DK147048B - ANALOGY PROCEDURE FOR THE PREPARATION OF Z-N, N-DIMETHYL-3- (4-BROMOPHENYL) -3- (3-PYRIDYL) -ALLYLAMINE DIHYDROCHLORIDE MONOHYDRATE - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF Z-N, N-DIMETHYL-3- (4-BROMOPHENYL) -3- (3-PYRIDYL) -ALLYLAMINE DIHYDROCHLORIDE MONOHYDRATE Download PDFInfo
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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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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Description
\p.éy\ p.éy
(19) DANMARK(19) DENMARK
φ (12) FREMLÆGGELSESSKRIFT (11) 147048 Bφ (12) PUBLICATION WRITING (11) 147048 B
DIREKTORATET FORDIRECTORATE OF
PATENT- OG VAREMÆRKEVÆSENETTHE PATENT AND TRADEMARKET SYSTEM
(21) Patentansøgning nr.: 2211/77 (51) Int.CI.3: C 07 D 213/38 (22) Indleveringsdag: 20 maj 1977 (41) Alm. tilgængelig: 22 nov 1977 (44) Fremlagt: 26 mar 1984 (86) International ansøgning nr.: - (30) Prioritet: 21 maj 1976 SE 7605780 (71) Ansøger: *ASTRA LAEKEMEDEL AKTIEBQLAG; S-151 85 Soedertaelje, SE.(21) Patent Application No .: 2211/77 (51) Int.CI.3: C 07 D 213/38 (22) Filing Date: May 20, 1977 (41) Alm. available: 22 Nov 1977 (44) Submitted: 26 Mar 1984 (86) International Application No: - (30) Priority: 21 May 1976 SE 7605780 (71) Applicant: * ASTRA LEKEMEDEL SHARE SHEET; S-151 85 Soedertaelje, SE.
(72) Opfinder: Thore Oskar Vaerner *Rydh; SE, Carl Bengt Johan *Ulff; SE.(72) Inventor: Thore Oskar Vaerner * Rydh; SE, Carl Bengt Johan * Ulff; SEE.
*· (74) Fuldmægtig: Kontor for Industriel Eneret_ (54) Analogifremgangsmåde til fremstilling af Z-N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridyl)· -allylamin-dihydroklorid-monohydrat* · (74) Plenipotentiary: Office of Industrial Enerent_ (54) Analogous Process for Preparation of Z-N, N-Dimethyl-3- (4-Bromophenyl) -3- (3-Pyridyl) -allylamine Dihydrochloride Monohydrate
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af den hidtil ukendte forbindelse Z-N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridy1)-allylamin-dihydroklorid-monohydrat, og fremgangsmåden ifølge opfindelsen er ejendommelig ved det i patent-kravete kendetegnende del angivne. Formålet med opfindelsen er at tilvejebringe en fremgangsmåde til fremstilling af en forbindelse med forbedrede lagringsegenskaber og som kan fremstilles på en teknisk fordelagtig måde i sammenligning med lignende, tidligere kendte for-^ bindeiser.The present invention relates to an analogous process for the preparation of the novel compound ZN, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate, and the process of the invention is characterized by patent-claim characterizing part disclosed. The object of the invention is to provide a process for the preparation of a compound having improved storage properties and which can be prepared in a technically advantageous manner in comparison with similar, prior art binding claims.
qq Fra belgisk patentskrift nr. 781 105 kendes der forbin- delser med den almene formel r- * Ω 2 1Λ 7 O 4 8 R ·Υ\ R2 \ ch3 C=CHCH2N^ i ^ch3 1 2 hvor R og R uafhængigt af hinanden betegner hydrogen, klor eller brom, og hvor pyridylgruppen er bundet i 2-, 3- eller 4-stilling.qq From Belgian Patent Specification No. 781 105 there are known compounds of the general formula r- * Ω 2 1Λ 7 O 4 8 R · Υ \ R2 \ ch3 C = CHCH2N ^ i ^ ch3 1 2 where R and R are independent of each other represents hydrogen, chlorine or bromine and wherein the pyridyl group is bonded in the 2-, 3- or 4-position.
