Amino acid conjugates of quetiapine, process for making and using the same

Abstract

The presently described technology provides a novel class of prodrugs of quetiapine that can be synthesized by chemically conjugating amino acids, such as Lysine to quetiapine. The present technology also provides methods of treating patients, pharmaceutical compositions and methods of synthesizing conjugates of the present technology.

1 . A composition for treating a psychiatric disorder in a subject comprising 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol (quetiapine) conjugated to lysine via an ester bond, a pharmaceutically acceptable salt of the conjugate, or their combination. 
     
     
         2 . The composition of  claim 1 , wherein the composition is formulated for oral, parenteral, or suppository administration. 
     
     
         3 . The composition of  claim 2 , wherein the composition formulated for oral administration is selected from the group consisting of a tablet, capsule, caplet, pill, troche, lozenge, liquid solution, suspension, elixir, powder, syrup, dragée, gel, slurry, granule, wafer, and oral thin film. 
     
     
         4 . The composition of  claim 1 , wherein the conjugate is present in an amount of between about 1 mg and about 2000 mg per unit dose. 
     
     
         5 . The composition of  claim 3 , wherein the conjugate is present in an amount of between about 150 and about 800 mg per unit dose. 
     
     
         6 . The composition of  claim 5 , wherein the presence of quetiapine is based on molar equivalent of unconjugated quetiapine. 
     
     
         7 . The composition of  claim 1 , further comprising one or more of: lithium, divalproex, adjuvants, antiadherents, binders, coatings, disintegrants, fillers, flavors and colors, glidants, lubricants, preservatives, sorbents, sweeteners or a combination thereof. 
     
     
         8 . (canceled) 
     
     
         9 . The composition of  claim 8 , wherein the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a sulfate, a phosphate, an organic acid salt, a nitrate, a benzoate, and mixtures thereof. 
     
     
         10 . The composition of  claim 9 , wherein the organic acid salt is selected from the group consisting of a mesylate salt, a besylate salt, a tosylate salt, an oxalate salt, a fumarate salt, a triflate salt, a citrate salt, a malate salt, a tartrate salt, or mixtures thereof. 
     
     
         11 . A composition for treating schizophrenia in a subject comprising a conjugate of quetiapine, an active metabolite of quetiapine or derivatives of quetiapine conjugated to lysine wherein the conjugate is represented by any one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The composition of  claim 11 , wherein the composition comprises a pharmaceutically acceptable salt of the conjugate. 
     
     
         13 . The composition of  claim 12 , wherein the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a sulfate, a phosphate, an organic acid salt, a nitrate, a benzoate, and mixtures thereof. 
     
     
         14 . The composition of  claim 13 , wherein the organic acid salt is selected from the group consisting of a mesylate salt, a besylate salt, a tosylate salt, an oxalate salt, a fumarate salt, a triflate salt, a citrate salt, a malate salt, a tartrate salt, or mixtures thereof. 
     
     
         15 . The composition of  claim 1 , wherein the conjugate is a prodrug. 
     
     
         16 . The composition of  claim 15 , wherein the composition comprises a pharmaceutically acceptable salt of the prodrug. 
     
     
         17 . The composition of  claim 11 , wherein the conjugate is a prodrug 
     
     
         18 . The composition of  claim 17 , wherein the composition comprises a pharmaceutically acceptable salt of the prodrug. 
     
     
         19 . A method of treating schizophrenia comprising a step of administering to a subject a composition comprising a therapeutically effective amount of 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol (quetiapine) conjugated to lysine via an ester bond or a pharmaceutically acceptable salt thereof. 
     
     
         20 . A composition comprising 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol (quetiapine) conjugated to lysine via an ester bond, a salt of the conjugate, or their combination. 
     
     
         21 . The composition of  claim 20 , wherein the salt is a pharmaceutically acceptable salt. 
     
     
         22 . The composition of  claim 21 , wherein the composition has a higher relative bioavailability than non-conjugated quetiapine when administered orally. 
     
     
         23 . The composition of  claim 21 , wherein the composition is formulated for oral, suppository, or parenteral administration. 
     
     
         24 . The composition of  claim 23 , wherein the composition formulated for oral administration is selected from the group consisting of a tablet, capsule, caplet, pill, troche, lozenge, liquid solution, suspension, elixir, powder, syrup, dragée, gel, slurry, granule, wafer, and oral thin film. 
     
     
         25 . The composition of  claim 21 , wherein the conjugate is present in an amount of between about 1 mg and about 2000 mg per unit dose. 
     
     
         26 . The composition of  claim 24 , wherein the conjugate is present in an amount of between about 150 and about 800 mg per unit dose. 
     
     
         27 . The composition of  claim 25 , wherein the presence of quetiapine is based on molar equivalent of unconjugated quetiapine. 
     
     
         28 . The composition of  claim 26 , wherein the presence of quetiapine is based on molar equivalent of unconjugated quetiapine. 
     
     
         29 . The composition of  claim 21 , further comprising one or more of: lithium, divalproex, adjuvants, antiadherents, binders, coatings, disintegrants, fillers, flavors and colors, glidants, lubricants, preservatives, sorbents, sweeteners, or a combination thereof. 
     
     
         30 . The composition of  claim 21 , wherein the salt is selected from the group consisting of a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a sulfate, a phosphate, an organic acid salt, a nitrate, a benzoate, and mixtures thereof. 
     
     
         31 . The composition of  claim 30 , wherein the organic acid salt is selected from the group consisting of a mesylate salt, a besylate salt, a tosylate salt, an oxalate salt, a fumarate salt, a triflate salt, a citrate salt, a malate salt, a tartrate salt, and mixtures thereof. 
     
     
         32 . The composition of  claim 20 , wherein the conjugate is a prodrug. 
     
     
         33 . The composition of  claim 32 , wherein the composition comprises a pharmaceutically acceptable salt of the prodrug. 
     
     
         34 . A composition comprising a conjugate of quetiapine, an active metabolite of quetiapine or derivatives of quetiapine conjugated to lysine wherein the conjugate is represented by any one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The composition of  claim 34 , wherein the salt is a pharmaceutically acceptable salt. 
     
     
         36 . The composition of  claim 35 , wherein the salt is selected from the group consisting of a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a sulfate, a phosphate, an organic acid salt, a nitrate, a benzoate, and mixtures thereof. 
     
     
         37 . The composition of  claim 36 , wherein the organic acid salt is selected from the group consisting of a mesylate salt, a besylate salt, a tosylate salt, an oxalate salt, a fumarate salt, a triflate salt, a citrate salt, a malate salt, a tartrate salt, or mixtures thereof. 
     
     
         38 . The composition of  claim 34 , wherein the conjugate is a prodrug. 
     
     
         39 . The composition of  claim 38 , wherein the composition comprises a pharmaceutically acceptable salt of the prodrug. 
     
     
         40 . A compound represented by one of the following structures: