NO863944L - L-DOPA DERIVATIVES, THE PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL MIXTURE CONTAINING THESE DERIVATIVES. - Google Patents
L-DOPA DERIVATIVES, THE PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL MIXTURE CONTAINING THESE DERIVATIVES.Info
- Publication number
- NO863944L NO863944L NO863944A NO863944A NO863944L NO 863944 L NO863944 L NO 863944L NO 863944 A NO863944 A NO 863944A NO 863944 A NO863944 A NO 863944A NO 863944 L NO863944 L NO 863944L
- Authority
- NO
- Norway
- Prior art keywords
- dopa
- derivative
- stated
- glycerol
- different
- Prior art date
Links
- 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 description 36
- 238000000034 method Methods 0.000 title claims description 11
- 239000000203 mixture Substances 0.000 title description 3
- 238000002360 preparation method Methods 0.000 title description 3
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 25
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 208000018737 Parkinson disease Diseases 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000012374 esterification agent Substances 0.000 claims description 3
- 150000002314 glycerols Chemical class 0.000 claims description 3
- 230000002093 peripheral effect Effects 0.000 claims description 3
- 102100038238 Aromatic-L-amino-acid decarboxylase Human genes 0.000 claims description 2
- 108010035075 Tyrosine decarboxylase Proteins 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
- 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
- 239000000969 carrier Substances 0.000 claims description 2
- 238000012512 characterization method Methods 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 claims description 2
- 239000007903 gelatin capsule Substances 0.000 claims description 2
- OYBLYDGMPPILJI-UHFFFAOYSA-N glycerol radical Chemical compound OC[C](O)CO OYBLYDGMPPILJI-UHFFFAOYSA-N 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
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- 230000008569 process Effects 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000005809 transesterification reaction Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 31
- 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 14
- 229960003638 dopamine Drugs 0.000 description 9
- 125000005456 glyceride group Chemical group 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 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 5
- GFAZGHREJPXDMH-UHFFFAOYSA-N 1,3-dipalmitoylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCC GFAZGHREJPXDMH-UHFFFAOYSA-N 0.000 description 5
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 5
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 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 5
- 229960003147 reserpine Drugs 0.000 description 5
- 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 5
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
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- 229910052799 carbon Inorganic materials 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010015995 Eyelid ptosis Diseases 0.000 description 2
- 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
- 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
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- 210000004185 liver Anatomy 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
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- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 1
- 206010006100 Bradykinesia 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
- 229920000084 Gum arabic Polymers 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 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
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
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- ZZVJLPROFSCODQ-UHFFFAOYSA-N hexadecanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCC(O)=O ZZVJLPROFSCODQ-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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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
Description
Oppfinnelsen angår hittil ukjente derivater av. L-dopa eller L-3,4-dihydroksyfenylalanin med egenskaper som er forbedret The invention relates to hitherto unknown derivatives of L-dopa or L-3,4-dihydroxyphenylalanine with improved properties
i forhold til egenskapene av L-dopa selv, samt fremgangsmåter til fremstilling derav og farmasøytiske preparater inneholdende slike forbindelser, og den dekker også deres anvendelse, særlig i humanmedisin. L-dopa er vanlig brukt ved behandling av de mest invalidiserende symptomer på Parkinsons sykdom (skjelvinger, stivhet, bradyki-nesia). Skjønt behandlingen kan være effektiv i flere år, in relation to the properties of L-dopa itself, as well as methods for its production and pharmaceutical preparations containing such compounds, and it also covers their use, particularly in human medicine. L-dopa is commonly used in the treatment of the most disabling symptoms of Parkinson's disease (tremors, stiffness, bradykinesia). Although the treatment may be effective for several years,
lider denne behandling ikke desto mindre av vesentlige ulemper på grunn av den ekstremt korte biologiske halveringstid av L-dopa og dets hurtige nedbrytning til dopamin, som fører til vesentlige og hurtige svingninger i blodkonsentrasjonen og forekomst av bivirkninger på grunn av sirkulerende dopamin, og disse fenomener er ansvarlige for alvorlige og uønskede virkninger såsom dyskinesia, gastrointestinale- og kardio-vaskulære forstyrrelser. Denne sakens tilstand skyldes i meget høy grad en meget sterk første passasje-virkning på levernivå, men særlig på det gastrointestinale nivå. this treatment nevertheless suffers from significant disadvantages due to the extremely short biological half-life of L-dopa and its rapid degradation to dopamine, which leads to significant and rapid fluctuations in blood concentration and occurrence of side effects due to circulating dopamine, and these phenomena are responsible for serious and unwanted effects such as dyskinesia, gastrointestinal and cardio-vascular disturbances. The condition of this case is due to a very high degree to a very strong first-pass effect at the level of the liver, but especially at the gastrointestinal level.
