Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-18
2001-05-01
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S286000, C544S283000
Reexamination Certificate
active
06225317
ABSTRACT:
FIELD OF THE INVENTION
The potent reverse transcriptase inhibitor (−)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone is produced in solvate and preferred crystalline form. These forms are designated Forms 1 and 2, respectively, and characterized by x-ray powder diffraction and differential scanning calorimetry. Pharmaceutical compositions and methods are useful for the treatment of the human immunodeficiency virus (HIV).
BACKGROUND OF THE INVENTION
Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication.
An extremely promising and active area of research is in the discovery of non-nucleoside HIV reverse transcriptase inhibitors. Quinazolinones represent a class of compounds which have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase. Commonly assigned U.S. patent application Ser. No. 09/056,820 discloses the novel quinazolinone (−)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone as a particularly active non-nucleoside inhibitor of HIV reverse transcriptase with efficacy against HIV reverse transcriptase resistance.
(−)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone is represented structurally as formula (I):
Solvate and crystalline forms of (I) have not been known to exist previously. The discovery of such forms which exhibit chemical and physical advantages for manufacture, purification, and formulation are necessary for feasible commercialization of (I).
Treatment or prevention of the foregoing disorders is accomplished by administering a therapeutically effective amount of the solvate or crystalline form of compound (I) to a human or animal subject in need of such treatment or prevention. Treatment with such forms of compound (I) may be accomplished by its use as a single compound, as a pharmaceutical composition ingredient, or in combination with other antivirals, immunomodulators, antibiotics and vaccines. The compound may be administered enterally or parenterally in solid or liquid dosage forms.
SUMMARY OF THE INVENTION
In one aspect, the present invention is directed to solvate and crystalline forms of (−)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (I). A related aspect resides in novel solvate forms and crystalline forms of (I), designated Form 1 and Form 2, respectively. Form 1 has been characterized by differential scanning calorimetry (DSC), powder x-ray diffraction analysis (XRD), and nuclear magnetic resonance spectroscopy (NMR). Form 2 has been characterized by differential scanning calorimetry (DSC), and powder x-ray diffraction analysis (XRD).
Further aspects of the invention involve pharmaceutical compositions of (−)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone in its forms. The Forms of this invention may be formulated into conventional solid pharmaceutical dosage forms or used for the preparation of liquid dosage forms by combining a therapeutically effective amount of the forms of the drug with a pharmaceutically acceptable carrier. The Forms may be administered in pharmaceutical compositions which may combine other antivirals, immunomodulators, antibiotics or vaccines.
In another aspect, the present invention involves a method for inhibiting reverse transcriptase which comprises administering an amount of Form 1 or Form 2 of (−)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, sufficient to result in reverse transcriptase being contacted with an effective inhibitory amount of the active drug substance. In particular aspects, the invention involves methods for treating retroviral infections such as human immunodeficiency virus and disorders involving viral replication, which comprise administering a therapeutically effective amount of a pharmaceutical composition comprising the novel forms of this invention.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (−)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone existing as Forms 1 or 2, with one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
REFERENCES:
patent: 6124302 (2000-09-01), Corbett et al.
patent: 9845276 (1998-10-01), None
patent: 9950253 (1998-10-01), None
patent: 9950253 (1999-10-01), None
Parsons, Jr. Rodney Lawrence
Patel Mona
Rabel Shelley R.
DuPont Pharmaceuticals Company
Patel Sudhaker B.
Shah Mukund J.
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