In the present article, we describe SAR studies within a series of N-hydroxy-dihydronaphthyridinone HIV integrase inhibitors that led to a candidate compound, PF-4776548, of high potency and with an excellent resistance profile. Uncertainties around the human pharmacokinetic predictions for PF-4776548 led to the compound being taken into a human microdose study to confirm its human pharmacokinetics, the results of which are described herein.
A library of 4,6-diaryl-1,4-dihydropyridines was synthesized using a CAN-catalyzed, Hantzsch-related three component reaction starting from ammonium acetate, β-dicarbonyl compounds and a variety of α,β-unsaturated ketones including chalcones, their vinylogs and heteroanalogues. These compounds lack the structural features needed for vascular activity and were found to prevent calcium overload and behave as neuroprotective agents. One of the compounds, bearing a 2-thienyl substituent at C-4, showed the highest neuroprotective activity and was also a moderate antioxidant, being a good lead compound for further studies in this area.
The vast majority of countries do not present a specific mention in the Law for polymorphic form patent application, but still many patents are granted. The polymorphic forms are expressly regulated in India, as long as patentability requirements are met and efficiency is increased.
Both second medical use and new polymorphic forms are currently patentable according to Law, evaluating the novelty and inventive activity in Brazil; however, the guidelines were not clear. A guideline proposal for the evaluation of patent application for new polymorphic forms is being prepared.
Guideline Proposal for the Evaluation of new polymorphic forms
– Definitions were established for: polymorphism, crystalline and amorphous forms, medicine, pharmaceutical composition, pharmaceutical formulation, adjuvant, excipient and monocrystal.
– It is indispensable that the descriptive report has the necessary characteristics to the complete description of new polymorphic forms, according to technologies inherent to its perfect characterization, such as the following examples, or validated alternative techniques that best identify them:
a) Single-crystal X-ray diffraction (monocrystal XRD);
b) X-Ray Powder Diffraction Method; (XRD Powder Method);
c) Solid-state carbon-13 nuclear magnetic resonance spectroscopy (NMR-13C)
d) Infrared Spectroscopy;
e) Raman Spectroscopy;
f) Electronic Microscopy (hot stage);
g) Thermal Analysis: Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (ATG) and Differential Thermal Analysis (DTA).
– In case of a monocrystal of the chemical substance, the XRD technique of single crystal is sufficient for the prefect characterization of the crystalline structure.
In case of absence of monocrystal of the chemical substance, the X-Ray Powder Diffraction Method technique with indexing must be used, that is, the Miller index of the interplanar distances, the Bragg angles and the relative intensities of at least 20 reflections must be presented, in addition to the unitary cell parameters.
– If the indexing is not presented, the presentation of the other described parameters is necessary, and also the complementation of the X-Ray Powder Diffraction Method with other analysis methods (minimum of 2), in addition to the proof of sample purity.
The analysis technique used for the determination of the chemical substanceand its purity level pharmaceutically acceptable must be informed, since sample impurities may cause interferences in the quality of the characterization analysis results of the crystalline structure.
The inventive activity of a polymorphic form shall be checked by verification of an effect solving a problem of the prior art that is sufficiently differentiating, for instance: stability increase, apparent solubility and processability.
Pharmaceutical Composition of the Polymorphic Form
A composition is a grouping of ingredients for a certain purpose. The composition presents a novelty when one of the constituents is a crystalline form different from the one disclosed in the prior art.
The inventive activity to be presented by the composition containing the new polymorphic form, there must be an evaluation of the differentiated effect authentically solving a technical problem, based on its giving special attention to comparative specific parameters in relation to the prior art, the proof of its physical and chemical stability for its industrial use.
Process for Obtaining the Polymorphic Form
The process must be new, inventive and clearly described in order to allow the reproducibility by a person skilled in the art.
Parameters as exemplified below, or alternative parameters best describing such process, must disclose the following:
a) concentrations of the different solutions used, which are critical to the process;
c) cooling rate;
e) temperature of the different stages of the process;
f) torque or addition of seeds of the desired crystalline form. The seed preparation process must also be clearly and sufficiently described in the application when the crystallization process is developed with seeding.
The same criteria are applied to the pharmaceutical and medication formulation, repressing it.
Process for Obtaining the Pharmaceutical Composition
The process for obtaining a pharmaceutical composition containing a new polymorphic form is new. The inventive activity shall be evaluated whenever it is not evidently originating from the prior art (for the person skilled in the art).
As new polymorphic forms may disclose different physical and mechanic properties, including particle size, density, hardness, outflow and compactness, they may have sufficiently differentiated characteristics solving a problem of the prior art, which may bring an inventive activity requisite to the obtaining process of the pharmaceutical composition.
The same criteria apply to the process for obtaining the pharmaceutical and medication formulation.