Nutritional supplements and therapeutic compositions comprising (r)-3- hydroxybutyrate derivatives

Abstract

Novel compounds and compositions containing (R)-3-hydroxybutyrate derivatives are disclosed. The compounds and compositions can be used as nutritional supplements to increase physical performance and as therapeutics to ameliorate symptoms of medical conditions, particularly neurological conditions, such as Alzheimer's and similar conditions. Novel methods for making R-3-hydroxybutyrate derivatives also are disclosed. Exemplary methods employ a supercritical solvent, such as supercritical carbon dioxide, and employ a lipase catlyzed esterification or transesterification reaction to produce the (R)-3-hydroxybutyrate derivatives.

1 . A compound according to the formula  
     
       
         
         
             
             
         
       
       wherein R is a polyhydric alcohol residue;  
       n, m and x represent integers; and  
       m is less than or equal to x.  
     
   
   
       2 . The compounds according to  claim 1 , wherein R comprises an altrose, arabinose, dextrose, erythrose, fructose, galactose, glucose, gulose, idose, lactose, lyxose, mannose, ribose, sucrose, talose, threose, xylose, galactosamine, glucosamine, mannosamine, N-acetylglucosamine, mannitol, sorbitol, threitol, ribitol, xylitol, (S)-1,2-propanediol or (R)-1,3-butanediol residue.  
   
   
       3 . The compound according to  claim 1 , wherein n is from 1 to about 100.  
   
   
       4 . The compound according to  claim 1 , wherein n is from 1 to about 20.  
   
   
       5 . The compound according to  claim 1 , wherein n is 3.  
   
   
       6 . The compound according to  claim 1 , wherein x is from 4 to about 20.  
   
   
       7 . The compound according to  claim 1 , wherein m is from 1 to about 20.  
   
   
       8 . The compound according to  claim 1 , wherein x is from 1 to about 8.  
   
   
       9 . The compound according to  claim 1 , wherein R is (R)-1,3-butanediol.  
     
       
         
         
             
             
         
       
     
   
   
       10 . The compound according to  claim 1  having the formula  
     
       
         
         
             
             
         
       
     
   
   
       11 . A compound having the formula  
     
       
         
         
             
             
         
       
     
     where n and m independently are integers from 1 to about 100.  
   
   
       12 . The compound according to  claim 11 , wherein n and m are the same.  
   
   
       13 . The compound according to  claim 11 , wherein n and m are different.  
   
   
       14 . The compound according to  claim 11 , wherein n and m are 3.  
   
   
       15 . An ester of R-3-hydroxybutyrate according to the formula  
     
       
         
         
             
             
         
       
       wherein n is an integer from 1 to about 100.  
     
   
   
       16 . The ester according to  claim 11 , wherein n is 3.  
   
   
       17 . A method for elevating the blood concentration of ketone bodies in a subject, comprising administering to the subject a compound of  claim 1 .  
   
   
       18 . The method according to  claim 17 , wherein R comprises an altrose, arabinose, dextrose, erythrose, fructose, galactose, glucose, gulose, idose, lactose, lyxose, mannose, ribose, sucrose, talose, threose, xylose, galactosamine, glucosamine, mannosamine, N-acetylglucosamine, mannitol, sorbitol, threitol, ribitol, xylitol, (S)-1,2-propanediol or (R)-1,3-butanediol residue.  
   
   
       19 . The method according to  claim 17 , wherein n is from 1 to about 100.  
   
   
       20 . The method according to  claim 17 , wherein n is from 1 to about 20.  
   
   
       21 . The method according to  claim 17 , wherein n is 3.  
   
   
       22 . The method according to  claim 17 , wherein x is from 4 to about 20.  
   
   
       23 . The method according to  claim 17 , wherein m is from 1 to about 20.  
   
   
       24 . The method according to  claim 17 , wherein x is from 1 to about 8.  
   
   
       25 . The method according to  claim 17 , wherein administering the compound raises the blood ketone body concentration to between 0.1 mM and 20 mM.  
   
   
       26 . The method according to  claim 17 , wherein administering the compound raises the blood ketone body concentration to between 0.2 mM and 10 mM.  
   
   
       27 . The method according to  claim 17 , wherein administering the compound raises the blood ketone body concentration to between 2 mM and 8 mM.  
   
   
       28 . The method according to  claim 17 , wherein administering comprises administering from about 5 grams to about 70 grams of the compound.  
   
   
       29 . The method according to  claim 17 , wherein administering comprises administering from about 70 milligrams to about 5 grams per kilogram of the subject's body weight.  
   
   
       30 . The method according to  claim 17 , wherein administering comprises administering from about 1 gram to about 4 grams per kilogram of the subject's body weight.  
   
   
       31 . The method according to  claim 17 , wherein administering comprises administering from about 1.5 grams to about 3 grams per kilogram of body weight.  
   
   
       32 . The method according to  claim 17 , wherein the method comprises a method of treating a neurological disorder.  
   
