NO122299B - - Google Patents
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- NO122299B NO122299B NO327868A NO327868A NO122299B NO 122299 B NO122299 B NO 122299B NO 327868 A NO327868 A NO 327868A NO 327868 A NO327868 A NO 327868A NO 122299 B NO122299 B NO 122299B
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- Prior art keywords
- phenthiazine
- carboxylate
- formula
- methyl
- activity
- Prior art date
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- 238000000034 method Methods 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 238000006114 decarboxylation reaction Methods 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000001414 amino alcohols Chemical class 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 20
- 239000000047 product Substances 0.000 description 13
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical class C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 239000000739 antihistaminic agent Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 230000001387 anti-histamine Effects 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229940125715 antihistaminic agent Drugs 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- FZASHPCRPMSFEG-UHFFFAOYSA-N 3-(dimethylamino)-2-methylpropan-1-ol Chemical compound OCC(C)CN(C)C FZASHPCRPMSFEG-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 229940035674 anesthetics Drugs 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000003193 general anesthetic agent Substances 0.000 description 2
- 239000003326 hypnotic agent Substances 0.000 description 2
- 230000000147 hypnotic effect Effects 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- -1 3-dimethylamino-2-methyl-1-propyl- Chemical group 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 229940124326 anaesthetic agent Drugs 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000008925 spontaneous activity Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B42—BOOKBINDING; ALBUMS; FILES; SPECIAL PRINTED MATTER
- B42F—SHEETS TEMPORARILY ATTACHED TOGETHER; FILING APPLIANCES; FILE CARDS; INDEXING
- B42F21/00—Indexing means; Indexing tabs or protectors therefor
- B42F21/06—Tabs detachably mounted on sheets, papers, cards, or suspension files
- B42F21/08—Tabs detachably mounted on sheets, papers, cards, or suspension files in one of a number of predetermined positions
Description
Fremgangsmåte for fremstilling av terapeutisk aktive fenthiazinderivater. Process for the preparation of therapeutically active phenthiazine derivatives.
Nærværende oppfinnelse vedrører en The present invention relates to a
fremgangsmåte for fremstilling av visse method for the manufacture of certain
terapeutisk aktive fenthiazinderivater. therapeutically active phenthiazine derivatives.
Det er kjent at forskjellige 10-amino-alkylfenthiaziner er i besiddelse av inte-ressante terapeutiske egenskaper. Noen er Various 10-amino-alkylphenthiazines are known to possess interesting therapeutic properties. Someone is
anvendelige som antihistaminika, synapto-lytika, antispasmodika, lokalanestika og applicable as antihistamines, synaptolytics, antispasmodics, local anesthetics and
analgetika (se f. eks. norsk patent nr. analgesics (see e.g. Norwegian patent no.
74 052) og andre er anvendelige som potensiatorer for analgetika, hypnotika og ane-stetåka. Utstrakte forsøks- og eksperimen-teringsarbeider har imidlertid vist at både 74 052) and others are useful as potentiators for analgesics, hypnotics and anesthetic mists. However, extensive trial and experimentation work has shown that both
størrelsen av den terapeutiske indeks og the size of the therapeutic index and
naturen for den terapeutiske effekt som nature for the therapeutic effect which
oppvises av visse forbindelser av denne art is exhibited by certain compounds of this kind
radikalt kan endres selv ved små forand-ringer i kjemisk struktur. Særlig er dette can be radically changed even by small changes in chemical structure. This is particularly so
tilfellet med variasjoner i naturen og leng-den av alkylensidekjeden som er bundet til the case of variations in the nature and length of the alkylene side chain to which it is attached
nitrogenatomet i 10-stilling og ved substi-tusjon i fenthiazinkjernen. the nitrogen atom in the 10-position and by substitution in the phenthiazine nucleus.
