US2018194792A1PendingUtilityA1

Compounds and methods for treating bacterial infections

57
Assignee: UNIV WASHINGTONPriority: May 30, 2013Filed: Mar 8, 2018Published: Jul 12, 2018
Est. expiryMay 30, 2033(~6.9 yrs left)· nominal 20-yr term from priority
Inventors:James JanetkaZhenfu HanScott HultgrenJerry PinknerCorinne Cusumano
A61P 31/00A61P 31/04A61P 1/00A61P 13/02A61P 1/04C07H 15/203A61K 31/7042A61K 31/706C07H 15/26A61K 31/7034A61K 31/7064A61K 31/7056A61K 45/06Y02A50/30
57
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Claims

Abstract

The present invention encompasses compounds and methods for treating and preventing bacterial infections specifically urinary tract infections and those caused by bacteria containing type 1 pili and FimH. The present invention also encompasses compounds and methods for treating inflammatory bowel disease specifically Crohn's Disease.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A compound, the compound comprising Formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 X is selected from the group consisting of hydrogen and OR 2 ; 
 R 2  is independently selected from the group consisting of hydrogen, PO(OH) 2 , acetyl, COR 5 , CO(OR 5 ), CO(NR 5 R 6 ), CO(CH 2 ) n NR 5 R 6 , hydrocarbyl and substituted hydrocarbyl; 
 n is an integer from 1 to 10; 
 Z is O; 
 Y is selected from the group consisting of O, CH(OH), CH(OR 5 ), CHNR 5 R 6 , CH 2 , S, and NR 5 ; 
 R 1  is selected from the group consisting of CH 3 , CF 3 , halogen, Cl, F, Br, I, OH, NH 2 , NR 5 R 6 , OCH 3 , CO 2 CH 3 , CONHCH 3 , alkyl, cyclopropyl, OR 5 , CO 2 R 5 , CONR 5 R 6 , hydrocarbyl, and substituted hydrocarbyl; 
 R 3  is selected from the group consisting of formula (IA) and formula (IB): 
 
       
       
         
           
           
               
               
           
         
         
           A is independently selected from the group consisting of CR 5  and N; 
           G is independently selected from the group consisting of S, NR 5  and O; 
           a is an integer from 1 to 4; 
           R 4  is selected from the group consisting of CONHCH 3 , COOCH 3 , COOH, CONR 5 , CONH(heterocycle), heterocycle, H, alkyl, cyclopropyl, aryl, OR 5 , NR 5 R 6 , NR 5 COR 6 , NR 5 COOR 6 , NR 5 CONR 6 , NR 5 SO 2 R 6 , COR 5 , SO 2 R 5 , halogen, CN, NO 2 , COOR 5 , CONR 5 R 6 , NCOR 7 , NCONR 7 , NCOOR 7 , SO 2 NR 5 R 6 , and NHSO 2 R 7 , or when a is greater than or equal to 2, R 4  may optionally form an optionally substituted cycloalkyl, aryl or heterocyclo 5 or 6 membered ring; 
           R 5  is selected from the group consisting of H and an optionally substituted alkyl, aryl, heterocycle, and cycloalkyl; 
           R 6  and R 7  are selected from the group consisting of an optionally substituted alkyl, cycolalkyl, aryl, and heterocycle. 
         
       
     
     
         2 . The compound of  claim 1 , wherein the compound comprising Formula (I) comprises Formula (II): 
       
         
           
           
               
               
           