   
       33 . The method according to  claim 17 , wherein the neurological disorder comprises Alzheimer's disease, Parkinson's disease, Pick's disease, amyotrophic lateral sclerosis or epilepsy.  
   
   
       34 . The method according to  claim 17 , wherein the method comprises a method of treating a muscular dystrophic state.  
   
   
       35 . The method according to  claim 34 , wherein the muscular dystrophic state is comprises muscle wasting, muscular dystrophy or Friedreich's ataxia.  
   
   
       36 . The method according to  claim 17 , wherein the method comprises increasing metabolic efficiency.  
   
   
       37 . The method according to  claim 36 , wherein the method comprises treating a condition comprising a hypoxic state, angina pectoris, intermittent claudication, stroke, high altitude sickness or heart failure.  
   
   
       38 . The method according to  claim 37 , wherein the method comprises a method of improving exercise efficiency.  
   
   
       39 . The method according to  claim 17 , wherein the method comprises a method of improving cognitive performance.  
   
   
       40 . The method according to  claim 17 , wherein the method comprises treating a disorder of glucose metabolism.  
   
   
       41 . The method according to  claim 40 , wherein the disorder of glucose metabolism comprises insulin resistance.  
   
   
       42 . The method according to  claim 41 , wherein the disorder of glucose metabolism comprises Leprechaunism, Rabson-Mendenhall syndrome, type II diabetes or hypoglycemic episodes.  
   
   
       43 . A method for elevating the blood concentration of ketone bodies in a subject, comprising administering to the subject a compound of  claim 1 .  
   
   
       44 . The method according to  claim 43 , wherein the method comprises a method for treating acyl coenzyme A dehydrogenase deficiency, autoimmune disorders, inflammatory diseases, Down's syndrome, astrocytoma, Duchenne's muscular dystrophy, Becker's muscular dystrophy, glucose transporter defects, Hallervorden-Spatz disease, Huntington's chorea, coronary ischemia, Lafora body dementia, myoclonus epilepsy associated with ragged-red fibers syndrome, Kearns-Sayre syndrome, Leigh's syndrome, mitochondrial myopathy encephalopathy lactacidosis stroke syndrome, myoclonus, carnitine palmitoyl transferase deficiency types I and II, maple syrup urine disease, multi-infarct dementia, ischemia, ischemic reperfusion injury, thromboembolic stroke, hemorrhagic stroke, chronic obstructive pulmonary disease, hypoxia, anoxia, resuscitation injury, spinal cord trauma, diabetic angiopathy, emphysema, asthma, neoplasia, Crohn's disease, uveitis, cataracts, age-related macular degeneration, obesity, type I diabetes or Wilson's disease.  
   
   
       45 . A method for synthesizing a derivative of R-3-hydroxybutyrate, comprising transesterifying a compound having the formula  
     
       
         
         
             
             
         
       
     
     to produce a compound having the formula  
     
       
         
         
             
             
         
       
     
     where R is an alkoxy group.  
   
   
       46 . The method according to  claim 45  where transesterifying comprises lipase catalyzed transesterification.  
   
   
       47 . The method according to  claim 45  where transesterifying is performed in supercritical carbon dioxide.  
   
   
       48 . A composition comprising a compound of  claim 2;  and 
 a carrier.    
   
   
       49 . The composition according to  claim 48 , wherein the compound has the formula  
     
       
         
         
             
             
         
       
     
   
   
       50 . The composition according to  claim 37 , wherein n is 3.  
   
   
       51 . A method for making (R)-3-hydroxybutyrate, comprising: 
 providing poly-(R)-3-hydroxybutyric acid; and    contacting the poly-(R)-3-hydroxybutyric acid with supercritical carbon dioxide; and    depolymerizing the poly-(R)-3-hydroxybutyric acid.    
   
   
       52 . The method according to  claim 51 , further comprising contacting the poly-(R)-3-hydroxybutyric acid with an acidic catalyst in the supercritical carbon dioxide.  
   
   
       53 . The method according to  claim 51 , wherein the method produces an oligomer selected from the group consisting of dimers, trimers, tetramers, pentamers, hexamers, heptamers, octamers, and combinations thereof.  
   
   
       54 . The method according to  claim 51 , further comprising contacting the poly-(R)-3-hydroxybutyric acid with a depolymerase enzyme in the supercritical carbon dioxide.  
   
   
       57 . The method according to  claim 51 , further comprising contacting the poly-(R)-3-hydroxybutyric acid with a hydrogenation catalyst.  
   
   
       56 . The method according to  claim 53 , wherein the depolymerase enzyme is a member of the subgroup EC 3.1.1.75.  
   
   
       57 . The method according to  claim 53 , wherein the depolymerase enzyme is selected from the family PhaZ1-PhaZ7.  
   
   
       58 . The method according to  claim 53 , wherein the depolymerase favors production of pentameric poly-(R)-3-hydroxybutyric acid.  
   
   
       59 . The method according to  claim 53 , wherein the depolymerase favors production of monomeric (R)-3-hydroxybutyric acid.