C5-substituted carbapenem antibiotics, compositions containing such compounds, and methods of use in treatment of mycobacterium tuberculosis and non-tubercular mycobacteria

A method of making any one of compounds 1 to 11 comprising:

• and wherein the molecule has the formula 1
• R1 is H or CH3
• R2 is not H, and is CH3, or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including C═CH2;
• R3 is H, CH3, or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl;
• and
• R4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group;
• or
• R4 is an SRa, where Ra is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group;
• or
• R4 is a CH2ORb, where Rb=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl, or a heteroaryl groups;
• and
• wherein M is a carboxylic acid group, M is a negative charge in a carboxylate anion, M is an ester-forming group of a pharmaceutically acceptable ester, or M is a carboxyl protecting group of a carboxylic acid.

An antibiotic compound of formula 1, or a pharmaceutically acceptable salt thereof, comprising:

• R1 is H or CH3
• R2 is not H, and is CH3, or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including C═CH2;
• R3 is H, CH3, or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl;
• and
• R4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group;
• or
• R4 is an SRa, where Ra is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group, or a functional group that is positively charged, or has a positive charge in aqueous solution at pH 7;
• or
• R4 is a CH2ORb, where Rb=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl, or a heteroaryl groups, wherein M is a carboxylic acid group, M is a negative charge of a carboxylate anion, M is an ester forming group of a pharmaceutically acceptable ester, or M is a carboxyl protecting group of a carboxylic acid;
• and
• one or more pharmaceutically acceptable excipients.

A method of treating a Mycobacterium sp. infection in a subject comprising:

• contacting the Mycobacterium sp. with an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof, comprising:
• R1 is H or CH3
• R2 is not H, and is CH3, or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including C═CH2;
• R3 is H, CH3, or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl;
• and
• R4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group;
• or
• R4 is an SRa, where Ra is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group, or a functional group that is positively charged, or which bears a positive charge when in aqueous solution at pH 7;
• or
• R4 is a CH2ORb, where Rb=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl, or a heteroaryl groups, wherein M is a carboxylic acid group, M is a negative charge of a carboxylate anion, M is an ester forming group of a pharmaceutically acceptable ester, or M is a carboxyl protecting group of a carboxylic acid;
• and
• wherein the compound inhibits the growth of the bacterium in the subject.