Antibacterial agents: n(alpha)-aroyl-n-aryl-phenylalaninamides

Patent metadata

Field	Value
Publication number	US-2016347708-A1
Application number	US-201515116787-A
Country	US
Kind code	A1
Filing date	Feb 6, 2015
Priority date	Feb 6, 2014
Publication date	Dec 1, 2016
Grant date	—

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 - 29 . (canceled)

30 . A method of inhibiting a bacterial RNA polymerase, comprising contacting a bacterial RNA polymerase with a compound according to general structural formula (I), (II), (III), or (IV), or a salt thereof
formula (I),

where X, Y, and Z are each independently aryl or heteroaryl;
provided that, where X is unsubstituted 2-thiophenyl and Y is unsubstituted phenyl, Z is not 2-morpholino-phenyl;
provided that, where X is unsubstituted 2-thiophenyl and Y is unsubstituted phenyl, Z is not 2-ethoxy-phenyl; and
provided that, where X and Y are unsubstituted phenyl, Z is not 2-methyl-phenyl;

formula (II):

where X′, Y′, and Z′ are each independently aryl or heteroaryl; and
where the configuration of the Cα atom of the amino acid moiety containing Y′ is D;
provided that, where X′ is unsubstituted 2-thiophenyl and Y′ is unsubstituted phenyl, Z′ is not 2-morpholino-phenyl;
provided that, where X′ is unsubstituted 2-thiophenyl and Y′ is unsubstituted phenyl, Z′ is not 2-ethoxy-phenyl; and
provided that, where X′ and Y′ are unsubstituted phenyl, Z′ is not 2-methyl-phenyl;

formula (III):

where X″, Y″, and Z″ are each independently phenyl, pyridyl, pyrazinyl, furyl, thiophenyl, pyrrolyl, oxazoyl, thioxazoyl, isoxazoyl, thioisoxazoyl, napthyl, benzofuranyl, benzothiofuranyl, or indoyl, each optionally substituted with C1-C5 alkyl, C1-C5 acyl, C1-C5-O-acyl, C1-C5-NH-acyl, carboxy, C1-C5 ester, C1-C5 amide, C1-C5 alkoxy, C1-C5-monoalkylamino, C1-C5 dialkylamino, amino, hydroxy, or halogen;
provided that, where X″ is unsubstituted 2-thiophenyl and Y″ is unsubstituted phenyl, Z″ is not 2-morpholino-phenyl;
provided that, where X″ is unsubstituted 2-thiophenyl and Y″ is unsubstituted phenyl, Z″ is not 2-ethoxy-phenyl; and
provided that, where X″ and Y″ are unsubstituted phenyl, Z″ is not 2-methyl-phenyl;

formula (IV):

where X′″, Y′″, and Z′″ each independently is one of phenyl, pyridyl, pyrazinyl, furyl thiophenyl, pyrrolyl, oxazoyl, thioxazoyl, isoxazoyl, thioisoxazoyl, napthyl, benzofuranyl, benzothiofuranyl, or indoyl, each optionally substituted with C1-C5 alkyl, C1-C5 acyl, C1-C5-O-acyl, C1-C5-NH-acyl, carboxy, C1-C5 ester, C1-C5 amide, C1-C5 alkoxy, C1-C5-monoalkylamino, C1-C5 dialkylamino, amino, hydroxy, or halogen; and
where the configuration of the Cα atom of the amino acid moiety containing Y′″ is D;
provided that, where X′″ is unsubstituted 2-thiophenyl and Y′″ is unsubstituted phenyl, Z′″ is not 2-morpholino-phenyl;
provided that, where X′″ is unsubstituted 2-thiophenyl and Y′″ is unsubstituted phenyl, Z′″ is not 2-ethoxy-phenyl; and
provided that, where X′″ and Y′″ are unsubstituted phenyl, Z′″ is not 2-methyl-phenyl.

31 . A method of inhibiting one of the growth and the viability of a bacterium, comprising contacting a bacterium with a compound according to general structural formula (I), (II), (III), or (IV) as described in claim 30 , or a salt thereof.

32 . A method of preventing a bacterial infection, comprising administering to a mammal a compound according to general structural formula (I), (II), (III), or (IV) as described in claim 30 or a salt thereof.

33 . A method of treating a bacterial infection, comprising administering to a mammal a compound according to general structural formula (I), (II), (III), or (IV) as described in claim 30 , or a salt thereof.

34 . A formulation comprising a compound according to general structural formula (I), (II), (III), or (IV) as described in claim 30 , or a salt thereof, for administration to a mammal to prevent a bacterial infection.

35 . A formulation comprising a compound according to general structural formula (I), (II), (III), or (IV) as described in claim 30 , or a salt thereof, for administration to a mammal to treat a bacterial infection.

36 - 37 . (canceled)

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

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

Assignees

• Univ Rutgers

Inventors

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

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D215/40

  attached in position 8 · CPC title

• C07D217/22

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring · CPC title

• C07D317/66

  Nitrogen atoms not forming part of a nitro radical · CPC title

• A61K31/341

  not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine · CPC title