Formålet med den foreliggende oppfinnelse er i det vesentligeThe purpose of the present invention is essentially
å skaffe nye forbindelser og farmasøytiske forbindelser inneholdende disse forbindelser som gjør det mulig å unngå de ovenfor angitte ulemper. to obtain new compounds and pharmaceutical compounds containing these compounds which make it possible to avoid the above-mentioned disadvantages.
Den strategi som ble valgt for å overvinne disse problemer, besto i syntetisering av et L-dopa-derivat ved kobling av L-dopa til et glycerolderivat under dannelse av en esterbinding med en hydroksylgruppe i glycerolen, mens minst én av de resterende hydroksylstillinger ble forestret med en acylkjede og den andre resterende hydroksylstilling på samme måte ble forestret; enten med en acylkjede som er identisk med eller forskjellig fra den første kjede/ eller med et forestringsmiddel som har en annen karakter, men er farmakologisk akseptabelt. The strategy chosen to overcome these problems consisted in synthesizing an L-dopa derivative by coupling L-dopa to a glycerol derivative forming an ester bond with a hydroxyl group in the glycerol, while at least one of the remaining hydroxyl positions was esterified with an acyl chain and the other remaining hydroxyl position was similarly esterified; either with an acyl chain which is identical to or different from the first chain/ or with an esterification agent which has a different character but is pharmacologically acceptable.
Innlemmelse av L-dopa i en glyceridstruktur forbedrer den terapeutiske verdi av L-dopa på flere måter: Incorporation of L-dopa into a glyceride structure enhances the therapeutic value of L-dopa in several ways:
- ved å redusere den intestinale og hepatiske førstepassasje-effekt og dermed de bivirkninger som henger sammen med dannelsen av visse stoffski fteprodukter (særlig dopamin), - ved å sikre blodkonsentrasjoner som er mer jevnt fordelt over en tidsperiode, hvorved man eliminerer de for store svingninger i blodkonsentrasjoner som observeres med L-dopa, - ved kortslutning av det aktive transportsystem som sikrer tarmens resorpsjon av L-dopa, hvilket i det minste delvis er ansvarlig for den terapeutiske reaksjon. - by reducing the intestinal and hepatic first-pass effect and thus the side effects associated with the formation of certain metabolic products (especially dopamine), - by ensuring blood concentrations that are more evenly distributed over a period of time, thereby eliminating excessive fluctuations in blood concentrations observed with L-dopa, - by short-circuiting the active transport system that ensures intestinal resorption of L-dopa, which is at least partially responsible for the therapeutic reaction.
Foretrukne forbindelser ifølge oppfinnelsen kan uttrykkesPreferred compounds according to the invention can be expressed
ved den generelle formelby the general formula
hvor R i er en glycerolrest og R 2 og R 3 som kan være identiske eller forskjellige, hver betegner en acylgruppe med 4-22 karbonatomer eller resten av en farmakologisk akseptabel syre, idet minst ett av disse to symboler betegner en acylgruppe med 4-22 karbonatomer. where R i is a glycerol residue and R 2 and R 3 which may be identical or different, each denotes an acyl group with 4-22 carbon atoms or the residue of a pharmacologically acceptable acid, at least one of these two symbols denotes an acyl group with 4-22 carbon atoms.
