US2018057474A1PendingUtilityA1
2,3-Fluorinated Glycosides as Neuraminidase Inhibitors and Their Use as Anti-Virals

Assignee: UNIV BRITISH COLUMBIAPriority: Jul 15, 2009Filed: Feb 16, 2017Published: Mar 1, 2018
Est. expiryJul 15, 2029(~3 yrs left)· nominal 20-yr term from priority
Inventors:Stephen Withers Andrew Graham Watts Jin Hyo Kim Tom Wennekes
A61P 43/00C07H 13/00C07H 1/00A61K 31/351C07H 13/04C07D 309/14C07H 13/12C07H 15/12A61K 31/655C07H 15/18A61P 31/16
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Claims
Abstract

Compounds having a structure of Formula I and compositions comprising these compounds are provided. Uses of such compounds and compositions are provided for treatment or prophylaxis of viral infection. In particular, compounds and compositions may be for use in the treatment or prophylaxis of viral influenza.
Claims

exact text as granted — not AI-modified
1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 T is C(O)NH 2 , COOH or COOR 1 ,
 wherein R 1  is a C 1-10  linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group, 
 wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and 
 wherein zero to five backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S; 
 
 Z is F, Cl, Br, or OSO 2 R 2 ,
 wherein R 2  is a C 1-10  linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group, 
 wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and 
 wherein zero to five backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S; 
 
 A is selected from the group consisting of: H, F, Cl, Br, OH, CN, OR 3 , and NO 2 ,
 wherein R 3  is a C 1-10  linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group, 
 wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and 
 wherein zero to five backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S; 
 
 D is selected from the group consisting of: H, F, Cl, Br, OH, CN, OR 4 , and NO 2 , provided A and D are not both H, and
 wherein R 4  is a C 1-10  linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group, 
 wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and 
 wherein zero to five backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S; 
 
 X is selected from the group consisting of: NH 2 , NHR 5 , NHC(NH)NH 2 , NHC(NH)NHR 5 , NR 5 R 6 , and NHC(NH)N(R 5 )R 6 ,
 wherein R 5  and R 6  are independently C 6 H 5 , CH 2 C 6 H 5  or a C 1-8  alkyl group; 
 
 E is selected from the group consisting of: NH 2 , NHC(O)CH 3 , OR 7 , NHR 7  and N(R 7 )(R 8 ),
 wherein R 7  and R 8  are independently a C 1-10  linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group, 
 wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and 
 wherein zero to five backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S; 
 
 Q is selected from the group consisting of: CH 2 OH, CH 2 R 9 , CH(R 9 )(R 10 ), C(R 9 )(R 10 )(R 11 ), 
 
       
         
           
           
               
               
           
         
         
           wherein
 R 9 , R 10  and R 11  are independently CH 3  or CH 2 CH 3 , and 
 each of J and G is independently selected from the group consisting of: H, OH, OAc, OC(O)CH 3 , F, Cl, Br, NO 2 , CN, OR 12 , SO 2 R 12 , COR 12  and SR 12 , 
 wherein R 12  is CH 3 , CH 2 CH 3  or CH 2 CH 2 CH 3 , and 
 M is H, OH, OAc, OC(O)CH 3 , NH 2 , F or Cl, and 
 L is H, OH, OAc, OC(O)R 13  or NH 2 , 
 wherein R 13  is a C 1-10  linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group, 
 wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and 
 wherein zero to five backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S, 
 or a salt thereof. 
 
         
       
     
     
         2 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 T is C(O)NH 2 , COOH or COOR 1 ,
 wherein R 1  is a C 1-10  linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group, 
 wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and 
 wherein zero to five backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S; 
 
 Z is F or Cl; 
 A is F or Cl; 
 D is H; 
 X is selected from the group consisting of: NH 2 , NHCH 3 , NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 2 CH 3 , and NHC(NH)NH 2 ; 
 E is NH 2  or NHC(O)CH 3 ; 
 Q is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         
           wherein
 each of J and G is independently selected from the group consisting of: H, OH, OAc, OC(O)CH 3 , F, Cl, Br, NO 2 , CN and OCH 3 , 
 M is H, OH, or OAc; and 
 L is H, OH, or OAc, or a salt thereof. 
 
         
       
     
     
         3 . The compound of  claim 1 , wherein T is COOH or COOR 1 ,
 wherein R 1  is a C 1-10  linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,   wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and   wherein zero to five backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S.   
     
     
         4 . The compound of  claim 1 , wherein T is C(O)OCH 3 , C(O)OCH 2 CH 3 , C(O)OCH 2 CH 2 CH 3 , C(O)OCH 2 CH 2 CH 2 CH 3 , C(O)OCH 2 CH 2 CH 2 CH 2 CH 3 , C(O)OCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , C(O)OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , C(O)OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , or COOH. 
     
     
         5 . The compound of  claim 1 , wherein A is selected from the group consisting of: F, Cl, Br, OH, CN, and NO 2 . 
     
     
         6 . The compound of  claim 1 , wherein A is selected from the group consisting of: F, Cl, and OR 3 ,
 wherein R 3  is a C 1-10  linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,   wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 .   
     
