CH493520A - Antiviral isoquinoline derivs esp 1-phenoxymethyl-3 4 - Google Patents
Antiviral isoquinoline derivs esp 1-phenoxymethyl-3 4Info
- Publication number
- CH493520A CH493520A CH1738465A CH1738465A CH493520A CH 493520 A CH493520 A CH 493520A CH 1738465 A CH1738465 A CH 1738465A CH 1738465 A CH1738465 A CH 1738465A CH 493520 A CH493520 A CH 493520A
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- dihydroisoquinoline
- phenoxymethyl
- hydrogen
- hydrochloride
- Prior art date
Links
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title 2
- 230000000840 anti-viral effect Effects 0.000 title 1
- 239000002253 acid Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 6
- 150000007513 acids Chemical class 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract 4
- 238000000034 method Methods 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- VTHPMBVZXKLEQS-UHFFFAOYSA-N 1-(phenoxymethyl)-3,4-dihydroisoquinoline Chemical class N=1CCC2=CC=CC=C2C=1COC1=CC=CC=C1 VTHPMBVZXKLEQS-UHFFFAOYSA-N 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 239000012024 dehydrating agents Substances 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 3
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 239000012442 inert solvent Substances 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 abstract description 6
- 230000003000 nontoxic effect Effects 0.000 abstract description 6
- 241000712461 unidentified influenza virus Species 0.000 abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 239000003443 antiviral agent Substances 0.000 abstract 1
- -1 alkyl radicals Chemical class 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002585 base Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- YHDHSSBAHPSMPM-UHFFFAOYSA-N 1-[(4-chlorophenoxy)methyl]-3,4-dihydroisoquinoline Chemical compound C1=CC(Cl)=CC=C1OCC1=NCCC2=CC=CC=C12 YHDHSSBAHPSMPM-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
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- 239000003960 organic solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- XWPQCMLTRJWFKB-UHFFFAOYSA-N 1-[(4-chlorophenoxy)methyl]-3,4-dihydroisoquinoline;hydrochloride Chemical compound Cl.C1=CC(Cl)=CC=C1OCC1=NCCC2=CC=CC=C12 XWPQCMLTRJWFKB-UHFFFAOYSA-N 0.000 description 2
- XUMWBPBVHHGEFI-UHFFFAOYSA-N 1-[(4-fluorophenoxy)methyl]-3,4-dihydroisoquinoline Chemical compound C1=CC(F)=CC=C1OCC1=NCCC2=CC=CC=C12 XUMWBPBVHHGEFI-UHFFFAOYSA-N 0.000 description 2
- NOCSCLPQKGWLDB-UHFFFAOYSA-N 1-[(4-methoxyphenoxy)methyl]-3,4-dihydroisoquinoline Chemical compound C1=CC(OC)=CC=C1OCC1=NCCC2=CC=CC=C12 NOCSCLPQKGWLDB-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
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- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
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- IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
(A) Cpds. of general formula (I):- where R1,R2,R3 = H, alkyl (1-4 C) X = H, alkyl (1-5 C), alkoxy (1-5 C), F, Cl, Br (B) Salts of (I) with non-toxic acids. (I) are non-toxic antiviral agents (active by oral or parenteral admin.), partic. active against the influenza virus. (I; R1=R2=R3=H, X=MeO (part. p-MeO)).
Description
Verfahren zur Herstellung von 1-Phenoxymethyl-3,4-dihydroisochinolinen und ihren Säureanlagerungssalzen
Gegenstand der Erfindung ist ein Verfahren zur Her stellung von 1 -Phenoxymethyl-3,4-dihydroisochinolinei der Formel
EMI1.1
in der R1, R und R3 Wasserstoff oder Alkylreste mit 1 bis 4 Kohlenstoffatomen bedeuten und X Wasserstoff, ein
Alkylrest mit 1 bis 5 Kohlenstoffatomen oder Alkoxyrest mit 1 bis 5 Kohlenstoffatomen, Fluor, Chlor oder Brom ist.
