Compounds and methods for treating mammalian gastrointestinal microbial infections

Patent metadata

Field	Value
Publication number	US-10125116-B2
Application number	US-201414571673-A
Country	US
Kind code	B2
Filing date	Dec 16, 2014
Priority date	Mar 20, 2009
Publication date	Nov 13, 2018
Grant date	Nov 13, 2018

Abstract

Described herein are compounds, and pharmaceutically acceptable salts and prodrugs thereof, which are useful as inhibitors of IMPDH. In certain embodiments, a compound of the invention selectively inhibits a parasitic IMPDH versus a host IMPDH. Further, the invention provides pharmaceutical compositions comprising one or more compounds of the invention. The invention also relates to methods of treating various parasitic and bacterial infections in mammals. 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 thereof, represented by Formula XIII:

wherein, independently for each occurrence,
X is O;
m is 1;
one occurrence of R 2 is hydrogen, and the other occurrence of R 2 is alkyl;

p is 0, 1, 2, or 3;
q is 0, 1, 2, 3, or 4; and
R 5 is halo, azido, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heterocycloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, haloalkyloxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, carboxylic acid, acyloxy, alkylthio, sulfonate, sulfonyl, sulfonamido, formyl, cyano, oxime, or isocyano;
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, formyl, cyano, and isocyano.

2. The compound of claim 1 , wherein

3. The compound of claim 1 , wherein

4. The compound of claim 1 , wherein

5. The compound of claim 1 , wherein

6. The compound of claim 1 , wherein

7. The compound of claim 1 , wherein

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

9. The compound of claim 1 , wherein one occurrence of R 2 is hydrogen, and the other occurrence of R 2 is methyl.

10. 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 .

11. The method of claim 10 , wherein said microbe is a protozoon, a bacterium, or a fungus.

12. The method of claim 10 , wherein said microbe is a protozoon or a bacterium selected from the group consisting of the genera Eimeria, Cryptosporidium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Tritrichomonas, Leishmania, Trypanosoma, Helicobacter, Borrelia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.

13. The method of claim 11 , wherein said microbe is a protozoon; and said protozoon is selected from the group consisting of the genera Eimeria, Cryptosporidium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Tritrichomonas, Leishmania and Trypanosoma.

14. The method of claim 11 , wherein said microbe is a bacterium; and said bacterium is selected from the group consisting of the genera Helicobacter, Borrelia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.

15. A method of treating or preventing a microbial infection in a mammal comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 .

16. The method of claim 15 , wherein said microbial infection is caused by a protozoon, a bacterium, or a fungus.

17. The method of claim 15 , wherein said microbial infection is caused by a protozoon or a bacterium selected from the group consisting of the genera Eimeria, Cryptosporidium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Leishmania, Trypanosoma, Helicobacter, Borrelia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.

18. The method of claim 16 , wherein said microbial infection is caused by a protozoon; and said protozoon is selected from the group consisting of the genera Eimeria, Cryptosporidium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Tritrichomonas, Leishmania and Trypanosoma.

19. The method of claim 15 , wherein said microbial infection is caused by a bacterium; and said bacterium is selected from the group consisting of the genera Helicobacter, Borrelia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.

20. The method of claim 13 , wherein the protozoon is of the genera Cryptosporidium.

21. The method of claim 18 , wherein the protozoon is of the genera Cryptosporidium.

Assignees

• Univ Brandeis
• Univ Georgia
• Brigham & Womens Hospital Inc

Inventors

• Hedstrom Lizbeth K
• Cuny Gregory D
• Gollapalli Deviprasad R
• Kirubakaran Sivapriya
• Maurya Sushil K
• Striepen Boris
• Gorla Suresh K
• Johnson Corey R
• Kavitha Mandapati
• Khan Jihan

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/04

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

• C07C233/15

  with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring · CPC title