Det er nå funnet at visse 10-amino-alkylfenthiaziner som har som alkylen-gruppen en spesiell art forgrenet kjede og It has now been found that certain 10-amino-alkylphenthiazines which have as the alkylene group a special type of branched chain and
substituert i 3-stilllngen med en alkylgruppe eller methoxy- eller ethoxygruppe substituted in the 3-position with an alkyl group or methoxy or ethoxy group
har fremragende terapeutisk anvendelighet has outstanding therapeutic utility
i sammenligning med produkter som tidligere er beskrevet og også dem som er angitt i norsk patent nr. 94 734 i hvilke alkylensidekjeden i det spesielle 10-amino-alkylfenthiazin som der er beskrevet er en in comparison with products previously described and also those indicated in Norwegian patent no. 94 734 in which the alkylene side chain in the particular 10-amino-alkylphenthiazine described there is a
rett kjede med 2 eller 3 carbonatomer. straight chain with 2 or 3 carbon atoms.
Det er formålet ved nærværende opp- That is the purpose of the present
finnelse å fremskaffe en ny fremgangsmåte for fremstillingen av 10-aminoalkylfenthiazinene med den generelle formel: invention to provide a new process for the preparation of the 10-aminoalkylphenthiazines with the general formula:
hvor X betegner en alkylgruppe med ikke mere enn 3 carbonatomer eller en methoxy-eller ethoxygruppe, og syreaddisjons- og kvaternære ammoniumsalter av disse. Disse kjernesubstituerte fenthiazinderivater med en isobutylensidekiede, som kan eksistere i optisk aktive former, er i besiddelse av en aktivitet i forhold til sentralnervesystemet som potensiatorer for analgetika, hypnotika og anestetika, og er meget aktive antihistaminika. De kan anvendes i human- og vete-rinærmedisinen, blant annet som hjelp ved narkoser, inhibitorer for det vegetative nervesystem, og som hjelp i psykiatri, og som antihistaminika. Fenthiazinderivater som har anvendelig aktivitet enten som potenslatorer som foran angitt eller anti-histamiin aktivitet er kjent, men 10-amino- where X denotes an alkyl group with no more than 3 carbon atoms or a methoxy or ethoxy group, and acid addition and quaternary ammonium salts thereof. These core-substituted phenthiazine derivatives with an isobutylene side chain, which may exist in optically active forms, possess central nervous system activity as potentiators of analgesics, hypnotics and anesthetics, and are highly active antihistamines. They can be used in human and veterinary medicine, including as an aid in anaesthetics, inhibitors for the vegetative nervous system, and as an aid in psychiatry, and as antihistamines. Phenthiazine derivatives which have useful activity either as potentiators as stated above or antihistamine activity are known, but 10-amino-
alkylfenthiazinene med formel I er i besiddelse av begge de nevnte aktiviteter i en markert grad. Den uventede dobbelte aktivitet stammer særlig fra nærværet av den forgrenede isobutylen kjede i forbindelsene. Av særlig anvendelighet med hensyn til potensierende egenskaper er de individu-elle isomerer og racemater av 3-(3-methoxy-10-f enthiazinyl)-2-methyl-1-dimet-hylaminopropan og 3-(3-ethyl-10-fenthi-azinylO-2-methyl-l-dimethylaminopropan. the alkylphenthiazines of formula I possess both of the aforementioned activities to a marked degree. The unexpected dual activity derives in particular from the presence of the branched isobutylene chain in the compounds. Of particular utility with regard to potentiating properties are the individual isomers and racemates of 3-(3-methoxy-10-phenthiazinyl)-2-methyl-1-dimethylaminopropane and 3-(3-ethyl-10-phenthi -azinylO-2-methyl-1-dimethylaminopropane.
Den særegne dobbelte aktivitet for The peculiar double activity for
fenthiazinderivatene med formel I vises klart fra de forsøk som det refereres til nedenfor og resultatene som oppnås med typiske produkter og også tidligere kjente forbindelser og én spesielt beskrevet i patent nr. 94 734. the phenthiazine derivatives of formula I is clearly shown from the experiments referred to below and the results obtained with typical products and also previously known compounds and one particularly described in patent No. 94,734.
Forbindelsene K; L og M er beskrevet The compounds K; L and M are described
i norsk patent nr. 94 734, forbindelse J [3-klor-10-(3-dimethylaminopropyl) f enthi-azin] er den tidligere kjente forbindelse som har størst kjent aktivitet på sentralnervesystemet, mens forbindelse N [10-(2-dimethylamino-2-methylethyl) fearthiaztø] er inkludert som den av de tidligere kjente forbindelser med best antihistamin aktivitet. in Norwegian patent no. 94 734, compound J [3-chloro-10-(3-dimethylaminopropyl)phenthiazine] is the previously known compound which has the greatest known activity on the central nervous system, while compound N [10-(2-dimethylamino -2-methylethyl) fearthiaztø] is included as the one of the previously known compounds with the best antihistamine activity.