         
         wherein:
 X is selected from the group consisting of hydrogen and OR 2 ; 
 R 2  is independently selected from the group consisting of hydrogen, PO(OH) 2 , acetyl, COR 5 , CO(OR 5 ), CO(CH 2 ) n NR 5 R 6 , hydrocarbyl and substituted hydrocarbyl; 
 n is an integer from 1 to 10; 
 Z is O; 
 Y is selected from the group consisting of O, CH(OH), CH(OR 5 ), CHNR 5 R 6 , CH 2 , S, and NR 5 ; 
 A is independently selected from the group consisting of CR 5  and N; 
 R 1  is selected from the group consisting of CH 3 , CF 3 , halogen, Cl, F, Br, I, OH, NH 2 , NR 5 R 6 , OCH 3 , CO 2 CH 3 , CONHCH 3 , alkyl, cyclopropyl, OR 5 , CO 2 R 5 , CONR 5 R 6 , hydrocarbyl, and substituted hydrocarbyl; 
 R 8 , R 9 , R 10  and R 11  are independently selected from the group consisting of CONHCH 3 , COOCH 3 , COOH, CONH(heterocycle), heterocycle, H, alkyl, cyclopropyl, aryl, OR 5 , NR 5 R 6 , NR 5 COR 6 , NR 5 COOR 6 , NR 5 CONR 6 , NR 5 SO 2 R 6 , COR 5 , SO 2 R 5 , halogen, CN, NO 2 , COOR 5 , CONR 5 R 6 , NCOR 7 , NCONR 7 , NCOOR 7 , SO 2 NR 5 R 6 , NHSO 2 R 7 , and R 8  and R 9  together can optionally form an optionally substituted cycloalkyl, aryl or heterocyclo 5 or 6 membered ring; and R 9  and R 10  together can optionally form an optionally substituted cycloalkyl, aryl or heterocyclo 5 or 6 membered ring; 
 R 5  is selected from the group consisting of H and an optionally substituted alkyl, aryl, heterocycle, and cycloalkyl; 
 R 6  and R 7  is selected from the group consisting of an optionally substituted alkyl, cycolalkyl, aryl and heterocycle. 
 
       
     
     
         3 . The compound of  claim 1 , wherein the compound comprising Formula (I) comprises Formula (III): 
       
         
           
           
               
               
           
         
         wherein:
 X is selected from the group consisting of hydrogen and OR 2 ; 
 R 2  is independently selected from the group consisting of hydrogen, PO(OH) 2 , acetyl, COR 5 , CO(OR 5 ), CO(CH 2 ) n NR 5 R 6 , hydrocarbyl and substituted hydrocarbyl; 
 n is an integer from 1 to 10; 
 Z is O; 
 Y is selected from the group consisting of O, CH(OH), CH(OR 5 ), CHNR 5 R 6 , CH 2 , S, and NR 5 ; 
 R 1  is selected from the group consisting of CH 3 , CF 3 , halogen, Cl, F, Br, I, OH, NH 2 , NR 5 R 6 , OCH 3 , CO 2 CH 3 , CONHCH 3 , alkyl, cyclopropyl, OR 5 , CO 2 R 5 , CONR 5 R 6 , hydrocarbyl, and substituted hydrocarbyl; 
 A is independently selected from the group consisting of CR 5  and N; 
 R 5  is selected from the group consisting of H and an optionally substituted alkyl, aryl, heterocycle, and cycloalkyl; 
 R 6  and R 7  are selected from the group consisting of an optionally substituted alkyl, cycolalkyl, aryl, and heterocycle; 
 R 8  and R 11  are independently selected from the group consisting of CONHCH 3 , COOCH 3 , COOH, CONH(heterocycle), heterocycle, H, alkyl, cyclopropyl, aryl, OR 5 , NR 5 R 6 , NR 5 COR 6 , NR 5 COOR 6 , NR 5 CONR 6 , NR 5 SO 2 R 6 , COR 5 , SO 2 R 5 , halogen, CN, NO 2 , COOR 5 , CONR 5 R 6 , NCOR 7 , NCONR 7 , NCOOR 7 , SO 2 NR 5 R 6 , and NHSO 2 R 7 ; 
 R 12  is substituted at the O or N and is selected from the group consisting of H, alkyl, CH 2 R 13 , CH 2 COR 13 , CH 2 CONHR 13 , CH 2 CONHR 13 R 14 , CH 2 CONH(CH 2 ) 2 R 14 , (CH 2 ) 2 NR 13 , (CH 2 ) n NR 13 , CH 2 COOH, CH 2 CONH(CH 2 ) 2 NH 2 , and (CH 2 ) 2 N(CH 3 ) 2 ; 
 R 13  is selected from the group consisting of —OH and an optionally substituted heterocycle, hydrocarbyl, and substituted hydrocarbyl; 
 R 14  is selected from the group consisting of alkyl and NH 2 . 
 
