Oxaspiro[2.5]Octane Derivatives and Analogs

Abstract

The invention provides oxaspiro[2.5]octane derivatives and analogs, methods for preparation thereof, intermediates thereto, pharmaceutical compositions, and uses thereof in the treatment of various disorders and conditions, such as overweight and obesity.

What is claimed is: 
     
         1 . A compound represented by: 
       
         
           
           
               
               
           
         
       
       wherein
 R 25  is C 1-12  straight or branched saturated alkyl, optionally substituted by a substituent selected from the group consisting of —COOH or —O—R 26 ; 
 R 26  is C 1-4  alkyl; 
 and pharmaceutically acceptable salts or stereoisomers thereof. 
 
     
     
         2 . The compound of  claim 1 , represented by: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , represented by: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein R 25  is C 8-12  straight saturated alkyl. 
     
     
         5 . The compound of  claim 1 , wherein R 25  is selected from the group consisting of C 9  straight saturated alkyl or C 10  straight saturated alkyl. 
     
     
         6 . The compound of  claim 1 , wherein R 25  is C 7-10  alkylene substituted on the terminal end by —C(O)OH, —C(O)—O-Me, or C(O)-Et. 
     
     
         7 . The compound 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts or stereoisomers thereof. 
       
     
     
         8 . A pharmaceutically acceptable composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         9 . A method of treating and/or controlling obesity, comprising administering to a patient in need thereof an effective amount of the compound of  claim 1 . 
     
     
         10 . The method of  claim 9 , wherein the patient is a human. 
     
     
         11 . The method of  claim 10 , wherein the patient has a body mass index greater than or equal to about 25 kg/m 2  before the administration. 
     
     
         12 . The method of  claim 1 , wherein after administration, thioredoxin 1 is not significantly present in the testes of male patient. 
     
     
         13 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester or pro-drug thereof; 
       wherein
 each of X 5  and X 7  independently is a C, O, N or S atom, and one or more of R 5′ , R 5″ , R 7′  and R 7″  is absent when X 5  or X 7  is a O, S, or N at the respective positions; 
 X 6  is a C, O, or N atom; 
 Z is a C, O, S or N, and the bond between X 6  and Z is a single bond or a double bond, wherein when Z is a O, S, or N, or when the bond between X 6  and Z a double bond, one or more of R 6′ , R 6″ , R 6′″  is absent; 
 Y is a C, O, N or S atom, and one or more of R 3′  and R 3″  is absent when Y is a O or S, and wherein R 3′  and R 3″  may together with atoms attached thereto form a cyclic, heterocyclic, aromatic cyclic, or aromatic heterocyclic group; 
 R 4  is a H, —OH, a halogen, a C 1 -C 6  alkyl; 
 each of R 6′ , R 6″  and R 6′″  is independently H, alkyl, aryl, halogen, —OH, alkoxy, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl and alkylthioether, and two of R 6′ , R 6″  and R 6′″  may together form a closed ring; 
 each of R 3′ , R 3″ , R 5′ , R 5″ , R 7′ , R 7″ , R 8′  and R 8″  is independently H, alkyl, aryl, halogen, —OH, alkoxy, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl and alkylthioether, and wherein R 3′  and R 3″  may together form a closed ring; R 5′  and R 5″  may together form a closed ring; R 7′  and R 7″  may together form a closed ring; and R 8′  and R 8″  may together form a closed ring; and 
 R 10  is a H, a halogen, —OH, or a C 1 -C 6  alkyl group. 
 
     
     
         14 . The compound of  claim 13 , wherein Z is C. 
     
     
         15 . The compound of  claim 14 , having Formula IIa or IIb: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 15 , having Formula IIIa or IIIb: