US2012116090A1PendingUtilityA1

Chiral Diacylhydrazine Ligands for Modulating the Expression of Exogenous Genes via an Ecdysone Receptor Complex

59
Assignee: HORMANN ROBERT EUGENEPriority: May 29, 2007Filed: Dec 6, 2011Published: May 10, 2012
Est. expiryMay 29, 2027(~0.9 yrs left)· nominal 20-yr term from priority
Inventors:Robert Eugene HormannBing Li
A61P 43/00A61P 35/00A61P 17/00C07D 317/68C07C 241/04C12N 15/8217C07C 243/38C07B 2200/07C07D 307/68A01N 43/10A01N 43/30C12N 15/8238A01N 43/40C07C 269/06C07D 333/38A01N 43/32C07D 319/18C07D 213/82C07D 217/24A01N 43/08A61K 48/00A01N 37/18C07C 281/02C07C 271/08C07C 2601/14A61F 5/00C07D 317/46C07D 319/16
59
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Claims

Abstract

The present invention provides diacylhydrazine ligands and chiral diacylhydrazine ligands for use with ecdysone receptor-based inducible gene expression systems. Thus, the present invention is useful for applications such as gene therapy, large scale production of proteins and antibodies, cell-based screening assays, functional genomics, proteomics, metabolomics, and regulation of traits in transgenic organisms, where control of gene expression levels is desirable. An advantage of the present invention is that it provides a means to regulate gene expression and to tailor expression levels to suit the user's requirements.

Claims

exact text as granted — not AI-modified
1 . (canceled) 
     
     
         2 . An enantiomerically enriched compound of Formula II 
       
         
           
           
               
               
           
         
       
       wherein
 A is alkoxy, arylalkyloxy, aryloxy, arylalkyl, optionally substituted aryl or optionally substituted heteroaryl; 
 B is optionally substituted aryl or optionally substituted heteroaryl; and 
 R 1  and R 2  are independently optionally substituted alkyl, arylalkyl, hydroxyalkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl or optionally substituted heteroaryl; 
 with the proviso that R 1  does not equal R 2 ; 
 wherein the absolute configuration at the asymmetric carbon atom bearing R 1  and R 2  is predominantly S; 
 
       or a pharmaceutically acceptable salt, hydrate, crystalline form or amorphous form thereof. 
     
     
         3 . An enantiomerically enriched compound of Formula III 
       
         
           
           
               
               
           
         
         wherein 
         A is alkoxy, arylalkyloxy, aryloxy, arylalkyl, optionally substituted aryl or optionally substituted heteroaryl; 
         B is optionally substituted aryl or optionally substituted heteroaryl; and 
         R 1  and R 2  are independently optionally substituted alkyl, arylalkyl, hydroxyalkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl or optionally substituted heteroaryl; 
         with the proviso that R 1  does not equal R 2 ; 
         wherein the absolute configuration at the asymmetric carbon atom bearing R 1  and R 2  is predominantly R; 
         or a pharmaceutically acceptable salt, hydrate, crystalline form or amorphous form thereof. 
       
     
     
         4 - 7 . (canceled) 
     
     
         8 . The compound of  claim 3  wherein
 A is —OC(CH 3 ) 3 , —OCH 2 Ph, optionally substituted aryl or optionally substituted heteroaryl; 
 B is optionally substituted aryl; 
 R 1  is optionally substituted (C 1 -C 6 )alkyl, hydroxy(C 1 -C 4 )alkyl or optionally substituted (C 2 -C 6 )alkenyl; and 
 R 2  is optionally substituted (C 1 -C 6 )alkyl, aryl(C 1 -C 4 )alkyl, optionally substituted (C 3 -C 7 )cycloalkyl or optionally substituted aryl. 
 
     
     
         9 . The compound of  claim 8  wherein A is optionally substituted aryl or optionally substituted heteroaryl. 
     
