 n is any integer from 1 to m, where m is the maximum number of substitutions permissible on the cyclo-group Y; or 
 alternatively Z may be selected from a peptido radical; and 
 R 3  and R 4  independently represent any variable substituent; 
 formula (III) is 
 
       
         
           
           
               
               
           
         
       
       wherein
 X is —CO—(Y) k -(Z) n  or SO 2 —(Y) k -(Z) n ; 
 k is 0 or 1 
 Y is a cycloalkyl or polycyloalkyl group; 
 or Y is a cycloalkenyl or polycycloalkenyl group; 
 each Z is independently selected from hydrogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, charged alkylaminotrialkyl or charged alkylcarboxylate radical of 1 to 20 carbon atoms; 
 or each Z is independently selected from fluoro, chloro, bromo, iodo, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, charged aminotrialkyl, or carboxylate radical; and 
 n is any integer from 1 to m, where m is the maximum number of substitutions permissible on the cyclo-group Y; or 
 alternatively Z may be selected from a peptido radical; and 
 R 2 , R 3  and R 4  independently represent any variable substituent, or formula (IV) is 
 
       
         
           
           
               
               
           
         
       
       wherein
 X is —CO—(Y) k -(Z) n  or SO 2 —(Y) k -(Z) n ; 
 k is 0 or 1 
 Y is a cycloalkyl or polycyloalkyl group; 
 or Y is a cycloalkenyl or polycycloalkenyl group; 
 each Z is independently selected from hydrogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, charged alkylaminotrialkyl or charged alkylcarboxylate radical of 1 to 20 carbon atoms; 
 or each Z is independently selected from fluoro, chloro, bromo, iodo, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, charged aminotrialkyl, or carboxylate radical; and 
 n is any integer from 1 to m, where m is the maximum number of substitutions permissible on the cyclo-group Y; or 
 alternatively Z may be selected from a peptido radical; and 
 R 2  and R 3  independently represent any variable substituent. 
 
     
     
         50 . The method according to  claim 49  wherein the GPCR to be modulated is selected from the group consisting of adrenalin receptors, endothelin receptors, chemokine receptors, EDG receptors, VIP/PECAP receptors, dopamine receptors, serotonin receptors, purine receptors, metabotropic gluatmate receptors, acetyl choline receptors, C5a receptors, FMLP receptors, glucagon or GLP receptors, NPY receptors, MSH receptors, glycoprotein hormone receptors, protease activated receptors (PARs), somatostain receptors, angiotensin receptors, cholecystokinin receptors and melatonin receptors 
     
     
         51 . The method according to  claim 1 ,  2 ,  3  or  4  wherein the R 1  radical has a key carbon which is di-substituted with the same or different groups selected from: alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl and alkylamino radicals. 
     
     
         52 . The method according to  claim 51  wherein the key carbon is chiral. 
     
     
         53 . The method according to  claim 51  wherein the key carbon has sp3 hybridised bonds. 
     
     
         54 . The method according to  claim 51  wherein the key carbon has essentially tetrahedral bond angles. 
     
     
         55 . The method according to  claim 1 ,  2 ,  3  or  4  wherein the ring or rings of Y constrain the bond angles at the key carbon to be essentially tetrahedral. 
     
     
         56 . A method of treatment, amelioration or prophylaxis of the symptoms of disease or condition selected from the group consisting of hypertension, atherosclerosis, asthma, obesity, neurodegenerative disorders, autoimmune disorders or psychopathic disorders by the administration to a patient of an effective amount of pharmaceutical composition comprising, as active ingredient, a compound of general formula (I), (II), or (IV), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and/or carrier, wherein formula (I) is 
       
         
           
           
               
               
           
         
       
       wherein
 X is —CO—(Y) k -(Z) n  or SO 2 —(Y) k -(Z) n ; 
 k is 0 or 1 
 Y is a cycloalkyl or polycyloalkyl group; 
 or Y is a cycloalkenyl or polycycloalkenyl group; 
 each Z is independently selected from hydrogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, charged alkylaminotrialkyl or charged alkylcarboxylate radical of 1 to 20 carbon atoms; 
 or each Z is independently selected from fluoro, chloro, bromo, iodo, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, charged aminotrialkyl, or carboxylate radical; and 
 n is any integer from 1 to m, where m is the maximum number of substitutions permissible on the cyclo-group Y; or 
 alternatively Z may be selected from a peptido radical; and 
 R 3  and R 4  independently represent any variable substituent; 
 formula (II) is 
 
       
         
           
           
               
               
           
         
       
       wherein
 X is —CO—(Y) k -(Z) n  or SO 2 —(Y) k -(Z) n ; 
 k is 0 or 1 
 Y is a cycloalkyl or polycyloalkyl group; 
 or Y is a cycloalkenyl or polycycloalkenyl group; 
 each Z is independently selected from hydrogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, charged alkylaminotrialkyl or charged alkylcarboxylate radical of 1 to 20 carbon atoms; 
 or each Z is independently selected from fluoro, chloro, bromo, iodo, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, charged aminotrialkyl, or carboxylate radical; and 
 n is any integer from 1 to m, where m is the maximum number of substitutions permissible on the cyclo-group Y; or 
 alternatively Z may be selected from a peptido radical; and 
 R 3  and R 4  independently represent any variable substituent; 
 formula (III) is 
 
       
         
           
           
               
               
           
         
       
       wherein
 X is —CO—(Y) k -(Z) n  or SO 2 —(Y) k -(Z) n ; 
 k is 0 or 1 
 Y is a cycloalkyl or polycyloalkyl group; 
 or Y is a cycloalkenyl or polycycloalkenyl group; 
 each Z is independently selected from hydrogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, charged alkylaminotrialkyl or charged alkylcarboxylate radical of 1 to 20 carbon atoms; 
 or each Z is independently selected from fluoro, chloro, bromo, iodo, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, charged aminotrialkyl, or carboxylate radical; and 
 n is any integer from 1 to m, where m is the maximum number of substitutions permissible on the cyclo-group Y; or 
 alternatively Z may be selected from a peptido radical; and 
 R 2 , R 3  and R 4  independently represent any variable substituent, or formula (IV) is 
 
       
         
           
           
               
               
           
         
       
       wherein
 X is —CO—(Y) k -(Z) n  or SO 2 —(Y) k -(Z) n ; 
 k is 0 or 1 
 Y is a cycloalkyl or polycyloalkyl group; 
 or Y is a cycloalkenyl or polycycloalkenyl group; 
 each Z is independently selected from hydrogen or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, charged alkylaminotrialkyl or charged alkylcarboxylate radical of 1 to 20 carbon atoms; 
 or each Z is independently selected from fluoro, chloro, bromo, iodo, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, charged aminotrialkyl, or carboxylate radical; and 
 n is any integer from 1 to m, where m is the maximum number of substitutions permissible on the cyclo-group Y; or 
 alternatively Z may be selected from a peptido radical; and 
 R 2  and R 3  independently represent any variable substituent.