NO150000B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE Z-N, N-DIMETHYL-3- (4-BROMPHENYL) -3- (3-PYRIDYL) -ALLYLAMINE-DIHYDROCHLORIDE MONOHYDRATE - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE Z-N, N-DIMETHYL-3- (4-BROMPHENYL) -3- (3-PYRIDYL) -ALLYLAMINE-DIHYDROCHLORIDE MONOHYDRATE Download PDF

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NO150000B
NO150000B NO771774A NO771774A NO150000B NO 150000 B NO150000 B NO 150000B NO 771774 A NO771774 A NO 771774A NO 771774 A NO771774 A NO 771774A NO 150000 B NO150000 B NO 150000B
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pyridyl
dimethyl
allylamine
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bromophenyl
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Thore Oskar Vaerner Rydh
Carl Bengt Johan Ulff
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Astra Laekemedel Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

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Description

Foreliggende oppfinnelse vedrører fremstilling av en ny, terapeutisk virksom forbindelse, nemlig Z-N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridyl)-allylamin-dihydroklorid-monohydrat. Denne forbindelse som også har gode lagringsegen-skaper, har formelen: The present invention relates to the production of a new, therapeutically active compound, namely Z-N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine dihydrochloride monohydrate. This compound, which also has good storage properties, has the formula:

Fra belgisk patent nr. 781.105 er det kjent forbindelser med den generelle formel: From Belgian patent no. 781,105 compounds with the general formula are known:

1 2 1 2

hvor R og R er valgt fra gruppen H, Cl og Br, og hvor pyridylgruppen er bundet i 2-, 3- eller 4-stilling. where R and R are selected from the group H, Cl and Br, and where the pyridyl group is bound in the 2-, 3- or 4-position.

Spesielt nevnte forbindelser er blant andre det vannfrie dihydrokloridet av forbindelsen Particularly mentioned compounds are, among others, the anhydrous dihydrochloride of the compound

Ifølge nevnte patent oppnås den vannfrie forbindelsen fra den tilsvarende base i eteroppløsning ved innføring av tørr HC1. Det har vist seg at ved opparbeiding av forbindelsen ved separasjon og tørking, er en betydelig del av den vannfrie forbindelsen i stor utstrekning uegnet for fremstilling av farmasøytiske preparater. For lignende forbindelser er krystallisering av dihydrokloridet fra etanol kjent fra patentet. Ved denne fremgangsmåte oppnås etanolatet. Det har imidlertid vist seg at ved opparbeidelse av denne forbindelsen ved separering og tørking tilbakeholdes en betydelig mengde oppløsningsmiddel. For å fjerne dette oppløs-ningsmiddel kreves tørking i omkring 1-2 døgn ved en temperatur på omkring 90 - 100°C. Disse betingelser som er ubekvemme i seg selv, kan videre forårsake misfarging og nedbrytning av produktet. Den vannfrie forbindelsen er ikke egnet for fremstilling av farmasøytiske preparater slik som tabletter, p.g.a. dens hygroskopiske egenskaper. Ved lagring absorberer den vannfrie forbindelsen fuktighet for dannelse av hårde kaker som må brytes opp før viderebe-handling . According to the aforementioned patent, the anhydrous compound is obtained from the corresponding base in ether solution by introducing dry HC1. It has been shown that when working up the compound by separation and drying, a significant part of the anhydrous compound is largely unsuitable for the production of pharmaceutical preparations. For similar compounds, crystallization of the dihydrochloride from ethanol is known from the patent. In this method, the ethanolate is obtained. However, it has been shown that when working up this compound by separation and drying, a significant amount of solvent is retained. To remove this solvent, drying is required for about 1-2 days at a temperature of about 90 - 100°C. These conditions, which are inconvenient in themselves, can further cause discoloration and degradation of the product. The anhydrous compound is not suitable for the production of pharmaceutical preparations such as tablets, due to its hygroscopic properties. During storage, the anhydrous compound absorbs moisture to form hard cakes which must be broken up before further processing.

Forbindelsen med formel I kan innblandes i forskjellige former for faste farmasøytiske preparater, slik som tabletter eller granulatet. Hensiktsmessig innblandes forbindelsen i farmasøytiske preparater for oral anvendelse. Vanligvis .-. utgjør det aktive stoff 0,1 - 95 vekt-% av preparatet, mer spesielt 2-50 vekt-% for preparat regnet for oral admini-strasjon . The compound of formula I can be incorporated into various forms of solid pharmaceutical preparations, such as tablets or granules. Appropriately, the compound is mixed into pharmaceutical preparations for oral use. Usually .-. the active substance constitutes 0.1-95% by weight of the preparation, more particularly 2-50% by weight for preparations intended for oral administration.

