Novel pharmaceutical agents containing carbohydrate moieties and methods of their preparation and use

Abstract

Hydrophilic N-linked pharmaceutical compositions, methods of their preparation and use in neuraxial drug delivery comprising a glycosyl CNS acting prodrug compound covalently N-linked with a saccharide through an amide or an amine bond and a formulary consisting of an additive, a stabilizer, a carrier, a binder, a buffer, an excipient, an emollient, a disintegrant, a lubricating agent, an antimicrobial agent or a preservative, with the proviso that the saccharide moiety is not a cyclodextrin or a glucuronide.

1 . A pharmaceutical composition for neuraxial delivery comprising both a hydrophilic N-linked glycosyl prodrug compound and a formulary, wherein said hydrophilic N-linked glycosyl prodrug compound comprises a CNS acting prodrug compound covalently linked with a saccharide through an amide or an amine bond and said formulary comprises an agent selected from the group consisting of an additive, a stabilizer, a carrier, a binder, a buffer, an excipient, an emollient, a disintegrant, a lubricating agent, an antimicrobial agent and a preservative, 
 with the proviso that said saccharide moiety is not a cyclodextrin or a glucuronide.    
   
   
       2 . The pharmaceutical composition of  claim 1 , further comprising a dosage form selected from the group consisting of a powder, a granule, an emollient cream, a tablet, a capsule, a lozenge, a trouch, a suppository, a perenteral solution, an injection solution, a syrup, an elixir, a nasal solution, a intrabronchial solution, an ophthalmic solution, a dermal patch and a bandage.  
   
   
       3 . The pharmaceutical composition of  claim 1 , wherein said hydrophilic N-linked glycosyl prodrug compound further comprises a compound according to FORMULA I:  
       A-B-D-E  Formula I  wherein, each of “-” comprises a single bond; A, comprises a CNS-acting prodrug compound; B, comprises a lower alkyl; D, comprises a nitrogen linker amine or amide; and, E comprises a saccharide, with the proviso that E is not a cyclodextrin or a glucuronide.    
   
   
       4 . The pharmaceutical composition of  claim 3  wherein said A-moiety comprises a CNS acting prodrug compound selected from the group consisting of a stimulants, an anti-depressant, a neurotransmitter, a dopaminergic agent, a metabolic precursor compound, a muscle relaxant, a tranquilizer, an analgesic, a narcotic, a sedative, a hypnotic, a narcotic antagonist, a narcotic analgesic, an anti-hypotensive agent, a β-blocker, an anti-hypertensive agent, a vasodilator, an anesthetic, an anti-epileptic compound, an anti-convulsant drug, a hormone, a sympatholytic agent, a centrally acting anti-cholinergic compound, a sympathetic stimulants, an adrenergic agent, a barbiturate antagonist, an anti-infective agent, an anticholinergic agent, an anticonvulsant, an sympatholytics, an ACE inhibitor, an anti-epilepsy agent, an antiviral agent, a gonadotropin synthesis stimulant, a diuretic and an emetic agent.  
   
   
       5 . The pharmaceutical composition of  claim 4 , wherein said CNS acting prodrug further comprises a dopaminergic agonist or antagonist.  
   
   
       6 . A process for preparing a hydrophilic N-linked glycosyl prodrug compound for neuraxial delivery, comprising the step of N-linking a CNS acting prodrug compound with a saccharide moiety under conditions suitable for formation of an amide or amine bond between said CNS acting prodrug compound and said saccharide moiety.  
   
   
       7 . The process of  claim 6 , wherein said hydrophilic N-linked glycosyl prodrug compound comprises a compound according to FORMULA I:  
       A-B-D-E  Formula I  wherein, each of “-” comprises a single bond; A, comprises said CNS-acting prodrug; B, comprises an optional lower alkyl; D, comprises said N-linker amine or amide; and, E comprises said saccharide, with the proviso that E is not a cyclodextrin or a glucuronide.    
   
   
       8 . A process for preparing a pharmaceutical composition comprising hydrophilic N-linked glycosyl prodrug compound for neuraxial delivery, comprising the steps of N-linking a CNS acting prodrug compound with a saccharide moiety under conditions suitable for formation of an amide or amine bond between said CNS acting prodrug compound and said saccharide moiety; and formulating said N-linked glycosyl prodrug compound into said pharmaceutical composition by addition of an agent selected from the group consisting of an additive, a stabilizer, a carrier, a binder, a buffer, an excipient, an emollient, a disintegrant, a lubricating agent, an antimicrobial agent and a preservative.  
   