     
         7 . The compound of  claim 1 , wherein A is F or Cl. 
     
     
         8 . The compound of  claim 1 , wherein A is F. 
     
     
         9 . The compound of  claim 1 , wherein D is selected from the group consisting of: H, F, Cl, Br, OH, CN, and NO 2 , provided A and D are not both H. 
     
     
         10 . The compound of  claim 1 , wherein D is selected from the group consisting of: H, F, and Cl, provided A and D are not both H. 
     
     
         11 . The compound of  claim 1 , wherein D is F or Cl. 
     
     
         12 . The compound of  claim 1 , wherein D is H, provided A and D are not both H. 
     
     
         13 . The compound of  claim 1 , wherein X is selected from the group consisting of: NH 2 , NHR 5 , NHCH 3 , NHCH 2 CH 3 , NHC(NH)NH 2 , NHC(NH)NHR 5 , and NR 5 R 6 , wherein R 5  and R 6  are independently C 6 H 5 , CH 2 C 6 H 5  or a C 1-8  alkyl group. 
     
     
         14 . The compound of  claim 1 , wherein X is selected from the group consisting of: NH 2 , NHCH 3 , NHCH 2 CH 3 , and NHC(NH)NH 2 . 
     
     
         15 . The compound of  claim 1 , wherein X is NH 2  or NHC(NH)NH 2 . 
     
     
         16 . The compound of  claim 1 , wherein E is selected from the group consisting of: NH 2 , NHC(O)CH 3 , OR 7 , NHR 7  and N(R 7 )(R 8 ),
 wherein R 7  and R 8  are independently a C 1-10  linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,   wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 .   
     
     
         17 . The compound of  claim 1 , wherein E is NH 2  or NHC(O)CH 3 . 
     
     
         18 . The compound of  claim 1 , wherein E is NHC(O)CH 3 . 
     
     
         19 . The compound of  claim 1 , wherein Q is selected from the group consisting of: CH 2 R 9 , CH(R 9 )(R 10 ), C(R 9 )(R 10 )(R 11 ), 
       
         
           
           
               
               
           
         
         wherein
 R 9 , R 10  and R 11  are independently CH 3  or CH 2 CH 3 , and 
 each of J and G is independently selected from the group consisting of: H, OH, OAc, OC(O)CH 3 , F, Cl, Br, NO 2 , CN, OR 12 , SO 2 R 12 , COR 12  and SR 12 , 
 wherein R 12  is CH 3 , CH 2 CH 3  or CH 2 CH 2 CH 3 , and 
 M is H, OH, OAc, OC(O)CH 3 , NH 2 , F or Cl, and 
 L is H, OH, OAc, OC(O)R 13  or NH 2 , 
 wherein R 13  is a C 1-10  linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group, and 
 wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2  and 
 wherein zero to five backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S. 
 
       
     
     
         20 . The compound of  claim 1 , wherein Q is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 each of J and G is independently selected from the group consisting of: H, OH, OAc, OC(O)CH 3 , F, Cl, Br, NO 2 , CN and OCH 3 , 
 M is H, OH, OAc, OC(O)CH 3 , NH 2 , F or Cl, and 
 L is H, OH, OAc, OC(O)R 13  or NH 2 . 
 wherein R 13  is a C 1-10  linear, branched or cyclic, saturated or unsaturated alkyl group, and 
 wherein zero to five backbone carbons of the alkyl group are optionally and independently substituted with O, N or S. 
 
     
     
         21 . The compound of  claim 1 , wherein Q is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 each of J and G is independently selected from the group consisting of: H, OH, and OAc, 
 M is H, OH, or OAc, and 
 L is H, OH, or OAc. 
 
     
     
         22 . The compound of  claim 1 , wherein Q is: 
       
         
           
           
               
               
           
         
       
       wherein
 each of J and G is independently selected from the group consisting of: H, OH, and OAc, 
 M is H, OH, or OAc, and 
 L is H, OH, or OAc. 
 
     
     
         23 . The compound of  claim 1 , wherein Q is: 
       
         
           
           
               
               
           
         
       
       wherein
 each of J and G is independently selected from the group consisting of: H OH, and OAc, 
 M is OH, or OAc, and 
 L is OH, or OAc. 
 
     
     
         24 .- 29 . (canceled) 
     
     
         30 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 
     
     
         31 . A pharmaceutical composition comprising a compound according to  claim 14  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 
     
     
         32 . A pharmaceutical composition comprising a compound according to  claim 16  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 
     
     
         33 . A pharmaceutical composition comprising a compound according to  claim 20  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 
     
     
         34 . A method of modulating viral neuraminidase activity, the method comprising contacting a viral neuraminidase with one or more compounds described in  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The method of  claim 34 , wherein the viral neuraminidase is a GH34 neuraminidase. 
     
     
         36 . The method of  claim 34 , wherein the modulation of viral neuraminidase activity comprises contacting the compound or the pharmaceutically acceptable salt thereof to an animal and is effective to treat influenza in the animal. 
     
     
         37 . The method of  claim 36 , wherein the animal is a human. 
     
     
         38 .- 42 . (canceled)
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