Forbindelser med den generelle formel II foretrekkes:Compounds of the general formula II are preferred:
2 3 2 3
og i ganske særlig grad de forbindelser hvor R og R hver betegner en acylgruppe med 4-22 karbonatomer. and to a very particular extent those compounds where R and R each denote an acyl group with 4-22 carbon atoms.
De forbindelser hvor R 2 og R 3 betegner identiske grupper, foretrekkes i særlig stor grad. The compounds where R 2 and R 3 denote identical groups are particularly preferred.
Forsåvidt det ene av symbolene R 2 og R 3 betegner en acylgruppe med 4-22 karbonatomer, kan det annet symbol imidlertid betegne en annen gruppe og kan f.eks. særlig være en fosforsyrerest. Provided that one of the symbols R 2 and R 3 denotes an acyl group with 4-22 carbon atoms, the other symbol may however denote another group and may e.g. in particular be a phosphoric acid residue.
Oppfinnelsen omfatter også forbindelser som er analoge medThe invention also includes compounds analogous to
de ovenfor angitte, hvor acylgruppen i L-dopa er bundet til stilling 1 eller 3 i glycerol istedenfor til stilling 2. those stated above, where the acyl group in L-dopa is bound to position 1 or 3 in glycerol instead of to position 2.
De ovenfor angitte forbindelser kan brukes som virksomt prinsipp ved behandling av Parkinsons sykdom, eller de kan tjene som mellomprodukter til karakterisering, rensing eller syntese av sådanne aktive produkter, særlig ved transforestring. The above-mentioned compounds can be used as active principle in the treatment of Parkinson's disease, or they can serve as intermediates for the characterization, purification or synthesis of such active products, in particular by transesterification.
Som eksempel på en forbindelse innenfor oppfinnelsens ramme,As an example of a compound within the scope of the invention,
som har vært underkastet særlige undersøkelser, skal nevnes forbindelsen med formel III: which has been subjected to special investigations, the compound with formula III must be mentioned:
Man kjenner allerede derivater av L-dopa, særlig dipeptider eller tripeptider, som imidlertid ikke har de samme fordeler som forbindelsene ifølge den foreliggende oppfinnelse, nemlig å muliggjøre resorpsjon via det lymfatiske system samtidig med at der unngås vesentlig ødeleggelse av forbindelsen i tarmkanalen eller av leveren. Tilførselen av store mengder L-dopa til pasienter, noe som for tiden er nødvendig for å sikre tilgjengelighet av dopamin i tilstrekkelig mengde for hjernen etter passasje gjennom blod/hjerne-barrieren, unngås herved. Som følge herav skjer der dessuten en reduksjon av skadelige bivirkninger på grunn av perifert dopamin som særlig er ansvarlig for kvalme og lignende. Derivatives of L-dopa, in particular dipeptides or tripeptides, are already known, which, however, do not have the same advantages as the compounds according to the present invention, namely enabling resorption via the lymphatic system while avoiding significant destruction of the compound in the intestinal tract or the liver . The supply of large amounts of L-dopa to patients, which is currently necessary to ensure the availability of dopamine in sufficient quantity to the brain after passage through the blood/brain barrier, is thereby avoided. As a result, there is also a reduction in harmful side effects due to peripheral dopamine, which is particularly responsible for nausea and the like.
Forbindelser ifølge oppfinnelsen tilføres fortrinnsvis oraltCompounds according to the invention are preferably administered orally
i form av farmasøytiske preparater fremstilt på vanlig måte ved velkjente galeniske teknikker ved tilsetning av de vanlige adjuvanser, eksipienser og bærere. Preparatene kan foreligge i form av emulsjoner, suspensjoner, gelatinkapsler eller særlig saft. in the form of pharmaceutical preparations prepared in the usual way by well-known galenic techniques by adding the usual adjuvants, excipients and carriers. The preparations can be in the form of emulsions, suspensions, gelatin capsules or especially juice.