Forbindelser med formel I: Compounds of formula I:
Produkt A X = CH,, (racemisk form) Product A X = CH,, (racemic form)
Produkt B X = C,H,- (racemisk form) Product B X = C,H,- (racemic form)
Produkt C X = C^H, (venstre form) Product C X = C^H, (left form)
Produkt D X = OCH3 (racemisk form) Product D X = OCH3 (racemic form)
Produkt E X = OCR, (venstre form) Product E X = OCR, (left form)
Tidligere kjente produkter og norsk patent nr. 94 734. Previously known products and Norwegian patent no. 94 734.
Forbindelser med den generelle formel: Compounds with the general formula:
Prøvebetingelsene var som følger: The test conditions were as follows:
(a) Potensiering av anestika ( ether). Produktet som skal undersøkes admi-nistreres subkutant til prøvedyret (mus) med en dose på 20 mg/kg. 30 minutter senere anbringes de således behandlede mus i en klokke i hvilken en forutbestemt mengde ether fordampes. Straks narkosen er opprettet, tas musene ut av klokken og varigheten av narkose i frisk luft opptegnes i minutter. Tallet som oppnås omdannes til forholdet mellom verdien for forbendelsen J og tallet som oppnås multipliseres med 100. Dette er det tall som angis i tabellen som følger hvor, ved definisjon, verdien for forbindelsen J er 100, og denne forbindelse tas som standard for sammenligning. (b) Winter og Flatakerprøven. Denne prøve består i å bestemme og sammenligne før og etter administreringen av produktet til en mus, ved en egnet foto-elektrisk anordning, antallet passasjer for musen gjennom en strålebunt innen et innelukke stort nok for dyret til å bevege seg fritt uten å føle seg fanget. Det be stemmes grafisk med sammenligning med å kontrollere dosen (i mg/kg) administrert peroralt (p.o.) iy2 time før prøven som forårsaker 50 pst. reduksjon i musens spon-tane aktivitet (ED,0). (c) Antihistamin aktivitet - Bovet-Staub- prøven. (a) Potentiation of anesthetics (ether). The product to be examined is administered subcutaneously to the test animal (mice) at a dose of 20 mg/kg. 30 minutes later, the mice thus treated are placed in a bell in which a predetermined amount of ether evaporates. As soon as the anesthesia is established, the mice are removed from the clock and the duration of anesthesia in fresh air is recorded in minutes. The number obtained is converted to the ratio of the value of compound J and the number obtained is multiplied by 100. This is the number given in the table that follows where, by definition, the value of compound J is 100, and this compound is taken as the standard for comparison. (b) Winter and the Flataker test. This test consists in determining and comparing before and after the administration of the product to a mouse, by a suitable photo-electric device, the number of passages of the mouse through a beam of radiation within an enclosure large enough for the animal to move freely without feeling trapped . That pray is plotted graphically with comparison to control dose (in mg/kg) administered orally (p.o.) iy 2 h before the test causing a 50% reduction in mouse spontaneous activity (ED,0). (c) Antihistamine activity - Bovet-Staub test.
Antallet av giftige histamin, admi-streres intravenøst, som kan tåles av mar-svin som er behandlet 30 minutter med 20 mg/kg av prøveforbindelsen ved sub-kutan injeksjon, bestemmes. The amount of toxic histamine, administered intravenously, which can be tolerated by guinea pigs treated for 30 minutes with 20 mg/kg of the test compound by subcutaneous injection, is determined.