For å fremstille farmasøytiske preparater inneholdende forbindelse I i form av doseenheter for oran anvendelse, kan forbindelsen blandes med en fast pulverformig bærer, f.eks. laktose, sakkarose, sorbitql', rttannitol, stivelser slik som potetstivelse, maisstivelse eller amylopektin, cellulose-derivater, eller gelatin, og et smøremiddel slik som magne-siumstearat, kalsiumstearat eller polyetylenglykolvokser, To prepare pharmaceutical preparations containing compound I in the form of dosage units for oral use, the compound can be mixed with a solid powdery carrier, e.g. lactose, sucrose, sorbitol, rittannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, or gelatin, and a lubricant such as magnesium stearate, calcium stearate or polyethylene glycol wax,

og deretter presses for dannelse av tabletter. Dersom tabletter med overtrekk er nødvendige, kan kjernene fremstilt som beskrevet ovenfor, dekkes med en konsentrert sukkeropp-løsning som kan inneholde f.eks. gummi arabicum, gelatin, talkum eller titandioksyd. Tablettene kan laternativt dekkes med en lakk oppløst i et lettflyktig organisk oppløsnings-middel eller en blanding av organiske oppløsningsmidler. Fargetoffer kan tilsettes til disse overtrekk for lett å kunne skille med tabletter inneholdende forskjellige aktive stoffer eller forskjellige mengder av den aktive forbindelse. and then pressed to form tablets. If tablets with a coating are necessary, the cores prepared as described above can be covered with a concentrated sugar solution which can contain e.g. gum arabic, gelatin, talc or titanium dioxide. Alternatively, the tablets can be covered with a varnish dissolved in a volatile organic solvent or a mixture of organic solvents. Dyes can be added to these coatings to easily distinguish between tablets containing different active substances or different amounts of the active compound.

Doseringsenheter for rektal anvendelse kan fremstilles av suppusitorier inneholdende det aktive stoff i blanding med en nøytral fettbase, eller rektale gelatinkapsler inneholdende det aktive stoff i blanding med vegetabilsk olje eller parafinolje. Dosage units for rectal use can be prepared from suppositories containing the active substance in admixture with a neutral fat base, or rectal gelatin capsules containing the active substance in admixture with vegetable oil or paraffin oil.

Den nye forbindelsen med formel I fremstilles ifølge foreliggende oppfinnelse ved at (a) basen N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridy1)-allyl-amin med formelen: The new compound of formula I is prepared according to the present invention by (a) the base N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridy1)-allyl-amine with the formula:

i in

i oppløsning omsettes med vannholdig klorhydrogen og den dannede felling oppsamles, eller at (b) vanrifri N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridy1)-allylamin-dihydroklorid in solution is reacted with aqueous hydrogen chloride and the precipitate formed is collected, or that (b) anhydrous N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridy1)-allylamine dihydrochloride

hydratiseres, hydrate,

og at Z-formen isoleres. and that the Z shape is isolated.

Reaksjon (a) gjennomføres hensiktsmessig et organisk opp-løsningsmiddel med avkjøling fortrinnsvis til omkring 0°C. Passende organiske oppløsningsmidler er polare oppløsnings-midler slik som aceton. Den vannholdige klorhydrogen er hensiktsmessig kontsentrert saltsyre. Alternativt kan I^O tilsettes til en oppløsning av basen hvoretter vannfri HCl tilsettes. Utgangsmaterialet for reaksjonen (a) kan oppnås Reaction (a) is suitably carried out in an organic solvent with cooling preferably to around 0°C. Suitable organic solvents are polar solvents such as acetone. The aqueous hydrogen chloride is suitably concentrated hydrochloric acid. Alternatively, I^O can be added to a solution of the base after which anhydrous HCl is added. The starting material for reaction (a) can be obtained

(aa) ved dehydratisering av en forbindelse ifølge formelen: (aa) by dehydrating a compound according to the formula:

Dehydratiseringen kan foretas ved behandling med svovelsyre og oppvarming av reaksjonsblandingen, ved andre typer av syrekatalysator eller ved katalyse med en fast hydratiser-ingskatalysator ved en temperatur på 300 - 500°C, (ab) ved alkylerings av dimetylamin med en forbindelse med formelen: The dehydration can be carried out by treatment with sulfuric acid and heating the reaction mixture, by other types of acid catalyst or by catalysis with a solid hydration catalyst at a temperature of 300 - 500°C, (ab) by alkylation of dimethylamine with a compound of the formula:

hvor Y er en avspaltningsgruppe, for dannelse av en forbindelse med formel II. where Y is a leaving group, to form a compound of formula II.

