WO1986004579A1 - L-dopa derivatives, preparation thereof and pharmaceutical compositions containing them - Google Patents
L-dopa derivatives, preparation thereof and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- WO1986004579A1 WO1986004579A1 PCT/BE1986/000002 BE8600002W WO8604579A1 WO 1986004579 A1 WO1986004579 A1 WO 1986004579A1 BE 8600002 W BE8600002 W BE 8600002W WO 8604579 A1 WO8604579 A1 WO 8604579A1
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- Prior art keywords
- dopa
- derivative
- glycerol
- residue
- acyl
- Prior art date
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- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical class OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 title description 5
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims abstract description 26
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000002252 acyl group Chemical group 0.000 claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 6
- 230000008569 process Effects 0.000 claims abstract description 5
- 239000012374 esterification agent Substances 0.000 claims abstract description 4
- 150000002314 glycerols Chemical class 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 230000002093 peripheral effect Effects 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 claims description 2
- 229960000911 benserazide Drugs 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229960004205 carbidopa Drugs 0.000 claims description 2
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 claims description 2
- 238000012512 characterization method Methods 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 238000005809 transesterification reaction Methods 0.000 claims description 2
- 229940081615 DOPA decarboxylase inhibitor Drugs 0.000 claims 1
- 239000012050 conventional carrier Substances 0.000 claims 1
- 239000000534 dopa decarboxylase inhibitor Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 30
- 239000003814 drug Substances 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 13
- GFAZGHREJPXDMH-UHFFFAOYSA-N 1,3-dipalmitoylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCC GFAZGHREJPXDMH-UHFFFAOYSA-N 0.000 description 9
- 229960003638 dopamine Drugs 0.000 description 9
- 125000005456 glyceride group Chemical group 0.000 description 9
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 6
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 6
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 6
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 6
- 229960003147 reserpine Drugs 0.000 description 6
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 4
- 206010044565 Tremor Diseases 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 206010015995 Eyelid ptosis Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 230000002631 hypothermal effect Effects 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 201000003004 ptosis Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000000648 anti-parkinson Effects 0.000 description 2
- 239000000939 antiparkinson agent Substances 0.000 description 2
- 230000036765 blood level Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 206010007776 catatonia Diseases 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010579 first pass effect Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000001926 lymphatic effect Effects 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- 102100038238 Aromatic-L-amino-acid decarboxylase Human genes 0.000 description 1
- 206010006100 Bradykinesia Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- -1 L-dopa ester Chemical class 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000002740 Muscle Rigidity Diseases 0.000 description 1
- 238000011785 NMRI mouse Methods 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 108010035075 Tyrosine decarboxylase Proteins 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000009056 active transport Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
Abstract
Description
Dérives de L-DOPA, leur preparation et
compositions pharmaceutiques les contenant.
La présente invention concerne des dérivés nouveaux de la L-Dopa ou (L)-dihydroxy-3,4-phénylalanine présentant des propriétés améliorées par rapport à la
L-Dopa elle-même, des procédés pour leur préparation, des compositions pharmaceutiques contenant de tels composés et s'étend à leur application en médecine humaine notamment.
La L-Dopa est communément utilisée dans le traitement des symptômes les plus invalidants de la maladie de Parkinson (tremblements, rigidité, bradykinésie). Néanmoins, bien que le traitement puisse être efficace durant plusieurs années, celui-ci souffre d'inconvénients importants dûs à la trop courte demi-vie biologique de la L-Dopa et à sa rapide dégradation en dopamine, ce qui amène des fluctuations importantes et rapides du taux sanguin et l'apparition d'effets secondaires dus à la dopamine circulante, phénomènes responsables d'effets indésirables néfastes tels que la dyskinésie, des troubles gastro-intestinaux et cardio-vasculaires. Cet état de fait est dû très largement à un effet de premier passage très marqué, au niveau hépatique, mais surtout au niveau gastro-intestinal.
Le but visé par la présente invention est essentiellement de fournir des composés nouveaux et des compositions pharmaceutiques contenant ces composés qui permettent d'éviter les inconvénients précités.
La stratégie qui a été adoptée pour combattre ces problèmes a consisté en la synthèse d'un dérivé de la
L-Dopa en couplant celle-ci à un dérivé du glycérol en formant une liaison ester avec une fonction hydroxyle du glycérol, au moins une des positions hydroxyle restantes étant estérifiée par une chaîne acyle et l'autre position hydroxyle restante étant également estérifiée soit par une chaîne acyle identique ou différente de la pre mière, soit par un agent d'estérification d'une autre nature mais pharmacologiquement acceptable.
