Anti-infective agents useful against multidrug-resistant strains of bacteria

• US 6,946,446 B2
• Filed: 02/23/2001
• Issued: 09/20/2005
• Est. Priority Date: 02/24/2000
• Status: Expired due to Term

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Zhang, Suoming, Nemoto, Peter, Ma, Zhenkun, Yong, Hong, Or, Yat Sun
• Primary Examiner(s): Peselev, Elli
• Application Number:
  US09/791,408
• Publication Number:
  US 20020019355A1
• Time in Patent Office: 1,670 Days
• Field of Search: 514/29, 536/7.3, 536/7.4
• US Class Current: 514/29
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: C07H 17/08 Hetero rings containing eight or more ring members, e.g. erythromycins

Abstract

The invention relates to novel methods for using macrolide anti-infective agents. The macrolide anti-infective agents demonstrate antibacterial activity against multi-drug resistant strains of bacteria and, in particular, methicillin-resistant Staphylococcus aureus (MRSA). Methods for inhibiting the activity of multi-drug resistant bacterial organisms and methods for treating a bacterial infection caused by such organisms are described herein.

Claims

1. A method of inhibiting the activity of methicillin-resistant bacteria in a mammal, comprising administering to the mammal an effective amount of a compound of the formula

a compound of the formula

a compound of the formula

wherein

R¹ is selected from the group consisting of

a hydrocarbon selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl, wherein 1 to 3 carbons of said hydrocarbon are optionally replaced by an O, S or N heteroatom or a group selected from the group consisting of —

C(O)—

, —

C═

N—

, —

C═

N—

O— and

—

N(R⁵)—

; and

wherein said hydrocarbon is optionally substituted with one to three substituents selected from the group consisting of —

C(O)R⁶, —

S(O)_nR⁶, —

NHC(O)R⁶, —

NHC(O)NR⁷R⁸, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl and heterocycloalkyl, wherein n is 1 or 2;

R² is selected from the group consisting of

(a) hydrogen,

(b) a hydrocarbon selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl, wherein 1 to 3 carbons of said hydrocarbon are optionally replaced by an O, S or N heteroatom or a group selected from the group consisting of —

C(O)—

, —

C═

N—

, —

C═

N—

O— and

—

N(R⁵)—

; and

wherein said hydrocarbon is optionally substituted with one to three substituents selected from the group consisting of —

C(O)R⁶, —

S(O)_nR⁶, —

NHC(O)R⁶, —

NHC(O)NR⁷R⁸, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl and heterocycloalkyl;

(c) optionally substituted aryl; and

(d) optionally substituted heteroaryl;

R³ is selected from the group consisting of

(a) —

H,

(b) —

OH,

(c) —

OC(O)R⁹,

(d) —

OC(O)NHR⁹, and

(e) —

OC(O)OR⁹;

R⁴ selected from the group consisting of

(a) —

H,

(b) —

C(O)R⁹,

(c) —

C(O)NHR⁹, and

(d) —

C(O)OR⁹;

R⁵ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl substituted with optionally substituted aryl or optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted heteroaryl;

R⁶ is hydrogen, alkyl optionally substituted with aryl or heteroaryl, optionally substituted aryl, or optionally substituted heteroaryl;

R⁷ and R₈ are independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl substituted with optionally substituted aryl or heteroaryl, optionally substituted aryl, or optionally substituted heteroaryl, or R⁷ and R⁸ taken together with the atoms to which they are attached form a C₃-C₁₂ cycloalkyl group; and

R⁹ is a hydrocarbon selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl, wherein 1 to 3 carbons of said hydrocarbon are optionally replaced by an O, S or N heteroatom, or a group selected from the group consisting of —

C(O)—

, —

C═

N—

, —

C═

N—

O— and

—

N(R⁵)—

; and

wherein said hydrocarbon is optionally substituted with one to three substituents selected from the group consisting of —

C(O)R⁶, —

S(O)_nR⁶, —

NHC(O)R⁶, —

NHC(O)NR⁷R⁸, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl and heterocycloalkyl.

2. The method according to claim 1, wherein R¹ is selected from the group consisting of —

CH₃;

—

CH₂CH═

CH;

—

CH₂(3-iodophenyl);

—

CH₂CH═

CH(3-quinolyl); and

—

CH₂(4-phenylphenyl).