Eksempler på gruppen Y er halogener slik som Cl, Br, I eller sulfonater slik som metansulfonat, toluensulfonat og benzen-sulfonat. Examples of the group Y are halogens such as Cl, Br, I or sulphonates such as methane sulphonate, toluene sulphonate and benzene sulphonate.

(ac) ved mono- eller di-metylering av en forbindelse med formelen: (ac) by mono- or dimethylation of a compound of the formula:

hvor R er CH eller II. where R is CH or II.

Utgangsmaterialer for reaksjonen (b) ovenfor kan oppnås ved å behandle forbindelsen oppnådd ifølge hvilken som helst av reaksjonene (aa), (ab) eller (ac) med tørr HC1. Starting materials for reaction (b) above can be obtained by treating the compound obtained according to any of reactions (aa), (ab) or (ac) with dry HCl.

Et isomerrent produkt med formel I kan oppnås ved isomer-separering eller omdannelse av en isomerblanding av enten sluttproduktet, et utgangsmateriale eller et mellomprodukt fra et reaksjonstrinn, forutsatt at sluttproduktets dobbeltbinding er tilstede i nevnte utgangsmateriale eller mellomprodukt og at denne dobbeltbinding ikke brytes i et følg-ende reaksjonstrinn. An isomerically pure product of formula I can be obtained by isomer separation or conversion of an isomer mixture of either the final product, a starting material or an intermediate product from a reaction step, provided that the double bond of the final product is present in said starting material or intermediate product and that this double bond is not broken in a subsequent -end reaction step.

Eksempel 1. Example 1.

90 g N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridyl)-allylamin ble oppløst i aceton (900 ml) og 2 ekvivalenter konsentrert saltsyre ble tilsatt under avkjøling. Etter avkjøling til omkring 0°C i 1 time, ble fellingen frafiltrert og vasket med aceton. Omkrystallisering ble foretatt fra isopropanol (800 ml) og vann (15 ml). (Z)-N,N-dimetyl-3-(4-brom-fenyl)-3-(3-pyridyl)-allylamin-dihydroklorid-monohydrat ble oppnådd etter vasking med isopropanol og tørking ved omkring 50°C. Smp. 195 - 200°C (dekomponering). Karl Fisher analyse viste et vanninnhold på 4,4 vekt-%. 90 g of N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine was dissolved in acetone (900 ml) and 2 equivalents of concentrated hydrochloric acid were added with cooling. After cooling to about 0°C for 1 hour, the precipitate was filtered off and washed with acetone. Recrystallization was carried out from isopropanol (800 ml) and water (15 ml). (Z)-N,N-dimethyl-3-(4-bromo-phenyl)-3-(3-pyridyl)-allylamine dihydrochloride monohydrate was obtained after washing with isopropanol and drying at about 50°C. Temp. 195 - 200°C (decomposition). Karl Fisher analysis showed a water content of 4.4% by weight.

Et IR-spektrum ble oppnådd med KBr-pellet-teknikken (1 mg An IR spectrum was obtained by the KBr pellet technique (1 mg

i 250 mg KBr). Område: 4000 - 650 cm<-1>. (Instrument: "Perkin-Elmer IR Spectrometer"). in 250 mg KBr). Range: 4000 - 650 cm<-1>. (Instrument: "Perkin-Elmer IR Spectrometer").

Markert absorbsjon (generelt mindre enn 50% transmittans) ble målt i de bølgetall som er angitt nedenfor med dets antatte motsvarende strukturelement: Marked absorption (generally less than 50% transmittance) was measured in the wavenumbers indicated below with its assumed corresponding structural element:

Et NMR-spektrum ble oppnådd fra en oppløsning av 100 mg An NMR spectrum was obtained from a solution of 100 mg

av forbindelsen i 0,5 ml deuteriumoksyd. Tetrametylsilan (TMS) ble benyttet som en intern standard. (Instrument: "Varian T 60 (60 MH2)"). De kjemiske skiftene gis som følger: of the compound in 0.5 ml of deuterium oxide. Tetramethylsilane (TMS) was used as an internal standard. (Instrument: "Varian T 60 (60 MH2)"). The chemical shifts are given as follows:

Eksempel 2. Example 2.

