Small molecule therapeutic compounds targeting thioesterase deficiency disorders and methods of using the same

Abstract

The invention provides methods of inhibiting the development or progression of a thioesterase deficiency disorder in a mammal by the administration of a compound that functionally mimics the enzymatic activity of all thioesterases in mammals. Such thioesterase deficiency disorders include cancers and adult- or infant-neuronal ceroid lipofuscinoses (NCLs). The invention also provides small molecule mimics of thioesterases useful in the methods of the invention and pharmaceutical compositions containing the therapeutically effective compounds and methods of using the same.

1 - 12 . (canceled) 
     
     
         13 . A pharmaceutical composition comprising at least one compound selected from the group consisting of: N-t-butyl hydroxylamine (NtBUHA), N-Methylhydroxylamine, N,N-Dimethylhydroxylamine, N,N-Diethylhydroxylamine, N-Cyclohexylhydroxylamine, N,O-Bis(trimethylsilyl) hydroxylamine, N-Benzylhydroxylamine, N-Benzyloxycarbonyl), N,O-Di-Boc-hydroxylamine, N-Benzoyl-N-phenyl hydroxylamine, N,N-Dibenzylhydroxylamine, N-tert-Butyl-O-[1-[4-(chloromethyl)phenyl]ethyl]-N-(2-methyl-1-phenylpropyl) hydroxylamine and pharmaceutically-acceptable salts thereof, with at least one pharmaceutically acceptable carrier. 
     
     
         14 - 16 . (canceled) 
     
     
         17 . The pharmaceutical composition of  claim 13 , wherein the compound is N-t-butyl hydroxylamine or a pharmaceutically-acceptable salt thereof. 
     
     
         18 . The pharmaceutical composition of  claim 13 , wherein the pharmaceutical composition is a mono-phasic pharmaceutical composition suitable for parenteral or oral administration consisting essentially of a therapeutically-effective amount of the compound, and a pharmaceutically acceptable carrier. 
     
     
         19 . The pharmaceutical composition of  claim 13 , wherein the pharmaceutical composition is a liquid oral dosage form selected from an elixir, a syrup, and a suspension. 
     
     
         20 . The pharmaceutical composition of  claim 13 , wherein the pharmaceutical composition is a solid oral dosage forms selected from a capsule, a tablet, and a powder. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the pharmaceutically acceptable carrier comprises at least one ingredient selected from the group consisting of lactose, starch, magnesium stearate, stearic acid, and cellulose derivatives. 
     
     
         22 . The pharmaceutical composition of  claim 20 , wherein the pharmaceutical composition is formulated as a sustained release product. 
     
     
         23 . The pharmaceutical composition of  claim 20 , wherein the pharmaceutical composition is sugar-coated or film-coated. 
     
     
         24 . A method of preventing, treating or ameliorating a neurodegenerative disease associated with a thioesterase deficiency in humans, comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound that functionally mimics a thioesterase enzymatic activity. 
     
     
         25 . The method of  claim 24 , wherein the compound mimics palmitoyl protein thioesterase-1 enzymatic activity. 
     
     
         26 . The method of  claim 25 , wherein the compound is selected from the group consisting of N-t-butyl hydroxylamine (NtBUHA), N-Methylhydroxylamine, N,N-Dimethylhydroxylamine, N,N-Diethylhydroxylamine, N-Cyclohexylhydroxylamine, N,O-Bis(trimethylsilyl) hydroxylamine; N-Benzylhydroxylamine; N-Benzyloxycarbonyl), N,O-Di-Boc-hydroxylamine, N-Benzoyl-N-phenyl hydroxylamine, N,N-Dibenzylhydroxylamine, N-tert-Butyl-O-[1-[4-(chloromethyl) phenyl]ethyl]-N-(2-methyl-1-phenylpropyl) hydroxylamine. 
     
     
         27 . The method of  claim 26 , wherein the compound is N-t-butyl hydroxylamine or a pharmaceutically-acceptable salts thereof. 
     
     
         28 . The method of  claim 26 , wherein the compound is administered to the mammal in a pharmaceutical composition. 
     
     
         29 . The method of  claim 28 , wherein the pharmaceutical composition is a mono-phasic pharmaceutical composition suitable for parenteral or oral administration consisting essentially of a therapeutically-effective amount of the compound, and a pharmaceutically acceptable carrier.