Methods for making valerenic acid derivatives and their use

Abstract

The present invention is directed to compounds, intermediates and methods for making valerenic acid and its derivatives as well as the use of such compounds as GABA A receptor ligands.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein the dotted line between C 10  and C 11  represents an optional double bond; 
         D is selected from the group of 5-membered rings consisting of the following structures: 
       
       
         
           
           
               
               
           
         
         R 1  is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C0-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C10)C(O)NR 11 R 12 , —(C0-C10)C(O)NHN 11 R 12  and —(C1-C10)OR 10 ;
 wherein R 10 , R 11  and R 12  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 
         R 2 , R 3 , R 4 , R 7 , R 8  and R 9  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —(C1-C10)OH, —NR 11 R 12 , —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C0-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C10)C(O)NR 11 R 12 , —C(O)NHNR 11 R 12  and —(C0-C10)OR 10 ;
 wherein R 10 , R 11  and R 12  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 
         R 5  is selected from the group consisting of O and CHR 13 ;
 wherein R 13  is selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 
         R 6  is selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —(C1-C10)OH, —NR 11 R 12 , —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C1-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C10)C(O)NR 11 R 12 , —C(O)NHN 11 R 12 , —(C1-C10)OR 10 , —OR 14  and —OC(O)R 14 ;
 wherein R 10 , R 11 , R 12  and R 14  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 or a pharmaceutically salt thereof or solvate thereof; 
 excluding the following compounds: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 . (canceled) 
     
     
         3 . A compound according to  claim 1  of formula (IA2): 
       
         
           
           
               
               
           
         
         wherein 
         the dotted line between C 10  and C 11  represents an optional double bond; 
         R 1  is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C0-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C10)C(O)NR 11 R 12 , —(C0-C10)C(O)NHN 11 R 12  and —(C1-C10)OR 10 ;
 wherein R 10 , R 11  and R 12  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 
         R 2 , R 3 , R 4 , R 7 , R 8  and R 9  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —(C1-C10)OH, —NR 11 R 12 , —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C0-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C10)C(O)NR 11 R 12 , —C(O)NHNR 11 R 12  and —(C0-C10)OR 10 ;
 wherein R 10 , R 11  and R 12  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 or a pharmaceutically salt thereof or solvate thereof. 
 
       
     
     
         4 . A compound according to  claim 1  of formula (IB): 
       
         
           
           
               
               
           
         
         wherein the dotted line between C 10  and C 11  represents an optional double bond; 
         R 1  is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C0-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C 10 )C(O)NR 11 R 12 , —(C0-C10)C(O)NHNR 11 R 12  and —(C1-C10)OR 10 ;
 wherein R 10 , R 11  and R 12  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 
         R 2 , R 3 , R 4 , R 7 , R 8  and R 9  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —(C1-C10)OH, —NR 11 R 12 , —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C0-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C10)C(O)NR 11 R 12 , —C(O)NHNR 11 R 12  and —(C0-C10)OR 10 ;
 wherein R 10 , R 11  and R 12  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 or a pharmaceutically salt thereof or solvate thereof. 
 
       
     
     
         5 . A compound according to  claim 1  of formula (IC): 
       
         
           
           
               
               
           
         
         wherein 
         the dotted line between C 10  and C 11  represents an optional double bond; 
         R 1  is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C0-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C 10 )C(O)NR 11 R 12 , —(C0-C10)C(O)NHNR 11 R 12  and —(C1-C10)OR 10 ;
 wherein R 10 , R 11  and R 12  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 
         R 2 , R 3 , R 4 , R 7 , R 8  and R 9  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —(C1-C10)OH, —NR 11 R 12 , —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C0-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C10)C(O)NR 11 R 12 , —C(O)NHNR 11 R 12  and —(C0-C10)OR 10 ;
 wherein R 10 , R 11  and R 12  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 or a pharmaceutically salt thereof or solvate thereof. 
 
