Phosphocholine linked prodrug derivatives

Abstract

Disclosed are compounds of general formula (I) that function as prodrugs, thereby increasing bioavailabilities of the linked therapeutic agents, wherein the LINKER is (i) substituted or unsubstituted alkyl, (ii) substituted or unsubstituted alkenyl, (iii) substituted or unsubstituted alkanoyl, (iv) substituted or unsubstituted alkenoyl wherein the double bond is cis, and (v) (ortho or para) carbonyl-substituted aryl; and wherein the substituent is each an independent group or linked together thereby forming a ring; and wherein X is one or more substituted or unsubstituted group containing one or more O, N, or S atom and wherein the substituent is each an independent group or linked together thereby forming a ring; and wherein the therapeutic agent is an alcohol-containing water-insoluble steroids or another alcohol containing compounds and methods to prepare such compounds.

1 : A compound having the general formula I:  
     
       
         
         
             
             
         
       
       wherein the LINKER is one or more of the groups selected from the group consisting of (i) substituted alkyl, (ii) substituted alkanoyl, and (iii) substituted or unsubstituted alkenoyl wherein the double bond is cis; and  
       wherein the substituent is each an independent group or linked together thereby forming a ring; and  
       wherein X is an O or S atom; and  
       wherein the therapeutic agent is selected from the group consisting of alcohol-containing water-insoluble steroids and other alcohol-containing compounds.  
     
   
   
       2 : A compound according to  claim 1 , wherein 
 (i) said alkyl has the formula CR 1 R 2 ,    (ii) said alkenyl has the formula CR 1 ═CR 3 —CR 4 ,    (iii) said alkanoyl has the formula CR 1 R 2 —CR 3 R 4 —CR 5 R 6 —CO,    (iv) said alkenoyl has the formula CR 1 R 2 —CR 3 ═CR 4 —CO and wherein the double bond is cis, and    (v) said substituted aryl has the formula aryl-CR 1 R 2 ; and    wherein R 1  R 2 , R 3 , R 4 , R 5 , and R 6  are the same or different and are selected from the group consisting of    (i) hydrogen;    (ii) linear, branched, and unsaturated C 1-12 -alkyl;    (iii) substituted C 1-8 -alkyl, wherein the substituent is selected from the group consisting of Y1-Y24, wherein    Y1 is hydroxy,    Y2 is C 1-8 -alkoxy,    Y3 is carbo-C 1-8 -alkoxy,    Y4 is C 1-8 -alkylamino,    Y5 is di-C 1-8 -alkylamino,    Y6 is C 6-12 -arylamino,    Y7 is C 6-12 -aryloxy,    Y8 is amino,    Y9 is amino-C 2 -C 8 -alkoxy,    Y10 is C 1-8 -alkylthio,    Y11 is C 6-12 -arylthio,    Y12 is acetamido,    Y13 is mercapto,    Y14 is benzamido,    Y15 is carboxamido,    Y16 is phthalimido,    Y17 is guanidino,    Y18 is ureido,    Y19 is isothioureido,    Y20 is carboxy,    Y21 is (C 6-12 ) aryl-(C 1-8 ) alkyl,    Y22 is (C 6-12 ) aryl-(C 2-8 ) alkenyl,    Y23 is aromatic heterocyclo (C 1-8 ) alkyl,    and Y24 is aromatic heterocyclo (C 2-8 )alkenyl wherein    the heterocyclic group of Y23 and Y24 have 5-10 ring atoms and comprises up to two O, N, or S heteroatoms; and    (iv) substituted Y21 or substituted Y23 wherein the substituent is selected from the group consisting of Y1, Y2, Y4, Y5, Y7, Y8, Y12, Y14, Y17-Y20, and Y25-Y29 wherein    Y25 is halogen,    Y26 is C 1-8 -alkyl,    Y27 is amino-C 1-8 -alkyl,    Y28 is C 6-12 -aroyl, and    Y29 is C 1-8 -alkanoyl.    
   
   
       3 : A compound according to  claim 2 , wherein said R 1  and R 2 ; R 1  and R 3 ; R 2  and R 3 ; R 3  and R 4 ; R 3  and R 5 ; and R 5  and R 6  are linked together thereby forming: 
 (i) a ring of three to six carbon atoms, or    (ii) a ring of two to five carbon atoms and one O, or S heteroatom, or substituted heteroatom NR 7 ; wherein R 7 , is selected from the group consisting of Y21, Y26, Y28, Y29, and Y30-Y31, wherein Y30 is C 3-8 -alkenyl, and Y31 is C 6-12 -aryl.    
   