L'incorporation de la L-Dopa dans une structure glycéridique améliore la valeur thêrapeutique de cette dernière de plusieurs façons: - en réduisant l'effet de premier passage intestinal et hépatique et de la sorte les effets secondaires liées à la formation de certains métabolites (en particulier, la dopamine) - en assurant des concentrations sanguines mieux étalées dans le temps, ce qui supprime les trop grandes fluctations des taux sanguins observées avec la L-Dopa, - en court-circuitant le système de transport actif qui assure la résorption intestinale de la L-Dopa, ce qui est en partie du moinsà l'origine de la variabilité de la réponse thérapeutique.
Des composés préférés de la présente invention peuvent être représentés par la formule (I)
EMI2.1
* = forme L dans laquelle R1 représente un reste de glycérol et R2 et R3, qui peuvent être identiques ou différents, représentent un reste acyle comportant de 4 à 22 atomes de carbone ou un reste d'acide pharmacologiquement acceptable, au moins un de ces deux restes étant un reste acyle comportant de 4 à 22 atomes de carbone.
On accorde la préference à des composés de la formule (II)
EMI2.2
* = forme L et tout particulièrement ceux dans lesquels R2 et R3 représentent un reste acyle comportant de 4 à 22 atomes de carbone.
Sont tout particulièrement préférés les composés dans lesquels R2 et R3 représentent des restes identiques.
Pour autant que l'un des restes R2 et R3 représente un reste acyle comportant de 4 à 22 atomes de carbone, l'autre reste peut cependant être différent et être notamment un reste d'acide phosphorique par exemple.
L'invention s'étend également aux composés analogues à ceux cités ci-dessus où le reste acyle de L-dopa au lieu d'être fixé en position 2 du glycérol, se trouve en position 1 ou 3.
Les composés précités peuvent être utilisés en tant que principe actif dans le traitement de la maladie de Parkinson ou servir de produits intermédiaires pour la caractérisation, la purification ou la synthèse de tels produits actifs, notamment par transestérification.
A titre d'exemple de cpmposé particulièrement étudié dans le cadre de la présente invention, ont peut citer le composé de formule (III)
EMI3.1
* = forme L
On connaît déjà des dérivés de L-Dopa, notamment des dipeptides ou des tripeptides qui ne présentent cependant pas les avantages des composés de la présente invention, à savoir de permettre une résorption par la voie lymphatique en évitant une destruction importante du composé dans le tractus intestinal ou par le foie.
L'administration aux patients de quantités importantes de L-Dopa qui est actuellement nécessaire pour une disponibilité en quantité suffisante au cerveau de dopamine après passage de la barrière hémato-encéphalique est ainsi évitée. En outre il en résulte une réduction des effets .secondaires néfastes dus à présence de dopamine périphérique, responsable notamment de nausées etc.
Les composés de l'invention sont de préférence administrés per os sous forme de préparations pharmaceutiques obtenues de la manière classique, par les techniques galéniques bien connues par adjonction d'adjuvants, excipients et supports classiques. Ils peuvent être présentés sous forme d'émulsions, de suspensions, de gélules ou de sirop notamment.
I1 convient de noter, dans la mesure où les substitutions sur le reste glycérol dans les molécules précitées ont pour conséquence de rendre un atome de carbone asymétrique que l'invention s'étend au mélange racémique et aux différentes formes diastéréoisomères résultant de la conjonction du carbone asymétrique de la partie L-dopa et du carbone asymétrique de la partie glycéridique.
On observe que les composés de l'invention permettent d'obtenir les mêmes effets pharmacologiques que ceux de la L-Dopa avec des propriétés pharmacocinétiques améliorées, notamment un effet de slow-release, ainsi que le démontreront les exemples qui suivent.
La dose et la posologie des compositions pharmaceutiques de l'invention dépendent des composés choisis.
L'homme de l'art pourra aise ment adapter les doses et la posologie choisies en fonction notamment de l'importance des atteintes observées et de l'état général du patient.
On choisira en principe des doses et des posologies suffisantes pour réaliser des valeurs de disponibilité cérébrale de la dopamine pour les composés de l'invention similaires à celles recommandées actuellement pour l'u sage de la L-Dopa, sachant qu'on admet actuellement qu'un pour cent seulement de la L-Dopa prise per os est transformée au niveau du système nerveux central en dopamine active. Il convient de noter que la réduction importante des effets secondaires résultant d'une meilleure utilisation du principe actif possible grâce aux composés de l'invention permet, si on le souhaite, d'accroître la dose administrée de ces composés.
Il relève également de l'invention d'associer les composés de l'invention à des inhibiteurs de la dopadécarboxylase périphérique, tels le bensérazide ou le carbidopa, ce qui permet, ainsi qu'il est connu, d'accroître.la disponibilité de la dopamine au cerveau.
L'association des composés de l'invention avec d'autres composés actifs relève également de l'invention.
