Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1998-11-03
2001-04-24
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C514S356000
Reexamination Certificate
active
06221335
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for enhancing the efficacy of known pharmaceuticals or drugs, and to the enhanced drugs so produced, by changing the isotopic form of the molecular structure of the known drug. More particularly, the present invention relates to the modification of the molecular structure of known drugs containing one or more hydrogen atoms by deuterating one or more of the hydrogen atoms to deuterium atoms. The resulting drug is significantly altered and has greatly improved activity over the known drug. Most particularly this invention relates to a method of deuterating a selected pharmaceutical compound such as a member of the dihydropyridine family (e.g., nifedipine), ceftazidime, members of the penicillin family, and the like whereby the deuterated product has an increased effect and an increased duration of action on mammals at lower concentration than does the original substance. The present invention has particular application to enhancing the effectiveness of antibacterial drugs.
When pharmaceuticals are synthesized, a carbon backbone is assembled having various substituents including carbon, hydrogen, oxygen, nitrogen, etc. Pharmaceuticals have been designed and synthesized by a number of modes including, for example, serendipity and molecular modification. These and other methods have generated a vast number of drugs over the course of time. As such modifications have allowed individual companies to keep a competitive edge in the marketplace, a significant part of the industry's time and resources is spent searching for novel agents within certain pharmacologic classifications, e.g., antihypertensives, anti-bacterials. Such novel agents often have different activities from the prototype compounds, thus justifying the monies spent for their development.
SUMMARY OF THE INVENTION
It is known that virtually all drugs now marketed include a number of hydrogen atoms, each of which has a molecular mass of one. It has now been found that when one or more of the hydrogen atoms on a drug are modified so that their molecular mass becomes two, the activity of the drug is significantly altered and is even greatly improved. Thus, for example, isotopic modification of a dihydropyridine, e.g., such as nifedipine, has resulted in an unexpected change in the hypotensive (blood pressure lowering) effect in mammals compared to nifedipine per se.
Accordingly, in one aspect of the invention there is provided pharmaceutical preparations containing at least one pharmacologically active ingredient which is a compound wherein at least one of the hydrogen atoms thereof is replaced with a deuterium atom, or wherein at least one carbon, nitrogen or oxygen atom is replaced by a different isotope thereof.
In another aspect, the present invention provides a method for making the deuterated dihydropyridine comprising: dissolving a dihydropyridine in a mixture of deuterochloroform and deuterium oxide to form a solution, adding trifluoroacetic anhydride and deuteroacetone to said solution, freezing and sealing said solution within a vessel, heating said solution at a temperature and for a period of time sufficient to deuterate all of the hydrogen atoms at the 2 and 6 position on said dihydropyridine, and recovering said deuterized dihydropyridine.
Still another aspect of the present invention provides a method of detecting whether a pharmaceutical compound is identical and/or bioequivalent to a known pharmaceutical compound comprising the steps of
(a) determining the molecular and isotopic structure of said known pharmaceutical compound by gas chromatography-isotope ratio mass spectrometry,
(b) determining the molecular and isotopic structure of said pharmaceutical compound subject to said detection by gas chromatography-isotope ratio mass spectrometry,
(c) comparing the results of said tow determinations to detect any isotope variation in the molecular structure of said pharmaceutical compound over that of the known pharmaceutical compound.
Nifedipine is marketed worldwide as an important drug used in the treatment of angina and hypertension. Its structure is as follows:
A feature of the present invention is the modification of nifedipine by replacing one or more hydrogens of the methyl groups with deuterium or by replacing one or more of the methyl groups with CD
3
. In this way the therapeutic properties of nifedipine can be altered and can even be significantly improved. For example, by modifying the nifedipine by replacing the two methyl groups at the 2 and 6 positions on the ring with two deuterated groups (CD
3
), i.e., replacing 6 hydrogen atoms with six deuterium atoms, the structure of the deuterated nifedipine is as follows:
Both of the above molecules are nifedipine and the latter structure is an isotopic form of the former.
In the same way, the modification of the antibacterial, ceftazidine, by deuteration will produce modified ceftazidine having altered properties compared to the unmodified product.
Penicillin and other antibiotics of the beta lactam structure can be modified in accordance with the invention and the deuterated product exhibits enhanced activities with respect to selected bacterial strains.
REFERENCES:
patent: 4572909 (1986-02-01), Campbell et al.
patent: 4879303 (1989-11-01), Davison et al.
patent: 5223269 (1993-06-01), Liepins
patent: 5310929 (1994-05-01), Ardecky et al.
Hartley Michael G.
Isotechnika Inc.
Smith, Grambrell & Russell, LLP
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