Treatment of neuropsychiatric disorders with neurosteriods and analogues thereof

Abstract

Described herein are neurosteroids and analogues thereof and derivatives thereof, including, but not limited to, allopregnanolone, allopregnanolone analogues, and derivatives thereof that can be used for treatment of a neuropsychiatric disorder and/or symptom thereof. Also described herein are pharmaceutical formulations containing an effective amount of a neurosteroids and analogues thereof and derivatives thereof, where the effective amount can be effective for treating a neuropsychiatric disorder and/or symptom thereof. Also described herein are methods of treating a neuropsychiatric disorder and/or a symptom thereof in a subject in need thereof.

We claim: 
     
         1 . A method of treating a neuropsychiatric disorder or a symptom thereof in a subject in need thereof, the method comprising:
 administering an effective amount of a neurosteroid or an analogue thereof or a derivative of a neruosteroid or a derivative of a neurosteroid analogue to the subject in need thereof.   
     
     
         2 . The method of  claim 1 , wherein the neurosteroid or analogue thereof or a derivative of a neruosteroid or an analogue thereof is allopregnanolone or an analogue thereof or a derivative of allopregnanolone or a derivative of an allopregnanolone analogue. 
     
     
         3 . The method of any one of  claim 1 , wherein the neurosteroid or the analogue thereof or the derivative of the neruosteroid or the derivative of a neurosteroid analogue has a formula according to Formula (I) 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of: 3-alpha or 3-beta hydroxy groups, 3-alpha or 3-beta O-allyl groups, 3-alpha or 3-beta O-propargyl groups, 3-alpha or 3-beta O-glycol groups, 3-alpha or 3-beta O-PEG groups, 3-alpha or 3-beta O-glycol-allyl groups and 3-alpha or 3-beta O-PEG-allyl groups, 
         wherein A is a carbon atom substituted by an atom selected from the group consisting of: 5-H alpha and 5-H beta, and wherein B is a methylene group; or wherein A and B are carbon atoms forming a 5,6-double bond; 
         wherein C is a carbon atom substituted by an atom selected from the group consisting of: 14-H alpha, 14-H beta, 14-alpha OH group and 14-beta OH, and wherein D is a methylene group; or wherein C and D are carbon atoms forming a 14,15-double bond; 
         wherein F is a carbon atom substituted by an atom selected from the group consisting of: 17-H alpha and 17-H beta; and wherein E is a methylene group or a carbon atom substituted by a group selected from the group consisting of: 16-alkyl-alpha, 16-alkyl-beta, 16-OR 2 -alpha and 16-OR 2 -beta, wherein R 2  is selected from the group consisting of: an allyl, a propargyl, a glycol, a PEG, glycol-allyl, a PEG-allyl; or wherein F is a carbon atom substituted by a group selected from the group consisting of: 17-alkyl-alpha, 17-alkyl-beta, 17-OR 2 -alpha and 17-OR 2 -beta, wherein R 2  is selected from the group consisting of: an allyl, an O-propargyl, a glycol, a PEG, a glycol-allyl, a PEG-allyl; and wherein E is a methylene group or a carbon atom substituted by group selected from the group consisting of: 16-alkyl-alpha, 16-alkyl-beta, 16-OR 2 -alpha and 16-OR 2 -beta, where R 2  can be an allyl, propargyl, a glycol, a PEG, a glycol-allyl, a PEG-allyl; or wherein E and F together form an epoxy cycle or a cyclopropyl and are selected from the group consisting of: 16,17-epoxy-alpha, 16,17-epoxy-beta, 16,17-methylene-alpha and 16,17-methylene-beta; or E and F are carbon atoms forming a 16,17-double bond; 
         and wherein G is a carbonyl, a methylene or a carbon atom substituted by a 12-OR 3 -alpha or 12-OR 3 -beta group, wherein R 3  is an H atom or a group selected from the group consisting of: acetyl, alkyl and aryl groups. 
       
