Aminothiazoles and their uses

Patent metadata

Field	Value
Publication number	US-9492496-B2
Application number	US-201414291572-A
Country	US
Kind code	B2
Filing date	May 30, 2014
Priority date	Dec 12, 2007
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

The present application describes organic compounds of Formula (I)

and pharmaceutical compositions thereof, and their use for the treatment, prevention and/or amelioration of diseases, particularly bacterial infections.

First claim

What is claimed is:

1. A compound of the formula I:

or a pharmaceutically acceptable salt thereof, including the pyridine N-oxide thereof,
wherein:
R 1 and R 1a , taken in combination, form a saturated, partially unsaturated or aromatic heterocycle having 4 to 7 ring atoms and having 0-3 additional ring heteroatoms selected from N, O and S, wherein the heterocycle is substituted by at least two residues independently selected from CO 2 H, —Z—CO 2 H, and -A-Z—CO 2 H;
A is independently selected at each occurrence from the group consisting of a —C(O)—, —C(O)O—, —C(O)N(R 8a )—, —S(O) 2 —, —S(O)—, —C(H)═N—, —S(O) 2 N(R 8a )—, and —S(O)N(R 8a )—;
Z is C 1 -C 10 alkylene, C 3 -C 8 cycloalkylene, C 3 -C 8 heterocycloalkylene, phenylene, or 5-6 membered heteroarylene, each of which is optionally substituted with one or more groups independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, amino, mono- and di-C 1 -C 6 alkylamino, C(O)OH, or halogen;
R 2a is selected from the group consisting of H, substituted or unsubstituted alkyl, OH, OR 4a , OC(O)R 4a , OC(O)N(R 8a ) 2 and N(R 8a ) 2 ;
R 2b is selected from the group consisting of absent, H and alkyl, or R 2a and R 2b may together form ═O or ═NH;
R 3 and R 12 are each, independently, selected from the group consisting of H, halogen, OR 4b , -A-J, and N(R 8a ) 2 ;
R 4a is selected from the group consisting of H, and alkyl;
R 4b is selected from the group consisting of alkyl and —(CH 2 —CH 2 —O—) n —R 9 , wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000;
R 5 is selected from the group consisting of H, alkyl, and R 4b ;
J is selected from the group consisting of H, F, O-alkyl, N(R 8a ) 2 , N + (R 8a ) 3 , N(R 8a )C(O)alkyl, CO 2 H, C(═O)N(R 8a ) 2 , CO 2 -alkyl, P(O)(OH) 2 , P(O)(O-alkyl) 2 , and a substituted nitrogen-containing heterocycle;
R 8a is absent, or selected from the group consisting of H, -(alkyl)-, -(cycloalkyl)-, C(alkyl) 2 -J, —R 4b , wherein R 8a can also cyclize with the atom to which R 8a is bonded to form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times with substituents that are the same or different; and
R 9 is selected from the group consisting of H, alkyl and CH 2 CO 2 H.

2. The compound of claim 1 , wherein R 2b , R 4b and R 5 are H, and R 4a is CH 3 .

3. The compound of claim 1 , wherein R 2b , R 4b and R 5 are H, R 4a is CH 3 , and R 12 is CH 2 —O—CH 3 .

4. The compound of claim 1 , wherein formula I is represented by a compound of formula II:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein formula I is represented by a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein
D represents a five or six membered heterocyclic ring which is saturated or aromatic, which ring comprises 0-2 additional ring heteroatoms selected from N, O or S.

6. The compound of claim 5 , wherein R 2b , R 4b and R 5 are H, and R 4a is CH 3 .

7. The compound of claim 5 , wherein R 2b , R 4b and R 5 are H, R 4a is CH 3 , and R 12 is CH 2 —O—CH 3 .

8. The compound of claim 5 , wherein formula V is represented by a compound of formula VI:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein
A is selected from the group consisting of —C(O)O—, C(O)—NH—, —C(O)—, —S(O) 2 —, and —S(O) 2 NH—; and
Z is independently selected at each occurrence from the group consisting of C 1 -C 10 alkylene,

10. The compound of claim 1 , wherein R 2a is OH or OAc.

11. The compound of claim 1 , wherein the core pyridine functionality is of the following N-oxide formula:

12. A compound selected from the group consisting of:

13. A compound of formula VII:

or a pharmaceutically acceptable salt thereof, including the pyridine N-oxide thereof;
wherein
R 1 and R 1a , taken in combination, form a saturated, partially unsaturated or aromatic heterocycle having 4 to 7 ring atoms and having 0-3 additional ring heteroatoms selected from N, O and S, wherein the heterocycle is substituted by at least two residues independently selected from CO 2 H, —Z—CO 2 H, and -A-Z—CO 2 H;
A is independently selected at each occurrence from the group consisting of a —C(O)—, —C(O)O—, —C(O)N(R 8a )—, —S(O) 2 —, —S(O)—, —C(H)═N—, —S(O) 2 N(R 8a )—, and —S(O)N(R 8a )—;
Z is C 1 -C 10 alkylene, C 3 -C 8 cycloalkylene, C 3 -C 8 heterocycloalkylene, phenylene, or 5-6 membered heteroarylene, each of which is optionally substituted with one or more groups independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, amino, mono- and di-C 1 -C 6 alkylamino, C(O)OH, or halogen;
R 2 is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 0-6 alkyl, C 3-7 cycloalkylC 0-4 alkyl, arylC 0-4 alkyl, or a residue of the formula:

R 2a is selected from the group consisting of H, substituted or unsubstituted alkyl, OH, OR 4a , OC(O)R 4a , OC(O)N(R 8a ) 2 and N(R 8a ) 2 ;
R 2b is selected from the group consisting of absent, H and alkyl, or R 2a and R 2b may together form ═O or ═NH;
R 3 and R 12 are each, independently, selected from the group consisting of H, halogen, OR 4b , -A-J, and N(R 8a ) 2 ;
R 4a is selected from the group consisting of H, and alkyl;
R 4b is selected from the group consisting of alkyl and —(CH 2 —CH 2 —O—) n —R 9 , wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000;
R 5 is selected from the group consisting of H, alkyl, and R 4b ;
J is selected from the group consisting of H, F, O-alkyl, N(R 8a ) 2 , N + (R 8a ) 3 , N(R 8a )C(O)alkyl, CO 2 H, C(═O)N(R 8a ) 2 , CO 2 -alkyl, P(O)(OH) 2 , P(O)(O-alkyl) 2 , and a substituted nitrogen-containing heterocycle;
R 8a is absent, or selected from the group consisting of H, -(alkyl)-, -(cycloalkyl)-, C(alkyl) 2 -J, —R 4b , wherein R 8a can also cyclize with the

Assignees

• Bushell Simon
• Lamarche Matthew J
• Leeds Jennifer
• Whitehead Lewis
• Novartis Ag

Inventors

• Bushell Simon
• Lamarche Matthew J
• Leeds Jennifer
• Whitehead Lewis

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P17/02

  for treating wounds, ulcers, burns, scars, keloids, or the like · CPC title

• A61P17/10

  Anti-acne agents · CPC title