Antibacterial agents

• US 5,574,017 A
• Filed: 07/05/1994
• Issued: 11/12/1996
• Est. Priority Date: 07/05/1994
• Status: Expired due to Term

• Current Assignee: William G. Gutheil
• Original Assignee: William G. Gutheil
• Inventors: Gutheil, William G.
• Primary Examiner(s): SCHAIN, HOWARD
• Application Number:
  US08/270,818
• Time in Patent Office: 861 Days
• Field of Search: 530/331, 514/18, 514/19, 514/64, 548/110, 560/10, 560/18, 560/29, 560/37, 560/45, 560/80, 560/100, 560/110, 564/8, 562/445, 562/448, 562/558
• US Class Current: 514/2.4
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides methods and pharmaceutical preparations for inhibiting the growth of bacterial microorganisms.

Claims

1. A method of treating a bacterial infection in an animal, which method comprises administering to said animal an antibacterial amount of a compound sufficient to to inhibit bacterial cell wall biosynthesis by a penicillin binding protein of bacteria causing the infection, the compound represented by the general formula ##STR15## wherein W represents BY₁ Y₂, or C(═

O)R₅ ;

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or ##STR16## R₂ represents hydrogen, an alkyl, an alkenyl, an alkynyl, --(CH₂)m-R₇, --(CH₂)m-OH, --(CH₂)m-O-alkyl, --(CH₂)m-O-alkenyl, --(CH₂)m-O-alkynyl, --(CH₂)m-O-C(═

O)-alkyl, --(CH₂)m-O-C(═

O)-alkenyl, --(CH₂)m-O-C(═

O)-alkynyl --(CH₂)m-O-C(═

O)-(CH₂)m-R₇ ;

R₃ and R₄ each represent hydrogen, a alkyl, a alkenyl, a alkynyl, --(CH₂)m-R₇, --(CH₂)n-OH, --(CH₂)n-O-alkyl, --(CH₂)n-O-alkenyl, --(CH₂)n-O-alkynyl, --(CH₂)n-O-(CH₂)m-R₇, --(CH₂)n-SH, --(CH₂)n-S-alkyl, --(CH₂)n-S-alkenyl, --(CH₂)n-S-alkynyl, --(CH₂)n-S-(CH₂)m-R₇, an α

-carbon linked side chain of an amino acid or an amino acid analog, ##STR17## R₂ and R₃ taken together can complete a ring having from 4 to 8 atoms in the ring structure,

or, provided R₂ and R₃ are not taken together forming a ring, R₃ and R₄ taken together can complete a ring having from 3 to 8 atoms in the ring structure,

Y₁ and Y₂ can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y₁ and Y₂ are connected via a ring having from 5 to 8 atoms in the ring structure,

R₅ represents H, an alkyl, an alkenyl, an alkynyl, --(CH₂)m-R₇, --(CH₂)n-OH, --CH₂)n-O-alkyl, --(CH₂)n-O-alkenyl, --(CH₂)n-O-alkynyl, --(CH₂)n-O-(CH₂)m-R₇, --(CH₂)n-SH, --(CH₂)n-S-alkyl, --(CH₂)n-S-alkenyl, --(CH₂)n-S-alkynyl, --(CH₂)n-S--(CH₂)m-R₇, --CH₂ O-R₁₀,

R₆ represents hydrogen, a halogen, a alkyl, a alkenyl, a alkynyl, an aryl, --(CH₂)_m -R₇, --(CH₂)_m -OH, --(CH₂)_m -O-alkyl, --(CH₂)_m -O-alkenyl, --(CH₂)_m -O-alkynyl, --(CH₂)_m -O-(CH₂)_m -R₇, --(CH₂)_m SH, --(CH₂)_m -S-alkyl, --(CH₂)_m -S-alkenyl, --(CH₂)_m S-alkynyl, --(CH₂)_m -S-(CH₂)_m -R₇, ##STR18## R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, --(CH₂)_m -R₇, --C(═

O)-alkyl, --C(═

O)-alkenyl, --C(═

O)-alkynyl, --C(═

O)-(CH₂)m-R₇,

or R₈ and R₉ taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure;

R₁₀ represents represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, ##STR19## m is zero or an integer in the range of 1 to 8; and

n is an integer in the range of 1 to 8.