RéSUME DE L'ETAT DE LA TECHNIQUE
Il convient de noter que différentes molécules présentant une certaine similtude de structure avec ceux de l'invention ont été décrites dans la littérature. On peut citer notamment les documents US-A-4 360 533 (A.A.
PATCHETT); US-A-4 134 991 (J.J. BALDWIN et al.) qui correspond à FR-A-2 365 341 (SYNTHELABO) US-A-4 254 273 (B.F. POWELL et al.) qui correspond à FR-A-2 313 922 (MERCK) et EP-A-O 030 734 (MFRCK).
Parmi ces documents seulement US-A-4 134 991 (J.J. BALDWIN et al.) mentionnent une application pour le traitement de la maladie de Parkinson.
Aucun des documents ne permettait de prévoir que les produits en question agiraient en améliorant la valeur thérapeutique comme les produits de l'invention pour le traitement de la maladie de Parkinson.
PROCÉDÉS DE SYNTHÈSE
Différentes voies de synthèse sont possibles pour obtenir les composés de l'invention. Ces voies de synthèse seront illustrées en référence aux exemples qui suivent portant sur un composé particulier de l'invention de formule III et schématisé dans la Figure 1 annexée.
Exemple 1 : (Méthode A de la figure 1)
Ester (L)-N,O,O'-tricarbobenzyloxydopa de la dipalmitine-l,3 (3 > .
À une solution de 28,4 g de dipalmitate de trihy droxy-l,2,3-propane (dipalmitine-1,3) (2) (50 mmol) et 30,1 g de (L)-N,O,O'-tricarbobenzyloxydopa (1) (50 mmol) dans 250 ml de dichlorométhane, agitée magnétiquement et refroidie à O"C au moyen d'un bain de glace, on ajoute en une seule portion 10,3 g de dicyclohexyl-carbodiimide (50 mmol) et 100 mg de pyrrolidino-4-pyridine. Après une heure, on enlève le bain de glace. Le mélange réactionnel est ensuite agité durant 25h à température ambiante.
On essore le précipité de dicyclohexylurée et le filtrat est lavé par de l'eau (l0Oml), du bicarbonate de sodium à 5% (100 ml) (p/v), puis à l'acide chlorhydrique 0,05M (100 ml). La solution organique est séchée sur sulfate de magnésium, filtrée et évaporée à sec. Le résidu est chromatographié sur gel de silice et le composé désiré (3) est élué au moyen d'un mélange n-hexane : diéthyléther (70:30, v/v). Après évaporation à sec des fractions contenant 3, le résidu est recristallisé dans l'éthanol.
Rendement = 388. Le produit est caractérisé par son point de fusion de 75"C et son pouvoir rotatoire [a125
D de -3,14 (C 3, méthanol).
Ester de la L-dopa de la dipalmitine-l,3.
I (1)
Une solution de 10,0 g de 3 dans le tétrahydrofurane (150 ml) est hydrogénolysé en présence de palladium sur charbon (l,0 g) sous une pression initiale de 250 kPa pendant 18h. La suspension est ensuite filtrée et le filtrat est évaporé à sec. Le résidu est purifié par chromatographie dans les mêmes conditions que pour 3. La recristallisation dans l'éthanol fournit un produit de point de fusion 78"C et d'un pouvoir rotatoire [aJ25 de
D -6,23 (C 3,2, DMF).
Analyse élémentaire (C44H77108)
Valeurs calculées C 70,64% trouvées 70,61
H 10,37 10,25
O 17,11 16,94
N 1,87 2,20
Spectre de masse (m/e) : 747 (M+), 477, 256,
239.
Exemple 2 : (Méthode B de la Figure 1)
Le même composé (III) peut être synthétisé par la voie B de la Figure 1. Les rendements qui nécessitent encore une optimalisation sont cependant plus faibles.
Exemple 3 : (Méthode C de la Figure 1)
Par la méthode C il est également possible d'obtenir le composé de formule III. Des remarques similaires à celles de l'exemple 2 s'appliquent aussi.
Exemple 4 : Evaluations pharmacologique et pharmacocinétique
Le dérivé obtenu selon l'exemple- l a été évalué au point de vue de son activité antiparkinsonienne au moyen de c-ux tests classiques; le test à l'oxotrémorine et le test à la réserpine suivant le protocole général décrit par Horst et al. (réf. Burop.J.Pharmacol.21, 337342, 1973). Dans le test à la réserpine, l'efficacité se mesure par l'inhibition de la ptose et de la catatonie; dans le test à l'oxotrémorine par l'inhibition du tremor et de l'hypothermie, le calcul des ED50 a été effectué suivant la méthode classique de Litchfield et Wilcoxon (J.Pharmacol. Exptl. Therap., 96, 69...(1949)).
