Synthesis of chirally purified substituted benzothiazole diamines

Abstract

Methods for preparing chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamines such as, for example, (6R)2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole and purifying a dominant enantiomer of substituted 4,5,6,7-tetrahydro-benzothiazole diamines from entantiomerically enriched mixtures of substituted 4,5,6,7-tetrahydro-benzothiazole diamines are provided herein.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 12 / 049,235, filed Mar. 14, 2008, which claims priority to U.S. Provisional Appln. No. 60 / 894,829, filed Mar. 14, 2007 and U.S. Provisional Appln. No. 60 / 894,814, filed Mar. 14, 2007, all of which are incorporated herein by reference in their entireties.GOVERNMENT INTERESTS[0002]Not applicablePARTIES TO A JOINT RESEARCH AGREEMENT[0003]Not applicableINCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC[0004]Not applicableBACKGROUND[0005]1. Field of Invention[0006]Not applicable[0007]2. Description of Related Art[0008]The compound 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is a synthetic aminobenzothiazole derivative whose (6S) enantiomer, commonly known as pramipexole and commercially available under the Mirapex® name, is a potent dopamine agonist, and thus, mimics the effects of the neurotransmitter dopamine. Pramipexole has also been shown to have bo...

AI Technical Summary

Benefits of technology

The invention is about a process for making a chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine. The process involves heating a solution containing an entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine in a solvent, adding an alkyl sulfonate or alkyl halide, and recovering the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine. The process results in a high purity of the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine. The invention also provides specific examples of alkyl sulfonates and alkyl halides that can be used in the process.

Problems solved by technology

Recent studies also link the premature neuronal death associated with ALS to mutated mitochondrial genes which lead to abnormalities in functioning of the energy production pathways in mitochondria.

However, the pramipexole's agonistic effect on of the D2 family of dopamine receptors only requires therapeutic doses that range between 0.5 and 5.0 mg / day, and even these relatively low doses adverse side effects have been reported.

Thus, a clinical use of pramipexole as a mitochondria-targeted antioxidant is unlikely, as the high doses needed for the neuroprotective or anti-oxidative / mitochondrial normalization action are not accessible due to high dopamine receptor affinity associated with the (6S) enantiomer.

Third, the (6R) enantiomer of pramipexole may block the apoptotic cell death pathways which are produced by pharmacological models of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis diseases and mitochondrial impairment.

These known processes for the production of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole are expensive, labor intensive, and utilize hydride reducing agents that pose safety risks.

Furthermore, there are currently no known processes for the direct synthesis of the pure (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine from a diamine.

Therefore, the R isomer must be synthesized as a mixture of the optical isomers that is purified by expensive and time consuming methods that may utilize other problematic substances.

Moreover, known processes involving deamination result in a loss of enantiomeric purity, and methods useful for resolution of the optical isomers from mixtures fall short of producing chirally and chemically pure preparations of the R enantiomer or the S enantiomer.

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