30,0 g urent N,N-dimetyl-3-(4-bromfenyl)-2-(3-pyridyl)-allyl-amin ble oppløst i 300 ml eter og 95 ml 2,6N HC1 i eter ble tilsatt. Det urene, vannfrie dihydrokloridet ble således oppnådd, frafiltrert og vakuumtørket. Det vannfrie dihydrokloridet ble oppløst i 150 ml isopropanol og 4 inl vann (5 ekv.) under oppvarming og produktet fikk krystalliseres. Utbytte 20 g (Z)-N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridyl)-allylamin-dihydroklorid-monohydrat. Karl Fisher-analyse viste et vanninnhold på 4,5 vekt-%. 30.0 g of impure N,N-dimethyl-3-(4-bromophenyl)-2-(3-pyridyl)-allyl-amine was dissolved in 300 ml of ether and 95 ml of 2.6N HCl in ether was added. The impure, anhydrous dihydrochloride was thus obtained, filtered off and vacuum dried. The anhydrous dihydrochloride was dissolved in 150 ml of isopropanol and 4 inl of water (5 eq.) under heating and the product was allowed to crystallize. Yield 20 g of (Z)-N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine dihydrochloride monohydrate. Karl Fisher analysis showed a water content of 4.5% by weight.

Eksempel 3. Example 3.

Fremstilling av mellomprodukter. Production of intermediate products.

Trinn 1: 1-( 4- bromfenyl)- 3- dimetylamino- l- propan. Step 1: 1-(4-bromophenyl)-3-dimethylamino-1-propane.

Denne forbindelse ble fremstilt ved å omsette 4-bromaceto-fenon med paraformaldehyd og dimetylhydrokloric<1> i en kon-vensjonell Mannich-reaksjon. This compound was prepared by reacting 4-bromoacetophenone with paraformaldehyde and dimethyl hydrochloric<1> in a conventional Mannich reaction.

Trinn 2: 1-( 4- bromfenyl)- 1-( 3- pyridyl)- 3- dimetylamino-1- propanol. Step 2: 1-(4-bromophenyl)-1-(3-pyridyl)-3-dimethylamino-1-propanol.

Mellomproduktet 3-pyridyllitium, dannet ved behandling av 3-brompyridin med butyllitium i eter ved lav temperatur, The intermediate 3-pyridyllithium, formed by treating 3-bromopyridine with butyllithium in ether at low temperature,

ble behandlet med 1-(4-bromfenyl)-1-dimetylamino-l-propanon oppløst i eter, for oppnåelse av 1-(4-bromfenyl)-1-(3-pyri-dyl ) -3-dimetylamino-l-propanol. was treated with 1-(4-bromophenyl)-1-dimethylamino-1-propanone dissolved in ether, to obtain 1-(4-bromophenyl)-1-(3-pyridyl)-3-dimethylamino-1-propanol .

Reaksjonsblandingen ble hydrolysert med is og vann, vann-fasen ble ekstrahert med metylenklorid ved pH 4, fulgt av eterekstraksjon ved pH 10. Resten etter inndamping ble revet med petroleumeter og eter. Det krystallinske produkt ble omkrystallisert fra isopropanol. The reaction mixture was hydrolyzed with ice and water, the water phase was extracted with methylene chloride at pH 4, followed by ether extraction at pH 10. The residue after evaporation was triturated with petroleum ether and ether. The crystalline product was recrystallized from isopropanol.

Trinn 3: N, N- dimetyl- 3-( 4- bromfenyl)- 3-( 3- pyridyl)-allylamin. Step 3: N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine.

Produktet fra trinn 2 ble dehydratisert med eddiksyreanhydrid og svovelsyre. Reaksjonsblandingen ble helt på is og vann-fasen ekstrahert med eter ved pH 10. Inndamping av oppløs-ningsmidlet ga basen. The product from step 2 was dehydrated with acetic anhydride and sulfuric acid. The reaction mixture was poured onto ice and the water phase extracted with ether at pH 10. Evaporation of the solvent gave the base.

Sammenligningsforsøk. Comparison experiment.

Stabilitet ved konstant fuktighet og romtemperatur Stability at constant humidity and room temperature

Forbindelsen ifølge oppfinnelsen ble sammenlignet med det tilsvarende vannfrie dihydrokloridet og dihydroklorid inneholdende 1 ekvivalent etanol. The compound according to the invention was compared with the corresponding anhydrous dihydrochloride and dihydrochloride containing 1 equivalent of ethanol.

Resultat: Monohydratet er stabilt ved 40 og 60% relativ fuktighet ved romtemperatur under hvilke betingelser den vannfrie forbindelsen og etanolatet ikke er stabile. Result: The monohydrate is stable at 40 and 60% relative humidity at room temperature under which conditions the anhydrous compound and the ethanolate are not stable.

Stabilitet ved vakuumtørking. Stability during vacuum drying.