Repräsentative Verbindungen dieser Art sind z.B. 1 -(p-Chlorphenoxymethyl)- 3,4- dihydroisochinolin, 1-(p- - Fluorphenoxymethyl)- 3,4-dihydroisochinolin und 1- (p- -Methoxyphenoxymethyl)-3,4 - dihydroisochinolin sowie deren nicht-toxische, pharmazeutisch geeignete Säurean lagerungssalze, wie die Hydrohalogenide. Diese Verbin dungen besitzen ausgezeichnete Wirksamkeit gegen Viren, insbesondere gegen den Influenza-Virus.
Das erfindungsgemässe Verfahren ist dadurch gekenn zeichnet, dass man ein entsprechendes N-Phenoxyacetyl -p-phenyläthylamin, vorzugsweise in einem inerten orga nischen LösungsmitteL mit einem stark sauren Dehydrati sierungsmittel in Berührung bringt. Es handelt sich hier vor allem um Dehydratisierungsmittel, wie sie bei der Bischler-Napieralski-Umsetzung verwendet werden.
Die erfindungsgemässe Cyclisierung des Amids tritt nach der folgenden Gleichung ein:
EMI1.2
In diesem Schema haben R1, R und R3 sowie X die oben angegebene Bedeutung. Bevorzugte saure, cyclisierend wirkende Dehydratisierungsmittel im erfindungsgemässen Verfahren sind z.B. Phosphorpentoxid, 85%ige Polyphosphorsäure, Polyphosphonsäure, Phosphorpentachlorid, Aluminiumchlorid, Zinkchlorid, Phosphoroxychlorid, Phosphoroxybromid, Thionylchlorid und ähnliche. Die Umsetzung wird normalerweise in dem oben genannten Lösungsmittel bei Temperaturen zwischen etwa 150 und etwa 1300C etwa 1 bis 12 Stunden lang durchgeführt. Im erfindungsgemässen Verfahren können aromatische Kohlenwasserstofflösungsmittel, wie Benzol, Toluol, Xylol und Nitrobenzol verwendet werden.
Diese Lösungsmittel werden bevorzugt, doch sind auch halogenierte Kohlenwasserstofflösungsmittel, wie Methylenchlorid, Äthylendichlorid, Chloroform, Tetrachlorkohlenstoff und s-Tetrachloräthan brauchbar. Es ist auch möglich, einen Überschuss des Dehydratisierungsmittels, z.B. 85%ige Polyphosphor- oder Polyphosphonsäure, als Reaktionsmedium zu verwenden, und der Zusatz eines organischen Lösungsmittels unterbleibt dann. In beiden Fällen kann nach der Beendigung der Umsetzung die gewünschte Dihydroisochinolinbase entweder als solche aus dem Reaktionsgemisch isoliert oder zuerst in ein Säure nnlagerungssalz umgewandelt werden, das dann nach üblichen Methoden aus dem Gemisch gewonnen wird.
Das Säureanlagerungssalz kann dann gereinigt und falls es pharmazeutisch geeignet ist, als solches verwendet werden, oder man kann es in die freie Base oder in ein pharmazeutisch geeignetes Säureanlagerungssalz umwandeln, wenn dies erwünscht ist.
Das N-Phenoxyacetyl-1(3-phenyläthylamin, das als Ausgangsstoff verwendet wird, kann leicht nach üblichen Methoden hergestellt werden, und zwar entweder aus der entsprechenden p-Phenyläthylaminbase und einem entsprechenden Phenoxyacetylhalogenid oder aus einem entsprechenden Phenoxyessigsäureester. Von beiden Möglichkeiten wird die vom Phenoxyacetylhalogenid (z.B. p -Chlorphenoxyacetylchlorid) ausgehende bevorzugt, da bei diesem Verfahren nur die beiden Reaktionsteilnehmer in einem aromatischen Kohlenwasserstofflösungsmittel, wie Benzol, unter Rückfluss erhitzt werden müssen, wobei ein Überschuss an ,(3-Phenyläthylamin zur Entfernung des Halogenwasserstoff-Nebenprodukts verwendet wird.