Specielt nævnt blandt andre forbindelser er det vandfri dihydroklorid af forbindelsen "Ok C=CHCH,N 11 ζΓ “· som har terapeutisk værdi til behandling af depressive tilstande.Particularly mentioned among other compounds is the anhydrous dihydrochloride of the compound "Ok C = CHCH, N 11 ζΓ" · which has therapeutic value for treating depressive conditions.
I henhold til det nævnte patentskrift vindes det vandfri dihydroklorid ud fra den tilsvarende base i æteropløsning ved indførelse af tørt HCl. Det har imidlertid vist sig at det vandfri dihydroklorid er fugtighedsfølsomt og ved oparbejdning af forbindelsen ved separation og tørring danner den vandfri forbindelse klumper, så den dårligt kan oparbejdes til faste farmaceutiske præparater. For lignende forbindelser kendes krystallisation af dihydroklorider-ne fra ætanol fra det nævnte patentskrift. Ved denne fremgangsmåde vindes vedkommende ætanolat. Det har imidlertid vist sig at der ved oparbejdning af ætanolatet ved separation og tørring tilbageholdes en betydelig mængde opløsningsmiddel.According to said patent, anhydrous dihydrochloride is recovered from the corresponding base in ether solution by introduction of dry HCl. However, it has been found that the anhydrous dihydrochloride is moisture sensitive and upon working up the compound by separation and drying, the anhydrous compound forms clumps so that it can be poorly processed into solid pharmaceutical compositions. For similar compounds, crystallization of the ethanol dihydrochlorides of the aforementioned patent is known. In this process, the ethanolate is obtained. However, it has been found that by processing the ethanolate by separation and drying a considerable amount of solvent is retained.
For at fjerne dette opløsningsmiddel behøves tørring i omkring 1-2 døgn ved en temperatur på omkring 90-100°C. Disse betingelser, som 3 147048 er ubekvemme i sig selv, kan desuden bevirke misfarvning og sønderfald af produktet. Den vandfri forbindelse er ikke velegnet til fremstilling af farmaceutiske præparater såsom tabletter på grund af dens hygroskopiske egenskaber. Ved lagring absorberer den vandfri forbindelse fugtighed under dannelse af hårde kager, der må brydes op før den videre behandling.To remove this solvent, drying is required for about 1-2 days at a temperature of about 90-100 ° C. Furthermore, these conditions, which are inconvenient in themselves, can cause discoloration and decomposition of the product. The anhydrous compound is not suitable for the preparation of pharmaceutical compositions such as tablets due to its hygroscopic properties. When stored, the anhydrous compound absorbs moisture to form hard cakes that must be broken up before further processing.
Ulemperne ved den tidligere kendte forbindelse er med held overvundet ved den foreliggende opfindelse, der tilvejebringer en fremgangsmåde til fremstilling af det hidtil ukendte dihydro- . klorid-monohydrat af Z-isomeren af forbindelsen med den ovenfor viste formel II, dvs. N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridyl)-allylamin-dihydroklorid-monohydråt.The disadvantages of the prior art compound have been successfully overcome by the present invention which provides a process for the preparation of the novel dihydro-. chloride monohydrate of the Z isomer of the compound of formula II shown above, i.e. N, N-dimethyl-3- (4-bromfenyl) -3- (3-pyridyl) -allylamin dihydrochloride-monohydråt.
Denne forbindelse eksisterer i to steroisomere former, dvs i en E-form og en Z-form. De terapeutiske egenskaber af forbindelsen ligger hovedsageligt hos den ene af de nævnte isomerer, nemlig Z-isomeren, og derfor fremstilles Z-N,N-dimetyl-3-(4-bromfenyl)-This compound exists in two steroisomeric forms, ie in an E form and a Z form. The therapeutic properties of the compound are mainly in one of the isomers mentioned, namely the Z isomer, and therefore Z-N, N-dimethyl-3- (4-bromophenyl) is prepared.
