Cytokine Modulators Using Cyclic Glycerides of Essential Polyunsaturated Fatty Acids

Abstract

A method of treating a patient in need of therapy for a cytokine dysregulation comprising administering to that patient a therapeutically effective dose of a compound of general formula: (I) wherein R 1 and R 2 together form a group —(CH 2 ) n —CR 4 R 5 —(CH 2 ) m — wherein n and m are independently selected integers 0, 1 or 2 and R 4 and R 5 are independently selected from H, C 1-18 alkyl, C 1-18 alkoxy, C 1-18 n hydroxyalkyl, C 2-18 alkenyl and C 6-18 aryl or aralyalkyl and R 3 is the fatty acyl group of an essential polyunsaturated fatty acid.

1 . A method of treating a patient in need of cytokine modulation comprising administering to that patient a therapeutically effective dose of a glyceride or compound of general formula I 
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  together form a group
   —(CH 2 ) n —CR 4 R 5 —(CH 2 ) m — 
 
       wherein n and m are independently selected integers 0, 1 or 2 
       and R 4  and R 5  are independently selected from H, C 1-18  alkyl, C 1-18  alkoxy, C 1-18  hydroxyalkyl, C 2-18  alkenyl and C 6-18  aryl or aralykyl 
       and R 3  is the a fatty acyl group of an essential polyunsaturated fatty acid. 
     
   
   
       2 . A method as claimed in  claim 1  wherein the polyunsaturated fatty acyl group is selected from those of n−3, n−6 and n−9 fatty acids, more preferably n−3 and n−6 fatty acids, still more preferably being γ-linolenoyl, γ-dihomolinolenoyl and arachidonoyl. 
   
   
       3 . A method as claimed in  claim 1  wherein R 1  and R 2  form a group —CR 4 R 5  wherein R 4  and R 5  are independently selected from H and C 1-6  alkyl. 
   
   
       4 . A method as claimed in  claim 1  wherein R 1  and R 2  form a group —CH 2 — or —CH 2 CH 2 —. 
   
   
       5 . A method as claimed in  claim 1  wherein the compound of formula is a 5-essential fatty acyloxy-1,3-dioxans. 
   
   
       6 . A method as claimed in  claim 1  wherein the compound of  claim 1  is an n3-fatty acyloxy-1,3-dioaxan or an n−6 fatty acyloxy-1,3-dioxans. 
   
   
       7 . A method as claimed in  claim 1  wherein the compound of formula I is selected from a 5-γ-linolenoyloxy-1,3-dioxans, 5-dihomo-γ-linolenoyloxy-1,3-dioxans and 5-arachidonoyl-1,3-dioxans. 
   
   
       8 . A method as claimed in  claim 1  wherein the patient is in need of therapy for cytokine dysregulation. 
   
   
       9 . A method as claimed in  claim 1  wherein the patient is in need of therapy to prevent demyelination in a neurodegenerative disease. 
   
   
       10 . A method as claimed in  claim 1  wherein the modulated cytokines are one or more of TGF-β1, TNF-α, IL-1, IL4, IL5, IL6, IL8, IL10, IL13, and γ-IFN. 
   
   
       11 . A method as claimed in  claim 1  wherein the treatment is for abnormalities of the immune system. 
   
   
       12 . A method as claimed in  claim 11  wherein the treatment is for a condition selected from the group consisting of systemic lupus erythematosus (SLE), allergy, asthma, crohn's disease and rheumatoid arthritis, multiple sclerosis, neurodegenerative diseases sequelae of stroke, head trauma, bleeds and the chronic abnormalities of Alzheimer's and Parkinson's disease, coronary heart disease (CHD) abnormalities of pre-mature infants and sepsis. 
   
   
       13 . A compound of formula I 
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  together form a group
   —(CH 2 ) n —CR 4 R 5 —(CH 2 ) m — 
 
       wherein n and m are independently selected integers 0, 1 or 2 
       and R 4  and R 5  are independently selected from H, C 1-18  alkyl, C 1-18  alkoxy, C 1-18  hydroxyalkyl, C 2-18  alkenyl and C 6-18  aralkyl 
       and R 3  is a fatty acyloxy group of an essential polyunsaturated fatty acid. 
     
   
   
       14 . A compound as claimed in  claim 13  wherein R 3  is a polyunsaturated fatty acyl groups of an n−3, n−6 and n−9 fatty acids, more preferably n−3 and n−6 fatty acids, still more preferably being γ-linolenoyl, γ-dihomolinolenoyl and arachidonoyl. 
   