Det er verd å merke seg at ettersom substitusjonene på glycerol-radikalet i de ovenfor angitte molekyler fører til at et karbonatom blir asymmetrisk, så omfatter oppfinnelsen den racemiske blanding og de forskjellige diastereoisomere former som stammer fra koblingen av det asymmetriske karbonatom i L-dopa-delen til det asymmetriske karbonatom i glyceriddelen. It is worth noting that, as the substitutions on the glycerol radical in the above-mentioned molecules lead to a carbon atom becoming asymmetric, the invention encompasses the racemic mixture and the various diastereoisomeric forms that derive from the coupling of the asymmetric carbon atom in L-dopa- part to the asymmetric carbon atom in the glyceride part.
Det bemerkes at forbindelsene ifølge oppfinnelsen gjør det mulig å oppnå de samme farmakologiske virkninger som dem man oppnår med L-dopa og med forbedrende farmakokinetiske egenskaper, særlig en virkning med hensyn til langsom avgivelse, slik det skal vises i de følgende eksempler. It is noted that the compounds according to the invention make it possible to achieve the same pharmacological effects as those achieved with L-dopa and with improving pharmacokinetic properties, in particular an effect with regard to slow release, as will be shown in the following examples.
Dosen og doseringsområdet for de farmasøytiske preparater ifølge oppfinnelsen avhenger av de valgte forbindelser. Fag-folk på området kan lett tilpasse dosene og doseringsområdene under hensyntagen særlig til den grad i hvilken pasienten lider av de konstaterte".angrep og pasientens almentilstand. Doser og doseringsområder velges teoretisk slik at de er til-strekkelige til å frembringe verdier for cerebral tilgjengelighet av dopamin ut fra forbindelsene ifølge oppfinnelsen, som svarer til de verdier som for tiden anbefales ved anvendelse av L-dopa, idet man tar i betraktning at det er generelt aksep-tert at kun én prosent av det oralt tilførte L-dopa omdannes til aktivt dopamin på sentralnervesystemets nivå. Det er verd å merke seg at den vesentlige reduksjon av bivirkninger som følger av forbedret utnyttelse av det aktive prinsipp, noe som er gjort mulig med forbindelsene ifølge oppfinnelsen, tillater at der om ønskelig gis økede doser av disse forbindelser . The dose and dosage range for the pharmaceutical preparations according to the invention depend on the selected compounds. Professionals in the field can easily adapt the doses and dosage ranges, taking into account in particular the extent to which the patient suffers from the identified "attacks" and the patient's general condition. Doses and dosage ranges are selected theoretically so that they are sufficient to produce values for cerebral availability of dopamine from the compounds according to the invention, which correspond to the values currently recommended for the use of L-dopa, taking into account that it is generally accepted that only one percent of the orally administered L-dopa is converted into active dopamine at the level of the central nervous system. It is worth noting that the significant reduction of side effects resulting from improved utilization of the active principle, which is made possible with the compounds according to the invention, allows increased doses of these compounds to be given if desired.
Det ligger også innenfor oppfinnelsens omfang å kombinere forbindelsene ifølge oppfinnelsen med inhibitorer av perifer dopa-dekarboksylase såsom benserazid eller karbidopa, hvilket som bekjent gjør det mulig å øke tilgjengeligheten av dopamin i hjernen. It is also within the scope of the invention to combine the compounds according to the invention with inhibitors of peripheral dopadecarboxylase such as benserazide or carbidopa, which as is known makes it possible to increase the availability of dopamine in the brain.
Kombinasjon av forbindelsene ifølge oppfinnelsen med andre virksomme forbindelser ligger også innenfor oppfinnelsens omfang. Combination of the compounds according to the invention with other active compounds is also within the scope of the invention.
Resymé av teknikkens standSummary of the state of the art
Det skal bemerkes at der i litteraturen er beskrevet forskjellige molekyler som har en viss strukturlikhet med forbindelsene ifølge oppfinnelsen. Følgende dokumenter skal særlig nevnes: US-A-4 360 533 (A. A. Patchett), US-A-4 134 991 (J. J. Baldwin et al.) som svarer til FR-A-2 365 341 (Synthelabo), US-A-4 254 273 (B. F. Powell et al.) som svarer til FR-A-2 313 922 (Merck) og EP-A-0 030 734 (Merck). It should be noted that different molecules are described in the literature which have a certain structural similarity to the compounds according to the invention. The following documents should be particularly mentioned: US-A-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 (Merck).