   
       9 . A method for treating a neurological dysfunction in a subject in need thereof comprising the step of administering to the subject a pharmaceutical composition comprising a compound according to FORMULA I:  
       A-B-D-E  Formula I  wherein, each of “-” comprises a single bond; A, comprises a CNS-acting prodrug; B, comprises a lower alkyl; D, comprises a nitrogen linker amine or amide; and, E comprises a saccharide, with the proviso that E is not a cyclodextrin.    
   
   
       10 . The method of  claim 9 , wherein said compound further comprises a compound according to FORMULA IV,  
     
       
         
         
             
             
         
       
       wherein,  
       Ring 1 comprises a cyclic or heterocyclic ring, or aryl or heteroaryl ring, all of said rings comprising 4 to 8 carbon atoms, among which atoms are counted “X” and “Y”;  
       R 0 , R 1 , R 2 , R 3  and R 4  comprise substituents of Ring 1;  
       either of X or Y is optional; each of X and Y, when present comprise a carbon atom, a halogen atom or a lower alkyl;  
       Z, R 5  and R 5′  are optional; when Z is present it comprises a lower alkyl having substituents R 5 , R 5′ ;  
       R 6  and R 6′  comprise substituents on a carbon atom linking Z with N through a single bond, or when Z is absent, linking N with Ring 1;  
       N comprises a nitrogen atom of an amine or an amide linked with E through a single bond and having R 7  as a substituent; and  
       E comprises a saccharide;  
       with the proviso that when E is a monosaccharide it is not a C 6  glucuronic acid and when E is an oligosaccharide it is not a cyclodextrin.  
     
   
   
       11 . The method of  claim 10 , wherein said Ring 1 comprises an optionally substituted aryl or heteroaryl ring wherein either one of X or Y comprises a halogen or oxygen and the remaining of X or Y comprises a carbon atom.  
   
   
       12 . The method of  claim 11 , wherein said R 2  and R 3  are hydroxyl.  
   
   
       13 . The method of  claim 12 , wherein said R 1  and R 4  are selected from the group consisting of hydrogen, hydroxyl, halogen, halo-lower alkyl, alkoxy, alkoxy-lower alkyl, halo-alkoxy, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl and alkylamine-carbonyl.  
   
   
       14 . The method of  claim 10 , wherein each of X and Y comprise a lower alkyl chain having 2 carbon atoms.  
   
   
       15 . The method of  claim 10 , wherein each of X and Y comprise a lower alkyl chain having 1 carbon atom.  
   
   
       16 . The method of  claim 10 , wherein Z comprises a lower alkyl having 1 or 2 carbon atoms.  
   
   
       17 . The method of  claim 16 , wherein said R 5  and R 5  are selected from the group consisting of hydrogen, hydroxyl, alkoxyl, carboxyl, alkoxylcarbonyl, aminocarbonyl, alkylamino-carbonyl and dialkylamino-carbonyl.  
   
   
       18 . The method of  claim 17 , wherein said R 6  and R 6 , are selected from the group consisting of hydrogen, hydroxyl, alkoxyl, carboxyl, alkoxylcarbonyl, aminocarbonyl, alkylamino-carbonyl and dialkylamino-carbonyl.  
   
   
       19 . The method of  claim 10 , wherein Z and R 6  comprise a carbonyl group, N comprises an amide and R 7  is hydrogen.  
   
   
       20 . The method of  claim 10 , wherein R 7  comprises a hydrogen and N comprises an amine.  
   
   
       21 . The method of  claim 10 , wherein said E substituent is selected from the group consisting of a radical of a monosaccharide, a disaccharide, a trisaccharide and an oligosaccharide  
   
   
       22 . The method of  claim 10 , wherein said E monosaccharide comprises a radical of a sugar selected from the group consisting of aldose, ketoaldose, alditols, ketoses, aldonic acids, ketoaldonic acids, aldaric acids, ketoaldaric acids, amino sugars, keto-amino sugars, uronic acids, ketouronic acids, lactones and keto-lactones.  
   
   
       23 . The method of  claim 22 , wherein said radical of a sugar is further selected from the group consisting of triosyl, tetraosyl, pentosyl, hexosyl, heptosyl, octosyl and nonosyl radicals and derivatives thereof.  
   