Le protocole opératoire suivi par ces deux tests est repris ci-après.
A) TEST A LA RESERPINE.
1. La réserpine est administrée i.p. à la dose de 5 mg/kg
2. Quatre heures après, les composés à tester : L-dopa et
son dérivé glyceridique sont administrés p.o. à
différentes doses et ce à raison de cinq souris par
dose.
3. L'évolution des effets induits par la réserpine
catatonie et ptose est suivie à différents temps : 15,
30, 60, 90, 120 min.
4 h 15, 30, 60, 90, 120 min
Réserpine L-dopa et son déri- catatonie et
Smg/kg, i.p. vé glycéridique, p.o. ptose
B) TEST A L'OXOTREMORINE,
1. Les composés à tester : L-;dopa et son dérivé
glycéridique sont administrés p,o. à différentes doses
et ce à raison de cinq souris par dose.
2. L'oxotrémorine (0,5 mg/kg i.p.) est administrée aux
souris prétraitées après différents temps : 15, 45,
90, 120 min.
3. La réponse des animaux aux effets de ltoxotrémorine e
hypothermie et tremor est mesurée respectivement 15 et
30 min après l'administration de l'agent cholinergique
15, 45, 90, 120 min 15 min 15 min
L-dopa et son déri- oxotrémorine hypothermie tremor
vé glycéridique, p.o. 0,5 mg/kg ,i.p.
Pour ces deux tests, ont été utilisées des souris NMRI mâles pesant entre 22 et 25 g.
La L-dopa et son dérivé glycéridique sont administres par gavage en suspension dans une solution à 5% de gomme arabique.
Les effets observés ont été repris sous forme de graphiques dans les Figures 2 à 5 qui suivent.
Il apparaît de ces deux tests que le dérivé glycéridique III - présente une activité antiparkinsonienne sensiblement du même ordre de grandeur, mais cette activité perdure à des temps approximativement doubles de ceux observés pour la L-Dopa.
Du point de vue pharmacocinétique, les Figures 6 et 7 démontrent de façon spectaculaire l'effet lymphotrope produit par le greffage de la dipalmitine-l,3 sur la L-Dopa. On constate en effet qu'après administration per os d'une dose équivalente de 0,5 m mol/kg soit de
L-Dopa, soit du dérivé glycéridique de la L-dopa (III), on obtient des taux lymphatiques plus de 40 fois plus importants dans le cas de III que dans celui de la
L-Dopa, laquelle apparaît d'ailleurs de façon prépondérante sous forme de son métabolite, la dopamine.
L-DOPA derivatives, their preparation and
pharmaceutical compositions containing them.
The present invention relates to new derivatives of L-Dopa or (L)-dihydroxy-3,4-phenylalanine having improved properties compared to the
L-Dopa itself, processes for their preparation, pharmaceutical compositions containing such compounds and extends to their application in human medicine in particular.
L-Dopa is commonly used in the treatment of the most debilitating symptoms of Parkinson's disease (tremors, rigidity, bradykinesia). Nevertheless, although the treatment may be effective for several years, it suffers from significant drawbacks due to the too short biological half-life of L-Dopa and its rapid degradation into dopamine, which leads to significant fluctuations and rapid blood levels and the appearance of side effects due to circulating dopamine, phenomena responsible for harmful side effects such as dyskinesia, gastrointestinal and cardiovascular disorders. This state of affairs is very largely due to a very marked first-pass effect, at the hepatic level, but especially at the gastrointestinal level.
The aim of the present invention is essentially to provide new compounds and pharmaceutical compositions containing these compounds which make it possible to avoid the aforementioned drawbacks.
The strategy which was adopted to combat these problems consisted in the synthesis of a derivative of the
L-Dopa by coupling the latter to a derivative of glycerol by forming an ester bond with a hydroxyl function of the glycerol, at least one of the remaining hydroxyl positions being esterified by an acyl chain and the other remaining hydroxyl position also being esterified either by an acyl chain identical to or different from the first, or by an esterification agent of another nature but pharmacologically acceptable.
The incorporation of L-Dopa into a glyceride structure improves the therapeutic value of the latter in several ways: - by reducing the intestinal and hepatic first-pass effect and thus the side effects linked to the formation of certain metabolites ( in particular, dopamine) - by ensuring blood concentrations that are better spread over time, which eliminates the excessive fluctuations in blood levels observed with L-Dopa, - by bypassing the active transport system which ensures intestinal resorption of L-Dopa, which is at least partly responsible for the variability of the therapeutic response.
Preferred compounds of the present invention may be represented by formula (I)
EMI2.1
* = form L in which R1 represents a glycerol residue and R2 and R3, which may be identical or different, represent an acyl residue comprising from 4 to 22 carbon atoms or a pharmacologically acceptable acid residue, at least one of these two residues being an acyl residue comprising from 4 to 22 carbon atoms.