       
     
     
         6 . A compound according to  claim 1  of formula (ID): 
       
         
           
           
               
               
           
         
         wherein 
         the dotted line between C 10  and C 11  represents an optional double bond; 
         R 1  is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C0-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C 10 )C(O)NR 11 R 12 , —(C0-C10)C(O)NHNR 11 R 12  and —(C1-C10)OR 10 ;
 wherein R 10 , R 11  and R 12  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 
         R 2 , R 3 , R 4 , R 7 , R 8  and R 9  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —(C1-C10)OH, —NR 11 R 12 , —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C0-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C10)C(O)NR 11 R 12 , —C(O)NHNR 11 R 12  and —(C0-C10)OR 10 ;
 wherein R 10 , R 11  and R 12  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 
         R5 is selected from the group consisting of O and CHR 13 ;
 wherein R 13  is selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 or a pharmaceutically salt thereof or solvate thereof. 
 
       
     
     
         7 . A compound according to  claim 1 , wherein the bond between C 10  and C 11  is a double bond. 
     
     
         8 . A compound according to  claim 1 , wherein R 3  is H. 
     
     
         9 . A compound according to  claim 1 , wherein R 8  is H. 
     
     
         10 - 14 . (canceled) 
     
     
         15 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to  claim 1 , optionally in the form of an ester prodrug. 
     
     
         16 - 17 . (canceled) 
     
     
         18 . Process for the preparation of compound (9) having the following structure: 
       
         
           
           
               
               
           
         
         comprising either the following steps: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or the following steps: 
       
       
         
           
           
               
               
           
         
         wherein X is selected from protecting groups including TBSO, PMBO; and wherein R 1  is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C0-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C10)C(O)NR 11 R 12 , —(C0-C10)C(O)NHNR 11 R 12  and —(C1-C10)OR 10 ;
 wherein R 10 , R 11  and R 12  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; 
 
         R 2 , R 3 , R 7 , R 8  and R 9  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —(C1-C10)OH, —NR 11 R 12 , —(C0-C10)C(O)R 10 , —(C0-C10)C(O)OR 10 , —(C0-C10)OC(O)R 10 , —(C1-C10)SR 10 , —(C0-C10)C(O)NR 11 R 12 , —C(O)NHNR 11 R 12  and —(C0-C10)OR 10 ;
 wherein R 10 , R 11  and R 12  independently from each other are selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C4-C8 cycloalkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. 
 
       
     
     
         19 . Process for the preparation of a compound according to  claim 3  having the following structure: 
       
         
           
           
               
               
           
         
         comprising the following steps: 
       
       
         
           
           
               
               
           
         
         wherein X′ is selected from protecting groups including TfO, AcO. 
       
     
     
         20 . Process for the preparation of a compound according to  claim 4  having the following structure: 
       
         
           
           
               
               
           
         
         comprising the following steps: 
       
       
         
           
           
               
               
           
         
         wherein X′ is selected from protecting groups including TfO, AcO. 
       
     
     
         21 . Process for the preparation of a compound according to  claim 5  having the following structure: 
       
         
           
           
               
               
           
         
         comprising the following steps: 
       
       
         
           
           
               
               
           
         
         wherein X′ is selected from protecting groups including TfO, AcO. 
       
     
     
         22 . Process for the preparation of a compound according to  claim 6  having the following structure: 
       
         
           
           
               
               
           
         
         comprising the following steps: 
       
       
         
           
           
               
               
           
         
       
     
     
         23 . Process according to  claim 18  for the preparation of valerenic acid having the following structure: 
       
         
           
           
               
               
           
         
         comprising either the following steps: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or the following steps: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein X is selected from protecting groups including TsO, MsO; 
         wherein X′ is selected from protecting groups including TBSO, PMBO; 
         wherein X″ is selected from C1-C10 alkyl, C2-C10 alkenyl, substituted or unsubstituted aryl; 
         wherein X′″ is selected from protecting groups including TfO and AcO.