3-(3-pyridyl)-allylamin-dihydroklorid-monohydrat med formel III3- (3-Pyridyl) -allylamine dihydrochloride monohydrate of formula III
"XX."XX.
• c=c• c = c
\ , 2HC1 , H-0 III\, 2HC1, H-0 III
^ NCH2H(CB3)j^ NCH2H (CB3) j
VV
Farmaceutiske præparater af den angivne forbindelse kan tilvejebringes ved at indblande forbindelsen i forskellige former for faste farmaceutiske præparater såsom tabletter eller granulater. Hensigtsmæssigt indblandes forbindelsen i farmaceutiske præparater til oral anvendelse. Sædvanligvis udgør det virksomme stof 0,1 - 95 vægt% af præparatet, navnlig 2-50 vægt% i præparater egnet til oral indgift.Pharmaceutical compositions of the indicated compound may be provided by admixing the compound in various forms of solid pharmaceutical compositions such as tablets or granules. Conveniently, the compound is incorporated into pharmaceutical compositions for oral use. Usually, the active substance is from 0.1 to 95% by weight of the composition, in particular from 2 to 50% by weight, in compositions suitable for oral administration.
4 1470484 147048
For at fremstille farmaceutiske præparater indeholdende den angivne forbindelse i form af dosisenheder til oral anvendelse kan forbindelsen blandes med en fast pulverformig bærer som fx laktose, sakkarose, sorbitol, mannitol, stivelsesarter såsom kartoffelstivelse, majsstivelse eller amylopektin, cellulosederivat eller gelatine, og med et smøremiddel såsom magniumstearat, kalciumstearat eller polyætylenglykolvokser, og blandingen presses derefter til dannelse af tabletter. Hvis der ønskes overtrukne tabletter kan tabletkærner fremstilles som beskrevet og derefter overtrækkes med en koncentreret sukkeropløsning som kan indeholde fx gummiarabikum, gelatine, talkum eller titandioxyd. Tabletterne kan også dækkes med en lak opløst i et letflygtigt organisk opløsningsmiddel eller en blanding af organiske opløsningsmidler. Der kan sættes farvestoffer til disse overtræk så at man let kan skelne mellem tabletter der indeholder forskellige aktive stoffer eller forskellige mængder af samme aktive stof.To prepare pharmaceutical compositions containing the stated compound in dosage units for oral use, the compound can be mixed with a solid powdered carrier such as, for example, lactose, sucrose, sorbitol, mannitol, starch species such as potato starch, corn starch or amylopectin, cellulose derivative or gelatin. such as magnesium stearate, calcium stearate or polyethylene glycol waxes, and then the mixture is pressed to form tablets. If coated tablets are desired, tablet cores can be prepared as described and then coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talc or titanium dioxide. The tablets may also be covered with a varnish dissolved in a volatile organic solvent or a mixture of organic solvents. Dyes can be added to these coatings so that one can easily distinguish between tablets containing different active substances or different amounts of the same active substance.
Doseringsenheder til rektal anvendelse kan fremstilles af suppositorier indenholdende det virksomme stof i blanding med et neutralt fedtgrundlag, eller rektale gelatinekapsler indeholdende det virksomme stof i blanding med vegetabilsk olie eller parafinolie.Dosage units for rectal use can be made 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 omhandlede forbindelse fremstilles enten a) ved omsætning af basen N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridyl)-allylamin (II) med vandigt hydrogenklorid, idet omsætningen sker i et polært organisk opløsningsmiddel og under afkøling, fortrinsvis til ca. 0°C. Et egnet organisk opløsningsmiddel er acetone. Det vandige hydrogenklorid er hensigtsmæssigt koncentreret saltsyre. Det er også muligt at sætte H20 til en opløsning af basen og derefter tilsætte vandfrit HC1.The subject compound is prepared either a) by reaction of the base N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) allylamine (II) with aqueous hydrogen chloride, the reaction taking place in a polar organic solvent and under cooling, preferably to ca. 0 ° C. A suitable organic solvent is acetone. The aqueous hydrogen chloride is suitably concentrated hydrochloric acid. It is also possible to add H 2 O to a solution of the base and then add anhydrous HCl.
b) eller ved hydratisering af vandfrit dihydroklorid af forbindelsen ifølge formel II.b) or by hydration of anhydrous dihydrochloride of the compound of formula II.