Blant disse dokumenter er det bare US-A-4 134 991 (J. J. Baldwin et al.) som nevner anvendelse til behandling av Parkinsons sykdom. Among these documents, only US-A-4 134 991 (J. J. Baldwin et al.) mentions use for the treatment of Parkinson's disease.
Det har ikke vært mulig ut fra noen av disse dokumenter å forutsi at de omtalte produkter ville bevirke en forbedring av den terapeutiske verdi for behandling av Parkinsons sykdom, slik som produktene ifølge oppfinnelsen. It has not been possible from any of these documents to predict that the mentioned products would effect an improvement in the therapeutic value for the treatment of Parkinson's disease, such as the products according to the invention.
SynteseprosesserSynthesis processes
Forskjellige synteseveier er mulige for fremstilling av forbindelsene ifølge oppfinnelsen. Visse synteseveier belyses nærmere i de følgende eksempler som angår en særlig forbindelse ifølge oppfinnelsen, den med formel III, og syntesene er vist skjematisk på tegningens figur 1 . Different synthesis routes are possible for the preparation of the compounds according to the invention. Certain synthesis routes are elucidated in more detail in the following examples which relate to a particular compound according to the invention, that of formula III, and the syntheses are shown schematically in figure 1 of the drawing.
Eksempel 1 ( metode A på fig. 1 ) Example 1 (method A in Fig. 1)
( L)- N, 0, 0'- trikarbobenzoksydopa- 1, 3- dipaImitinester ( 3)( L)- N, 0, 0'- tricarbobenzoxidopa- 1, 3- dipaimitine ester ( 3)
Til en oppløsning av 28,4 g (50 mmol) 1,2,3-trihydroksypropan- dipalmitat (1 , 3-dipalmitin) (2) og 30,1 g (50 mmol) (L)-N,0,0'-trikarbobenzoksydopa (1) i 250 ml diklormetan, magnetisk omrørt og avkjølt til 0°C i et isbad, tilsettes der i en enkelt porsjon 10,3 g (50 mmol) dicykloheksylkarbodiimid og 100 mg 4-pyrroli-dinopyridin. Etter 1 time fjernes isbadet. Deretter omrøres reaksjonsblandingen i 25 timer ved værelsetemperatur. Bunnfallet av dicykloheksylurinstoff filtreres av og filtratet vaskes med 100 ml vann, 100 ml 5%'s vekt/volum natriumbikarbonat og deretter 100 ml 0,05 M saltsyre. Den organiske oppløsning tørkes over magnesiumsulfat, filtreres og dampes inn til tørrhet. Residuet kromatograferes på silikagel og den ønskede forbindelse (3) elueres ved hjelp av en blanding av n-heksan/dietyleter 70:30 (regnet på volum). Etter inndamping til tørrhet av de fraksjoner som inneholder forbindelsen 3 omkrystalliseres residuet fra metanol. Utbytte 38%. Produktet karakteriseres ved sitt smeltepunkt på 75 o C og sin optiske dreining [ct]D 25 pao To a solution of 28.4 g (50 mmol) 1,2,3-trihydroxypropane dipalmitate (1 , 3-dipalmitin) (2) and 30.1 g (50 mmol) (L)-N,0,0' -tricarbobenzoxidopa (1) in 250 ml of dichloromethane, magnetically stirred and cooled to 0°C in an ice bath, 10.3 g (50 mmol) of dicyclohexylcarbodiimide and 100 mg of 4-pyrrolidinopyridine are added there in a single portion. After 1 hour, the ice bath is removed. The reaction mixture is then stirred for 25 hours at room temperature. The precipitate of dicyclohexylurea is filtered off and the filtrate is washed with 100 ml of water, 100 ml of 5% w/v sodium bicarbonate and then 100 ml of 0.05 M hydrochloric acid. 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 a mixture of n-hexane/diethyl ether 70:30 (calculated by volume). After evaporation to dryness of the fractions containing compound 3, the residue is recrystallized from methanol. Dividend 38%. The product is characterized by its melting point of 75 o C and its optical rotation [ct]D 25 pao
-3,14 (c =3 i metanol).-3.14 (c = 3 in methanol).