     
         10 . The compound of  claim 9  wherein
 A is 
 
       
         
           
           
               
               
           
         
         R 3a , R 3b , R 3c , R 3d  and R 3e  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR c , —SO 2 R d , —N(R e )COR f , —N(R e )SO 2 R g  or —N(R e )C═N(R h )-amino; or 
         R 3a  and R 3b  taken together with the carbon atoms to which they are attached form a five, six or seven membered fused cycloalkyl or heterocycle ring; or 
         R 3b  and R 3c  taken together with the carbon atoms to which they are attached form a five, six or seven membered fused cycloalkyl or heterocycle ring; 
         R 4a , R 4b , R 4c , R 5a , R 5b , R 6a , R 6b  and R 6c  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR c , —SO 2 R d , —N(R e )COR f , —N(R e )SO 2 R g  or —N(R e )C═N(R h )-amino; 
         X is O or S; 
         B is 
       
       
         
           
           
               
               
           
         
         R 3f , R 3g , R 3h , R 3i  and R 3j  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR c , —SO 2 R d , —N(R e )COR f , —N(R e )SO 2 R g  or —N(R e )C═N(R h )-amino; or 
         R 3f  and R 3g  taken together with the carbon atoms to which they are attached form a five, six or seven membered fused cycloalkyl or heterocycle ring; or 
         R 3g  and R 3h  taken together with the carbon atoms to which they are attached form a five, six or seven membered fused cycloalkyl or heterocycle ring; 
         wherein 
         R c  is hydrogen, hydroxy, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, alkoxy, aryloxy or arylalkyloxy; 
         R d  is haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl or optionally substituted heteroaryl; 
         R e  is hydrogen, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl or optionally substituted heteroaryl; 
         R f  is hydrogen, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, alkoxy, aryloxy, arylalkyloxy or amino; 
         R g  is haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl or amino; and 
         R h  is hydrogen, alkyl, aryl, cyano or nitro. 
       
     
     
         11 . The compound of  claim 10  wherein
 R 1  is (C 1 -C 6 )alkyl, hydroxy(C 1 -C 4 )alkyl or (C 2 -C 4 )alkenyl; and 
 R 2  is optionally substituted (C 1 -C 6 )alkyl. 
 
     
     
         12 . The compound of  claim 11  wherein
 A is 
 
       
         
           
           
               
               
           
         
         R 3a , R 3b , R 3c , R 3d  and R 3e  are independently selected from hydrogen, halo, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy; and 
         R 3f , R 3g , R 3h , R 3i  and R 3j  are independently selected from hydrogen, halo, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy. 
       
     
     
         13 - 14 . (canceled) 
     
     
         15 . The compound of  claim 12  having an enantiomeric excess of at least 85%. 
     
     
         16 . The compound of  claim 15  having an enantiomeric excess of at least 95%. 
     
     
         17 . The compound of  claim 3  selected from:
 (R)—N′-(1-tert-Butyl-butyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid benzyl ester; 
 (R)—N′-(1-tert-Butyl-butyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid tert-butyl ester; 
 (R)—N′-(1-tert-Butyl-4-hydroxy-butyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid benzyl ester; 
 (R)—N′-(1-tert-Butyl-4-hydroxy-butyl)-N′-(3,5-dimethyl-benzoyl)-hydrazine carboxylic acid benzyl ester; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N′-benzoyl-N-(1-tert-butyl-butyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-methyl-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-methoxy-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-fluoro-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-chloro-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N′-(2-bromo-benzoyl)-N-(1-tert-butyl-butyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(3-methyl-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(3-methoxy-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(3-chloro-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(4-methyl-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(4-ethyl-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(4-methoxy-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(4-chloro-benzoyl)-hydrazide; 
 (R)-3,5′-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2,6-difluoro-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2,6-dichloro-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(3,4-dimethoxy-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(3,5-difluoro-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N-(3,5-dimethoxy-4-methyl-benzoyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N-(4-methyl-benzo[1,3]dioxole-5-carbonyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(5-ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(naphthalene-1-carbonyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(naphthalene-2-carbonyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(thiophene-2-carbonyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N-(2,5-dimethyl-furan-3-carbonyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N-(2-chloro-pyridine-3-carbonyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N-(6-chloro-pyridine-3-carbonyl)-hydrazide; 
 (R)-3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(3-methoxy-2-methyl-benzoyl)-hydrazide; 
 (R)-3,5-Dimethoxy-4-methyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(3-methoxy-2-methyl-benzoyl)-hydrazide; or 
 (R)-3,5-Dimethyl-benzoic acid N′-(4-ethyl-benzoyl)-N-(1-phenethyl-but-3-enyl)-hydrazide. 
 