Etanolat: Tørking ved 110°C i omkring 24 timer er nødvendig for å minske mengden av etanol til det akseptable nivået mindre enn 0,5%. Etter tørking var det tegn på dekomponering på qrunn av øket turbiditet, farge (A.-.^ =0,165) og ekstra Ethanol: Drying at 110°C for about 24 hours is necessary to reduce the amount of ethanol to the acceptable level of less than 0.5%. After drying, there were signs of decomposition on qrunn of increased turbidity, color (A.-.^ =0.165) and additional

J 4 0bnm J 40bnm

flekker på TLC. spots on TLC.

Monohydrat: Tørking ved 40°C i omkring 2-4 timer var nødvendig for å oppnå et produkt egnet for fremstilling av faste farmasøytiske preparater. Dekomponering kunne ikke oppdages ved å studere turbiditet, farge eller TLC. Etter lag3 ring ^ ved 45°C i 6 døgn var A4 .n0 5c nm=0,05. Monohydrate: Drying at 40°C for about 2-4 hours was necessary to obtain a product suitable for the manufacture of solid pharmaceutical preparations. Decomposition could not be detected by studying turbidity, color or TLC. After layer 3 ring ^ at 45°C for 6 days, A4 .n0 5c nm=0.05.

Claims (1)

Analogifremgangsmåte til fremstilling av terapeutisk aktive Z-N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridyl)-allylamindi-hydrokloridmonohydrat med formelen:Analogous process for the preparation of therapeutically active Z-N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine dihydrochloride monohydrate with the formula: karakterisert ved at (a) basen N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridyl)-allylamin med formelen:characterized in that (a) the base N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine of the formula: i oppløsning omsettes med vannholdig klorhydrogen og den dannede felling oppsamles, eller at (b) vannfri N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridyl)-in solution is reacted with aqueous hydrogen chloride and the precipitate formed is collected, or that (b) anhydrous N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)- allylamin-dihydrokloridallylamine dihydrochloride hydratiseres,hydrate, og at Z-formen isoleres.and that the Z shape is isolated.
NO771774A 1976-05-21 1977-05-20 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE Z-N, N-DIMETHYL-3- (4-BROMPHENYL) -3- (3-PYRIDYL) -ALLYLAMINE-DIHYDROCHLORIDE MONOHYDRATE NO150000C (en)

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SE7605780A SE409706B (en) 1976-05-21 1976-05-21 PROCEDURE FOR PREPARING N, N-DIMETHYL-3- (4-BROMOPHENYL) -3-3 (3-PYRIDYL) -ALLYLAMINE DIHYDROCHLORIDE MONOHYDRATE

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NO150000B true NO150000B (en) 1984-04-24
NO150000C NO150000C (en) 1984-08-01

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SE7909514L (en) 1979-11-16 1981-05-17 Astra Laekemedel Ab NEW HALOPHENYL-PYRIDYL-ALLYLAMINE DERIVATIVES
US4639338A (en) * 1984-08-06 1987-01-27 Ciba-Geigy Corporation Preparation of crystalline disodium 3-amino-1-hydroxypropane-1,1-diphosphonate pentahydrate
EP0919550A1 (en) * 1997-11-26 1999-06-02 Ucb, S.A. Pseudopolymorphic forms of 2-2-4-bis(4-fluorophenyl)methyl-1-piperazinyl-ethoxy acetic acid dihydrochloride

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SE361663B (en) * 1971-04-28 1973-11-12 Haessle Ab

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AU2513577A (en) 1978-11-16
IE45385L (en) 1977-11-21
JPS539311A (en) 1978-01-27
GB1561286A (en) 1980-02-20
FI67696B (en) 1985-01-31
SG60682G (en) 1983-09-02
LU77244A1 (en) 1977-08-22
CA1093560A (en) 1981-01-13
FI67696C (en) 1985-05-10
DK147048C (en) 1984-09-03
CY1171A (en) 1983-06-10
FR2351964B1 (en) 1981-03-20
IE45385B1 (en) 1982-08-11
NL7705529A (en) 1977-11-23
BE842368A (en) 1976-09-16
NO771774L (en) 1977-11-22
NZ184146A (en) 1979-07-11
FR2351964A1 (en) 1977-12-16
HK55782A (en) 1983-01-07
AU512004B2 (en) 1980-09-18
NO150000C (en) 1984-08-01
DK221177A (en) 1977-11-22
FI771591A (en) 1977-11-22
SE409706B (en) 1979-09-03
DK147048B (en) 1984-03-26
SE7605780L (en) 1977-11-22
MY8400046A (en) 1984-12-31
DE2721857A1 (en) 1977-12-01

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