L- dopa- 1, 3- dipalmitinesterL- dopa- 1, 3- dipalmitine esters
En oppløsning av 10,0 g av forbindelsen 3 i 150 ml tetrahydro-furan hydrogenolyseres i nærvær av 1,0 g palladium på kull under et begynnelsestrykk på 250 kPa i 18 timer. Suspensjonen filtreres deretter, og filtratet inndampes til tørrhet. Residuet renses ved kromatografering under de samme betingelser som for forbindelsen 3. Omkrystallisasjon i etanol gir et produkt med smp. 78°C og en optisk dreining [a]^på -6,23° (c = 3,2 A solution of 10.0 g of compound 3 in 150 ml of tetrahydrofuran is hydrogenolysed in the presence of 1.0 g of palladium on charcoal under an initial pressure of 250 kPa for 18 hours. The suspension is then filtered, and the filtrate is evaporated to dryness. The residue is purified by chromatography under the same conditions as for compound 3. Recrystallization in ethanol gives a product with m.p. 78°C and an optical rotation [a]^of -6.23° (c = 3.2
i DMF).in DMF).
Beregnet for C^H-^NOg: C 70, 64 H 10,37 0 17,1 1 N 1,87Calculated for C^H-^NOg: C 70, 64 H 10.37 0 17.1 1 N 1.87
Funnet: C 70,61 H 10,25 0 16,94 N 2,20% Massespektrum, (m/e): 747 (M<+>), 477, 256, 239. Found: C 70.61 H 10.25 0 16.94 N 2.20% Mass spectrum, (m/e): 747 (M<+>), 477, 256, 239.
Eksempel 2 ( metode B på fig. 1)Example 2 (method B in Fig. 1)
Den samme forbindelse (III) kan syntetiseres via rute B påThe same compound (III) can be synthesized via route B on
fig. 1. Utbyttene, som krever ytterligere optimering, er imidlertid lavere. fig. 1. However, the yields, which require further optimization, are lower.
Eksempel 3 ( metode C på fig. 1)Example 3 (method C in Fig. 1)
Det er også mulig å utvinne forbindelsen med formel III ved fremgangsmåte C. De samme kommentarer som i eksempel 2 gjelder her. It is also possible to recover the compound of formula III by method C. The same comments as in example 2 apply here.
Eksempel 4Example 4
Farmakologisk og farmakokinetisk bedømmelsePharmacological and pharmacokinetic assessment
Det ifølge eksempel 1 utvunne derivat ble bedømt med hensynThe derivative obtained according to example 1 was evaluated with consideration
til dets aktivitet overfor Parkinsons sykdom ved hjelp av to klassiske prøver: oksotremorinprøven og reserpinprøven, etterfulgt av den generelle protokoll som er beskrevet av Horst et al. (se Europ. J. Pharmacol. 21, 337-342, 1973). to its activity against Parkinson's disease using two classic tests: the oxotremorine test and the reserpine test, followed by the general protocol described by Horst et al. (see Europ. J. Pharmacol. 21, 337-342, 1973).
Ved reserpinprøven måles effektiviteten ved inhibering av ptosis og katatoni, og ved oksotremorinprøven ved inhibering av skjelvinger og hypotermi, idet beregning av ED^Q-verdiene utføres i henhold til Litchfield og Wilcoxons klassiske metode (J. Pharmacol. Exptl. Therap., 96, 69 ... (1949)). In the reserpine test, the effectiveness is measured in the inhibition of ptosis and catatonia, and in the oxotremorine test in the inhibition of tremors and hypothermia, the calculation of the ED^Q values being carried out according to Litchfield and Wilcoxon's classic method (J. Pharmacol. Exptl. Therap., 96, 69 ... (1949)).
Den arbeidsprotokoll som følges ved disse to prøver, er beskrevet nedenunder. The working protocol that is followed for these two tests is described below.