   
       15 . A compound as claimed in  claim 13  wherein R 1  and R 2  form a group —CR 4 R 5  where R 4  and R 5  are independently selected from H and C 1-6  alkyl. 
   
   
       16 . A compound as claimed in  claim 13 , wherein R 1  and R 2  form a group —CH 2 — or —CH 2 CH 2 —. 
   
   
       17 . A compound as claimed in  claim 13  being a 5-acyloxy-1,3-dioxan. 
   
   
       18 . A compound as claimed in  claim 13  being an n−3-fatty acyl or n−6 fatty acyloxy-1,3-dioxans. 
   
   
       19 . A compound as claimed in  claim 13  being a 5-γ-linolenyloxy-1,3-dioxan, a 5-dihomo-γ-linolenyloxy-1,3-dioxan or a 5-arachidonyloxy-1,3-dioxan. 
   
   
       20 . A compound as claimed in  claim 13  for use in therapy. 
   
   
       21 . A method for synthesis of a compound of general formula I comprising reacting a 5-hydroxy-1,3-dioxan with an essential fatty acid or an essential fatty acid halide. 
   
   
       22 . A composition for use in the method of the present invention comprising a compound of formula I together with a pharmaceutically or nutraceutically acceptable carrier, coating, capsule, diluent and/or preservative. 
   
   
       23 . A composition as claimed in  claim 22  comprising a preservative which is an antioxidant or inhibitor of transesterification. 
   
   
       24 . A composition as claimed in  claim 23  comprising 0.05 mg/g or less of Vitamin E. 
   
   
       25 . A pharmaceutical composition for regulating the immune system comprising a compound of general formula I as defined in  claim 1 . 
   
   
       26 . Use of a compound of formula I as described in  claim 1  for the manufacture of a medicament for the treatment of dysregulation of cytokines or for the modulation of cytokine disorders. 
   
   
       27 . Use as claimed in  claim 26  wherein the use is for manufacture of a medicament for treating neurodegenerative diseases. 
   
   
       28 . Use as claimed in  claim 27  wherein the medicament is for the arresting and reversing of neurodegeneration in multiple sclerosis of all types but particularly relapsing remitting, primary progressive and chronic progressive and the restoration, in part or completely, of neuronal integrity function such as measured, eg. By MRI or CAT scan or by EDSS score. 
   
   
       29 . A method as claimed in  claim 1  wherein the neurodegenerative disease involves demyelination. 
   
   
       30 . A method as claimed in  claim 1  wherein the treatment specifically arrests underlying neurodegeneration and restores neuronal function. 
   
   
       31 . A method as claimed in  claim 1  which normalises neuronal membrane composition with respect to γ-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid lipid content. 
   
   
       32 . A method as claimed in  claim 1  which restores healthy TGF-β1/TNFα ratios as measured from spontaneous release from peripheral blood mononuclear cell release. 
   
   
       33 . A method as claimed in  claim 1  wherein the disease is relapsing remitting multiple sclerosis, primary progressive multiple sclerosis or chronic progressive multiple sclerosis. 
   
   
       34 . A method as claimed in  claim 1  wherein the treatment is of cerebral impairment after stroke, head trauma and intracranial bleeding, Alzheimer's disease or Parkinson's disease where there is demyelination or neuronal damage. 
   
   
       35 . A method as claimed in  claim 1  wherein the lipid is administered for a duration and at a dose sufficient to maintain or elevate TGF-β1 levels in the patient to therapeutic levels. 
   
   
       36 . A method as claimed in  claim 1  wherein the lipid is administered for a duration and at a dose sufficient to maintain or elevate TGF-β1 levels in the patient to a TGF-β1/TNF-α ratio released spontaneously from peripheral blood mononuclear cells isolated from the blood of a patient, after 18 months of daily dosing, of 0.4 to 3.0, at least 0.5, more preferably at least 0.75 and most preferably at least 1. 
   
   
       37 . A method as claimed in  claim 1  wherein the dose is such as to produce a TGF-β1/IL-1β ratio in PBMCs isolated from blood of a patient, after 18 months of daily dosing, of at least of at least 0.75. 
   
   
       38 . A method as claimed in  claim 1  wherein the amount of compound administered is between 0.5 and 30 grams, typically 3 to 5 grams, per day. 
   
   
       39 . A method, use or composition as claimed in  claim 1  wherein R 3  is γ-linolenyl or dihomo-γ-linolenyl and the dose is between 1 and 10 grams/day. 
   
   
       40 . A method, use or composition as claimed in  claim 39  wherein the dose is between 2 and 10 grams/day.