Granted Patent B2

US 10,639,318 · App. 16/188,982 · Granted May 5, 2020

Abstract

Claims (63)

1. A sterile container comprising:

an antibacterial agent in solid form; and

a compound of Formula (I) in solid form having the structure:

or a pharmaceutically acceptable salt thereof, wherein:

Y is a 1-4 atom alkylene or 2-4 atom alkenylene linker, optionally substituted by one or more substituents selected from the group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 , wherein said alkylene or alkenylene linker is optionally fused to an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

R 1 is selected from a group consisting of —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, —NR 9 R 10 , —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , -carbocyclyl-R 11 , —CH(OH)C 1-9 alkylR 9 , —CH(OH)C 2-9 alkenylR 9 , —CH(OH)C 2-9 alkynylR 9 , —CH(OH)carbocyclyl-R 9 , —C(═O)R 9 , —C(═O)C 1-9 alkylR 9 , —C(═O)C 2-9 alkenylR 9 , —C(═O)C 2-9 alkynylR 9 , —C(═O)C 2-9 carbocyclyl-R 9 , —C(═O)NR 9 R 10 , —N(R 9 )C(═O)R 9 , —N(R 9 )C(═O)NR 9 R 10 , —N(R 9 )C(═O)OR 9 , —N(R 9 )C(═O)C(═NR 10 )R 9 , —N(R 9 )C(═O)C(═CR 9 R 10 )R 9 , —N(R 9 )C(═O)C 1-4 alkylN(R 9 )C(═O)R 9 , —N(R 9 )C(═NR 10 )R 9 , —C(═NR 10 )NR 9 R 10 , —N═C(R 9 )NR 9 R 10 , —N(R 9 )SO 2 R 9 , —N(R 9 )SO 2 NR 9 R 10 , —N═CHR 9 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl;

R 6 is selected from a group consisting of H, —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, carbocyclyl, —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , -carbocyclyl-R 11 , —C(═O)OR 9 , —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , —C 2-9 alkynylCO 2 R 9 , and -carbocyclyl-CO 2 R 9 , or alternatively:

(i) R 6 and an R 7 are taken together with the atoms to which they are attached to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, or

(ii) R 6 is absent when the carbon to which it is attached is a ring atom in an aryl or heteroaryl ring;

each R 7 is independently selected from a group consisting of H, halo, —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, —NR 9 R 10 , —OR 9 , —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , —C 2-9 alkynylCO 2 R 9 , and -carbocyclyl-CO 2 R 9 , or independently:

(i) R 6 and an R 7 are taken together with the atoms to which they are attached to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, or

(ii) R 7 and an R 8 are taken together with the atoms to which they are attached to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;

each R 8 is independently selected from a group consisting of H, halo, —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, —NR 9 R 10 , —OR 9 , —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , —C 2-9 alkynylCO 2 R 9 , and -carbocyclyl-CO 2 R 9 , or independently:

(i) an R 7 and an R 8 are taken together with the atoms to which they are attached to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl,

(ii) a geminal R 7 and R 8 together form —C 2-9 alkenylenylCO 2 R 9 , or

(iii) each R 8 attached to a ring atom forming part of an optionally substituted aryl is absent;

each R 9 is independently selected from a group consisting of H, —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, carbocyclyl, —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , -carbocyclyl-R 11 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —(CH 2 ) 0-3 carbocyclyl, and optionally substituted heterocyclyl;

each R 10 is independently selected from a group consisting of H, —C 1-9 alkyl, —OR 9 , —CH(═NH), —C(═O)OR 9 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl;

each R 11 is independently selected from a group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl;

X is selected from a group consisting of —CO 2 R 12 and a carboxylic acid isostere;

R 12 is selected from a group consisting of H, —C 1-9 alkyl, —(CH 2 ) 0-3 —R 11 , —C(R 13 ) 2 OC(O)C 1-9 alkyl, —C(R 13 ) 2 OC(O)R 11 , —C(R 13 ) 2 OC(O)OC 1-9 alkyl, and —C(R 13 ) 2 OC(O)OR 11 ;

each R 13 is independently selected from a group consisting of H and —C 1-4 alkyl; and

m is independently zero or an integer from 1 to 2,

wherein each —C 1-9 alkyl, —C 2-9 alkenyl, and —C 2-9 alkynyl is independently optionally substituted.