Preference is given to compounds of formula (II)
EMI2.2
* = form L and most particularly those in which R2 and R3 represent an acyl residue containing from 4 to 22 carbon atoms.
The compounds in which R2 and R3 represent identical residues are very particularly preferred.
Provided that one of the residues R2 and R3 represents an acyl residue comprising from 4 to 22 carbon atoms, the other residue may however be different and in particular be a phosphoric acid residue for example.
The invention also extends to compounds analogous to those mentioned above where the acyl residue of L-dopa, instead of being fixed in position 2 of the glycerol, is in position 1 or 3.
The aforementioned compounds can be used as active principle in the treatment of Parkinson's disease or serve as intermediate products for the characterization, purification or synthesis of such active products, in particular by transesterification.
As an example of a compound particularly studied in the context of the present invention, mention may be made of the compound of formula (III)
EMI3.1
* = L-shape
L-Dopa derivatives are already known, in particular dipeptides or tripeptides which do not however have the advantages of the compounds of the present invention, namely to allow resorption via the lymphatic route while avoiding significant destruction of the compound in the tract. intestinal or via the liver.
The administration to patients of large quantities of L-Dopa which is currently necessary for the availability of dopamine in sufficient quantities to the brain after crossing the blood-brain barrier is thus avoided. In addition, this results in a reduction of the harmful side effects due to the presence of peripheral dopamine, responsible in particular for nausea, etc.
The compounds of the invention are preferably administered per os in the form of pharmaceutical preparations obtained in the conventional manner, by well-known galenic techniques by addition of conventional adjuvants, excipients and carriers. They can be presented in the form of emulsions, suspensions, capsules or syrup in particular.
It should be noted, insofar as the substitutions on the glycerol residue in the aforementioned molecules have the consequence of making an asymmetric carbon atom that the invention extends to the racemic mixture and to the various diastereoisomeric forms resulting from the conjunction of the carbon asymmetric carbon of the L-dopa part and asymmetric carbon of the glyceride part.
It is observed that the compounds of the invention make it possible to obtain the same pharmacological effects as those of L-Dopa with improved pharmacokinetic properties, in particular a slow-release effect, as will be demonstrated by the examples which follow.
The dose and dosage of the pharmaceutical compositions of the invention depend on the compounds chosen.
Those skilled in the art will be able to easily adapt the doses and the posology chosen according in particular to the importance of the damage observed and the general condition of the patient.
In principle, sufficient doses and posologies will be chosen to achieve cerebral dopamine availability values for the compounds of the invention similar to those currently recommended for the use of L-Dopa, knowing that it is currently accepted that Only one percent of L-Dopa taken orally is transformed in the central nervous system into active dopamine. It should be noted that the significant reduction in side effects resulting from a better possible use of the active ingredient thanks to the compounds of the invention makes it possible, if desired, to increase the administered dose of these compounds.
It is also part of the invention to combine the compounds of the invention with inhibitors of peripheral dopadecarboxylase, such as benserazide or carbidopa, which makes it possible, as is known, to increase the availability of the dopamine in the brain.
The combination of the compounds of the invention with other active compounds also falls within the scope of the invention.
SUMMARY OF STATE OF THE ART
It should be noted that various molecules exhibiting a certain structural similarity with those of the invention have been described in the literature. Mention may in particular be made of documents US Pat. No. 4,360,533 (A.A.
patchett); US-A-4 134 991 (J.J. BALDWIN et al.) which corresponds to FR-A-2 365 341 (SYNTHELABO) US-A-4 254 273 (B.F. POWELL et al.) which corresponds to FR-A-2 313 922 (MERCK) and EP-A-0 030 734 (MFRCK).
Among these documents only US-A-4,134,991 (J.J. BALDWIN et al.) mention an application for the treatment of Parkinson's disease.
None of the documents predicted that the products in question would act to improve therapeutic value like the products of the invention for the treatment of Parkinson's disease.
SYNTHESIS PROCESSES
Different synthetic routes are possible to obtain the compounds of the invention. These synthetic routes will be illustrated with reference to the examples which follow relating to a particular compound of the invention of formula III and schematized in the appended FIG.
Example 1: (Method A of Figure 1)
(L)-N,O,O'-tricarbobenzyloxidopa ester of 1,3-dipalmitin (3 > .
To a solution of 28.4 g of trihydroxy-l,2,3-propane dipalmitate (1,3-dipalmitin) (2) (50 mmol) and 30.1 g of (L)-N,O,O '-tricarbobenzyloxidopa (1) (50 mmol) in 250 ml of dichloromethane, stirred magnetically and cooled to O "C by means of an ice bath, 10.3 g of dicyclohexyl-carbodiimide (50 mmol ) and 100 mg of pyrrolidino-4-pyridine. After one hour, the ice bath is removed. The reaction mixture is then stirred for 25 hours at room temperature.