2. The method of claim 1, wherein the compound is introduced into the body by injection.

3. The method according to claim 2, wherein the method of injection is selected from the group consisting of subcutaneous, intramuscular,intraperitoneal and intravenous injection.

4. The method of claim 1, wherein the compound is introduced by a method selected from the group consisting of aerosol inhalation, transdermal or transbuccal absorption and rectal suppository.

5. The method of claim 1, wherein W is repesented by the formula ##STR20## wherein R₁₁ and R₁₂ each independently represent hydrogen, a alkyl, or a pharmaceutically acceptable salt, or R₁₁ and R₁₂ taken together with the O-B-O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure.

6. The method of claim 1, wherein W is represented by the formula ##STR21## wherein R₁₃ is a hydrogen or ##STR22## and X₁, X₂ and X₃ each represent a hydrogen or a halogen.

7. The method of claim 1, wherein R₃ is a methyl and R₄ is a hydrogen, and the carbon to which R₃ and R₄ are bonded is a (D)-isomer.

8. The method of claim 1, wherein the bacterial infection is selected from the group consisting of a Staphylococcus infection, a Streptococcus infection, an Enterobacteriaceae infection, and Enterococcus infection, a Mycobacterium infection, a Neisseria infection, a Pseudomonas infection, a Shigella infection, an Escherichia infection, a Bacillus infection, a Micrococcus infection, an Arthrobacter infection, and a Peptostreptococcus infection.

16. The method of claim 1, wherein the compound is represented by the general formula:

##STR38## wherein R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or ##STR39## R₆ represents hydrogen, a halogen, a alkyl, a alkenyl, a alkynyl, an aryl, --(CH₂)_m -R₇, --(CH₂)_m -OH, --(CH₂)_m -O-alkyl, --(CH₂)_m -O-alkenyl, --(CH₂)_m -O-alkynyl, --(CH₂)_m -O-(CH₂)_m -R₇, --(CH₂)_m -SH, --(CH₂)m-S-alkyl, --(CH₂)m-S-alkenyl, --(CH₂)_m -S-alkynyl, --(CH₂)_m -S-(CH₂)_m -R₇, ##STR40## R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, --(CH₂)_m -R₇, --C(═

O)-alkyl, --C(═

O)-alkenyl, --C(═

O)-alkynyl, --C(═

O)-(CH₂)_m -R₇,

or R₈ and R₉ taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure;

R₁₁ and R₁₂ each independently represent hydrogen, a alkyl, or a pharmaceutically acceptable salt, or R₁₁ and R₁₂ taken together with the O-B-O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;

m is zero or an integer in the range of 1 to 8; and

n is an integer in the range of 1 to 8.

17. The method of claim 1, wherein the compound is represented by the general formula:

##STR41## wherein R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or ##STR42## R₆ represents hydrogen, a halogen, a alkyl, a alkenyl, a alkynyl, an aryl, --(CH₂)_m -R₇, --(CH₂)_m -OH, --(CH₂)_m -O-alkyl, --(CH₂)_m -O-alkenyl, --(CH₂)_m -O-alkynyl, --(CH₂)_m -O-(CH₂)_m -R₇, --(CH₂)_m -SH, --(CH₂)_m -S-alkyl, --(CH₂)_m -S-alkenyl, --(CH₂)_m -S-alkynyl, (CH₂)_m -S-(CH₂)_m -R₇, ##STR43## R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, --(CH₂)_m -R₇, --C(═

O)-alkyl, --C(═

O)-alkenyl, --C(═

O)-alkynyl, --C(═

O)-(CH₂)_m -R₇,

or R₈ and R₉ taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; and

m is zero or an integer in the range of 1 to 8; and

n is an integer in the range of 1 to 8.

