Compounds and methods for treating bacterial infections

Patent metadata

Field	Value
Publication number	US-2016145289-A1
Application number	US-201414894927-A
Country	US
Kind code	A1
Filing date	May 30, 2014
Priority date	May 30, 2013
Publication date	May 26, 2016
Grant date	—

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.

First claim

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, CON R 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 0;
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 (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 NRS;
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 (V):

wherein:
X is selected from the group consisting of hydrogen and OR 2 ;
R 2 is

Assignees

• Janetka James W
• Han Zhenfu
• Hultgren Scott
• Pinkner Jerry
• Cusumano Corinne
• Univ Washington

Inventors

• Janetka James W
• Han Zhenfu
• Hultgren Scott
• Pinkner Jerry
• Cusumano Corinne

Classifications

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P13/02

  of urine or of the urinary tract, e.g. urine acidifiers · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title