Methylphenidate-Prodrugs, Processes of Making and Using the Same

Abstract

The present technology is directed to prodrugs and compositions for the treatment of various diseases and/or disorders comprising methylphenidate, or methylphenidate derivatives, conjugated to at least one alcohol, amine, oxoacid, thiol, or derivatives thereof. In some embodiments, the conjugates further include at least one linker. The present technology also relates to the synthesis of methylphenidate, or methylphenidate derivatives, conjugated to at least one alcohol, amine, oxoacid, thiol, or derivatives thereof or combinations thereof.

1 . A compound of the following structure 
       
         
           
           
               
               
           
         
         or salt thereof wherein G 2  is selected from the group consisting of standard amino acids, nonstandard amino acids and synthetic amino acids; and 
         wherein the amino acid is attached to the rest of the molecule by an amide linkage. 
       
     
     
         2 . The compound of  claim 1 , wherein the amino acid is threonine or serine. 
     
     
         3 . The compound of  claim 2 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein the salt of the compound is a pharmaceutically acceptable anionic salt form, amphoteric salt form, zwitterionic salt form, cationic salt form, or salt mixtures thereof. 
     
     
         5 . The compound of  claim 4 , wherein the anionic salt form is selected from the group consisting of acetate, l-aspartate, besylate, bicarbonate, carbonate, d-camsylate, l-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate, l-lactate, d,l-lactate, d,l-malate, l-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, d-tartrate, l-tartrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsufate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesufonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, and undecylenate. 
     
     
         6 . The compound of  claim 4 , wherein the anionic salt form is selected from the group consisting of sodium, potassium, calcium, magnesium, zinc, aluminium, lithium, cholinate, lysinium, ammonium and tromethamine. 
     
     
         7 . A method for treating a patient having a disease, disorder or condition mediated by controlling, preventing, limiting, or inhibiting neurotransmitter uptake or hormone uptake comprising orally administering to a patient a pharmaceutically effective amount of a composition comprising at least one compound of  claim 1 , a salt thereof, or a combination thereof. 
     
     
         8 . The method of  claim 7  wherein the disease or condition is attention-deficit hyperactivity disorder, attention deficit disorder, autistic spectrum disorder, autism, Asperger's disorder, pervasive developmental disorder, sleep disorder, obesity, depression, bipolar disorder, eating disorder, chronic fatigue syndrome, schizophrenia, major depressive disorder, narcolepsy, postural orthostatic tachycardia syndrome, lethargy, depression, neural insult or obesity. 
     
     
         9 . The method of  claim 7 , wherein the hormone is a catecholamine. 
     
     
         10 . The method of  claim 7 , wherein the neurotransmitter is serotonin, dopamine or norepinephrine. 
     
     
         11 . A method for treating a patient having a disorder or condition requiring stimulation of the central nervous system of the patient, comprising orally administering to a patient a pharmaceutically effective amount of a composition comprising at least one compound of  claim 1 , a salt thereof, or a combination thereof. 
     
     
         12 . A method for treating a patient having stimulant abuse and addiction, for improving battle field alertness, and/or for combating fatigue comprising orally administering to a patient a pharmaceutically effective amount of a composition comprising at least one compound of  claim 1 , a salt thereof, or a combination thereof. 
     
     
         13 . The method of  claim 12  wherein the stimulant is cocaine or methamphetamine. 
     
     
         14 . A pharmaceutical kit comprising a specified amount of individual doses in a package containing a pharmaceutically effective amount of at least one compound of  claim 1  and at least one inorganic or organic oxoacid, a salt thereof, or a combination thereof. 
     
     
         15 . The pharmaceutical kid of  claim 14 , wherein the kit further comprises instructions for use of the kit in a method of treating or preventing attention deficit hyperactivity disorder symptoms in a human or animal patient. 
     
     
         16 . The pharmaceutical kit of  claim 14 , wherein the kit further comprises instructions for use of the kit in a method of treating or preventing attention deficit disorder symptoms in a human or animal patient. 
     
     
         17 . The pharmaceutical kit of  claim 14 , wherein the kit further comprises instructions for use of the kit in a method for treating or preventing drug withdrawal symptoms in a human or animal patient. 
     
     
         18 . The pharmaceutical kit of kit of  claim 14 , wherein the patient is a pediatric, normative, or elderly patient. 
     
     
         19 . The pharmaceutical kit of  claim 14 , wherein the individual dosages comprise at least about 0.5 mg or higher of at least one compound of  claim 1 . 
     
     
         20 . The pharmaceutical kit of  claim 14 , wherein the kit comprises from about 1 to about 60 individual doses. 
     
     
         21 . The pharmaceutical kit of  claim 14 , wherein the compound further comprises at least one linker.