The dicyclohexylurea precipitate is filtered off and the filtrate is washed with water (10Oml), 5% sodium bicarbonate (100 ml) (w/v), then with 0.05M hydrochloric acid (100 ml) . The organic solution is dried over magnesium sulphate, filtered and evaporated to dryness. The residue is chromatographed on silica gel and the desired compound (3) is eluted using an n-hexane:diethyl ether (70:30, v/v) mixture. After evaporation of the fractions containing 3 to dryness, the residue is recrystallized from ethanol.
Yield = 388. The product is characterized by its melting point of 75"C and its optical rotation [a125
D of -3.14 (C 3, methanol).
L-dopa ester of 1,3-dipalmitin.
I (1)
A solution of 10.0 g of 3 in tetrahydrofuran (150 ml) is hydrogenolyzed in the presence of palladium on carbon (1.0 g) under an initial pressure of 250 kPa for 18 h. The suspension is then filtered and the filtrate is evaporated to dryness. The residue is purified by chromatography under the same conditions as for 3. Recrystallization from ethanol gives a product with a melting point of 78"C and an optical rotation [aJ25 of
D-6.23 (C-3.2, DMF).
Elemental Analysis (C44H77108)
Calculated values C 70.64% found 70.61
H 10.37 10.25
O 17.11 16.94
N 1.87 2.20
Mass spectrum (m/e): 747 (M+), 477, 256,
239.
Example 2: (Method B of Figure 1)
The same compound (III) can be synthesized by route B of Figure 1. The yields which still require optimization are however lower.
Example 3: (Method C of Figure 1)
By method C it is also possible to obtain the compound of formula III. Remarks similar to those of Example 2 also apply.
Example 4: Pharmacological and pharmacokinetic evaluations
The derivative obtained according to example-1 was evaluated from the point of view of its antiparkinsonian activity by means of c-ux conventional tests; the oxotremorine test and the reserpine test following the general protocol described by Horst et al. (ref. Burop.J.Pharmacol.21, 337342, 1973). In the reserpine test, efficacy is measured by inhibition of ptosis and catatonia; in the oxotremorine test by inhibition of tremor and hypothermia, the calculation of ED50 was carried out according to the classic method of Litchfield and Wilcoxon (J.Pharmacol. Exptl. Therap., 96, 69... (1949)).
The operating protocol followed by these two tests is given below.
A) RESERPINE TEST.
1. Reserpine is administered i.p. at a dose of 5 mg/kg
2. Four hours later, the compounds to be tested: L-dopa and
its glyceride derivative are administered p.o. to
different doses and this at the rate of five mice per
dose.
3. The evolution of reserpine-induced effects
catatonia and ptosis is monitored at different times: 15,
30, 60, 90, 120 mins.
4:15, 30, 60, 90, 120 mins
Reserpine L-dopa and its dericatatonia and
Smg/kg, i.p. ve glyceride, p.o. ptosis
B) OXOTREMORINE TEST,
1. Compounds to be tested: L-;dopa and its derivative
glyceride are administered p,o. at different doses
and this at the rate of five mice per dose.
2. Oxotremorine (0.5 mg/kg i.p.) is administered to
mice pretreated after different times: 15, 45,
90, 120 mins.
3. The response of animals to the effects of toxotremorine e
hypothermia and tremor is measured respectively 15 and
30 min after administration of the cholinergic agent
15, 45, 90, 120 mins 15 mins 15 mins
L-dopa and its deri- oxotremorine hypothermia tremor
glyceride, p.o. 0.5 mg/kg, i.p.
For these two tests, male NMRI mice weighing between 22 and 25 g were used.
L-dopa and its glyceride derivative are administered by gavage in suspension in a 5% gum arabic solution.
The effects observed have been reproduced in the form of graphs in Figures 2 to 5 which follow.
It appears from these two tests that the glyceride derivative III − exhibits an antiparkinsonian activity substantially of the same order of magnitude, but this activity lasts for times approximately double those observed for L-Dopa.
From a pharmacokinetic point of view, Figures 6 and 7 dramatically demonstrate the lymphotropic effect produced by the grafting of 1,3-dipalmitin onto L-Dopa. It is observed that after oral administration of an equivalent dose of 0.5 m mol/kg is
L-Dopa, or the glyceride derivative of L-dopa (III), we obtain lymphatic levels more than 40 times higher in the case of III than in that of
L-Dopa, which also appears predominantly in the form of its metabolite, dopamine.