   
       24 . The method of  claim 23 , wherein said pentosyl sugar radical comprises a straight carbon chain, a furanosyl ring or a derivative thereof.  
   
   
       25 . The method of  claim 23 , wherein said hexosyl sugar radical comprises a straight carbon chain, a furanosyl ring, a pyranosyl ring or a derivative thereof.  
   
   
       26 . The method of  claim 23 , wherein said hexosyl radical is further selected from the group consisting of allose, altrose, glucose, mannose, gulose, idose, galactose, talose, fructose, ribo-hexulose, arabino-hexulose, lyxo-hexulose and derivatives thereof.  
   
   
       27 . The method of  claim 23 , wherein said pentosyl radical is further selected from the group consisting of ribose, arabinose, xylose, lyxose, ribulose, xylulose and derivatives thereof.  
   
   
       28 . The method of  claim 23 , wherein said heptosyl residue comprises sedoheptulose and derivatives thereof.  
   
   
       29 . The method of  claim 23 , wherein said nonosyl residue comprises N-acetylneuraminic acid, N-glycolylneuraminic acid, diacetylneuranminic acid, and derivatives thereof.  
   
   
       30 . The method of  claim 26 , wherein said compound further comprises glucose, galactose, fructose or derivatives thereof.  
   
   
       31 . The method of  claim 21 , wherein said disaccharide, trisaccharide and oligosaccharide comprise a sugar homopolymer or a sugar heteropolymer.  
   
   
       32 . The method of  claim 31 , wherein said sugar homopolymer comprises a glycoside selected from the group consisting of erythran, threan, riban, arabinan, xylan, lyxan, allan, altran, glucan, mannan, gulan, idan, galactan, talan, fructan and derivatives thereof.  
   
   
       33 . The method of  claim 31 , wherein said sugar heteropolymer further comprises a glycoside selected from the group consisting of erythroside, threoside, riboside, arabinoside, xyloside, lyxoside, alloside, altroside, glucoside, mannoside, guloside, idoside, galactoside, taloside, fructoside and derivatives thereof.  
   
   
       34 . The method of  claim 33 , wherein said sugar heteropolymer further comprises a glycoside metabolized in a mammal to a glucosyl or a galactosyl monosaccharide.  
   
   
       35 . The method of  claim 32 , wherein said glycoside further comprises a riban, an arabinan, a glucan, a galactan, a mannan and derivatives thereof.  
   
   
       36 . The method of  claim 33 , wherein said glycoside further comprises a riboside, an arabinoside, a glucoside, a galactoside, a mannoside, a fructoside and derivatives thereof.  
   
   
       37 . The method of  claim 34 , wherein said glucan comprises maltose, amylose, glycogen, cellobiose, amylopectin, heparin and derivatives thereof.  
   
   
       38 . The method of  claim 35 , wherein said glucoside comprises sucrose and derivatives thereof.  
   
   
       39 . The method of  claim 35 , wherein said fructoside comprises fucosidolactose and derivatives thereof.  
   
   
       40 . The method of  claim 35 , wherein said galactoside comprises lactose, hyaluronic acid, pectin and derivatives thereof.  
   
   
       41 . A method for improving the aqueous solubility and blood brain barrier penetrability of a drug, comprising the step of forming a covalent chemical bond between the drug and a sugar or oligosaccharide, wherein said drug comprises an amide or amine group and said drug bonded to said sugar or oligosaccharide comprises a compound according to FORMULA I:  
       A-B-D-E  Formula I  wherein, each of “-” comprises a single bond; A, comprises a CNS-acting prodrug; B, comprises a lower alkyl; D, comprises a nitrogen linker amine or amide; and, E comprises a saccharide, with the proviso that E is not a cyclodextrin.    
   
   
       42 . A method of treating a subject in need thereof to effect a metabolic replacement therapy, comprising the step of administering to said subject a therapeutic compound, wherein said therapeutic compound comprises a hydrophilic compound transportable intact by an intestinal glucose transporter, transportable intact in blood, transportable intact by endothelial cells at a blood brain barrier and metabolizable by a neuronal cell, wherein said therapeutic compound further comprises a compound binding to a dopamine receptor and metabolizable in said neuronal cell to effect said metabolic replacement therapy and said subject comprises a patient with a neurological dysfunction, a Parkinson's disease or a Parkinson's related disease.