A) ReserpinprøvenA) The reserpine test
1. Reserpin gis i.p. i en dose på 5 mg/kg.1. Reserpine is given i.p. in a dose of 5 mg/kg.
2. 4 timer senere gis de forbindelser som skal prøves, nemlig L-dopa og dets glyceridderivat p.o. i forskjellige doser, 2. 4 hours later, the compounds to be tested, namely L-dopa and its glyceride derivative, are given p.o. in different doses,
dette skjer med fem mus pr. dose.this happens with five mice per dose.
3. Forandringene i de virkninger som fremkalles av reserpin, nemlig katatoni og ptosis, følges på forskjellige tids-punkter: 15, 30, 60, 90, 120 min. 3. The changes in the effects induced by reserpine, namely catatonia and ptosis, are followed at different time points: 15, 30, 60, 90, 120 min.
B) Oksotremorinprøven B) The oxotremorine test
1. De forbindelser som skal utprøves, nemlig L-dopa og dets glyceridderivat, gis p.o. ved forskjellige doser, og dette 1. The compounds to be tested, namely L-dopa and its glyceride derivative, are given p.o. at different doses, and this
gjøres med fem mus pr. dose.done with five mice per dose.
2. Oksotremorin (0,5 mg/kg i.p.) gis til de forbehandlede mus etter forskjellige tidsrom: 15, 45, 90, 120 min. 2. Oxotremorine (0.5 mg/kg i.p.) is given to the pretreated mice after different periods of time: 15, 45, 90, 120 min.
3. Dyrenes reaksjon på virkningen av oksotremorin, nemlig hypotermi og skjelvingermåles henholdsvis 15 og 30 min etter at de er blitt gitt det kolinerge middel. 3. The animals' reaction to the effects of oxotremorine, namely hypothermia and tremors, are measured respectively 15 and 30 min after they have been given the cholinergic agent.
Til disse to prøver ble der anvendt hanmus av stammen NMRI med en vekt på mellom 22 og 25 g. L-dopa og dets glyceridderivat gis med sonde i form av suspensjoner i en 5%'s oppløsning av gummiarabicum. For these two tests, male mice of the strain NMRI were used with a weight of between 22 and 25 g. L-dopa and its glyceride derivative are given by probe in the form of suspensions in a 5% solution of gum arabic.
De iakttatte virkninger er vist i grafisk form på fig. 2-5. The observed effects are shown graphically in fig. 2-5.
Det kan ses av disse to prøver at glyceridderivatet III har en virkning mot Parkinsons sykdom, som i alt vesentlig er av samme størrelsesorden som L-dopa, men virkningen derav varer i perioder som er ca. dobbelt så lange som dem som er observert for L-dopa. It can be seen from these two samples that the glyceride derivative III has an effect against Parkinson's disease, which is essentially of the same order of magnitude as L-dopa, but its effect lasts for periods of approx. twice as long as those observed for L-dopa.
Fra et farmakokinetisk-standpunkt viser fig. 6 og 7 dramatisk den lymfotrope virkning som frembringes ved å pode 1,3-dipalmitin på L-dopa. Det viser seg faktisk at etter oral tilførsel av en dose svarende til 0,5 mmol/kg av enten L-dopa eller glyceridderivatet av L-dopa (III) oppnår man lymfatiske nivåer som i tilfellet for forbindelsen III er mer enn 40 ganger høyere enn det som oppnås med L-dopa, og dertil kommer at det sistnevnte overveiende viser seg i form av metabolitten dopamin. From a pharmacokinetic standpoint, fig. 6 and 7 dramatically the lymphotropic effect produced by grafting 1,3-dipalmitin onto L-dopa. Indeed, it turns out that after oral administration of a dose corresponding to 0.5 mmol/kg of either L-dopa or the glyceride derivative of L-dopa (III) one achieves lymphatic levels which, in the case of compound III, are more than 40 times higher than that which is achieved with L-dopa, and in addition, the latter predominantly manifests itself in the form of the metabolite dopamine.