5 1470485 147048
Eksempel 1 90 g N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridyl)-aiiylamin opløstes i 900 ml acetone og der tilsattes under afkøling 2 ækvivalenter koncentreret saltsyre. Efter afkøling til ca. 0°C i 1 time frafiltreredes udfældningen og vaskedes med acetone. Omkrystallisation foretoges fra isopropanol (800 ml) og vand (15 ml). Der vandtes (Z)-N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridyl)-allylamin-dihydroklorid-monohydrat efter vask med isopropanol og tørring ved ca. 50°C. Smeltepunkt 195-200°C (sønderdeling). Karl Fischer-analyse viste et vandindhold på 4,4 vægt%.EXAMPLE 1 90 g of N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) alkylamine were dissolved in 900 ml of acetone and 2 equivalents of concentrated hydrochloric acid were added under cooling. After cooling to approx. 0 ° C for 1 hour, the precipitate was filtered off and washed with acetone. Recrystallization was done from isopropanol (800 ml) and water (15 ml). (Z) -N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) allylamine dihydrochloride monohydrate was washed after washing with isopropanol and drying at ca. 50 ° C. Melting point 195-200 ° C (dec.). Karl Fischer analysis showed a water content of 4.4% by weight.
Der tilvejebragtes et IR-spektrum ved KBr-pelletteknikken (1 mg i 250 mg KBr). Områder: 4000-650 cm Indtrument: Perkin-Elmer IR spektrometer.An IR spectrum was provided by the KBr pellet technique (1 mg in 250 mg KBr). Areas: 4000-650 cm Instrument: Perkin-Elmer IR spectrometer.
Markeret absorption (i almindelighed mindre end 50% transmittens) måltes i de bølgetal som anført nedenfor sammen med deres formodede tilsvarende strukturelementer.Marked absorption (generally less than 50% transmittance) was measured in the wave numbers listed below along with their presumed corresponding structural elements.
Bølgetal cm ^ Strukturelement 3300 OH~ i vand 2600-2400 ammonium 1650 kulstofdobbeltbinding (transmittens ~ 60%) 1490 og 1470 aromatisk, dobbeltbinding 820 disubstitueret benzenWave number cm ^ Structural element 3300 OH ~ in water 2600-2400 ammonium 1650 carbon double bond (transmittance ~ 60%) 1490 and 1470 aromatic, double bond 820 disubstituted benzene
Der opnåedes et NMR-spektrum fra en opløsning af 100 mg af forbindelsen i 0,5 ml deuteriumoxyd. Der brugtes tetrametylsilan (TMS) som intern standard. Instrument: Varian T 60 (60 MH2).An NMR spectrum was obtained from a solution of 100 mg of the compound in 0.5 ml of deuterium oxide. Tetramethylsilane (TMS) was used as an internal standard. Instrument: Varian T 60 (60 MH2).
De kemiske skifter anføres nedenfor.The chemical shifts are listed below.
