L-dopa and/or dopa decarboxylse inhibitors conjugated to sugar for the treatment of dopamine-responsive disorders

A conjugate comprising a sugar and one or more a) L-DOPA molecules;

• b) inhibitors of DOPA decarboxylase;
• or c) a combination of L-DOPA molecules and inhibitors of DOPA decarboxylase, wherein said sugar is conjugated a) to the carboxyl group of each of said L-DOPA molecules;
• b) to the carboxyl group of the DOPA decarboxylase inhibitor;
• or c) to the carboxyl group of a spacer bound to said one or more inhibitors of DOPA decarboxylase, via a hydroxyl group of said sugar.

A process for producing a conjugate of mannitol and one to six L-DOPA molecules or a process for producing an extended release form of L-DOPA and mannitol, comprising the steps of:

• a. combining L-DOPA with SOCl2 and CH3OH to produce methyl-L-DOPA hydrochloride;
• b. combining said methyl-L-DOPA hydrochloride with K2CO3, KI, tetrabutyl ammonium bromide and benzyl bromide in acetonitrile to produce tetrabenzyl methyl L-DOPA;
• c. removing methyl group from tetrabenzyl methyl L-DOPA by hydrolyzing tetrabenzyl methyl L-DOPA with NaOH to produce tetrabenzyl L-DOPA;
• d. combining tetrabenzyl L-DOPA with (i) diisopropylidene mannitol, (ii) 1,3:4,6 di-O-benzylidene-D-mannitol, or (iii) (2R,3R,4R,5R)-3,4-bis(benzyloxy)hexane-1,2,5,6-tetraol to produce (i) (1)S,2R)-1,2-bis((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyethyl 3-(3,4-bis(benzyloxy)phenyl)-2-(dibenzylamino)propanoate, (ii) (4R,4′R,5R,5′R)-2,2′-diphenyl-4,4′-bi(1,3-dioxane)-5,5′-diyl bis(3-(3,4-bis(benzyloxy)phenyl)-2-(dibenzylamino)propanoate), or (iii) (2R,3R,4R,5R)-3,6-bis(benzyloxy)hexane-1,2,4,5-tetrayl tetrakis(3-(3,4-bis(benzyloxy)phenyl)-2-(dibenzylamino)propanoate), respectively;
• e. removing benzyl groups from the product of step (d) by hydrogenation with H2, using Pd/C or PdOH/C as a catalyst,
• thereby producing a conjugate of mannitol and one to six L-DOPA molecules.

A process for producing a conjugate of mannitol and one to six carbidopa molecules comprising the steps of:

• a. esterifying the carboxylic acid of carbidopa;
• b. protecting the amine group of the esterified carbidopa of step (a) with tert-Butyloxycarbonyl (Boc);
• c. protecting the compound from step (b) by a benzyl group;
• d. hydrolyzing the ester group of the compound of step (c), to obtain a carboxylic group;
• e. reacting the compound from step (d) with dibenzyl mannitol to obtain one or more carbidopa molecules conjugated to the mannitol;
• f. removing the protecting group from the compound from step (e);
• and
• g. hydrogenating the benzylic groups from the compound from step (f);
• thus producing a conjugate of mannitol and one to six carbidopa molecules.