Resultatene som oppnås er samlet sam-men i den følgende tabell: The results obtained are collected together in the following table:
* *
Det vil bemerkes at jo høyere antallet i prøve (a) og prøve (c), er, jo mere aktiv er forbindelsen, og i prøve (b) angir det laveste tall den mere aktive forbindelse. Resultatene viser klart at produktene i formel I er i besiddelse av både antihistamin aktivitet og aktivitet overfor sentralnervesystemet, mens den beste av de øvrige forbindelser bare i anvendelig grad har en slik virkning, d.v.s. forbindelsene J, K, L og M er aktive på sentralnervesystemet og uanvendellge som antihistaminika, og forbindelse N er anvendelig som et antihistaminika men har ingen anvendelig aktivitet på sentralnervesystemet. It will be noted that the higher the number in sample (a) and sample (c), the more active the compound, and in sample (b) the lower number indicates the more active compound. The results clearly show that the products in formula I possess both antihistamine activity and activity towards the central nervous system, while the best of the other compounds only have such an effect to a usable extent, i.e. compounds J, K, L and M are active on the central nervous system and unusable as antihistamines, and compound N is useful as an antihistamine but has no useful activity on the central nervous system.
I patent nr. 94 734 er vernet en generell fremgangsmåte for fremstillingen av N- Patent no. 94 734 protects a general method for the production of N-
aminoalkylfenthiaziner ved å omdanne et N-ikke-substituert fenthiazin til en amino-alkylester av en fenthiazin-10-carboxylsyre og decarboxylere det resulterende amino-alkylfenthiazinyl-10-carboxylat ved oppvarmning. lO-aminoalkylfenthiazinene med formel I med fremragende terapeutisk anvendelighet som vist foran kan fremstilles ved anvendelse av fremgangsmåten ifølge det nevnte patent. aminoalkylphenthiazines by converting an N-unsubstituted phenthiazine to an aminoalkylester of a phenthiazine-10-carboxylic acid and decarboxylating the resulting aminoalkylphenthiazinyl-10-carboxylate by heating. The 10-aminoalkylphenthiazines of formula I with outstanding therapeutic utility as shown above can be prepared using the method according to the aforementioned patent.
Ifølge nærværende oppfinnelse fremstilles racemiske og optisk aktive fenthiazinderivater med formel I, eller syreaddisjons- eller kvaternære ammonlumsalter av disse, ved decarboxylering av et fenthiazin-10-carboxylat av en aminoalko-hol med den generelle formel: According to the present invention, racemic and optically active phenthiazine derivatives of formula I, or acid addition or quaternary ammonium salts thereof, are prepared by decarboxylation of a phenthiazine-10-carboxylate of an amino alcohol with the general formula:
hvor X er som foran definert, ved å oppvarme carboxylatet hensiktsmessig ved en temperatur over 100°C, og fortrinnsvis mellom 150 og 220°C, og eventuelt omdanne den sSik oppnådde fenthiazinbase til et syreaddisjons- eller kvaternært amtmonram-salt. Det er ingen fordel å arbeide ved høye-re temperaturer, som eventuelt kan for-årsake misfarvning av reaksjonsproduk-tene. where X is as defined above, by heating the carboxylate appropriately at a temperature above 100°C, and preferably between 150 and 220°C, and optionally converting the thus obtained phenthiazine base into an acid addition or quaternary amtmonram salt. There is no advantage to working at higher temperatures, which could possibly cause discolouration of the reaction products.
Reaksjonen kan utføres med fenthiazin-10-carboxylatet alene, d.v.s. uten et fortynningsmiddel, eller i et inert medium slik som flytende parafin, difenyl- eller difenyloxyd, eller i de klassiske fortyn-ningsmidler for decarboxylertnger, slik som f. eks. kinolin eller svake baser. The reaction can be carried out with the phenthiazine-10-carboxylate alone, i.e. without a diluent, or in an inert medium such as liquid paraffin, diphenyl or diphenyl oxide, or in the classic diluents for decarboxylation, such as e.g. quinoline or weak bases.
Utgangsmaterialene med formel III kan oppnås ved kjente metoder. For eksempel kan de fremstilles ved innvirkning av et halogenid (eller en ester) av en fenthiazin-10-carboxylsyre på 3-dimethylamino-2-methylpropan-l-ol, ved innvirkning av et halogenalkylfenthiazin-10-carboxylat på dimethyliamin, eller ved innvirkning av et egnet fenthiazin på klorcarbonatet av 3-dimethylamino-2-methylpropan-1 -ol. The starting materials of formula III can be obtained by known methods. For example, they can be prepared by the action of a halide (or an ester) of a phenthiazine-10-carboxylic acid on 3-dimethylamino-2-methylpropan-l-ol, by the action of a haloalkylphenthiazine-10-carboxylate on dimethyliamine, or by the action of a suitable phenthiazine on the chlorocarbonate of 3-dimethylamino-2-methylpropan-1-ol.