147048 6147048 6
Proton Kemisk skifte (ppm) A 3,12 B 4,12 C 4,88 D 6,73 E 7,23 - 7,84 F 8,24 - 8,87 G 8,90 - 9,30 ΒΓγ% © © @ © \/ © , 2HC1 , H20 / \ © © H ^ s-\ CH„ ® | ® ch3 ch3 ® ® 7 147048Proton Chemical Change (ppm) A 3.12 B 4.12 C 4.88 D 6.73 E 7.23 - 7.84 F 8.24 - 8.87 G 8.90 - 9.30 ΒΓγ% © © @ © \ / ©, 2HC1, H20 / \ © © H ^ s- \ CH „® | ® ch3 ch3 ® ® 7 147048
Eksempel 2 30,0 g rå N,N-dimetyl-3-(4-bromfenyl)-3-(3-pyridyl)-allylamin opløstes i 300 ml æter og der tilsattes 95 ml 2,6 N HC1 i æter. Der vandtes det rå vandfri dihydroklorid som frafiltrere-des og vakuumtørredes. Det vandfri dihydroklorid opløses i 150 ml isopropanol og 4 ml vand (5 ækvivalenter) under opvarmning, og man lod produktet krystallisere. Udbytte 20 g (Z)-N,N-dimetyl-3-(4-brom-fenyl)-3-(3-pyridyl)-allylamin-dihydroklorid-monohydrat. Karl Fischer analyse viste et vandindhold på 4,5 vægt%.Example 2 30.0 g of crude N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) allylamine were dissolved in 300 ml of ether and 95 ml of 2.6 N HCl added in ether. There, the crude anhydrous dihydrochloride was obtained which was filtered off and vacuum dried. The anhydrous dihydrochloride is dissolved in 150 ml of isopropanol and 4 ml of water (5 equivalents) under heating and the product is crystallized. Yield 20 g (Z) -N, N-dimethyl-3- (4-bromo-phenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate. Karl Fischer analysis showed a water content of 4.5% by weight.
Sammenligningsforsøgcomparison Tests
Stabilitet ved konstant fugtighed og stuetemperaturStability at constant humidity and room temperature
Den omhandlede forbindelse sammenlignedes med det tilsvarende vandfri dihydroklorid og med dihydrokloridet indeholdende 1 ækvivalent ætanol.The subject compound was compared with the corresponding anhydrous dihydrochloride and with the dihydrochloride containing 1 equivalent of ethanol.
Tabel 1 Vægt efter lagring ved forskellig relativ fugtighedTable 1 Weight after storage at different relative humidity
Relativ Monohydrat Vandfri Ætanol fugtighed 40% uforandret øget 4,6% nedsat 5% (1 uge) (1 døgn) (4 døgn) 60% uforandret øget 4,6% nedsat 4% (1 uge) (1 døgn) (5 døgn) 90% øget 12% øget 50% uforandret (8 timer) (1 uge) (6 døgn) øget 11% (4 døgn) sønderdeltRelative Monohydrate Anhydrous Ethanol Humidity 40% unchanged increased 4.6% decreased 5% (1 week) (1 day) (4 days) 60% unchanged increased 4.6% decreased 4% (1 week) (1 day) (5 days) ) 90% increased 12% increased 50% unchanged (8 hours) (1 week) (6 days) increased 11% (4 days) broken down
Resultat: Monohydratet er stabilt ved 40% og 60% relativ fugtighed ved stuetemperatur, under hvilke omstændigheder den vandfri forbindelse og ætanolet ikke er stabile.Result: The monohydrate is stable at 40% and 60% relative humidity at room temperature, under which conditions the anhydrous compound and ethanol are not stable.
147048 8147048 8
Stabilitet ved vakuumtørring Ætanolatet: Tørring ved 110°C i ca. 24 timer behøvedes for at nedsætte mængden af ætanol til det acceptable niveau på 0,5%. Efter tørring var der tegn på sønderdeling, antydet af turbiditet, farve (A405 ητη=0,165) og ekstra pletter på TLC.Stability in vacuum drying Ethanolate: Drying at 110 ° C for approx. 24 hours was needed to reduce the amount of ethanol to the acceptable level of 0.5%. After drying, there were signs of decomposition, suggestive of turbidity, color (A405 ητη = 0.165) and extra spots on TLC.