   
       4 : A compound according to  claim 2 , wherein the group comprising up to two or more O, N, or S heteroatoms is selected from the group consisting of O, (O) CO, NR 8 , NR 8  CO, NR 8  CO NR 9 , NR 8  (SO 2 ), NR 8  CS, NR 8  CS NR 9 , ONR 8 , ONR 8 CO, NR 8 (O), NR 8 (O)CO, nitrogen heterocycles, amide and urea internal in therapeutic agent; and 
 wherein R 8  and R 9  are the same or different and are selected from the group consisting of    (i) hydrogen;    (ii) linear, branched, and unsaturated C 1-12 -alkyl;    (iii) substituted C 1-8 -alkyl, wherein the substituent is selected from the group consisting of Y1-Y13 and Y15-Y25;    (iv) substituted Y21 or substituted Y23 wherein the substituent is selected from the group consisting of Y1, Y2, Y4, Y5, Y7, Y8; Y12, Y14, Y17-Y20, and Y25-Y29.    
   
   
       5 : A compound according to  claim 4  wherein R 8  and R 9  are linked together thereby forming 
 (i) a ring of three to six carbon atoms, or    (ii) a ring of two to five carbon atoms and one O, or S heteroatom, or substituted heteroatom NR 7 ; wherein R 7  is selected from the group consisting of Y21, Y26, and Y28-Y31.    
   
   
       6 : A compound according to  claim 4  wherein R 8 , R 9 , or both are connected to the therapeutic agent molecule thereby forming an alkylene bridge comprising from one to five carbon atoms and one or two O, S or NR 7  heteroatoms; wherein R 7  is selected from the group consisting of Y21, Y26, and Y28-Y31; and the pharmaceutically acceptable salts thereof.  
   
   
       7 : A compound according to  claim 5 , wherein R 8 , R 9 , or both are connected to the therapeutic agent molecule thereby forming an alkylene bridge comprising from one to five carbon atoms and one or two O, S or NR 7 , heteroatoms; wherein R 7  is selected from the group consisting of Y21, Y26, and Y28-Y31; and the pharmaceutically acceptable salts thereof.  
   
   
       8 : A compound according to  claim 2 , wherein said (ortho or para) carbonyl-substituted aryl is selected from the group consisting of ortho-CR 1 R 2 -substituted aryl-CO, substituted aryl-ortho-CR 3 R 4 —CO, substituted aryl-ortho-CR 3 R 4 —CR 5 R 6 —CO, substituted aryl-ortho-CR 3 ═R 4 —CO wherein the double bond is cis, ortho-CR 1 R 2 -substituted aryl-CR 5 R 6 —CO, and substituted aryl-(ortho or para)-CO.  
   
   
       9 : A compound according to  claim 2 , wherein said aryl is selected from the group consisting of benzene, naphthalene, pyridine, pyrrole, thiophene, furan, imidazole, thiazole, oxazole, pyrimidine, indole, benzimidazole, benzthiazole, benzofuran, benzothiophene and quinoline, each bearing one or more of the group consisting of hydrogen, C 1-8 alkyl, C 1-8 -alkoxy, F, Cl, Br, C 1-8 -alkoxycarbonyl, amino, substituted amino, nitro, C 1-8 -alkylthio, C 1-8, -alkylsulfoxido, and C 1-8 -alkylsulfono.  
   
   
       10 : A compound according to  claim 2 , wherein R 1  is hydrogen.  
   
   
       11 : A compound according to  claim 2 , wherein R 1  and R 2  are hydrogen.  
   
   
       12 : A compound according to  claim 1 , wherein the therapeutic agent is selected from the group consisting anesthetic and sedative compounds, provided that the therapeutic agent is not propofol.  
   
   
       13 - 17 . (canceled)  
   
   
       18 : A method for enabling potential therapeutic agents to be rendered soluble comprising the steps of inserting one or more linker moieties having one or more primary alcohol group between a phosphocholine or a phosphocholine congener to the therapeutic agents having one or more alcohol group; wherein said one or more linker moieties is bonded to said therapeutic agent via an oxygen or sulfur atom of the linker.  
   
   
       19 : A method for increasing the bioavailability of a pharmaceutical agent comprising the steps of derivatizing the agent with one or more linker moieties, producing an intermediate, recovering and coupling the intermediate with phosphocholine or a phosphocholine-congener to the linkers, producing a final derivative and administering the final derivative to a mammal, wherein the agent in derivative form is significantly more soluble in aqueous media than the agent in non-derivatized form; wherein said one or more linker moieties is bonded to said agent via an oxygen or sulfur atom of the linker.  
   
   
       20 : The method of  claim 19  wherein the pharmaceutical agent is propofol.  
   
   
       21 : A pharmaceutical formulation for treating a mammal suffering from cancer comprising an isolated phosphocholine linked via a linker to paclitaxel and a physiologically acceptable vehicle, carrier, binder, preservative, stabilizer, or flavor as called for by accepted pharmaceutical practice.