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK437586A DK437586D0 (en) | 1985-02-04 | 1986-09-12 | NEW L-DOPA DERIVATIVES, PROCEDURES FOR PREPARING THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING SUCH RELATIONSHIPS |
NO863944A NO863944L (en) | 1985-02-04 | 1986-10-03 | L-DOPA DERIVATIVES, THE PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL MIXTURE CONTAINING THESE DERIVATIVES. |
FI871270A FI871270A (en) | 1985-02-04 | 1987-03-23 | L-DOPA DERIVATIVES, FOERFARANDE FOER FRAMSTAELLNING AV DEM OCH PHARMACEUTICAL SAMMANSAETTNINGAR SOM INNEHAOLLER DEM. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
LU85757A LU85757A1 (en) | 1985-02-04 | 1985-02-04 | NOVEL L-DOPA DERIVATIVES, METHODS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS RELATING TO SUCH COMPOUNDS |
LU85757 | 1985-02-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1986004579A1 true WO1986004579A1 (en) | 1986-08-14 |
Family
ID=19730402
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/BE1986/000002 WO1986004579A1 (en) | 1985-02-04 | 1986-01-27 | L-dopa derivatives, preparation thereof and pharmaceutical compositions containing them |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0250403A1 (en) |
JP (1) | JPS63501498A (en) |
DK (1) | DK437586D0 (en) |
FI (1) | FI871270A (en) |
LU (1) | LU85757A1 (en) |
NO (1) | NO863944L (en) |
WO (1) | WO1986004579A1 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998005678A2 (en) * | 1996-08-02 | 1998-02-12 | Max-Delbrück-Centrum für Molekulare Medizin | Novel cationic amphiphilic lipids for liposomal gene transfer |
WO2005121069A1 (en) | 2004-06-04 | 2005-12-22 | Xenoport, Inc. | Levodopa prodrugs, and compositions and uses thereof |
US7323585B2 (en) | 2004-06-04 | 2008-01-29 | Xenoport, Inc. | Levodopa prodrugs, and compositions and uses thereof |
WO2008079387A1 (en) * | 2006-12-21 | 2008-07-03 | Xenoport, Inc. | Catechol protected levodopa diester prodrugs, compositions, and methods of use |
US7563821B2 (en) | 2005-12-05 | 2009-07-21 | Xenoport, Inc. | Levodopa prodrug mesylate, compositions thereof, and uses thereof |
US7709527B2 (en) | 2006-12-21 | 2010-05-04 | Xenoport, Inc. | Levodopa dimethyl-substituted diester prodrugs compositions, and methods of use |
WO2010103273A3 (en) * | 2009-03-12 | 2010-11-04 | Amarin Neuroscience Limited | Essential fatty acid compounds |
US8399513B2 (en) | 2008-10-20 | 2013-03-19 | Xenoport, Inc. | Levodopa prodrug mesylate hydrate |
US8435562B2 (en) | 2009-11-09 | 2013-05-07 | Xenoport, Inc. | Pharmaceutical compositions and oral dosage forms of a levodopa prodrug and methods of use |
US9290445B2 (en) | 2008-10-20 | 2016-03-22 | Xenoport, Inc. | Methods of synthesizing a levodopa ester prodrug |
US20180362445A1 (en) * | 2015-03-30 | 2018-12-20 | Berlirem Gmbh | Water-soluble l-dopa esters |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2013043885A (en) * | 2011-08-26 | 2013-03-04 | Kansai Bunri Sogo Gakuen | Dehydroamino acid-containing glycerol derivative |
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FR2365341A1 (en) * | 1976-09-28 | 1978-04-21 | Synthelabo | L- (PHENYL-3 AMINO-2 PROPIONYLOXY) -2 ACETIC DERIVATIVES |
EP0030734A1 (en) * | 1979-12-17 | 1981-06-24 | Merck & Co. Inc. | Tyrosine derivatives, a process for preparing the same and a pharmaceutical composition containing the same for treating hypertension |
US4360533A (en) * | 1981-12-14 | 1982-11-23 | Merck & Co., Inc. | Glyceryl ester of 1-methyl-2-(3,4-dihydroxyphenyl)alanine |
-
1985
- 1985-02-04 LU LU85757A patent/LU85757A1/en unknown
-
1986
- 1986-01-27 WO PCT/BE1986/000002 patent/WO1986004579A1/en not_active Application Discontinuation
- 1986-01-27 EP EP86900721A patent/EP0250403A1/en not_active Withdrawn
- 1986-01-27 JP JP61500751A patent/JPS63501498A/en active Pending
- 1986-09-12 DK DK437586A patent/DK437586D0/en not_active Application Discontinuation
