Compositions and methods for treating beta-amyloid related diseases

Abstract

In alternative embodiments the invention provides compositions and methods for ameliorating diseases and conditions having a beta-amyloid component, including Alzheimer's disease (AD), Vascular Dementia (VD), dementia, pre-dementia, Cognitive Dysfunction Syndrome (CDS) and loss of cognition in humans and in non-human animal. In alternative embodiment the invention provides analogs of AB-007 and its acid form E64c (loxistatin), their preparation, and pharmaceutical compositions thereof and methods of making and using same. In alternative embodiments compositions of the invention are deuterated analogs of AB-007 (or E64d) and E64c (or loxistatin). In alternative embodiments compositions of the invention are metabolically blocked forms as compared to AB-007 and loxistatin. In alternative embodiments compositions of the invention are used to ameliorate (including treat, slow, reverse or prevent) a disease or condition which can be ameliorated by partial or complete inhibition of a cysteine protease, e.g., AD, VD, CDS. The invention also provides alternative dosage forms and formulations for AB-007 and loxistatin, and for compounds of this invention, which can be used e.g., to treat AD, VD and CDS, in humans and in non-human animals.

1 . A method of ameliorating, slowing the progress of, reversing, reducing or preventing a Cognitive Dysfunction Syndrome (CDS), or a Canine Cognitive Dysfunction (CCD), in a dog, comprising administering to a dog an effective amount of a compound comprising Formula I: 
       
         
           
           
               
               
           
         
         wherein X 1  through X 30  are independently selected from a member of the group consisting of —H (hydrogen), -D (deuterium), —F and —OH. 
       
     
     
         2 . The method of  claim 1 , wherein the compound comprising Formula I has a stereospecificity as set forth in Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein at least one of X 1  through X 30 , or any combination thereof, is a —H (hydrogen). 
     
     
         4 . The method of  claim 3 , wherein the compound comprising Formula I or Formula II is: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein:
 (a) at least one of X 1  through X 30 , or any combination thereof, is a -D (deuterium); or   (b) the method of (a), wherein X 2 , X 3  and X 4  are a -D (deuterium); X 5 , X 6  and X 7  are a -D; X 8  and X 9  are a -D; X 10  and X 11  are a -D; X 14  and X 15  are a -D; X 17 , X 18  and X 19  are a -D; X 20 , X 21  and X 22  are a -D; X 26  and X 27  are a -D; or, X 28 , X 29  and X 30  are a -D.   
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 5 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         8 - 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein:
 (a) at least one of X 1  through X 30 , or any combination thereof, is a —F or an —OH; or   (b) the method of (a), wherein X 1 , X 13  or X 16  is a —F or an —OH.   
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein:
 (a) the compound is formulated as a pharmaceutically acceptable salt, a hydrate, a stereoisomer or a solvate; or   (b) the method of (a), wherein the compound is formulated with a pharmaceutically acceptable carrier or excipient.   
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the compound comprises the hydrolysis product of Formula I: 
       
         
           
           
               
               
           
         
       
       or
 (b) the method of (a), wherein the compound comprising Formula III has a stereospecificity as set forth in Formula IV 
 
       
         
           
           
               
               
           
         
       
       or
 (c) the method of (a), wherein at least one of X 1  through X 26 , or any combination thereof, of the compound of Formula III is a —H (hydrogen); or 
 (d) the method of any of (a) to (c), wherein the compound is: 
 
       
         
           
           
               
               
           
         
       
       or
 (e) the method of any of (a) to (d), wherein at least one of X 1  through X 26 , or any combination thereof, of the compound of Formula III is a -D (deuterium); or 
 (f) the method of any of (a) to (e), wherein X 2 , X 3  and X 4  are a -D (deuterium); X 5 , X 6  and X 7  are a -D; X 8  and X 9  are a -D; X 10  and X 11  are a -D; X 14  and X 15  are a -D; X 17 , X 18  and X 19  are a -D; X 20 , X 21  and X 22  are a -D; X 24  is a -D; X 25  is a -D; or, X 26  is a -D; or 
 (g) the method of any of (a) to (f), wherein the compound is 
 
       
         
           
           
               
               
           
         
       
       or
 (g) the method of any of (a) to (f), wherein the compound is 
 
       
         
           
           
               
               
           
         
       
     
     
         15 - 21 . (canceled) 
     
     
         22 . The method of  claim 14 , wherein:
 (a) at least one of X 1  through X 26 , or any combination thereof, of the compound of Formula III is a —F or an —OH; or   (b) the method of (a), wherein X 1 , X 13  or X 16  is a —F or an —OH.   
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 1 , wherein:
 (a) the compound is conjugated to (or further comprises) a chemical delivery system (CDS);   (b) the method of (a), wherein the a chemical delivery system (CDS) comprises a pyridimium or a pyridimium derivative, a 1,4-dihydrotrigoneline esters, or a dihydroquinoline or a dihydroisoquinoline;   (c) the method of (b), wherein the pyridimium or a pyridimium derivative comprises a 3-methyl-1-propylpyridinium, a 1-butyl-3-methylpyridinium or a 1-butyl-4-methylpyridinium).   
     
     
         25 - 26 . (canceled) 
     
     
         27 . The method of  claim 1 , wherein:
 (a) the effective amount is between about 1 mg and about 400 mg; or is between about 1 mg and about 250 mg; or is about 5 mg and about 150 mg; or is between about 1 mg and about 75 mg; or is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg;   (b) the effective amount is between about 0.1 mg and about 2.0 mg per kg of body weight of the dog; or is between about 0.1 mg and about 1.0 mg per kg of body weight; or is about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, or about 1.0 mg of body weight;   (c) the compound is formulated for administration as (or in the form of) an injectable sterile formulation, a gel, a lotion, a spray, an aerosol, a powder, a liquid or a solid dosage form, a patch, an adhesive tape, a gel, a liquid or a suspension, a lyophilate, a lozenge, a pill, a geltab, a lozenge, a tablet, a capsule and/or an implant;   (d) the compound is administered as an injectable sterile formulation, a gel, a lotion, a spray, an aerosol, a powder, a liquid or a solid dosage form, a patch, an adhesive tape, a gel, a liquid or a suspension, a lyophilate, a lozenge, a pill, a geltab, a lozenge, a tablet, a capsule and/or an implant;   (e) the compound is formulated in combination with in combination with, or together with, a selegiline (e.g., selegiline hydrochloride) or a deprenyl, or ANIPRYL™;   (f) the compound is formulated as a chow, or a feed or a feed supplement;   (g) the compound is administered as a once a day, or a twice a day (bid), or a three times a day (tid) formulation, chow, feed or feed supplement;   (h) the compound is administered as an oral dosage, formulation, chow, feed or feed supplement;   (i) the compound is formulated in combination with or together with a nutritional supplement or a vitamin;   (j) the compound is formulated in combination with or together with a non-steroidal anti-inflammatory drug;   (k) the compound is formulated in combination with or together with an antioxidant;   (l) the compound is formulated for administration as an implantable infusion system, and the compound is administered by an implantable infusion system;   (m) the compound is formulated with microencapsulation to delay disintegration and adsorption in the gastrointestinal tract to provide a sustained action over a longer period; or   (n) the compound is formulated with a time delay material, and optionally the time delay material comprises a glyceryl monostearate or a glyceryl distearate.   
     
     
         28 - 41 . (canceled)