3. The method according to claim 1, wherein R² is selected from the group consisting of hydrogen;

—

CH₂-phenyl;

—

CH₂CH₃;

—

CH₂CH(CH₃)₂;

—

CH₃;

—

CH₂CH₂CH₂CH₃;

—

CH₂(4-nitrophenyl); and

—

CH₂CO(piperizine-N-phenyl).

4. The method according to claim 1, wherein the compound is selected from the group consisting of:

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂CH₃;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₃;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂CH(CH₃)₂;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂-phenyl;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂(4-nitrophenyl),

compound of formula I;

R¹ is —

CH₃, R² is —

CH₂CH(CH₃)₂ and R³ is —

OH;

compound of formula III;

R¹ is —

CH₃ and R² is —

CH₂-phenyl;

compound of formula I;

R¹ is —

CH₂(3-iodophenyl), R² is —

H and R³ is —

OH;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂CH₂CH₃;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂CH₂CH₂CH₃;

compound of formula III;

R¹ is —

CH₂CH═

CH₂ and R² is —

H;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂CO(piperizine-N-pbenyl); and

compound of formula I;

R¹ is —

CH₂(4-phenylphenyl) and R² is —

H and R³ is —

OH.

5. The method according to claim 1, wherein the bacteria is a methicillin-resistant strain of Staphylococcus aureus.

6. A method of treating bacterial infection caused by a methicillin-resistant strain of bacteria, comprising administering to a patient in need a therapeutically effective amount of a compound of the formula

a compound of the formula

a compound of the formula

wherein

R¹ is selected from the group consisting of

a hydrocarbon selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl, wherein 1 to 3 carbons of said hydrocarbon are optionally replaced by an O, S, or N heteroatom or a group selected from the group consisting of —

C(O)—

, —

C═

N—

, —

C═

N—

O— and

—

N(R⁵)—

; and

wherein said hydrocarbon is optionally substituted with one to three substituents selected from —

C(O)R⁶, —

S(O)_nR⁶, —

NHC(O)R⁶, —

NHC(O)NR⁷R⁸, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl and heterocycloalkyl, wherein n is 1 or 2;

R² is selected from the group consisting of

(a) hydrogen,

(b) a hydrocarbon selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl, wherein 1 to 3 carbons of said hydrocarbon are optionally replaced by an O, S or N heteroatom or a group selected from the group consisting of —

C(O)—

, —

C═

N—

, —

C═

N—

O— and

—

N(R⁵)—

; and

wherein said hydrocarbon is optionally substituted with one to three substituents selected from the group consisting of —

C(O)R⁶, —

S(O)_nR⁶, —

NHC(O)R⁶, —

NHC(O)NR⁷R⁸, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl and heterocycloalkyl;

(c) optionally substituted aryl; and

(d) optionally substituted heteroaryl;

R³ is selected from the group consisting of

(a) —

H,

(b) —

OH,

(c) —

OC(O)R⁹,

(d) —

OC(O)NHR⁹, and

(e) —

OC(O)OR⁹;

R⁴ is selected from the group consisting of

(a) —

H,

(b) —

C(O)R⁹,

(c) —

C(O)NHR⁹, and

(d) —

C(O)OR⁹;

R⁵ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl substituted with optionally substituted aryl or optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted heteroaryl;

R⁶ is hydrogen, alkyl optionally substituted with aryl or heteroaryl, optionally substituted aryl, or optionally substituted heteroaryl;

R⁷ and R⁸ are independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl substituted with optionally substituted aryl or heteroaryl, optionally substituted aryl, or optionally substituted heteroaryl, or R⁷ and R⁸ taken together with the atoms to which they are attached form a C₃-C₁₂ cycloalkyl group; and

R⁹ is a hydrocarbon selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl, wherein 1 to 3 carbons of said hydrocarbon are optionally replaced by an O, S or N heteroatom, or a group selected from the group consisting of —

C(O)—

, —

C═

N—

, —

C═

N—

O— and

—

N(R⁵)—

; and

wherein said hydrocarbon is optionally substituted with one to three substituents selected from the group consisting of —

C(O)R⁶, —

S(O)_nR⁶, —

NHC(O)R⁶, —

NHC(O)NR⁷R⁸, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl and heterocycloalkyl.