       
     
     
         4 . The compound of  claim 1 , wherein the compound comprising Formula (I) comprises Formula (IV): 
       
         
           
           
               
               
           
         
         wherein:
 X is selected from the group consisting of hydrogen and OR 2 ; 
 R 2  is independently selected from the group consisting of hydrogen, PO(OH) 2 , acetyl, COR 5 , CO(OR 5 ), CO(CH 2 ) n NR 5 R 6 , hydrocarbyl and substituted hydrocarbyl; 
 n is an integer from 1 to 10; 
 Z is O; 
 Y is selected from the group consisting of O, CH(OH), CH(OR 5 ), CHNR 5 R 6 , CH 2 , S, and NR 5 ; 
 R 1  is selected from the group consisting of CH 3 , CF 3 , halogen, Cl, F, Br, I, OH, NH 2 , NR 5 R 6 , OCH 3 , CO 2 CH 3 , CONHCH 3 , alkyl, cyclopropyl, OR 5 , CO 2 R 5 , CONR 5 R 6 , hydrocarbyl, and substituted hydrocarbyl; 
 R 5  is selected from the group consisting of H and an optionally substituted alkyl, aryl, heterocycle, and cycloalkyl; 
 R 6  and R 7  are selected from the group consisting of an optionally substituted alkyl, cycolalkyl, aryl, and heterocycle; 
 R 8  and R 11  are independently selected from the group consisting of CONHCH 3 , COOCH 3 , COOH, CONH(heterocycle), heterocycle, H, alkyl, cyclopropyl, aryl, OR 5 , NR 5 R 6 , NR 5 COR 6 , NR 5 COOR 6 , NR 5 CONR 6 , NR 5 SO 2 R 6 , COR 5 , SO 2 R 5 , halogen, CN, NO 2 , COOR 5 , CONR 5 R 6 , NCOR 7 , NCONR 7 , NCOOR 7 , SO 2 NR 5 R 6 , and NHSO 2 R 7 ; 
 R 12  is selected from the group consisting of H, alkyl, CH 2 R 13 , CH 2 COR 13 , CH 2 CONHR 13 , CH 2 CONHR 13 R 14 , CH 2 CONH(CH 2 ) 2 R 14 , (CH 2 ) 2 NR 13 , (CH 2 ) n NR 13 , CH 2 COOH, CH 2 CONH(CH 2 ) 2 NH 2 , and (CH 2 ) 2 N(CH 3 ) 2 ; 
 R 13  is selected from the group consisting of —OH and an optionally substituted heterocycle, hydrocarbyl, and substituted hydrocarbyl; 
 R 14  is selected from the group consisting of alkyl and NH 2 . 
 
       
     
     
         5 . The compound of  claim 1 , wherein the compound comprising Formula (I) comprises Formula (V): 
       
         
           
           
               
               
           
         
         wherein:
 X is selected from the group consisting of hydrogen and OR 2 ; 
 R 2  is independently selected from the group consisting of hydrogen, PO(OH) 2 , acetyl, COR 5 , CO(OR 5 ), CO(CH 2 ) n NR 5 R 6 , hydrocarbyl and substituted hydrocarbyl; 
 n is an integer from 1 to 10; 
 R 5  is selected from the group consisting of H and an optionally substituted alkyl, aryl, heterocycle, and cycloalkyl; 
 R 6  and R 7  are selected from the group consisting of an optionally substituted alkyl, cycolalkyl, aryl, and heterocycle; 
 Z is O; 
 Y is selected from the group consisting of O, CH(OH), CH(OR 5 ), CHNR 5 R 6 , CH 2 , S, and NR 5 ; 
 R 1  is selected from the group consisting of CH 3 , CF 3 , halogen, Cl, F, Br, I, OH, NH 2 , NR 5 R 6 , OCH 3 , CO 2 CH 3 , CONHCH 3 , alkyl, cyclopropyl, OR 5 , CO 2 R 5 , CONR 5 R 6 , hydrocarbyl, and substituted hydrocarbyl; 
 R 15  and R 16  are independently selected from the group consisting of hydrogen, NHCONH 2 , COOCH 3 , and CONHCH 3 , CONHCH 3 , COOCH 3 , COOH, CONH(heterocycle), heterocycle, alkyl, cyclopropyl, aryl, OR 5 , NR 5 R 6 , NR 5 COR 6 , NR 5 COOR 6 , NR 5 CONR 6 , NR 5 SO 2 R 6 , COR 5 , SO 2 R 5 , halogen, CN, NO 2 , COOR 5 , CONR 5 R 6 , NCOR 7 , NCONR 7 , NCOOR 7 , SO 2 NR 5 R 6 , and NHSO 2 R 7  or R 15  and R 16  can optionally form a cycloalkyl, aryl or heterocyclo ring. 
 
