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Compositions of (r)-pramipexole and methods of using the same

A technology of pramipexole and a composition, applied in the field of medicine, can solve the problems of limiting the timely development of neuroprotective potential, limiting the neuroprotective potential of enantiomers and the like

Inactive Publication Date: 2012-11-14
KNOPP BIOSCIENCES LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The presumed specific dose titration requirement of starting dosing at a very low dose and increasing the dose over a period of 7-8 weeks to the final therapeutically effective dose level severely limits the enantiomeric potential of (R)-pramipexole. neuroprotective potential of constructs
Additionally, the putative MTD would severely limit the timely exploitation of the neuroprotective potential of the (R)-pramipexole enantiomer for both acute and chronic neurodegenerative disorders

Method used

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  • Compositions of (r)-pramipexole and methods of using the same
  • Compositions of (r)-pramipexole and methods of using the same
  • Compositions of (r)-pramipexole and methods of using the same

Examples

Experimental program
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preparation example Construction

[0307] Preparation of (R)- and (S)-pramipexole

[0308] The preparation of pramipexole is described in US Patent No. 4,843,086 and US Patent No. 4,886,812 to Griss et al., each of which is incorporated herein by reference in its entirety. The (R)-pramipexole of the present invention can be obtained by the co-pending March 14, 2007 submission, entitled "Methods of Synthesizing and Purifying R(+) and S(-)pramipexole and Purifying R(+)and(S)-promipexole)", U.S. Provisional Application No. 60 / 894,829", and filed on March 14, 2007, entitled "Methods of Enantiomerically Purifying Chiral Compounds Purifying Chiral Compounds), which is incorporated herein by reference in its entirety. Specifically, preparations of pramipexole that are chirally pure for the R(+) enantiomer can be produced using a bimolecular nucleophilic substitution reaction (SN2). In a one-pot synthetic scheme, a diamine of the formula 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole is reacted with propyl sulfonate or...

Embodiment 1

[0363] Example 1 - Determination of dopamine receptor affinity for the R(+) and S(-) enantiomers of pramipexole.

[0364] The S(-) enantiomer of pramipexole has been characterized in the past as a high affinity dopamine receptor ligand at D2 (both S and L isomers), D3 and D4 receptors, although for The highest affinity was seen for the D3 receptor subtype. The dopamine receptor ligand affinities of S(-) pramipexole and R(+) pramipexole from journal publications have been tabulated (data reproduced in Table 10). Although each study or experiment was performed under slightly different conditions, and different radioligands were used, the data show comparable affinities for different dopamine receptors. Dopamine receptor affinity studies on pramipexole S(-) and R(+) enantiomers are also shown in Table 10. These data demonstrate an unexpectedly large difference in the affinity of the two enantiomers of pramipexole for all dopamine receptors. Table 10 shows that, contrary to exp...

Embodiment 2

[0372] Example 2 - Determination in dogs for the R(+) and S(-) enantiomers of 100% pure pramipexole, and a preparation of a mixture (R99.5% / S0.5%) In vivo studies of the MTD and NOAEL described above. The form of (R)-pramipexole is (R)-pramipexole dihydrochloride monohydrate.

[0373] The following in vivo study in Beagle dogs was performed to test the hypothesis that the R(+) and S(-) enantiomers of pramipexole play an important role in the receptor affinity observed Large differences would translate into large observed differences between the two enantiomers at the observed maximum tolerated dose (MTD) and / or no observable adverse effect level (NOAEL). Dogs were administered preparations of each enantiomer (within limits of analytical detection limit) of each enantiomer prepared as highly purified compounds, or prepared with 0.5% of pramipexole's S Preparation of R (+) enantiomer contaminated with (-) enantiomer.

[0374] In this study, three groups of 4 treated Male Be...

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Abstract

Compositions of predetermined amounts of R(+) pramipexole and S(-) pramipexole and methods of using the same, including for the treatment and prevention of Parkinson's disease, are provided.

Description

[0001] This application is a combination of PCT international application PCT / US2007 / 087639 submitted on December 14, 2007, which entered the Chinese national phase on August 14, 2009. A divisional application of the invention patent application for "materials and methods of using the composition". [0002] This application claims U.S. Provisional Application Serial No. 60 / 870,009 filed December 14, 2006; U.S. Provisional Application Serial No. 60 / 894,835 filed March 14, 2007; and U.S. Provisional Application Serial No. filed March 14, 2007 60 / 894,829; U.S. Provisional Application No. 60 / 894,799, filed March 14, 2007; U.S. Serial No. 11 / 733,642, filed April 10, 2007, and U.S. Serial No. 11 / 749,497, and the benefit of US Provisional Application Serial No. 60 / 979,409, filed October 10, 2007, each of which is hereby incorporated by reference in its entirety. technical field [0003] The invention relates to the field of medicine, in particular to a pharmaceutical composition an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/428A61P3/00A61P9/10A61P25/00A61P25/14A61P25/16A61P25/28A61P25/08
CPCA61K31/428A61K9/2054A61P3/00A61P9/10A61P21/00A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/28A61P29/00A61P43/00
Inventor M·E·博兹克T·小派特辛格V·格里布科夫
Owner KNOPP BIOSCIENCES LLC
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