En særlig fordelaktig fremgangsmåte for å utføre fremgangsmåten ifølge opp-finnelsen som1 ikke krever isolering i ren tilstand av utgangsmaterialet i formel III, består i å oppvarme et fenthiazin-10-carboxylat med formelen: A particularly advantageous method for carrying out the method according to the invention which does not require isolation in a pure state of the starting material in formula III consists in heating a phenthiazine-10-carboxylate of the formula:
hvor X er som foran definert og Q betegner resten av en flyktig alkohol, med 3-dlmet-hylammo-2-meth<y>l<p>ro<p>an-1 -ol. Reaks j o-nen foregår i to trinn som kan finne sted samtidig og som består av elimineringen av alkohol for å gi et carboxylat med formel where X is as defined above and Q denotes the residue of a volatile alcohol, with 3-dlmeth-hylammo-2-meth<y>l<p>ro<p>an-1 -ol. The reaction takes place in two steps which may take place simultaneously and which consist of the elimination of alcohol to give a carboxylate of formula
III, og elimineringen av carbondioxyd fra caboxylatet for å gi det ønskede fenthiazin-derivat med formel I. III, and the elimination of carbon dioxide from the carboxylate to give the desired phenthiazine derivative of formula I.
De optisk aktive isomerer kan oppnås ved spaltning av racematene, f. eks. som beskrevet i eksemplene 18 og 19 i patent nr. 93 257. The optically active isomers can be obtained by cleavage of the racemates, e.g. as described in examples 18 and 19 of patent no. 93,257.
Eksempel 1. Example 1.
3 - dimethylamino - 2 - me thyl -1 -pr opyl - 3-dimethylamino-2-methyl-1-propyl-
(3-methoxyfenthiazln-lO) -carboxylat (10 (3-Methoxyphenthiazln-10)-carboxylate (10
g) oppvarmes progressivt i en time fra 175° til 215°C inntil utvikling av carbondioksyd g) is heated progressively for one hour from 175° to 215°C until evolution of carbon dioxide
opphører. Det oljeaktige produkt som oppnås oppløses i ether, og den etherlske opp-løsning ekstraheres flere ganger med for-tynnet saltsyre. Etter å ha blitt gjort alka-lisk, ekstrahering med ether og fordamp-ning av oppløsningsmidlet, destilleres det oppnådde produkt under redusert trykk. 3- (3-methoxy-10-fenthiazinyl) -2-methyl-1-dimethylaminopropan (4,6 g), kokepunkt 187—191°C/0,2 mm Hg, og smeltepunkt 101—102°C, oppnås. ceases. The oily product that is obtained is dissolved in ether, and the ethereal solution is extracted several times with dilute hydrochloric acid. After making alkaline, extracting with ether and evaporating the solvent, the product obtained is distilled under reduced pressure. 3-(3-methoxy-10-phenthiazinyl)-2-methyl-1-dimethylaminopropane (4.6 g), boiling point 187-191°C/0.2 mm Hg, and melting point 101-102°C, is obtained.
Utgangsesteren kan oppnås ved kon-densasjon av 3-dimethylamino-2-methyl-propan-l-ol med 3-methoxyfenthiazin-10-carbonylklorid, selv fremstilt ved innvirkning av fosgen på 3-methoxyfemthiazin i nærvær av pyridin. The starting ester can be obtained by condensation of 3-dimethylamino-2-methyl-propan-1-ol with 3-methoxyphenthiazin-10-carbonyl chloride, itself prepared by the action of phosgene on 3-methoxyphenthiazine in the presence of pyridine.
Utgangsesterens hydrogenklorid smelter ved 195°C og dens methjodid ved 161°C. The hydrogen chloride of the starting ester melts at 195°C and its methiodide at 161°C.
Eksempel 2. Example 2.
