Antibacterial agents: Nα-aroyl-N-aryl-phenylalaninamides

Patent metadata

Field	Value
Publication number	US-9919998-B2
Application number	US-201515116787-A
Country	US
Kind code	B2
Filing date	Feb 6, 2015
Priority date	Feb 6, 2014
Publication date	Mar 20, 2018
Grant date	Mar 20, 2018

Abstract

The invention provides compounds having activity as bacterial RNA polymerase inhibitors and antibacterial agents, as well as compositions comprising the compounds and methods for their use. Specifically, phenylalanineamide and tyrosinamide compounds are disclosed that have inhibitory activity toward mycobacterium tuberculosis RNA polymerase. Use of these compounds in the treatment or prevention of M. tuberculosis infections in a mammal, is disclosed.

First claim

What is claimed is:

1. A compound of formula (V), or a salt thereof:

wherein T and U each is carbon;
V is carbon;
A and B each is carbon;
E is one of carbon (CH), nitrogen, oxygen, and sulfur;
G is one of hydrogen, halogen, carbon (CH), nitrogen, oxygen, and sulfur;
J is carbon, and J, together with T, U, V, and two additional carbon atoms, forms a phenyl;
R 1 and R 2 each independently is hydrogen, halogen, alkyl, alkoxy-substituted alkyl, or alkoxy, each optionally substituted by halogen;
R 3 and R 4 each independently is hydrogen, halogen, hydroxy; —O—C(═O)—C 1 -C 4 alkyl, —O—C(═O)-phenyl, or morpholino
R 5 , R 6 , R 7 , and R 8 each independently is absent, hydrogen, halogen, or alkyl which is optionally substituted by halogen; or R 5 and R 6 , together with E, form a cycle containing 5 to 9 atoms selected from carbon, nitrogen, oxygen, and sulfur, said cycle optionally substituted with halogen, amine, alkyl, or acyl; or R 7 and R 8 , together with G, form a cycle containing 5 atoms selected from carbon and nitrogen; and
R 9 , R 10 , and R 11 each independently is hydrogen or halogen;
provided that when E is carbon, G is hydrogen or is the carbon atom of an unsubstituted methyl group, R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , and R 11 are hydrogen; then E is bonded to no more than two hydrogen atoms and no more than two fluorine atoms;
provided that when E is oxygen, G is hydrogen, and R 1 , R 3 , R 9 , R 10 , and R 11 are hydrogen; then E is not bonded to hydrogen or unsubstituted ethyl; and
provided that when E is oxygen, G is hydrogen, and R 1 , R 2 , R 3 , R 9 , R 10 , and R 11 are hydrogen, and R 9 is chlorine; then E is not bonded to hydrogen or unsubstituted methyl.

2. The compound of claim 1 wherein the compound of formula (V) is a compound of formula (VI), or a salt thereof:

wherein the configuration of the Cα atom of the central amino acid moiety, the carbon identified with the *, has the indicated, D, absolute configuration.

3. The compound of claim 1 which is selected from the group consisting of:

and salts thereof.

4. A pharmaceutical composition comprising a compound as described in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

5. The compound of claim 1 , wherein R 3 and R 4 each independently is hydrogen or hydroxy.

6. The compound of claim 1 , wherein R 5 and R 6 each independently is absent, hydrogen, halogen, or alkyl which is optionally substituted by halogen.

7. The compound of claim 1 , wherein R 5 and R 6 , together with E, form a cycle containing 6 atoms selected from carbon, nitrogen, oxygen, and sulfur, said cycle optionally substituted with halogen, amine or acyl.

8. The compound of claim 1 , wherein G is hydrogen; and R 7 and R 8 are absent.

9. A compound of formula (V), or a salt thereof:

wherein T and U each is carbon;
V is carbon;
A and B each is carbon;
E is one of carbon (CH), nitrogen, oxygen, and sulfur;
G is one of carbon (CH), nitrogen, oxygen, and sulfur;
J is carbon, and J, together with T, U, V, and two additional atoms, forms a phenyl;
R 1 and R 2 each independently is hydrogen, halogen, or is alkyl which is optionally substituted by halogen;
R 3 and R 4 each independently is hydrogen, halogen, or hydroxy; and
R 6 and R 7 are absent and E and G, together with A and B, form a cycle containing 5 to 6 atoms selected from carbon, nitrogen, oxygen, and sulfur, said cycle optionally substituted with halogen or alkyl;
R 5 and R 8 each independently is absent, hydrogen, halogen, or alkyl; and
R 9 , R 10 , and R 11 each independently is hydrogen or halogen.

10. The compound of claim 9 wherein the compound of formula (V) is a compound of formula (VI), or a salt thereof:

wherein the configuration of the Cα atom of the central amino acid moiety, the carbon identified with the *, has the indicated, D, absolute configuration.

11. The compound of claim 9 which is selected from the group consisting of:

and salts thereof.

12. A compound of formula (V), or a salt thereof:

wherein T and U each is carbon;
V is carbon;
A and B each is carbon;
E is one of carbon (CH), nitrogen, oxygen, and sulfur;
G is one of hydrogen, halogen, carbon (CH), nitrogen, oxygen, and sulfur;
J is sulfur, and J, together with T, U, V, and one additional atom, forms a thiophenyl;
R 1 and R 2 each independently is hydrogen, halogen, or alkyl that is optionally substituted by halogen;
R 3 and R 4 each ind

Assignees

• Univ Rutgers

Inventors

• Ebright Richard H
• Ebright Yon W
• Mandal Soma
• Wilde Richard
• Li Shengjian

Classifications

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• A01N43/56

  1,2-Diazoles; Hydrogenated 1,2-diazoles · CPC title

• C07D211/58

  attached in position 4 · CPC title

• A01N43/40

  six-membered rings · CPC title