Brasofensine

Brasofensine (NS-2214, BMS-204756) is a phenyltropane that had been under development for the treatment of Parkinson's and Alzheimer's disease. Phase II trials were conducted in 1996 and brasofensine was shown to be both effective and well tolerated at a dose of 4 mg,^[1] however development was stopped after in vivo cis-anti isomerization of the 2α-methyloxime group was reported.^[2] In animal models of Parkinson's disease, brasofensine was effective in stimulating LMA and reversing akinesia.^[3]

The isomerization of brasofensine is not between the alpha and beta positions on the 2 position of the tropane ring but rather the E/Z isomerization of the imine (i.e. "methyl-aldoxime").^[4] It was believed that this process occurs in vivo although it cannot be ruled out as a possibility that some isomerization also occurs prior to ingestion.

The (Z)-isomer has been consigned the name BMS-205912

The inversion barrier for a methylaldoxime may or may not be measurable. The relative ratio of E/Z should lie in an equilibrium and this needs to be measured. It is not unreasonable to anticipate that this distribution can be influenced by complexation with various solvents under an appropriate choice of reaction temperature. This possibility should be considered. The inversion barrier for isomerization of a methylaldoxime -in brasofensine in particular- must be calculated so it is known how easily the isomeric forms are interconverted.

In PD, symptoms do not begin to manifest until there has been an 80% reduction in dopaminergic neurons, particularly in the substantia nigra brain region. Subsequently there is decreased dopaminergic neurotransmission, resulting in movement disorders, slurred speech, and the like. The object of a dopamine reuptake inhibitor is to "make the best out of" the dopamine that is still available. Additionally, a DRI can be expected to enhance the effectiveness of exogenously delivered dopamine, in the form of L-DOPA.

Metabolism and Distribution

NS-2214 is not particularly stable and is readily metabolized. 50 mg was the dosage that was tried on humans, although the starting dose was 2 mg.^[4] Interestingly, because rats metabolism is much greater than humans, the amount of metabolites detected in their urine (and feces) was also much greater than for humans, who excrete more of the product intact. For humans, most (~90%) of the ¹⁴C was detected in the urine, whereas for rats as much as 80% of the ¹⁴C was in their feces.

It is well-known that a Schiff base is more stable than a regular imine. Imine formation is a reversible process, and in the study by Zhu et al.,^[4] none of the aldehyde was recovered/detected by GC-MS. Instead, the breakdown products were N-demethyl metabolites.

Chemistry

The ester was first reduced to the alcohol, then oxidized to the aldehyde, followed by condensation with methoxyamine. Methods have been reported for the direct reduction of esters to aldehydes, however in practice there has been some difficulty in effecting this transformation.^[5] 17-20

In particular, the fragility of the aldehyde meant that it collapsed to the alcohol and was not isolable even though a wide assortment of reducing agents and reactions conditions were attempted.

Following this, Swern oxidation was employed to obtain the corresponding aldehyde.

Patents

• U.S. Patent 5,374,636
• U.S. Patent 5,554,626
• U.S. Patent 5,736,556

References