3-dimethylamino-2-methyl-l-propyl-(3-ethylfenthiazin-lO)-carboxylat (9 g) oppvarmes i en time fra 175° til 230°C og behandles derpå som i eksempel 1. Der oppnås til slutt 3-(3-ethyl-10i-fenthiazinyl) -2 - methyl-1 - dlmethylaminopropan (6,15 g), kokepunkt 177—179°C/0,17 mm Hg. Det tilsvarende hydrogenklorid smelter ved 160—163°C. 3-dimethylamino-2-methyl-1-propyl-(3-ethylphenthiazine-10)-carboxylate (9 g) is heated for one hour from 175° to 230°C and then treated as in example 1. There is finally obtained 3- (3-ethyl-10i-phenthiazinyl)-2-methyl-1-dlmethylaminopropane (6.15 g), bp 177-179°C/0.17 mm Hg. The corresponding hydrogen chloride melts at 160-163°C.
Utgangsesteren kan oppnås som i eksempel 1 ved bruk av 3-ethylfenthiazin-lO-carbonylklorid, selv fremstilt ved innvirkning av fosgen på 3-ethylfenthlazin. Hyd-rogenkloridet av utgangsesteren smelter ved 170—172° C og methjodidet ved 158°C (spaltning). The starting ester can be obtained as in example 1 using 3-ethylphenthiazine-10-carbonyl chloride, itself prepared by the action of phosgene on 3-ethylphenthlazine. The hydrogen chloride of the starting ester melts at 170-172°C and the methiodide at 158°C (decomposition).
Ved å følge fremgangsmåten beskrevet i foregående eksempel og bruke de egnede fenthiazin-10-carboxylater som utgangs-materiåiler kan følgende forbindelser fremstilles: 3- (3-methyl-lO-fenthiazinyl) -2-methyl-l-dimethylaminopropan, smeltepunkt 75°C. By following the procedure described in the previous example and using the suitable phenthiazine-10-carboxylates as starting materials, the following compounds can be prepared: 3-(3-methyl-10-phenthiazinyl)-2-methyl-1-dimethylaminopropane, melting point 75°C .
3-(3-n-propyl-10-fenthiazinyl)-2-methyl-l-dimethylaminopropan, hvis sure ma-lea t smelter ved 13 3 ° C. 3-(3-n-propyl-10-phenthiazinyl)-2-methyl-1-dimethylaminopropane, whose acid maleate melts at 13 3 °C.
3-(3-ethoxy-10-fenth,iazinyl)-2-methyl-l-dimethylaminopropan, hvis sure ma-leat' smelter ved 110°C. 3-(3-ethoxy-10-phenthiazinyl)-2-methyl-1-dimethylaminopropane, whose acid maleates melt at 110°C.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19671536625 DE1536625C3 (en) | 1967-08-25 | 1967-08-25 | Hanging receptacle for documents |
Publications (1)
Publication Number | Publication Date |
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NO122299B true NO122299B (en) | 1971-06-14 |
Family
ID=5675848
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NO327868A NO122299B (en) | 1967-08-25 | 1968-08-21 |
Country Status (6)
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AT (1) | AT291191B (en) |
BE (1) | BE719840A (en) |
FR (1) | FR1577104A (en) |
GB (1) | GB1228255A (en) |
NO (1) | NO122299B (en) |
SE (1) | SE341817B (en) |
Families Citing this family (1)
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DE2808482C2 (en) * | 1978-02-28 | 1986-06-12 | Elba-Ordner-Fabrik Kraut & Meienborn GmbH & Co., 5600 Wuppertal | Identification tab |
-
1968
- 1968-04-23 FR FR1577104D patent/FR1577104A/fr not_active Expired
- 1968-07-23 AT AT07091/68A patent/AT291191B/en not_active IP Right Cessation
- 1968-08-09 SE SE1076068A patent/SE341817B/xx unknown
- 1968-08-14 GB GB1228255D patent/GB1228255A/en not_active Expired
- 1968-08-21 NO NO327868A patent/NO122299B/no unknown
- 1968-08-23 BE BE719840D patent/BE719840A/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
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AT291191B (en) | 1971-06-15 |
SE341817B (en) | 1972-01-17 |
BE719840A (en) | 1969-02-03 |
GB1228255A (en) | 1971-04-15 |
FR1577104A (en) | 1969-08-01 |
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