5-[3-((R)(-)-5,7-Dibromo-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-propylamino]-4H-thieno[3,2-b]pyridine-7-one; optically active; new target antibiotic, inhibitor of bacterial methionyl tRNA synthetase; antibiotic resistance; Clostridium difficile infection; mostly in immunodeficient, elderly
Inventors
Guiles, Joseph • Sun, Xicheng • Janjic, Nebojsa • STRONG, Sarah • Gyorkos, Albert Charles
Assignees
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Publication Number
US-7973050-B2
Publication Date
2011-07-05
Expiration Date
Abstract
Novel compounds in enantiomeric excess that are inhibitors of bacterial methionyl synthetase (MetRS) are disclosed. Also disclosed are methods for their preparation and their use in therapy as antibacterial agents, and in particular their use in therapy for Clostridium difficile infection.
Core Innovation
The invention relates to optically active compounds of formula (IIa) or (IIb) defined by a bicyclic heteroaromatic framework with specified heteroatom selection, an index n, and stereochemical rules tied to asymmetric carbon configuration. The compounds include substituent groups R1 and R2 that are independently selected from the explicitly listed functional and substituent classes, including halogen, cyano, hydroxyl, (C1-6)alkyl, (C3-7)cycloalkyl, C(1-6)alkoxy, amino, mono- or di-(C1-6)alkylamino, acylamino, carboxy, (C1-6)alkoxycarbonyl, carboxy(C1-6)alkyloxy, (C1-6)alkylthio, (C1-6)alkylsulphinyl, (C1-6)alkylsulphonyl, sulphamoyl, mono- and di-(C1-6)alkylsulphamoyl, carbamoyl, mono- and di-(C1-6)alkylcarbamoyl, and heterocyclic.
The stereochemical definitions further specify conditions involving Z1, Z2, and Z3 where when Z1 is S then Z2 and Z3 are CH; when Z2 is S then Z1 and Z3 are CH; and when Z3 is S then Z1 and Z2 are CH. The disclosed family is used to provide enantiomerically enriched bicyclic heteroaromatic MetRS inhibitors, emphasizing that the compounds are antibacterial agents with potent and selective activity against Gram-positive bacteria and especially Clostridium difficile, while showing little/no inhibition of mammalian MetRS.
The document further specifies preferred structural embodiments including thienopyridone or quinolone targets, together with specific stereochemical definitions and preferred example compounds. A pharmaceutical relevance is described for treating bacterial infections, including C. difficile infection, and a pharmaceutical composition is disclosed that includes the optically active compound in an effective amount with a pharmaceutically acceptable carrier or excipient.
Claims Coverage
The claims cover optically active compounds defined by formulas (IIa) or (IIb) and stereochemical rules, with dependent claims refining the compound structure and stereochemical and substitution patterns, plus a dependent claim directed to a pharmaceutical composition for treating a Gram-positive bacterial infection in a human. The coverage is anchored on the inventive features of the formula (IIa)/(IIb) compound framework and the specific stereochemical assignment rules for the asymmetric carbon atom, with further constraints on substituent identity and positional substitution patterns.
Optically active bicyclic heteroaromatic MetRS inhibitor defined by formulas (IIa) or (IIb)
An optically active compound of the formula (IIa) or (IIb) in which X is selected from NH, O, S, SO2, or CH2; n is 1, 2 or 3; R1 and R2 are independently selected from the explicitly listed substituent classes; and Z1, Z2 and Z3 follow the specified CH/S conditions.
Stereochemical assignment rules for the asymmetric carbon atom in the formula (IIa)/(IIb)
An asymmetric carbon atom (*) is defined such that when n is 2 or 3, then * is R configuration; when n is 1 and X is CH2, then * is R configuration; and when n is 1 and X is selected from NH, O, S, or SO2, then * is S configuration.
Refinement to specific structural formula (III)
The optically active compound is the compound of formula (III).
Restricted substituent identity and positional substitution patterns on (R1)m
(R1)m is a 6,8-substituted moiety bearing substituents chosen from bromine, chlorine, iodine, and sulfane, with the 6,8 substituents optionally being the same or different; and/or (R1)m is a 5,7-substituted pattern with the 5,7 substituents optionally being the same or different and selected from bromine, chlorine, iodine, and sulfane.
Selected optically active example structures with defined stereochemistry and halogen/sulfane substitution
The optically active compound is selected from explicitly enumerated optically active substituted 5-[3-((R)/(S)-configured heterocycle-amino)-propylamino]-4H-thieno[3,2-b]pyridine-7-one structures with defined bromo/chloro substitution and stereochemical labels as explicitly stated.
Pharmaceutical composition for treating Gram-positive bacterial infection in a human
A pharmaceutical composition for treating a Gram-positive bacterial infection in a human, including a compound of claim 1 in an effective amount to reduce bacterial growth, together with a pharmaceutically acceptable carrier or excipient.
Overall, the claims are directed to optically active compounds having the specified formula (IIa)/(IIb) framework and stereochemical assignment rules based on n and X, with dependent claims narrowing to particular structural formulas, restricting substituent identity to bromine/chlorine/iodine/sulfane, specifying positional substitution patterns, and enumerating particular optically active example structures with defined stereochemistry and halogen/sulfane substitution. A dependent claim further covers a pharmaceutical composition for treating Gram-positive bacterial infections in a human by including the claimed compound in an effective amount to reduce bacterial growth.
Stated Advantages
Potent and selective inhibition of C. difficile MetRS compared with opposite enantiomer configuration.
Reduction of C. difficile growth.
Inhibition of toxin A/B production.
Reduction of spore production.
In vivo efficacy in a hamster model versus vancomycin.
Potent and selective activity against Gram-positive bacteria.
Especially active against Clostridium difficile.
Shows little/no inhibition of mammalian MetRS.
The pharmaceutical composition is intended to reduce bacterial growth.
Documented Applications
A pharmaceutical composition for treating a Gram-positive bacterial infection in a human, including a compound of claim 1 in an effective amount to reduce bacterial growth.
Inhibition-related applications described for C. difficile including reduction of growth, inhibition of toxin A/B production, and inhibition of spore production.
Treating bacterial infections in a human, including C. difficile infection, using a pharmaceutical composition comprising the claimed optically active compound in an effective amount.
Treating a Gram-positive bacterial infection in a human by reducing bacterial growth with a pharmaceutical composition including the compound and a pharmaceutically acceptable carrier or excipient.
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