Compounds and methods for treating mammalian gastrointestinal microbial infections

Patent metadata

Field	Value
Publication number	US-9447134-B2
Application number	US-201314421818-A
Country	US
Kind code	B2
Filing date	Aug 19, 2013
Priority date	Aug 17, 2012
Publication date	Sep 20, 2016
Grant date	Sep 20, 2016

Abstract

Disclosed are compounds and pharmaceutically acceptable salts thereof, which are useful as inhibitors of IMPDH. In certain embodiments, a compound selectively inhibits a parasitic IMPDH versus a host IMPDH. Also disclosed are pharmaceutical compositions comprising one or more compounds of the invention. Related methods of treating various parasitic and bacterial infections in mammals are disclosed. Moreover, the compounds may be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antimicrobials and immunosuppressants.

First claim

We claim:

1. A compound, or a pharmaceutically acceptable salt or ester thereof, selected from the group consisting of

2. A compound, or a pharmaceutically acceptable salt or ester thereof, represented by Formula X or Formula XIII:

wherein, independently for each occurrence,
X 3 X is C(R′) 2 , S, or NR′;
wherein R′ is hydrogen, halide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, aracyl, or heteroaracyl;

m is 0, 1, or 2;
n is 0, 1, 2, or 3;
R 14 X is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, aracyl, heteroaracyl sulfonate, sulfonyl, sulfonamido, formyl, carboxyl, alkoxycarbonyl, or acyloxy, or two R 14 X groups taken together form a non-aromatic 3-8 membered ring, or two R 14 X groups taken together form the side chain of a natural or non-natural D or L amino acid;
Z X is hydrogen, halo, azido, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, acyloxy, silyl, alkylthio, sulfonate, sulfonyl, sulfonamido, sulfhydryl, formyl, cyano, or isocyano;

 is hydrogen, halogen, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, halogen, amino, amido, acyl, aracyl, heteroaracyl, alkoxy, hydroxyl, carboxyl, alkoxylcarbonyl, acyloxy, silyl, alkylthio, sulfonate, sulfonyl, sulfonamido, sulfhydryl, formyl, cyano, isocyano, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; and

 is monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;

wherein, independently for each occurrence,
X 3 XIII is absent, O, C(R′) 2 , S, or NR′;
R 14 XIII is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, aracyl, heteroaracyl sulfonate, sulfonyl, sulfonamido, formyl, carboxyl, alkoxycarbonyl, or acyloxy, or two R 14 XIII groups taken together form a non-aromatic 3-8 membered ring, or two R 14 XIII groups taken together form the side chain of a natural or non-natural D or L amino acid;
Z XIII is halo, azido, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, acyloxy, silyl, alkylthio, sulfonate, sulfonyl, sulfonamido, sulfhydryl, formyl, cyano, or isocyano;

 is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, halogen, amino, amido, acyl, aracyl, heteroaracyl, alkoxy, hydroxyl, carboxyl, alkoxylcarbonyl, acyloxy, silyl, alkylthio, sulfonate, sulfonyl, sulfonamido, sulfhydryl, formyl, cyano, isocyano, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;

 is monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, or monocyclic or bicyclic heteroaryl;
p is 1, 2, or 3; and
wherein R′ and m are as defined for Formula X;
wherein, any of the aforementioned alkyl, aryl, or heteroaryl may be substituted with one or more groups independently selected from the group consisting of halo, azido, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, acyloxy, silyl, alkylthio, sulfonate, sulfonyl, sulfonamido, sulfhydryl, formyl, cyano, and isocyano.

3. A compound or a pharmaceutically acceptable salt or ester thereof, selected from the group consisting of

4. A method of killing or inhibiting the growth of a microbe, comprising the step of contacting said microbe with an effective amount of a compound of claim 1 .

5. The method of claim 4 , wherein said microbe is a protozoan or a bacterium.

6. The method of claim 4 , wherein said microbe is a protozoan or a bacterium selected from the group consisting of the genera Toxoplasma, Eimeria, Cryptosporidium, Plasmodium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Tritrichomonas, Leishmania, Trypanosoma, Helicobacter, Borrelia, Salmonella, Shigella, Yersinia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.

7. The method of claim 5 , wherein said microbe is a protozoan; and said protozoan is selected from the group consisting of the genera Cryptosporidium, Entamoeba, Leishmania and Trypanosoma.

8. The method of claim 7 , wherein said protozoan is selected from the genus Cryptosporidium.

9. The method of claim 5 , wherein said microbe is a bacterium; and said bacterium is selected from the group consisting of the genera Acinetobacter, Arcobacter, Bacillus, Bacteroides, Borrelia, Brachyspira, Brucella, Burkholderia, Campylobacter, Clostridia, Coxiella, Enterococcus, Erysipelothrix, Francisella, Fusobacterium, Helicobacter, Lactobacillus, Listeria, Mycobacterium, Neisseria, Pseudomonas, Staphylococcus and Streptococcus.

10. A method of treating or preventing a microbial infection in a mammal or bird comprising t

Assignees

• Univ Brandeis
• Brigham & Womens Hospital Inc

Inventors

• Hedstrom Lizbeth K
• Cuny Gregory D
• Gorla Suresh K
• Kavitha Mandapati

Classifications

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07C275/36

  with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• A61K31/277

  having a ring, e.g. verapamil · CPC title