18. The method of claim 1, wherein the compound is represented by the general formula:

##STR44## wherein R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or ##STR45## R₆ represents hydrogen, a halogen, a alkyl, a alkenyl, a alkynyl, an aryl, --(CH₂)_m -R₇, --(CH₂)_m -OH, --(CH₂)_m -O-alkyl, --(CH₂)_m -O-alkenyl, --(CH₂)_m -O-alkynyl, --(CH₂)_m -O-(CH₂)_m -R₇, --(CH₂)_m -SH, --(CH₂)_m -S-alkyl, --(CH₂)_m -S-alkenyl, --(CH₂)_m -S-alkynyl, --(CH₂)_m -S-(CH₂)_m -R₇, ##STR46## R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, --(CH₂)_m -R₇, --C(═

O)-alkyl, --C(═

O)-alkenyl, --C(═

O)-alkynyl, --C(═

O)-(CH₂)_m -R₇,

or R₈ and R₉ taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure;

X₁, X₂ and X₃ each represent a hydrogen or a halogen; and

m is zero or an integer in the range of 1 to 8; and

n is an integer in the range of 1 to 8.

20. The method of claim 17, wherein the bacterial infection is selected from the group consisting of a Staphylococcus infection, a Streptococcus infection, an Enterobacteriaceae infection, and Enterococcus infection, a Mycobacterium infection, a Neisseria infection, a Pseudomonas infection, a Shigella infection, an Escherichia infection, a Bacillus infection, a Micrococcus infection, an Arthrobacter infection, and a Peptostreptococcus infection.

21. The method of claim 18, wherein the bacterial infection is selected from the group consisting of a Staphylococcus infection, a Streptococcus infection, an Enterobacteriaceae infection, and Enterococcus infection, a Mycobacterium infection, a Neisseria infection, a Pseudomonas infection, a Shigella infection, an Escherichia infection, a Bacillus infection, a Micrococcus infection, an Arthrobacter infection, and a Peptostreptococcus infection.

9. A method of killing bacterial microorganisms dependent on a cell wall biosynthesis activity of a penicillin binding protein for viability, comprising contacting the microorganisms with an effective dosage of a penicillin binding protein inhibitor represented by the general formula ##STR23## wherein W represents BY₁ Y₂, or C(═

O)R₅

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or ##STR24## R₂ represents hydrogen, an alkyl, an alkenyl, an alkynyl, --(CH₂)m-R₇, --(CH₂)m-OH, --(CH₂)m-O-alkyl, --(CH₂)m-O-alkenyl, --(CH₂)m-O-alkynyl, --(CH₂)m-O-C(═

O)-alkyl, --(CH₂)m-O-C(═

O)-alkenyl, --(CH₂)m-O-C(═

O)-alkynyl, --(CH₂)m-O-C(CH₂)m-R₇ ;

R₃ and R₄ each represent hydrogen, a alkyl, a alkenyl, a alkynyl, --(CH₂)m-R₇, --(CH₂)n-OH, --(CH₂)n-O-alkyl, --(CH₂)n-O-alkenyl, --(CH₂)n-O-alkynyl, --(CH₂)n-O-(CH₂)m-R₇, --(CH₂)n-SH, --(CH₂)n-S-alkyl, --(CH₂)n-S-alkenyl, --(CH₂)n-S-alkynyl, --(CH₂)m-R₇, an α

-carbon linked side chain of an amino acid or an amino acid analog, ##STR25## R₂ and R₃ taken together can complete a ring having from 4 to 8 atoms in the ring structure,

or, provided R₂ and R₃ are not taken together forming a ring, R₃ and R₄ taken together can complete a ring having from 3 to 8 atoms in the ring structure,

Y₁ and Y₂ can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y₁ and Y₂ are connected via a ring having from 5 to 8 atoms in the ring structure,

R₅ represents H, an alkyl, an alkenyl, an alkynyl, --(CH₂)m-R₇, --(CH₂)n-OH, --(CH₂)n-O-alkyl, --(CH₂)n-O-alkenyl, --(CH₂)n-O-alkynyl, --(CH₂)n-O-(CH₂)m-R₇, --(CH₂)n-SH, --(CH₂)n-S-alkyl, --(CH₂)n-S-alkenyl, --(CH₂)n-S-alkynyl, --(CH₂)n-S-(CH₂)m-R₇, --CH₂ O-R₁₀,

