4-amino-3-phenylamino-6-phenylpyrazolo[3,4-d]pyrimidine derivatives, their manufacture and their use as antiviral active substances
Inventors
Wutzler, Peter • Schmidtke, Michaela • Makarov, Vadim
Assignees
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Publication Number
US-9790225-B2
Publication Date
2017-10-17
Expiration Date
Abstract
The present invention relates to 5-amino-3-phenylamino-6-phenylpyrazolo[3,4-d]pyrimidine derivatives of the general formula I or pharmaceutically acceptable salts or propharmacons thereof, wherein at least one hydrogen atom in at least one of the phenyl groups A and B is substituted by a substituent RH, which has a Hammett constant σp greater than 0.23. The present invention also concerns the method of its manufacture. For corresponding compounds, surprisingly a particularly high activity against viruses, in particular rhinoviruses and picornaviruses was determined. Furthermore, the compounds are tolerated very well. For these reasons the compounds are suitable for the treatment of viral infections and as drugs.
Core Innovation
The invention relates to pyrazolo[3,4-d]pyrimidine antiviral candidates, specifically 4-amino-3-phenylamino-6-phenylpyrazolo[3,4-d]pyrimidine derivatives of general formula I/II and IIa/IIb. The derivatives feature para-substitution on a phenyl ring where an originally hydrogen substituent is replaced by a group RH characterized by a Hammett constant σp>0.23, including groups such as CF3 and OCF3.
The described substituted 4-amino-3-phenylamino-6-phenyl derivatives are presented as maintaining strong antiviral activity against picornaviruses, especially rhinoviruses and enteroviruses, with nanomolar/micromolar antiviral activity reported in the document. In addition, the document states that the substitution pattern provides improved stability in liver microsomes and improved mouse bioavailability compared with state-of-the-art references.
The invention further includes pharmaceutical compositions comprising the disclosed compounds and optionally one or more additional active ingredients that are active against picornaviruses. It also encompasses pharmaceutically acceptable salt and prodrug forms, where conversion to the active compound in vivo is described.
Claims Coverage
The independent claim covers one chemical entity family, a 4-amino-3-phenylamino-6-phenylpyrazolo[3,4-d]pyrimidine of formula IIa, together with pharmaceutically acceptable salts and pro-pharmacons. The main structural coverage is defined by one inventive feature for the R substituent set.
Formula IIa 4-amino-3-phenylamino-6-phenylpyrazolo[3,4-d]pyrimidine with defined R group
A 4-amino-3-phenylamino-6-phenylpyrazolo[3,4-d]pyrimidine of formula IIa wherein R is selected from NO2, CN, CF3, CCl3, CBr3, OCF3, OCCl3, OCBr3, CHF2, CHCl2, CHBr2, OCHCl2, CHO, COOH, COMe, COEt, COOMe or COOEt.
Pharmaceutically acceptable salt or pro-pharmacon
The formula IIa compound is covered as a pharmaceutically acceptable salt or a pro-pharmacon thereof.
Overall claim coverage centers on a formula IIa 4-amino-3-phenylamino-6-phenylpyrazolo[3,4-d]pyrimidine scaffold with a specifically enumerated R substituent set, together with coverage for pharmaceutically acceptable salts and pro-pharmacons.
Stated Advantages
Improved stability in liver microsomes versus state-of-the-art references.
Improved mouse bioavailability versus state-of-the-art references.
Strong nanomolar/micromolar antiviral activity against picornaviruses, especially rhinoviruses and enteroviruses.
In vivo efficacy in mouse myocarditis models with CVB3, with CRCV-340 outperforming placebo and comparing favorably to pleconaril in the described models.
Documented Applications
Therapeutic treatment of rhinovirus or enterovirus infections in an animal by administering an effective amount of the formula IIa compound.
Pharmaceutical compositions for use against picornaviruses, optionally including one or more additional active ingredients that are active against picornaviruses.
Treatment/assessment in mouse myocarditis models induced by CVB3 in vivo (as described in the document).
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