2. The sterile container of claim 1 , wherein the compound has the structure of formula II:

or a pharmaceutically acceptable salt thereof, wherein:

the bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond with the proviso that the dashed and solid line can only be a double bond when n is 1;

R 1 is selected from a group consisting of —NR 9 R 10 , —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , -carbocyclyl-R 11 , —CH(OH)C 1-9 alkylR 9 , —CH(OH)C 2-9 alkenylR 9 , —CH(OH)C 2-9 alkynylR 9 , —CH(OH)carbocyclyl-R 9 , —C(═O)R 9 , —C(═O)C 1-9 alkylR 9 , —C(═O)C 2-9 alkenylR 9 , —C(═O)C 2-9 alkynylR 9 , —C(═O)C 2-9 carbocyclyl-R 9 , —C(═O)NR 9 R 10 , —N(R 9 )C(═O)R 9 , —N(R 9 )C(═O)NR 9 R 10 , —N(R 9 )C(═O)OR 9 , —N(R 9 )C(═O)C(═NR 10 )R 9 , —N(R 9 )C(═O)C(═CR 9 R 10 )R 9 , —N(R 9 )C(═O)C 1-4 alkylN(R 9 )C(═O)R 9 , —N(R 9 )C(═NR 10 )R 9 , —C(═NR 10 )NR 9 R 10 , —N═C(R 9 )NR 9 R 10 , —N(R 9 )SO 2 R 9 , —N(R 9 )SO 2 NR 9 R 10 , —N═CHR 9 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl;

R 2 and R 4 are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ;

R 3 and R 5 are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 , with the proviso that if the bond represented by a dashed and solid line is a double bond then R 3 and R 5 are absent;

R 6 is selected from a group consisting of H, —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , —C(═O)OR 9 , —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , and —C 2-9 alkynylCO 2 R 9 ;

each R 7 is independently selected from a group consisting of H, —NR 9 R 10 , —OR 9 , —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , and —C 2-9 alkynylCO 2 R 9 ;

each R 8 is independently selected from a group consisting of H, —NR 9 R 10 , —OR 9 , —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , and —C 2-9 alkynylCO 2 R 9 ;

each R 9 is independently selected from a group consisting of H, —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —(CH 2 ) 0-3 carbocyclyl, and optionally substituted heterocyclyl;

each R 10 is independently selected from a group consisting of H, —C 1-9 alkyl, —OR 9 , —CH(═NH), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl;

R 11 is as defined above;

X is —CO 2 H; and

n is independently zero or an integer from 1 to 2.

3. The sterile container of claim 2 , wherein n is 1.

4. The sterile container of claim 2 , wherein R 2 , R 3 , R 4 , and R 5 are hydrogen.

5. The sterile container of claim 1 , wherein the compound has a structure selected from the group consisting of formula IIIa, IIIb, IVa, IVb, and IVc:

or a pharmaceutically acceptable salt thereof, wherein:

the bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;

each R 2 and R 4 are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ; and

each R 3 and R 5 are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 , with the proviso that if the bond represented by a dashed and solid line is a double bond then R 3 and R 5 are absent.

6. The sterile container of claim 1 , wherein R 1 is —NHC(═O)Cl 19 alkylR 11 .

7. The sterile container of claim 6 , wherein R 11 is optionally substituted aryl or optionally substituted heteroaryl.

8. The sterile container of claim 7 , wherein R 11 is thien-2-yl.

9. The sterile container of claim 1 , wherein m is 1.

10. The sterile container of claim 1 , wherein R 6 and each R 7 and R 8 is hydrogen.

11. The sterile container of claim 1 , wherein X is —CO 2 H.

12. The sterile container of claim 1 , wherein the compounds has a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. The sterile container of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

14. The sterile container of claim 1 , wherein the compound and the antibacterial agent are blended.

15. The sterile container of claim 1 , wherein the compound and the antibacterial agent are not blended.

16. The sterile container of claim 1 , wherein the compound and the antibacterial agent are lyophiles.

17. The sterile container of claim 1 , wherein the molar ratio of the compound to the antibacterial agent is from 1:8 to 8:1.

18. The sterile container of claim 1 , wherein the molar ratio of the compound to the antibacterial agent is from 1:2 to 2:1.

19. The sterile container of claim 1 , wherein the molar ratio of the compound to the antibacterial agent is 1:1.

20. The sterile container of claim 1 , further comprising a pH adjuster.

21. The sterile container of claim 20 , wherein the pH adjuster is selected from the group consisting of NaOH, citric acid, and sodium carbonate.

Assignments (6)