Selective antibacterials for clostridium difficile infections
Inventors
Wright, George E. • Xu, Wei-Chu
Assignees
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Publication Number
US-8796292-B2
Publication Date
2014-08-05
Expiration Date
Abstract
The invention features compounds of formula (I): The compounds are useful as antibacterial agents, especially again Clostridium difficile-associated diseases.
Core Innovation
The invention relates to selective antibacterial agents for Clostridium difficile infections. The agents are defined as compounds having a formula in which R1 and R2 are independently H, halo, C1-6 haloalkyl, or C1-6 haloalkoxy, and in which R3 is (CH2)m—B with m being 1-3. B is H, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-8 heterocyclyl, or C1-10 heteroaryl, or OR12 wherein R12 is substituted C1-6 alkyl with the substituent being a heterocyclyl, and the compounds include optical isomers and pharmaceutically acceptable salts.
The problem addressed is treatment and prevention of Clostridium difficile-associated diarrhea and colitis, including C. difficile infections. The invention emphasizes selectivity, stating unexpected potency against C. difficile while sparing other Gram-positive anaerobes. It further characterizes a reduced resistance development mechanism associated with inhibition of DNA polymerase III (pol IIIC/pol IIIE) by mimicking purine deoxyribonucleoside-5-triphosphates.
Representative embodiments include named compounds such as cpd 362E, 363A, 258D, 359E and hydrochloride salt forms. The document describes formulation and combination use of the compounds and provides MIC data showing growth inhibition, together with in vivo efficacy in a Syrian golden hamster clindamycin-induced model demonstrating protection from lethal clindamycin-induced C. difficile infection, including for example 359E.
Claims Coverage
The partial content includes two independent claims: a compound claim defining a 7-substituted-2-benzylamino-6-oxopurine scaffold with defined R1/R2 and R3/B substituent patterns, and a method claim for in vitro inhibition of Clostridium difficile growth using that scaffold. Across the independent claims, inventive coverage is based on defined structural substituent ranges plus inclusion of optical isomers and pharmaceutically acceptable salts, with dependent claims narrowing to specific substituent selections and named embodiments.
7-Substituted-2-benzylamino-6-oxopurine compounds with defined R1, R2, and R3/B
A compound having a formula wherein R1 and R2 are independently H, halo, C1-6 haloalkyl, or C1-6 haloalkoxy; wherein R3 is (CH2)m—B with B being H, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-8 heterocyclyl or C1-10 heteroaryl, or OR12 in which R12 is substituted C1-6 alkyl with the substituent being a heterocyclyl; and m is 1-3; or an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
In vitro inhibition of Clostridium difficile growth with the defined compounds
A method of inhibiting growth of Clostridium difficile in vitro by contacting, in an appropriate culture medium in the absence of oxygen, Clostridium difficile with an effective amount of a compound having the formula with R1 and R2 independently chosen from H, halo, C1-6 haloalkyl, or C1-6 haloalkoxy; R3 as (CH2)m—B; B being substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-8 heterocyclyl or C1-10 heteroaryl, or OR12 wherein R12 is substituted C1-6 alkyl with the substituent being a heterocyclyl; and m being 1-3; or an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
The independent claim coverage centers on compounds defined by a 7-substituted 2-benzylamino 6-oxopurine-type scaffold with specified substituent classes (R1, R2, R3/m and B) and inclusion of optical isomers and pharmaceutically acceptable salts, and an in vitro method of inhibiting Clostridium difficile growth by contacting the organism with an effective amount of those compounds.
Stated Advantages
Unexpected potency against C. difficile.
Selectivity that spares other Gram-positive anaerobes.
Reduced resistance development associated with DNA polymerase III inhibition (pol IIIC/pol IIIE) via mimicking purine deoxyribonucleoside-5-triphosphates.
Protection from lethal clindamycin-induced C. difficile infection in a Syrian golden hamster model.
Documented Applications
Treatment and prophylaxis of C. difficile-associated diarrhea and C. difficile-associated colitis.
In vitro inhibition of growth of Clostridium difficile using the defined compounds.
An in vivo hamster use case demonstrating protection from lethal clindamycin-induced C. difficile infection in a Syrian golden hamster clindamycin-induced model.
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