7. The method according to claim 6, wherein the compound is selected from the group consisting of:

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂CH₃;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₃;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂CH(CH₃)₂;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂-phenyl;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂(4-nitrophenyl);

compound of formula I;

R¹ is —

CH₃, R² is —

CH₂CH(CH₃)₂ and R³ is —

OH;

compound of formula III;

R¹ is —

CH₃ and R² is —

CH₂-phenyl;

compound of formula I;

R¹ is —

CH₂(3-iodophenyl), R² is —

H and R³ is —

OH;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂CH₂CH₃;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂CH₂CH₂CH₃;

compound of formula III;

R¹ is —

CH₂CH═

CH₂ and R² is —

H;

compound of formula III;

R¹ is —

CH₂CH═

CH(3-quinolyl) and R² is —

CH₂CO(piperizine-N-phenyl); and

compound of formula I;

R¹ is —

CH₂(4-phenylphenyl) and R² is —

H and R³ is —

OH.

8. The method according to claim 6, wherein the bacteria is Staphylococcus aureus.

9. The method according to claim 6, wherein said compound is administered orally, parenterally, intraperitoneally, intracisternally, rectally, intravaginally, topically or bucally.

10. The method according to claim 6, wherein said compound is administered as a capsule, dragee, elixir, emulsion, granule, microemulsion, tablet, pill, powder, solution, suspension, syrup, spray, suppository, or patch.

11. The method according to claim 6, wherein said compound is administered to a human or an animal.

12. The method according to claim 6, wherein said compound is administered in an amount from about 0.1 milligram per kilogram of body weight to about 50 milligrams per kilogram of body weight.

13. The method according to claim 12, wherein said compound is administered in an amount from about 1 milligram per kilogram of body weight to about 25 milligrams per kilogram of body weight.

14. The method according to claim 12, wherein said compound is administered in a single dose.

15. The method according to claim 12, wherein said compound is administered in a divided dose to obtain a total daily dose in an amount from about 0.1 milligram per kilogram of body weight to about 50 milligrams per kilogram of body weight.

16. The method according to claim 15, wherein said compound is administered in an amount from about 1 milligram per kilogram of body weight to about 25 milligrams per kilogram of body weight.

17. A compound having the formula

or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, wherein

R¹ is selected from the group consisting of

a hydrocarbon selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl, wherein 1 to 3 carbons of said hydrocarbon is optionally replaced by an O, S or N heteroatom, or a group selected from the group consisting of —

C(O)—

, —

C═

N—

, —

C═

N—

O— and

—

N(R⁵)—

; and

wherein said hydrocarbon is optionally substituted with one to three substituents selected from the group consisting of —

C(O)R⁶, —

S(O)_nR⁶, —

NHC(O)R⁶, —

NHC(O)NR⁷R⁸, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl and heterocycloalkyl, wherein n is 1 or 2;

R² selected from the group consisting of

(a) hydrogen,

(b) a hydrocarbon selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl, wherein 1 to 3 carbons of said hydrocarbon is optionally replaced by an O, S or N heteroatom, or a group selected from the group consisting of —

C(O)—

, —

C═

N—

, —

C═

N—

O— and

—

N(R⁵)—

; and

wherein said hydrocarbon is optionally substituted with one to three substituents selected from the group consisting of —

C(O)R⁶, —

S(O)_nR⁶, —

NHC(O)R⁶, —

NHC(O)NR⁷R⁸, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl and heterocycloalkyl;

(c) optionally substituted aryl; and

(d) optionally substituted heteroaryl;

R³ is selected from the group consisting of

(a) —

H,

(b) —

OH,

(c) —

OC(O)R⁹,

(d) —

OC(O)NHR⁹, and

(e) —

OC(O)OR⁹;

R⁴ is selected from the group consisting of

(a) —

H,

(b) —

C(O)R⁹,

(c) —

C(O)NHR⁹, and

(d) —

C(O)OR⁹;

R⁵ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl substituted with optionally substituted aryl or optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted heteroaryl;

