Method of using deuterated calcium channel blockers

• US 6,818,200 B2
• Filed: 11/14/2001
• Issued: 11/16/2004
• Est. Priority Date: 03/25/1994
• Status: Expired due to Fees

• Current Assignee: Isotechnika Inc. (Endo International PLC)
• Original Assignee: Isotechnika Inc. (Endo International PLC)
• Inventors: Caille, Gilles, Foster, Robert T., Lewanczuk, Richard
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US09/987,370
• Publication Number:
  US 20020094995A1
• Time in Patent Office: 1,098 Days
• Field of Search: 424/1.81, 424/1.11, 514/356, 514/458, 546/167, 546/256, 546/263, 546/321
• US Class Current: 424/1.81
• CPC Class Codes: C07B 59/002 Heterocyclic compounds

Abstract

A method of enhancing the efficiency and increasing the duration of action of drugs (e.g. dihydropyridines and anti-bacterials) and particularly of nifedipine and penicillins wherein one or more hydrogen atoms are deuterated and wherein the deuterated drug has unexpectedly improved properties when used in much lower concentrations than unmodified drug. A method for determining the identity and bioequivalency of a new drug is also disclosed wherein the molecular and isotope structure of a new drug is determined by isotope ratio mass spectrometry and compared with the molecular and isotope structure of a known human drug.

Claims

1. A dihydropyridine compound wherein at least one of the hydrogen atoms is replaced with a deuterium atom, characterized in that said dihydropyridine compound is deuterated nifedipine having the formula

wherein:

X═

H, R¹ and R²═

each are CH₃ groups wherein each H atom of each CH₃ group of R¹ and R² may be replaced by a D atom, with the proviso that no more than 11 of 12 H atoms are D atoms and that when all 6 H atoms of R² are D atoms, at least one H atom in the CH₃ groups of R¹ is a D atom.

2. The dihydropyridine of claim 1 wherein at least one of the methyl groups in the 2,6-position is CD₃.

3. A pharmaceutical composition for use as a medicament comprising one or more dihydropyridine compounds of claim 1 as the active ingredient and a pharmaceutically acceptable support.

4. The pharmaceutical composition of claim 3 wherein the dihydropyridine compounds are characterized in that at least one of the methyl groups in the 2,6-position is CD₃.

5. A calcium channel blocking deuterated 1,4-dihydropyridine compound selected from nifedipine and nicardipine with an extended duration of action compared with a non-deuterated nifedipine and nicardipine, respectively, wherein at least one but at most 5 of the 6 hydrogen atoms of the methyl groups in the 2 and 6 positions are replaced with a deuterium atom.

6. A method of extending the duration of action of a calcium channel blocking undeuterated 1,4-dihydropyridine compound selected from nifedipine and nicardipine whereby at least one but at most 5 of the 6 hydrogen atoms of the methyl groups in the 2 and 6 positions are replaced with a deuterium atom.

7. A calcium channel blocking deuterated 1,4-dihydropyridine compound selected from nifedipine and nicardipine with an enhanced use dependency compared with a non-deuterated nifedipine and nicardipine, respectively, whereby at least one but at most 5 of the 6 hydrogen atoms of the methyl groups in the 2 and 6 positions are replaced with a deuterium atom.

8. A method of enhancing the use dependency of a calcium channel blocking 1,4-dihydropyridine compound selected from nifedipine and nicardipine, compared with a non-deuterated nifedipine and nicardipine, respectively, by deuterating at least one but at most 5 of the 6 hydrogen atoms of the methyl groups in the 2 and 6 positions are replaced with a deuterium atom.

9. A method of modifying the dose-response relationship of a calcium channel blocking 1,4-dihydropyridine compound selected from nifedipine and nicardipine, compared with a non-deuterated nifedipine and nicardipine, respectively, by deuterating at least one but at most 5 of the 6 hydrogen atoms of the methyl groups in the 2 and 6 positions are replaced with a deuterium atom.