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

Patent metadata

Field	Value
Publication number	US-2022016253-A1
Application number	US-201917311338-A
Country	US
Kind code	A1
Filing date	Dec 5, 2019
Priority date	Dec 5, 2018
Publication date	Jan 20, 2022
Grant date	—

Abstract

The present invention provides conjugates comprising a sugar such as mannitol and one or more L-DOPA and/or DOPA decarboxylse inhibitors including, inter alia, L-DOPA, carbidopa, benserazide, or a combination thereof, wherein the sugar is conjugated to the carboxyl group of the L-DOPA and/or DOPA decarboxylse inhibitor/ s) via a hydroxyl group of the sugar. The present invention further provides related pharmaceutical compositions and methods of producing the conjugates, as well as methods of use for treating medical disorders responsive to dopamininergic stimulation such as movement disorders including, inter alia, Parkinson's Disease.

First claim

1 .- 70 . (canceled)

71 . 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.

72 . The conjugate of claim 71 , wherein said conjugate comprises one molecule of mannitol and 1-4 molecules of L-DOPA; one molecule of mannitol and 1-6 molecules of the DOPA decarboxylase inhibitor, one molecule of mannitol, four molecules of L-DOPA, and one molecule of carbidopa; or a combination thereof.

73 . The conjugate of claim 71 , wherein said inhibitor of DOPA decarboxylase comprises carbidopa, methyldopa, alpha-Difluoromethyl-DOPA (DFMD), or a combination thereof.

74 . The conjugate of claim 71 , wherein said inhibitor of DOPA decarboxylase comprises benserazide and wherein said spacer comprises a dicarboxylic acid.

75 . The conjugate of claim 71 , wherein said sugar comprises mannitol, glucose, or galactose.

76 . A pharmaceutical composition comprising one or more conjugates of claim 71 and a pharmaceutically acceptable carrier.

77 . The pharmaceutical composition of claim 76 , wherein said pharmaceutical composition is formulated for intranasal, intravenous, subcutaneous, oral, rectal, transdermal, intraduodenal, inhalation, or intrapulmonary administration.

78 . The pharmaceutical composition of claim 77 , wherein said pharmaceutical composition is formulated for intranasal administration and wherein said pharmaceutically acceptable carrier is selected from sodium chloride, dextrose, sodium hydroxide, hydrochloric acid sulphuric acid, nitrogen, benzalkonium chloride, ethanol, propylene glycol, beczoyl alcohol, chlorobutanol, methyl paraben, sodium citrate, sodium phosphate, Polysorbate 80, Polysorbate 20, disodium EDTA, CMC, Na CMC, Alcohol, PEG 400, propylene glycol and glycerin.

79 . The pharmaceutical composition of claim 76 , further comprising a therapeutic compound comprising a prodrug of L-Dopa, one or more inhibitors of DOPA decarboxylase, a catechol-O-methyltransferase (COMT) inhibitor, or a combination thereof.

80 . The pharmaceutical composition of claim 79 , wherein said one or more inhibitors of DOPA decarboxylase comprises carbidopa, a prodrug of carbidopa, benserazide, methyldopa, alpha-Difluoromethyl-DOPA (DFMD), or a combination thereof.

81 . The pharmaceutical composition of claim 79 , wherein said COMT inhibitor comprises entacapone, tolcapone, opicapone, or a combination thereof.

82 . A method for treating, suppressing, or inhibiting a movement disorder responsive to dopaminergic stimulation comprising administering to a subject having said medical disorder a therapeutically effective amount of the pharmaceutical composition of claim 76 .

83 . The method of claim 82 , wherein said movement disorder requires continuous dopaminergic stimulation, comprises Parkinson's Disease (PD), symptomatic parkinsonism following carbon monoxide intoxication or manganese intoxication, dopamine-responsive dystonia, restless legs syndrome, one or more of the Parkinson plus syndromes, or a combination thereof.

84 . The method of claim 83 , wherein said PD comprises symptomatic PD, advanced Parkinson's disease with motor complications, idiopathic PD, iatrogenic PD, vascular PD, post-encephalitic parkinsonism, or a combination thereof; wherein said dopamine-responsive dystonia comprises Segawa syndrome; and wherein said Parkinson plus syndrome comprises a synucleinopathy, a tauopathy, multiple system atrophy (MSA), tauopathy-like fronto-temporal degeneration, corticobasal degeneration (CBD), Dementia with Lewy bodies (DLB), diffuse Lewy body dementia (DLBD), olivopontocerebellar atrophy, or a combination thereof.

85 . The method of claim 84 , wherein said tauopathy-like fronto-temporal degeneration comprises progressive supranuclear palsy (PSP), Pick's disease, or a combination thereof.

86 . The method of claim 82 , wherein said conjugate is administered to said subject in a daily dose of 10-3,000 mg.

87 . 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 SOCl 2 and CH 3 OH to produce methyl-L-DOPA hydrochloride; b. combining said methyl-L-DOPA hydrochloride with K 2 CO 3 , 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 H 2 , using Pd/C or PdOH/C as a catalyst, thereby producing a conjugate of mannitol and one to six L-DOPA molecules.

88 . The process of claim 87 , wherein the process of producing (2R,3R,4R,5R)-3,4-bis(benzyloxy)hexane-1,2,5,6-tetraol in step (d) comprises the steps of:
a. adding benzylic groups to diisopropylidene mannitol comprising the step of combining diisopropylidene mannitol with benzyl bromide to produce product (14) and b. removing the isopropylidene groups from product (14) comprising the step of combining product (14) with H 2 SO 4 /Silica to remove the isopropylidene groups, thereby producing (2R,3R,4R,5R)-3,4-bis(benzyloxy)hexane-1,2,5,6-tetraol from diisopropylidene mannitol.

89 . 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.

90 . The process of claim 89 , wherein said esterification at step (a) is performed with ethanol, methanol, t-butanol, propanol, or a combination thereof wherein at step (b) the amine group is protected with tert-Butyloxycarbonyl (Boc); wherein at step (c) the protecting of the compound of step (b) is performed in the presence of CsHCO 3 ; wherein at step (d) the compound of step (c) is mixed with H 2 O/CH 3 OH/THF in the presence of 0.33M LiOH, or a combination thereof.

Assignees

• B G Negev Technologies And Applications Ltd At Ben Gurion Univ

Inventors

• Heldman Eliahu
• Kushnir Moshe
• Shaubi Eleonora

Classifications

• C07H15/18

  Acyclic radicals, substituted by carbocyclic rings · CPC title

• A61K47/549 Primary

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• C07C227/18

  by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters · CPC title

• C07C241/02

  Preparation of hydrazines · CPC title

• A61K9/0043

  Nose · CPC title