2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione for suppressing and treating alpha-synucleinopathies, tauopathies, and other disorders

Abstract

Disclosed herein are methods of treating or suppressing a disorder selected from the group consisting of α-synucleinopathies, tauopathies, ALS, traumatic brain injury, and ischemic-reperfusion related injuries.ury, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula: or the hydroquinone form thereof; or a solvate or hydrate thereof.

1 . A method of treating or suppressing an α-synucleinopathy wherein the α-synucleinopathy is Parkinson's Disease comprising administering to a subject in need thereof a therapeutically effective amount of 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione: 
       
         
           
           
               
               
           
         
         or the hydroquinone form thereof; or a solvate or hydrate thereof; or 
         administering a pharmaceutical composition comprising 1) a therapeutically effective amount of 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione or the hydroquinone form thereof; or a solvate or hydrate thereof; and 2) a pharmaceutically acceptable solvent, carrier, or excipient. 
       
     
     
         2 . The method of  claim 1 , wherein the 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione is not a solvate or hydrate. 
     
     
         3 . The method of  claim 1 , wherein the 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione is in the quinone form. 
     
     
         4 . The method of  claim 1 , wherein the 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione is in the hydroquinone form. 
     
     
         5 . The method of  claim 1 , wherein α-synuclein aggregation is inhibited. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the Parkinson's Disease is genetic. 
     
     
         8 . The method of  claim 1 , wherein the Parkinson's Disease is idiopathic. 
     
     
         9 - 16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein the method is for treating Parkinson's Disease. 
     
     
         18 . The method of  claim 1 , wherein the method is for suppressing Parkinson's Disease. 
     
     
         19 . The method of  claim 1 , wherein the 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione or the pharmaceutical composition comprising 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione is administered orally. 
     
     
         20 . The method of  claim 1 , wherein the compound the 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione or the pharmaceutical composition comprising 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione is administered intravenously. 
     
     
         21 . A polymorph of an anhydrate of 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione, wherein a powder X-ray diffraction pattern for the polymorph comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 4.10, 12.12, and 16.14. 
     
     
         22 - 34 . (canceled) 
     
     
         35 . The method of  claim 1 , wherein the potency of the 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione is at least about 95% wherein the potency is calculated as follows: (% area purity by HPLC/100)*(100−% wt/wt water content (KF)−% wt/wt residual solvents−% wt/wt residue on ignition (ROI)). 
     
     
         36 . The method of  claim 1 , wherein the potency of the 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione is at least about 99% wherein the potency is calculated as follows: (% area purity by HPLC/100)*(100−% wt/wt water content (KF)−% wt/wt residual solvents−% wt/wt residue on ignition (ROI)). 
     
     
         37 - 42 . (canceled) 
     
     
         53 . (canceled) 
     
     
         54 . A method of recrystallizing 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione from a composition, comprising:
 a) contacting the composition with IPA and water such that the resulting ratio of IPA to water is about 75-87% isopropanol (IPA)/25-13% water (v:v), at a temperature of about 40-45° C.;   b) cooling the mixture to about 32° C.; and   c) filtering the 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione from the mixture.   
     
     
         55 - 71 . (canceled) 
     
     
         72 . A metastable melted amorphous form of 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione, having an XRPD plot substantially as shown in  FIG.  31   . 
     
     
         73 . The method of  claim 1 , wherein the subject in need thereof has a mutation in one or more of the following genes: MAPT (Microtubule-associated protein tau), PRKN (parkin), PINK1 (PINK1), LRRK2 (leucine-rich repeat kinase 2), GBA (glucocerebrosidase), SNCA (alpha synuclein), PARK7 (DJ-1), and/or UCHL1 (ubiquitin carboxyl-terminal esterase L1). 
     
     
         74 . The method of  claim 73 , wherein the subject in need thereof has a mutation in GBA (glucocerebrosidase). 
     
     
         75 . The method of  claim 1 , wherein the 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione or the pharmaceutical composition comprising 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione is administered as the sole active pharmaceutical agent. 
     
     
         76 . The method of  claim 1 , wherein the 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione or the pharmaceutical composition comprising 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione is the sole active agent that inhibits α-synuclein aggregation. 
     
     
         77 . The method of  claim 1 , wherein the 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione or the pharmaceutical composition comprising 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione is administered in combination with an additional active agent. 
     
     
         78 . The method of  claim 19 , wherein the pharmaceutical composition is a capsule for oral administration. 
     
     
         79 . The method of  claim 19 , wherein the pharmaceutical composition is a liquid dosage form for oral administration. 
     
     
         80 . The method of  claim 79 , wherein the liquid dosage form is a solution or suspension.