R₆ represents hydrogen, a halogen, a alkyl, a alkenyl, a alkynyl, an aryl, --(CH₂)m-R₇, --(CH₂)_m -OH, --(CH₂)_m -O-alkyl, --(CH₂)_m -O-alkenyl, --(CH₂)_m -O-alkynyl, --(CH₂)_m -O-(CH₂)_m -R₇, --(CH₂)_m -SH, --(CH₂)_m -S-alkyl, --(CH₂)_m -S-alkenyl, --(CH₂)_m -S-alkynyl, --(CH₂)_m -S-(CH₂)_m -R₇, ##STR26## R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, --(CH₂)_m -R₇, C(═

O)-alkyl, --C(═

O)-alkenyl, --C(═

O)-alkynyl, --C(═

O)-(CH₂)_m -R₇,

or R₈ and R₉ taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure;

R₁₀ represents represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, ##STR27## m is zero or an integer in the range of 1 to 8; and

n is an integer in the range of 1 to 8.

10. The method of claim 9, wherein the compound inhibits enzymatic bacterial cell wall biosynthesis by a penicillin binding protein.

11. The method of claim 9, which method is used to inhibit bacterial growth on non-living matter.

19. The method of claim 10, wherein the bacterial infection is selected from the group consisting of a Staphylococcus infection, a Streptococcus infection, an Enterobacteriaceae infection, and Enterococcus infection, a Mycobacterium infection, a Neisseria infection, a Pseudomonas infection, a Shigella infection, an Escherichia infection, a Bacillus infection, a Micrococcus infection, an Arthrobacter infection, and a Peptostreptococcus infection.

12. A pharmaceutical composition comprising, in a pharmaceutically-acceptable carrier, an antibacterial amount of a compound represented by the general formula ##STR28## wherein W represents BY₁ Y₂, or C(═

O)R₅

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or ##STR29## R₂ represents hydrogen, an alkyl, an alkenyl, an alkynyl, --(CH₂)m-R₇, --(CH₂)m-OH, --(CH₂)m-O-alkyl, --(CH₂)m-O-alkenyl, --(CH₂)m-O-alkynyl, --(CH₂)m-O-C(═

O)-alkyl, -(CH₂)m-O-C(═

O)-alkenyl, --(CH₂)m-O-C(═

O)-alkynyl --(CH₂)m-O-C(═

O)-(CH₂)m-R₇ ;

R₃ and R₄ each represent hydrogen, a alkyl, a alkenyl, a alkynyl, --(CH₂)m-R₇, --(CH₂)n-OH, --(CH₂)n-O-alkyl, --(CH₂)n-O-alkenyl, --(CH₂)n-O-alkynyl, --(CH₂)n-O-(CH₂)m-R₇, --(CH₂)n-SH, --(CH₂)n-S-alkyl, --(CH₂)n-S-alkenyl, --(CH₂)n-S-alkynyl, --(CH₂)n-S-(CH₂)m-R₇, an α

-carbon linked side chain of an amino acid or an amino acid analog, ##STR30## R₂ and R₃ taken together can complete a ring having from 4 to 8 atoms in the ring structure,

or, provided R₂ and R₃ are not taken together forming a ring, R₃ and R₄ taken together can complete a ring having from 3 to 8 atoms in the ring structure,

Y₁ and Y₂ can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y₁ and Y₂ are connected via a ring having from 5 to 8 atoms in the ring structure,

R₅ represents H, an alkyl, an alkenyl, an alkynyl, --(CH₂)m-R₇, --(CH₂)n-OH, -(CH₂)n-O-alkyl, --(CH₂)n-O-alkenyl, --(CH₂)n-O-alkynyl, --(CH₂)n-O-(CH₂)m-R₇, --(CH₂)n-SH, --(CH₂)n-S-alkyl, --(CH₂)n-S-alkenyl, --(CH₂)n-S-alkynyl, --(CH₂)n-S-(CH₂)m-R₇, --CH₂ O-R₁₀,

R₆ represents hydrogen, a halogen, a alkyl, a alkenyl, a alkynyl, an aryl, --(CH₂)_m -R₇, --(CH₂)_m -OH, --(CH₂)_m -O-alkyl, --(CH₂)_m -O-alkenyl, --(CH₂)_m -O-alkynyl, --(CH₂)_m -O-(CH₂)_m -R₇, --(CH₂)_m -SH, --(CH₂)_m -S-alkyl, --(CH₂)_m -S-alkenyl, --(CH₂)_m -S-alkynyl, --(CH₂)_m -S-(CH₂)_m -R₇, ##STR31## R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, --(CH₂)_m -R₇, --C(═