Monohydrat: Tørring ved 40°C i omkring 2-4 timer behøvedes for at opnå et produkt der var egnet til fremstilling af faste farmaceutiske præparater. Sønderfald kunne ikke opdages ved at studere turbiditet, farve eller TLC. Efter lagring ved 45°C i 6 døgn var A405nm= °Γ°5*Monohydrate: Drying at 40 ° C for about 2-4 hours was needed to obtain a product suitable for the preparation of solid pharmaceutical compositions. Decomposition could not be detected by studying turbidity, color or TLC. After storage at 45 ° C for 6 days, A405nm = ° Γ ° 5 *
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE7605780 | 1976-05-21 | ||
| 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 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK221177A DK221177A (en) | 1977-11-22 |
| DK147048B true DK147048B (en) | 1984-03-26 |
| DK147048C DK147048C (en) | 1984-09-03 |
Family
ID=20327944
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK221177A DK147048C (en) | 1976-05-21 | 1977-05-20 | ANALOGY PROCEDURE FOR THE PREPARATION OF Z-N, N-DIMETHYL-3- (4-BROMOPENYL) -3- (3-PYRIDYL) -ALLYLAMINE DIHYDROCHLORIDE MONO HYDRATE |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS539311A (en) |
| AU (1) | AU512004B2 (en) |
| BE (1) | BE842368A (en) |
| CA (1) | CA1093560A (en) |
| CY (1) | CY1171A (en) |
| DE (1) | DE2721857A1 (en) |
| DK (1) | DK147048C (en) |
| FI (1) | FI67696C (en) |
| FR (1) | FR2351964A1 (en) |
| GB (1) | GB1561286A (en) |
| HK (1) | HK55782A (en) |
| IE (1) | IE45385B1 (en) |
| LU (1) | LU77244A1 (en) |
| MY (1) | MY8400046A (en) |
| NL (1) | NL7705529A (en) |
| NO (1) | NO150000C (en) |
| NZ (1) | NZ184146A (en) |
| SE (1) | SE409706B (en) |
| SG (1) | SG60682G (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE361663B (en) * | 1971-04-28 | 1973-11-12 | Haessle Ab |
-
1976
- 1976-05-21 SE SE7605780A patent/SE409706B/en unknown
- 1976-05-31 BE BE167453A patent/BE842368A/en not_active IP Right Cessation
-
1977
- 1977-05-03 LU LU77244A patent/LU77244A1/xx unknown
- 1977-05-13 AU AU25135/77A patent/AU512004B2/en not_active Expired
- 1977-05-14 DE DE19772721857 patent/DE2721857A1/en not_active Withdrawn
- 1977-05-17 IE IE1009/77A patent/IE45385B1/en unknown
- 1977-05-18 NL NL7705529A patent/NL7705529A/en not_active Application Discontinuation
- 1977-05-19 NZ NZ184146A patent/NZ184146A/en unknown
- 1977-05-19 FI FI771591A patent/FI67696C/en not_active IP Right Cessation
- 1977-05-20 NO NO771774A patent/NO150000C/en unknown
- 1977-05-20 CA CA278,877A patent/CA1093560A/en not_active Expired
- 1977-05-20 FR FR7715612A patent/FR2351964A1/en active Granted
- 1977-05-20 DK DK221177A patent/DK147048C/en not_active IP Right Cessation
- 1977-05-20 CY CY1171A patent/CY1171A/en unknown
- 1977-05-20 GB GB21340/77A patent/GB1561286A/en not_active Expired
- 1977-05-21 JP JP5822377A patent/JPS539311A/en active Pending
-
1982
- 1982-12-01 SG SG606/82A patent/SG60682G/en unknown
- 1982-12-30 HK HK557/82A patent/HK55782A/en unknown
-
1984
- 1984-12-30 MY MY46/84A patent/MY8400046A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| 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 |
| NO150000B (en) | 1984-04-24 |
| 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 |
| SE7605780L (en) | 1977-11-22 |
| MY8400046A (en) | 1984-12-31 |
| DE2721857A1 (en) | 1977-12-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |