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

Patent metadata

Field	Value
Publication number	US-11234966-B2
Application number	US-202016879892-A
Country	US
Kind code	B2
Filing date	May 21, 2020
Priority date	Jun 12, 2017
Publication date	Feb 1, 2022
Grant date	Feb 1, 2022

Abstract

The present invention includes a composition, method of making and method of using a novel C5-substituted carbapenem antibiotic of formula 1:R1 is H or CH3R2 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; andR4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group; orR4 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; orR4 is a CH2ORb, where Rb=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl, or a heteroaryl groups.

First claim

What is claimed is:

1. A compound of formula 1, or a pharmaceutically acceptable salt thereof, comprising:

R 1 is H or CH 3
R 2 is not H, and is CH 3 , or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including C═CH 2 ;
R 3 is H, CH 3 , or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl; and
R 4 is a C1 to C6 alkyl, substituted alkyl group, or a substituent with a positive charge, or a hydroxyl group; or
R 4 is an SR a , where R a is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group; or
R 4 is a CH 2 OR b , where R b =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.

2. The compound of claim 1 , wherein R 3 is (CH 2 ) 2 NH 2 or (CH 2 ) 3 NH 2 .

3. The compound of claim 1 , wherein —CO 2 M is attached to the carbapenem nucleus at position 3 or a carboxylic acid group.

4. The compound of claim 1 , wherein M has a negative charge and is balanced by a counterion, wherein the counterion is an alkali metal cation selected from sodium, potassium, calcium, magnesium, zinc, ammonium, alkylammonium cations, tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, or meglumine, triethanolhydroammonium.

5. The compound of claim 1 , wherein the pharmaceutically acceptable salt is acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, or undecanoate.

6. The compound of claim 1 , wherein the molecule comprises a biolabile ester group.

7. The compound of claim 6 , wherein the biolabile ester group is selected from at least one of pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, or methoxymethyl.

8. The compound of claim 1 , wherein M is selected from an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group, or the groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups, or acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl, or (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl.

9. The compound of claim 1 , wherein the compound is further combined with a beta-lactamase inhibitor, clavulanic acid or avibactam, or a boronic acid based beta-lactamase inhibitor.

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

and wherein the molecule has the formula 1

R 1 is H or CH 3
R 2 is not H, and is CH 3 , or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including C═CH 2 ;
R 3 is H, CH 3 , or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl; and
R 4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group; or
R 4 is an SR a , where R a is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group; or
R 4 is a CH 2 OR b , where R b =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.

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

R 1 is H or CH 3
R 2 is not H, and is CH 3 , or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including C═CH 2 ;
R 3 is H, CH 3 , or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl; and
R 4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group; or
R 4 is an SR a , where R a 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
R 4 is a CH 2 OR b , where R b =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.

12. The antibiotic of claim 11 , wherein R 3 is (CH 2 ) 2 NH 2 or (CH 2 ) 3 NH 2 .

13. The antibiotic of claim 11 , wherein a —CO 2 M is attached to the carbapenem nucleus at position 3.

14. The antibiotic of claim 11 , wherein the pharmaceutically acceptable salt is —COOM, where M is a negative charge and is balanced by a counterion.

15. The antibiotic of claim 14 , wherein the counterion is an alkali metal cation selected from sodium, potassium, calcium, magnesium, zinc, ammonium, alkylammonium cations, tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, or meglumine, triethanolhydroammonium.

16. The antibiotic of claim 11 , wherein the pharmaceutically acceptable salt is acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, or undecanoate.

17. The antibiotic of claim 11 , wherein the compound comprises a biolabile ester group, pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl or methoxymethyl.

18. The antibiotic of claim 11 , wherein M is selected from an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthio

Assignees

• Univ Southern Methodist
• Univ Central Florida Res Found Inc

Inventors

• Buynak John D
• Al-Kharji Noora M S A
• Chai Weirui
• Nguyen Thu Q
• Alqurafi Maha
• Rohde Kyle
• Gupta Rashmi

Classifications

• C07D477/20

  Sulfur atoms · CPC title

• A61K31/407 Primary

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• C07D477/06

  from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents · CPC title

• C07D477/04

  by forming the ring or condensed ring systems · CPC title

• C07D477/00

  Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula: [IMAGE cpc-sch-C07D-0990.gif], e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring · CPC title