     
     
         4 . The method of  claim 3 , wherein the neurosteroid or the analogue thereof or the derivative of the neruosteroid or the derivative of a neurosteroid analogue is selected from the group consisting of: compound (1), compound (2), compound (3), compound (4), compound (5), compound (6), compound (7), compound (8), compound (9), BR053, BR338, BR297, BR351, ganaxolone, and any combination thereof. 
     
     
         5 . The method of  claim 3 , wherein the effective amount ranges from about 0.325 mg/kg to about 15 mg/mg. 
     
     
         6 . The method of  claim 1 , wherein the neuropsychiatric disorder is an anxiety disorder. 
     
     
         7 . The method of  claim 6 , wherein the neuropsychiatric disorder is post-traumatic stress disorder. 
     
     
         8 . The method of  claim 1 , wherein the neuropsychiatric disorder is a depression disorder. 
     
     
         9 . The method of  claim 8 , wherein the depression disorder is major depressive disorder. 
     
     
         10 . The method of  claim 1 , wherein the subject in need there of has not responded to treatment with one or more selective-serotonin reuptake inhibitors. 
     
     
         11 . The method of  claim 1 , further comprising the step of detecting a biomarker for post-traumatic stress disorder (PTSD) in a sample from the subject in need thereof. 
     
     
         12 . The method of  claim 11 , wherein the biomarker for PTSD is the amount of allopregnanolone in a bodily fluid sample of the subject in need thereof. 
     
     
         13 . The method of  claim 1 , further comprising the step of detecting a biomarker for major depressive disorder in a bodily fluid sample of the subject in need thereof. 
     
     
         14 . The method of  claim 13 , wherein the biomarker for major depressive disorder is the amount of allopregnanolone in a bodily fluid sample of the subject in need thereof. 
     
     
         15 . A pharmaceutical formulation comprising:
 a therapeutically effective amount of a neurosteroid or an analogue thereof or a derivative of a neruosteroid or a derivative of a neurosteroid analogue effective to treat a neuropsychiatric disorder in a subject in need thereof; and   a pharmaceutically acceptable carrier.   
     
     
         16 . The pharmaceutical formulation of  claim 15 , wherein the neurosteroid or the analogue thereof or the derivative of the neruosteroid or the derivative of a neurosteroid analogue has a formula according to Formula (I) 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of: 3-alpha or 3-beta hydroxy groups, 3-alpha or 3-beta O-allyl groups, 3-alpha or 3-beta O-propargyl groups, 3-alpha or 3-beta O-glycol groups, 3-alpha or 3-beta O-PEG groups, 3-alpha or 3-beta O-glycol-allyl groups and 3-alpha or 3-beta O-PEG-allyl groups, 
         wherein A is a carbon atom substituted by an atom selected from the group consisting of: 5-H alpha and 5-H beta, and wherein B is a methylene group; or wherein A and B are carbon atoms forming a 5,6-double bond; 
         wherein C is a carbon atom substituted by an atom selected from the group consisting of: 14-H alpha, 14-H beta, 14-alpha OH group and 14-beta OH, and wherein D is a methylene group; or wherein C and D are carbon atoms forming a 14,15-double bond; 
         wherein F is a carbon atom substituted by an atom selected from the group consisting of: 17-H alpha and 17-H beta; and wherein E is a methylene group or a carbon atom substituted by a group selected from the group consisting of: 16-alkyl-alpha, 16-alkyl-beta, 16-OR 2 -alpha and 16-OR 2 -beta, wherein R 2  is selected from the group consisting of: an allyl, a propargyl, a glycol, a PEG, glycol-allyl, a PEG-allyl; or wherein F is a carbon atom substituted by a group selected from the group consisting of: 17-alkyl-alpha, 17-alkyl-beta, 17-OR 2 -alpha and 17-OR 2 -beta, wherein R 2  is selected from the group consisting of: an allyl, an O-propargyl, a glycol, a PEG, a glycol-allyl, a PEG-allyl; and wherein E is a methylene group or a carbon atom substituted by group selected from the group consisting of: 16-alkyl-alpha, 16-alkyl-beta, 16-OR 2 -alpha and 16-OR 2 -beta, where R 2  can be an allyl, propargyl, a glycol, a PEG, a glycol-allyl, a PEG-allyl; or wherein E and F together form an epoxy cycle or a cyclopropyl and are selected from the group consisting of: 16,17-epoxy-alpha, 16,17-epoxy-beta, 16,17-methylene-alpha and 16,17-methylene-beta; or E and F are carbon atoms forming a 16,17-double bond; 
         and wherein G is a carbonyl, a methylene or a carbon atom substituted by a 12-OR 3 -alpha or 12-OR 3 -beta group, wherein R 3  is an H atom or a group selected from the group consisting of: acetyl, alkyl and aryl groups. 
       