Claims (10)
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 |
| PCT/BE1986/000002 WO1986004579A1 (en) | 1985-02-04 | 1986-01-27 | L-dopa derivatives, preparation thereof and pharmaceutical compositions containing them |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO863944D0 NO863944D0 (en) | 1986-10-03 |
| NO863944L true NO863944L (en) | 1986-12-01 |
Family
ID=19730402
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO863944A NO863944L (en) | 1985-02-04 | 1986-10-03 | L-DOPA DERIVATIVES, THE PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL MIXTURE CONTAINING THESE DERIVATIVES. |
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| EP (1) | EP0250403A1 (en) |
| JP (1) | JPS63501498A (en) |
| DK (1) | DK437586A (en) |
| FI (1) | FI871270A (en) |
| LU (1) | LU85757A1 (en) |
| NO (1) | NO863944L (en) |
| WO (1) | WO1986004579A1 (en) |
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| DE19631189A1 (en) * | 1996-08-02 | 1998-02-05 | Max Delbrueck Centrum | Novel cationic amphiphiles for liposomal gene transfer |
| MX339690B (en) * | 2004-06-04 | 2016-06-06 | 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 |
| US7563821B2 (en) | 2005-12-05 | 2009-07-21 | Xenoport, Inc. | Levodopa prodrug mesylate, compositions thereof, and uses thereof |
| JP2011502953A (en) | 2006-12-21 | 2011-01-27 | ゼノポート，インコーポレーテッド | Prodrugs, compositions and methods of use of dimethyl substituted levodopa diesters |
| TW200843731A (en) | 2006-12-21 | 2008-11-16 | Xenoport Inc | Catechol protected levodopa diester prodrugs, compositions, and methods of use |
| US8399513B2 (en) | 2008-10-20 | 2013-03-19 | Xenoport, Inc. | Levodopa prodrug mesylate hydrate |
| WO2010047775A2 (en) | 2008-10-20 | 2010-04-29 | Xenoport, Inc. | Methods of synthesizing a levodopa ester prodrug |
| GB0904300D0 (en) * | 2009-03-12 | 2009-04-22 | Amarin Neuroscience Ltd | Essential fatty acid compounds |
| NZ601747A (en) | 2009-11-09 | 2014-08-29 | Xenoport Inc | Pharmaceutical compositions and oral dosage forms of a levodopa prodrug and methods of use |
| JP2013043885A (en) * | 2011-08-26 | 2013-03-04 | Kansai Bunri Sogo Gakuen | Dehydroamino acid-containing glycerol derivative |
| JP2018514516A (en) * | 2015-03-30 | 2018-06-07 | ベルリレム ゲーエムベーハー | Water-soluble L-dopa ester |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK229876A (en) * | 1975-06-11 | 1976-12-12 | Merck & Co Inc | PROCEDURE FOR MAKING ESTERS OF ALFA-METHYL-3,4-DIHYDROXYPHENYLALANINE |
| FR2365341A1 (en) * | 1976-09-28 | 1978-04-21 | Synthelabo | L- (PHENYL-3 AMINO-2 PROPIONYLOXY) -2 ACETIC DERIVATIVES |
| GR72800B (en) * | 1979-12-17 | 1983-12-05 | Merck & Co Inc | |
| US4360533A (en) * | 1981-12-14 | 1982-11-23 | Merck & Co., Inc. | Glyceryl ester of 1-methyl-2-(3,4-dihydroxyphenyl)alanine |
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1985
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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/DK437586A/en not_active Application Discontinuation
- 1986-10-03 NO NO863944A patent/NO863944L/en unknown
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| Publication number | Publication date |
|---|---|
| FI871270A0 (en) | 1987-03-23 |
| EP0250403A1 (en) | 1988-01-07 |
| LU85757A1 (en) | 1986-09-02 |
| NO863944D0 (en) | 1986-10-03 |
| DK437586D0 (en) | 1986-09-12 |
| FI871270A (en) | 1987-03-23 |
| DK437586A (en) | 1986-09-12 |
| WO1986004579A1 (en) | 1986-08-14 |
| JPS63501498A (en) | 1988-06-09 |
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