       
     
     
         6 . The compound of  claim 1 , wherein the compound comprising Formula (I) comprises Formula (VI): 
       
         
           
           
               
               
           
         
         wherein:
 X is selected from the group consisting of hydrogen and OR 2 ; 
 R 2  is independently selected from the group consisting of hydrogen, PO(OH) 2 , acetyl, COR 5 , CO(OR 5 ), CO(CH 2 ) n NR 5 R 6 , hydrocarbyl and substituted hydrocarbyl; 
 n is an integer from 1 to 10; 
 R 5  is selected from the group consisting of H and an optionally substituted alkyl, aryl, heterocycle, and cycloalkyl; 
 R 6  and R 7  are selected from the group consisting of an optionally substituted alkyl, cycolalkyl, aryl, and heterocycle; 
 Z is O; 
 Y is selected from the group consisting of O, CH(OH), CH(OR 5 ), CHNR 5 R 6 , CH 2 , S, and NR 5 ; 
 R 1  is selected from the group consisting of CH 3 , CF 3 , halogen, Cl, F, Br, I, OH, NH 2 , NR 5 R 6 , OCH 3 , CO 2 CH 3 , CONHCH 3 , alkyl, cyclopropyl, OR 5 , CO 2 R 5 , CONR 5 R 6 , hydrocarbyl, and substituted hydrocarbyl; 
 A is independently selected from the group consisting of CR 5  and N; 
 L is independently selected from the group consisting of no atom, N, NH, O and S; 
 R 17 , R 18 , R 19  and R 20  are selected from the group consisting of H and an optionally substituted cycloalkyl, aryl or heterocyclo 5 or 6 membered ring, 5-6 fused ring or 6-6 fused ring including but not limited to the following examples, wherein the example is attached via any available CH position: 
 
       
       
         
           
           
               
               
           
         
       
     
     
         7 . A method of treating a urinary tract infection, the method comprising administering a compound of  claim 1  to a subject in need thereof. 
     
     
         8 . The method of  claim 7 , wherein the subject is further administered a bactericidal composition. 
     
     
         9 . A method of preventing a urinary tract infection, the method comprising administering a compound of  claim 1  to a subject in need thereof. 
     
     
         10 . The method of  claim 9 , wherein the subject is further administered a bactericidal composition. 
     
     
         11 . A method of reducing the resistance of a bacterium to a bactericidal compound, the method comprising administering a compound of  claim 1  to a subject in need thereof. 
     
     
         12 . A method of treating inflammatory bowel disease, the method comprising administering a compound of  claim 1  to a subject in need thereof. 
     
     
         13 . The method of  claim 12 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         14 . The method of  claim 12 , wherein treating comprises reducing symptoms associated with inflammatory bowel disease. 
     
     
         15 . A method of inhibiting FimH binding to mannose, the method comprising contacting a compound of  claim 1  with FimH, wherein the compound binds FimH and inhibits binding to mannose. 
     
     
         16 . The method of  claim 15 , wherein the mannose is exposed on a bladder cell. 
     
     
         17 . The method of  claim 15 , wherein the mannose is exposed on an intestinal cell. 
     
     
         18 . A method of treating a catheter-associated urinary tract infection, the method comprising administering a compound of  claim 1  to a subject in need thereof. 
     
     
         19 . The compound of  claim 1 , wherein the compound is selected from the group consisting of:

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