     
     
         18 - 19 . (canceled) 
     
     
         20 . A pharmaceutical composition comprising the compound of  claim 3 . 
     
     
         21 - 47 . (canceled) 
     
     
         48 . The compound of  claim 2  wherein
 A is —OC(CH 3 ) 3 , —OCH 2 Ph, optionally substituted aryl or optionally substituted heteroaryl; 
 B is optionally substituted aryl; 
 R 1  is optionally substituted (C 1 -C 6 )alkyl, hydroxy(C 1 -C 4 )alkyl or optionally substituted (C 2 -C 6 )alkenyl; and 
 R 2  is optionally substituted (C 1 -C 6 )alkyl, aryl(C 1 -C 4 )alkyl, optionally substituted (C 3 -C 7 )cycloalkyl or optionally substituted aryl. 
 
     
     
         49 . The compound of  claim 48  wherein A is optionally substituted aryl or optionally substituted heteroaryl. 
     
     
         50 . The compound of  claim 49  wherein
 A is 
 
       
         
           
           
               
               
           
         
         R 3a , R 3b , R 3c , R 3d  and R 3e  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR c , —SO 2 R d , —N(R e )COR f , —N(R e )SO 2 R g  or —N(R e )C═N(R h )-amino; or 
         R 3a  and R 3b  taken together with the carbon atoms to which they are attached form a five, six or seven membered fused cycloalkyl or heterocycle ring; or 
         R 3b  and R 3c  taken together with the carbon atoms to which they are attached form a five, six or seven membered fused cycloalkyl or heterocycle ring; 
         R 4a , R 4b , R 4c , R 5a , R 5b , R 6a , R 6b  and R 6c  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR c , —SO 2 R d , —N(R e )COR f , —N(R e )SO 2 R g  or —N(R e )C═N(R h )-amino; 
         X is O or S; 
         B is 
       
       
         
           
           
               
               
           
         
         R 3f , R 3g , R 3h , R 3i  and R 3j  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR c , —SO 2 R d , —N(R e )COR f , —N(R e )SO 2 R g  or —N(R e )C═N(R h )-amino; or 
         R 3f  and R 3g  taken together with the carbon atoms to which they are attached form a five, six or seven membered fused cycloalkyl or heterocycle ring; or 
         R 3g  and R 3h  taken together with the carbon atoms to which they are attached form a five, six or seven membered fused cycloalkyl or heterocycle ring; 
         wherein 
         R c  is hydrogen, hydroxy, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, alkoxy, aryloxy or arylalkyloxy; 
         R d  is haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl or optionally substituted heteroaryl; 
         R e  is hydrogen, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl or optionally substituted heteroaryl; 
         R f  is hydrogen, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, alkoxy, aryloxy, arylalkyloxy or amino; 
         R g  is haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl or amino; and 
         R h  is hydrogen, alkyl, aryl, cyano or nitro. 
       
     
     
         51 . The compound of  claim 50  wherein
 R 1  is (C 1 -C 6 )alkyl, hydroxy(C 1 -C 4 )alkyl or (C 2 -C 4 )alkenyl; and 
 R 2  is optionally substituted (C 1 -C 6 )alkyl. 
 
     
     
         52 . The compound of  claim 51  wherein
 A is 
 
       
         
           
           
               
               
           
         
         R 3a , R 3b , R 3c , R 3d  and R 3e  are independently selected from hydrogen, halo, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy; and 
         R 3f , R 3g , R 3h , R 3i  and R 3j  are independently selected from hydrogen, halo, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy. 
       
     
     
         53 . The compound of  claim 52  having an enantiomeric excess of at least 85%. 
     
     
         54 . The compound of  claim 53  having an enantiomeric excess of at least 95%. 
     
     
         55 . A pharmaceutical composition comprising the compound of  claim 2 .

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