O)-alkyl, --C(═

O)-alkenyl, --C(═

O)-alkynyl, --C(═

O)-(CH₂)_m -R₇,

or R₈ and R₉ taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure;

R₁₀ represents represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, ##STR32## m is zero or an integer in the range of 1 to 8; and

n is an integer in the range of 1 to 8.

13. The pharmaceutical composition of claim 12, comprising a purified or partially purified enantiomer or diastereomer of said antibacterial compound.

14. The pharmaceutical composition of claim 12, wherein said antibacterial compound is present in said composition in combination with other antibacterial agents.

15. A feedstock comprising an antibacterial amount of a compound represented by the general formula ##STR33## wherein W represents BY₁ Y₂, or C(═

O)R₅

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or ##STR34## R₂ represents hydrogen, an alkyl, an alkenyl, an alkynyl, --(CH₂)m-R₇, --(CH₂)m-OH, --(CH₂)m-O-alkyl, --(CH₂)m-O-alkenyl, --(CH₂)m-O-alkynyl, --(CH₂)m-O-C(═

O)-alkyl, --(CH₂)m-O-C(═

O)-alkenyl, --(CH₂)m-O-C(═

O)-alkynyl --(CH₂)m-O-C(═

O)-(CH₂)m-R₇ ;

R₃ and R₄ each represent hydrogen, a alkyl, a alkenyl, a alkynyl, --(CH₂)m-R₇, --(CH₂)n-OH, --(CH₂)n-O-alkyl, --(CH₂)n-O-alkenyl, --(CH₂)n-O-alkynyl, --(CH₂)n-O-(CH₂)m-R₇, --(CH₂)n-SH, --(CH₂)n-S-alkyl, --(CH₂)n-S-alkenyl, --(CH₂)n-S-alkynyl, --(CH₂)n-S-(CH₂)m-R₇, an α

-carbon linked side chain of an amino acid or an amino acid analog, ##STR35## R₂ and R₃ taken together can complete a ring having from 4 to 8 atoms in the ring structure,

or, provided R₂ and R₃ are not taken together forming a ring, R₃ and R₄ taken together can complete a ring having from 3 to 8 atoms in the ring structure,

Y₁ and Y₂ can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y₁ and Y₂ are connected via a ring having from 5 to 8 atoms in the ring structure,

R₅ represents H, an alkyl, an alkenyl, an alkynyl, --(CH₂)m-R₇, --(CH₂)n-OH, --(CH₂)n-O-alkyl, --(CH₂)n-O-alkenyl, --(CH₂)n-O-alkynyl, --(CH₂)n-O-(CH₂)m-R₇, --(CH₂)n-SH, --(CH₂)n-S-alkyl, --(CH₂)n-S-alkenyl, --(CH₂)n-S-alkynyl, --(CH₂)n-S-(CH₂)m-R₇, --CH₂ O-R₁₀,

R₆ represents hydrogen, a halogen, a alkyl, a alkenyl, a alkynyl, an aryl, --(CH₂)_m -R₇, --(CH₂)_m -OH, --(CH₂)_m -O-alkyl, --(CH₂)_m -O-alkenyl, --(CH₂)_m -O-alkynyl, --(CH₂)_m O-(CH₂)_m -R₇, --(CH₂)_m -SH, --(CH₂)_m -S-alkyl, --(CH₂)_m -S-alkenyl, --(CH₂)_m -S-alkynyl, --(CH₂)_m -S-(CH₂)_m -R₇, ##STR36## R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, --(CH₂)_m -R₇, --C(═

O)-alkyl, --C(═

O)-alkenyl, --C(═

O)-alkynyl, --C(═

O)-(CH₂)_m -R₇,

or R₈ and R₉ taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure;

R₁₀ represents represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, ##STR37## m is zero or an integer in the range of 1 to 8; and

n is an integer in the range of 1 to 8.