R⁶ is hydrogen, alkyl optionally substituted with aryl or heteroaryl, optionally substituted aryl, or optionally substituted heteroaryl;

R⁷ and R⁸ are independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl substituted with optionally substituted aryl or heteroaryl, optionally substituted aryl, or optionally substituted heteroaryl, or R⁷ and R⁸ taken together with the atoms to which they are attached form a C₃-C₁₂ cycloalkyl group; and

R⁹ is a hydrocarbon selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl, wherein 1 to 3 carbons of said hydrocarbon are optionally replaced by an O, S or N heteroatom, or a group selected from the group consisting of —

C(O)—

, —

C═

N—

, —

C═

N—

O— and

—

N(R⁵)—

; and

wherein said hydrocarbon is optionally substituted with one to three substituents selected from the group consisting of —

C(O)R⁶, —

S(O)_nR⁶, —

NHC(O)R⁶, —

NHC(O)NR⁷R⁸, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl and heterocycloalkyl.

18. A compound having the formula

wherein

R¹ is selected from the group consisting of a hydrocarbon selected from the group consisting of C₃-C₁₂ alkyl, C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl, wherein 1 to 3 carbons of said C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl are optionally replaced by an O, S or N heteroatom or a group selected from the group consisting of —

C(O)—

, —

C═

N—

, —

C═

N—

O— and

—

N(R⁵)—

; and

wherein said hydrocarbon is optionally substituted with one to three substituents selected from the group consisting of —

C(O)R⁶, —

S(O)_nR⁶, —

NHC(O)R⁶, —

NHC(O)NR⁷R⁸, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl and heterocycloalkyl, wherein n is 1 or 2;

R² is selected from the group consisting of

(a) hydrogen,

(b) a hydrocarbon selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl, wherein 1 to 3 carbons of said hydrocarbon are optionally replaced by an O, S or N heteroatom or a group selected from the group consisting of —

C(O)—

, —

C═

N—

, —

C═

N—

O— and

—

N(R⁵)—

; and

wherein said hydrocarbon is optionally substituted with one to three substituents selected from the group consisting of —

C(O)R⁶, —

S(O)_nR⁶, —

NHC(O)R⁶, —

NHC(O)NR⁷R⁸, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl and heterocycloalkyl;

(c) optionally substituted aryl; and

(d) optionally substituted heteroaryl;

R³ is selected from the group consisting of

(a) —

H,

(b) —

OH,

(c) —

OC(O)R⁹,

(d) —

OC(O)NHR⁹, and

(e) —

OC(O)OR⁹;

R⁴ is selected from the group consisting of

(a) —

H,

(b) —

C(O)R⁹,

(c) —

C(O)NHR⁹, and

(d) —

C(O)OR⁹;

R⁵ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl substituted with optionally substituted aryl or optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted heteroaryl;

R⁶ is hydrogen, alkyl optionally substituted with aryl or heteroaryl, optionally substituted aryl, or optionally substituted heteroaryl;

R⁷ and R⁸ are independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl substituted with optionally substituted aryl or heteroaryl, optionally substituted aryl, or optionally substituted heteroaryl, or R⁷ and R⁸ taken together with the atoms to which they are attached form a C₃-C₁₂ cycloalkyl group; and

R⁹ is a hydrocarbon selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl, and C₃-C₁₂ alkynyl, wherein 1 to 3 carbons of said hydrocarbon are optionally replaced by an O, S or N heteroatom, or a group selected from the group consisting of —

C(O)—

, —

C═

N—

, —

C═

N—

O— and

—

N(R⁵)—

; and

wherein said hydrocarbon is optionally substituted with one to three substituents selected from the group consisting of —

C(O)R⁶, —

S(O)_nR⁶, —

NHC(O)R⁶, —

NHC(O)NR⁷R⁸, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl and heterocycloalkyl.

19. The compound according to claim 18, wherein R¹ is selected from the group consisting of —

CH₂CH═

CH;

—

CH₂(3-iodophenyl);

—

CH₂CH═

CH(3-quinolyl); and

—

CH₂(4-phenylphenyl).

20. The compound according to claim 18, wherein R² is —

CH₂CO(piperizine-N-phenyl).