L-Dopa esters

DR Cooper, C Marrel, H Van de Waterbeemd, B Testa, P Jenner, C D Marsden. L-Dopa esters as potential prodrugs Behavioural activity in experimental models of parkinson s disease. J Pharm Pharmacol 39 627-635, 1987. 

Here, we present the hydrolysis of a series of L-dopa esters whose pharmacodynamic behavior has also been reported [28-31]. As shown in Table 8.1, the compounds are esters incorporating a simple primary, secondary, or... 

The L-dopa esters were also examined for their enzymatic hydrolysis in human plasma and/or by purified pig liver carboxylesterase (EC 3.ELI Table 8.1). In human plasma under the conditions of study, hydrolysis again followed pseudo-first-order kinetics. In all but two cases examined, enzymatic hydrolysis was slightly faster than chemical hydrolysis. For the methyl ester, rates of chemical and enzymatic hydrolysis were comparable, whereas the /erf-butyl ester was not hydrolyzed in plasma and was protected from chemical hydrolysis presumably by becoming bound to plasma proteins. 

D. R. Cooper, C. Marrel, H. van de Waterbeemd, B. Testa, P. Jenner, C. D. Marsden, l-Dopa Esters as Potential Prodrugs Behavioural Activity in Experimental Models of Parkinson s Disease , J. Pharm. Pharmacol. 1987, 39, 627 - 635 D. R. Cooper, C. Marrel, H. van de Waterbeemd, B. Testa, P. Jenner, C. D. Marsden, L-Dopa Esters as Potential Prodrugs Effect on Brain Concentration of Dopamine Metabolites in Reserpi-nized Mice , J. Pharm. Pharmacol. 1987, 39, 809-818. 

H. van de Waterbeemd, B. Testa, C. Marrel, D. R. Cooper, P. Jenner, C. D. Marsden, Multivariate Statistical Analysis of L-Dopa Esters as Potential Anti-Parkinsonian Prodrugs , Drug Design Delivery 1987, 2, 135-143. 

The chiral phase-transfer catalysis of le was further applied to the facile synthesis of L-Dopa ester and its analogue, which usually have been prepared by either asymmetric hydrogenation of eneamides or enzymatic processes, and tested as potential drugs for the treatment of Parkinson s disease. Phase-transfer-catalyzed alkylation of 2 with the requisite benzyl bromide 35a in toluene-50% KOH aqueous solution proceeded smoothly at 0 °C under the influence of (R,R)-le to furnish fully protected L-Dopa tert-butyl ester this was subsequently hydrolyzed to afford the corresponding amino ester 36a in 81% yield with 98% ee. Debenzylation of 36a under... 

SCHEME 23 Stereoselective ssmthesis of L-Dopa ester 118 and its analogue 119. 

Chira.lHydrogena.tion, Biological reactions are stereoselective, and numerous dmgs must be pure optical isomers. Metal complex catalysts have been found that give very high yields of chiral products, and some have industrial appHcation (17,18). The hydrogenation of the methyl ester of acetamidocinnamic acid has been carried out to give a precusor of L-dopa, ie, 3,4-dihydroxyphenylalanine, a dmg used in the treatment of Parkinson s disease. 

Finally, as an old example of kinetic resolution of racemic mixtures, mention must be made on the report of Kise and Tomiuchi on the significant effect of acetonitrile on the enantioselectivity of different proteases toward the kinetic resolution of aromatic amino acid ethyl esters (5-8). For instance, (l)-DOPA (8) was obtained with 99% ee in the presence of 90% v/v acetonitrile [9]. 

Others have also tried to develop L-dopa prodrugs. L-Dopa carboxyl esters were studied by Cooper and colleagues [5,6] and were not long-lasting. Garzon... 

The ability of NB-355 to stimulate locomotor activity and induce dyskinesia in MPTP-treated squirrel monkeys was studied (MPTP induces parkinsonism) [9], NB-355 was similar to L-dopa in stimulating locomotor activity. Furthermore, NB-355 induced less severe dyskinesia than was seen with L-dopa. Some other prodrugs of L-dopa include short-chain alkyl esters (methyl, ethyl, isopropyl, butyl, hydroxypropyl, and hydroxybutyl) intended for rectal absorption [10], These esters of L-dopa have high water solubility (>600 mg/mL). Initial bioavailability studies indicated that all of these esters, with the exception of the hydroxypropyl ester, resulted in significantly greater bioavailability than that obtained with L-dopa itself. However, given the high level of esterase activity in the small intestine, the use of these compounds is limited to rectal administration. 