- 1986-10-03 NO NO863944A patent/NO863944L/en unknown
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1987
- 1987-03-23 FI FI871270A patent/FI871270A/en not_active IP Right Cessation
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FR2313922A1 (en) * | 1975-06-11 | 1977-01-07 | Merck & Co Inc | PERFECTED PROCESS FOR PREPARING ALPHA-METHYL-3,4-DIHYDROXYPHENYLALANINE ESTERS |
FR2365341A1 (en) * | 1976-09-28 | 1978-04-21 | Synthelabo | L- (PHENYL-3 AMINO-2 PROPIONYLOXY) -2 ACETIC DERIVATIVES |
EP0030734A1 (en) * | 1979-12-17 | 1981-06-24 | Merck & Co. Inc. | Tyrosine derivatives, a process for preparing the same and a pharmaceutical composition containing the same for treating hypertension |
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Cited By (28)
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WO1998005678A3 (en) * | 1996-08-02 | 1999-02-25 | Max Delbrueck Centrum | Novel cationic amphiphilic lipids for liposomal gene transfer |
WO1998005678A2 (en) * | 1996-08-02 | 1998-02-12 | Max-Delbrück-Centrum für Molekulare Medizin | Novel cationic amphiphilic lipids for liposomal gene transfer |
AU2005252220B2 (en) * | 2004-06-04 | 2011-06-02 | Xenoport, Inc. | Levodopa prodrugs, and compositions and uses thereof |
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US7956212B2 (en) | 2004-06-04 | 2011-06-07 | Xenoport, Inc. | Levodopa prodrugs, and compositions and uses thereof |
US7563821B2 (en) | 2005-12-05 | 2009-07-21 | Xenoport, Inc. | Levodopa prodrug mesylate, compositions thereof, and uses thereof |
US7893105B2 (en) | 2005-12-05 | 2011-02-22 | Xenoport, Inc. | Levodopa prodrug mesylate, compositions thereof, and uses thereof |
US7968597B2 (en) | 2005-12-05 | 2011-06-28 | Xenoport, Inc. | Levodopa prodrug mesylate, compositions thereof, and uses thereof |
US8193242B2 (en) | 2005-12-05 | 2012-06-05 | Xenoport, Inc. | Levodopa prodrug mesylate, compositions thereof, and uses thereof |
US7829592B2 (en) | 2006-12-21 | 2010-11-09 | Xenoport, Inc. | Catechol protected levodopa diester prodrugs, compositions, and methods of use |
WO2008079387A1 (en) * | 2006-12-21 | 2008-07-03 | Xenoport, Inc. | Catechol protected levodopa diester prodrugs, compositions, and methods of use |
US7709527B2 (en) | 2006-12-21 | 2010-05-04 | Xenoport, Inc. | Levodopa dimethyl-substituted diester prodrugs compositions, and methods of use |
US8324273B2 (en) | 2006-12-21 | 2012-12-04 | Xenoport, Inc. | Catechol protected levodopa diester prodrugs, compositions, and methods of use |
US8324272B2 (en) | 2006-12-21 | 2012-12-04 | Xenoport, Inc. | Levodopa dimethyl-substituted diester prodrugs, compositions, and methods of use |
US8399513B2 (en) | 2008-10-20 | 2013-03-19 | Xenoport, Inc. | Levodopa prodrug mesylate hydrate |
US8722733B2 (en) | 2008-10-20 | 2014-05-13 | Xenoport, Inc. | Levodopa prodrug mesylate hydrate |
US9290445B2 (en) | 2008-10-20 | 2016-03-22 | Xenoport, Inc. | Methods of synthesizing a levodopa ester prodrug |
WO2010103273A3 (en) * | 2009-03-12 | 2010-11-04 | Amarin Neuroscience Limited | Essential fatty acid compounds |
US8435562B2 (en) | 2009-11-09 | 2013-05-07 | Xenoport, Inc. | Pharmaceutical compositions and oral dosage forms of a levodopa prodrug and methods of use |
US20180362445A1 (en) * | 2015-03-30 | 2018-12-20 | Berlirem Gmbh | Water-soluble l-dopa esters |
EP3277660B1 (en) * | 2015-03-30 | 2019-10-16 | Berlirem GmbH | Water-soluble l-dopa esters |
US11046640B2 (en) | 2015-03-30 | 2021-06-29 | Berlirem Gmbh | Water-soluble L-DOPA esters |
Also Published As
Publication number | Publication date |
---|---|
FI871270A0 (en) | 1987-03-23 |
DK437586A (en) | 1986-09-12 |
NO863944L (en) | 1986-12-01 |
FI871270A (en) | 1987-03-23 |
JPS63501498A (en) | 1988-06-09 |
NO863944D0 (en) | 1986-10-03 |
EP0250403A1 (en) | 1988-01-07 |
LU85757A1 (en) | 1986-09-02 |
DK437586D0 (en) | 1986-09-12 |
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