     
     
         17 . The pharmaceutical formulation of  claim 16 , wherein the neurosteroid or the analogue thereof or the derivative of the neruosteroid or the derivative of a neurosteroid analogue is selected from the group consisting of: compound (1), compound (2), compound (3), compound (4), compound (5), compound (6), compound (7), compound (8), compound (9), BR053, BR338, BR297, BR351, ganaxolone, and any combination thereof. 
     
     
         18 . The pharmaceutical formulation of  claim 16 , wherein the effective amount ranges from about 0.325 mg/kg to about 15 mg/mg. 
     
     
         19 . A kit for treating a neuropsychiatric disorder in a subject in need thereof, the kit comprising:
 a pharmaceutical formulation comprising an effective amount of a compound according to Formula (I)   
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of: 3-alpha or 3-beta hydroxy groups, 3-alpha or 3-beta O-allyl groups, 3-alpha or 3-beta O-propargyl groups, 3-alpha or 3-beta O-glycol groups, 3-alpha or 3-beta O-PEG groups, 3-alpha or 3-beta O-glycol-allyl groups and 3-alpha or 3-beta O-PEG-allyl groups, 
         wherein A is a carbon atom substituted by an atom selected from the group consisting of: 5-H alpha and 5-H beta, and wherein B is a methylene group; or 
         wherein A and B are carbon atoms forming a 5,6-double bond; 
         wherein C is a carbon atom substituted by an atom selected from the group consisting of: 14-H alpha, 14-H beta, 14-alpha OH group and 14-beta OH, and wherein D is a methylene group; or wherein C and D are carbon atoms forming a 14,15-double bond; 
         wherein F is a carbon atom substituted by an atom selected from the group consisting of: 17-H alpha and 17-H beta; and wherein E is a methylene group or a carbon atom substituted by a group selected from the group consisting of: 16-alkyl-alpha, 16-alkyl-beta, 16-OR 2 -alpha and 16-OR 2 -beta, wherein R 2  is selected from the group consisting of: an allyl, a propargyl, a glycol, a PEG, glycol-allyl, a PEG-allyl; or wherein F is a carbon atom substituted by a group selected from the group consisting of: 17-alkyl-alpha, 17-alkyl-beta, 17-OR 2 -alpha and 17-OR 2 -beta, wherein R 2  is selected from the group consisting of: an allyl, an O-propargyl, a glycol, a PEG, a glycol-allyl, a PEG-allyl; and wherein E is a methylene group or a carbon atom substituted by group selected from the group consisting of: 16-alkyl-alpha, 16-alkyl-beta, 16-OR 2 -alpha and 16-OR 2 -beta, where R 2  can be an allyl, propargyl, a glycol, a PEG, a glycol-allyl, a PEG-allyl; or wherein E and F together form an epoxy cycle or a cyclopropyl and are selected from the group consisting of: 16,17-epoxy-alpha, 16,17-epoxy-beta, 16,17-methylene-alpha and 16,17-methylene-beta; or E and F are carbon atoms forming a 16,17-double bond; 
         and wherein G is a carbonyl, a methylene or a carbon atom substituted by a 12-OR 3 -alpha or 12-OR 3 -beta group, wherein R 3  is an H atom or a group selected from the group consisting of: acetyl, alkyl and aryl groups; and 
         a pharmaceutically acceptable carrier. 
       
     
     
         20 . The kit of  claim 19 , wherein the neuropsychiatric disorder is post-traumatic stress disorder or major depressive disorder.