I. Ester derivatives L-Dopa Carboxyl ester, e.g., methyl catechol mono-o-pivaloyl. 4-6,8-10... 

AJ Repta. Short-chain alkyl esters of L-dopa as prodrugs for rectal absorption. Pharm Res 6(6) 501-505, 1989. 

One must be careful not to generalize from the above discussion that hydrolysis of pivaloyl esters will always be slow. Indeed, a notable exception may well exist for monoesters of catechols, where intramolecular catalysis accelerates hydrolysis. This was seen for L-3-[3-hydroxy-4-(pivaloyl-oxy)phenyl] alanine (8.81 4-pivaloyl-L-dopa), a potentially valuable prodrug of L-dopa [114], When given to rats and dogs, 4-pivaloyl-L-dopa displayed markedly longer duration of action and a higher bioavailability of L-dopa than the drug itself complete conversion to L-dopa was noted in rat. The... 

M. Brunner-Guenat, P. A. Carrupt, G. Lisa, B. Testa, S. Rose, K. Thomas, P. Jenner, P. Ventura, Esters of L-Dopa Structure-Hydrolysis Relationships and Ability to Induce Circling Behaviour in an Experimental Model of Hemiparkinsonism , J. Pharm. Pharmacol. 1995, 47, 861 -869. 

Wulff and his collaborators reported, in 1989, the preparation of imprinted polymers able to perform enantioselective synthesis [11, 12]. The imprinting complex was prepared by reacting 3,4-di-hydroxy-phenyl-alanine methyl-ester (l-DOPA methyl ester) (16) with the 4-vinyl-salicylaldehyde (17) to form the corresponding Schiff s base (18), which was further reacted with the 4-vinyl-phenyl-boronic acid (19) to afford to the corresponding ester (20) (Scheme 4). The imprinting complex obtained was then polymerised and the template removed. The resulting polymers were incubated with sodium glycinate to allow formation... 

Reaction 9.1 has been extensively studied to establish the mechanism of asymmetric hydrogenation. The catalytic cycle proposed for the asymmetric hydrogenation of the methyl ester of a-acetamido cinamic acid with 9.14 as the precatalyst is shown in Fig. 9.3. As mentioned earlier, this reaction is one of the early examples of industrial applications of asymmetric catalysis for the manufacture of L-DOPA (see Table 1.1). 

Chiral catalysis is employed in several industrial processes leading to enan-tiomerically pure products, such as the amino acid L-dihydroxyphenylalanine (L-DOPA) required for the treatment of Parkinson s disease, L-menthol, and car-bapenems.7 8 The hydrogenation of prochiral functionalized alkenes, notably a-acetamidocinnamic esters, has attracted particular attention ... 

C. Wiese and co-workers have synthesized 5-fluoro-D/L-dopa and the corresponding [ F]5-Fluoro-L-dopa starting from 5-nitrovanillin via malonic ester synthesis, the Balz-Schiemann reaction, and the separation of the racemic mixture [ F]5-fluoro-D/L-dopa utilizing a chiral FIPLC system. The inactive 5-fluoro-D/L-dopa was obtained in an eight-step synthesis with an overall yield of 10%. 

M.E. Jung and co-workers have developed a synthesis of selectively protected L-Dopa derivatives from L-tyrosine via a Reimer-Tiemann reaction followed by the modified Dakin oxidation. The formyl group introduced by the Reimer-Tlemann reaction had to be converted to the corresponding phenol. After trying many sets of conditions, the Syper process was chosen, which uses arylselenium compounds as activators for the oxidation. Treatment of the aromatic aldehyde with 2.5 equivalents of 30% hydrogen peroxide in the presence of 4% diphenyl diselenide in dichloromethane for 18h gave the aryl formate in excellent yield. This ester was cleaved by treatment with methanolic ammonia for 1h to afford the desired phenol in good yield. 

Hydrolases - Chymotrypsin is the best documented hydrolase. It has a very broad and predictable stereospecificlty and is widely used in resolution of racemic esters.1 L-DOPA has been prepared in this way.41 Several esterases also exhibit enantiotopic specificity. This is exploited in the synthesis of R-mevalonolactone 22 from 21.42... 

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