Zur Herstellung der neuen pharmazeutisch geeigneten Säureanlagerungssalze können Säuren verwendet werden, die nicht-toxische Salze bilden, d.h. Säuren mit pharmakologisch geeigneten Anionen. Bevorzugte Säuren sind Chlorwasserstoff-, Bromwasserstoff- und Jodwasserstoffsäure, Salpetersäure, Schwefelsäure, Phosphorsäure, Essigsäure, Milchsäure, Zitronensäure, Weinsäure, Oxalsäure, Benzoesäure, Bernsteinsäure, Maleinsäure, Methansulfonsäure, Äthansulfonsäure, Benzolsulfonsäure u.
p-Toluolsulfonsäure.
Wie zuvor angegeben, sind die neuen 1-Phenoxymethyl-3,4-Dihydroisochinoline gegen Viren wirksam, insbesondere gegen den Influenza-Virus. Z.B. wurde gefunden, dass die typische und bevorzugte Verbindung 1 -(p-Chlorphenoxymethyl) -3,4- dihydroisochinolin-Hydrochlorid eine wesentliche Verlängerung der mittleren Überlebenszeit bei Mäusen bewirkte, die mit dem Influenza Virus PR8 infiziert waren, ohne dass unerwünschte Nebenwirkungen beobachtet wurden. Dazu kommt, dass die erfindungsgemäss herstellbaren Verbindungen als gegen Viren wirksame Mittel sowohl oral wie auch parenteral verabreicht werden können. Im allgemeinen werden sie in Dosen von etwa 1 mg bis etwa 25 mg/kg Körpergewicht/Tag angewendet, obwohl Abweichungen selbstverständlich möglich sind und vom Gewicht des behandelten Menschen oder Tieres und dem gewählten Verabreichungsweg abhängig sind.
Die Verfahrensprodukte können entweder allein oder zusammen mit pharmazeutisch geeigneten Trägern in der oben angegebenen Weise verabreicht werden. Die Verabreichung kann in Einzel- oder Mehrfachdosierungen erfolgen. Mit anderen Worten, die Verfahrensprodukte können in einer Vielzahl verschiedener Dosierungsformen zur Anwendung kommen, d.h. sie können mit verschiedenen pharmazeutisch geeigneten inerten Trägern in die Form von Tabletten, Kapseln, Lutschpastillen, Pudern, Sprays (für die oberen Atemwege), wässrigen Suspensionen, injizierbaren Lösungen, Elixieren, Sirups u.ä.
gebracht werden. Solche Träger umfassen vor allem feste Verdünnungs- oder Füllmittel, sterile wässrige Medien und verschiedene nicht-toxische organische Lösungsmittel usw. Darüber hinaus können die oral zu verabreichenden Präparate in geeigneter Weise gesüsst und/oder mit Geruchs- und Geschmacksstoffen versetzt werden. Mittel für diese Zwecke sind hinreichend bekannt. In den oben genannten Präparaten sind die neuen, therapeutisch wirksamen Verbindungen in der Regel in einer Konzentration von etwa 0,5 bis etwa 90 Gew.-% des Gesamtpräparates vorhanden, d.h. in Mengen, die ausreichen, um die oben angegebene gewünschte Einheitsdosis bereitzustellen.
Für die orale Verabreichung eignen sich Tabletten, die verschiedene Träger, wie Natriumzitrat, Kalziumkarbonat und Dikalziumphosphat, zusammen mit verschiedenen, den Zerfall der Tabletten bewirkenden Mitteln enthalten, wie Stärke und vorzugsweise Kartoffel- oder Tapiokastärke, Alginsäure und bestimmte komplexe Silikate sowie Bindemittel, wie Polyvinylpyrrolidon, Saccharose, Gelatine und Acacia. Bei der Tablettierung sind ferner Gleitmittel wie Magnesiumstearat, Natriumlaurylsulfat und Talkum oft sehr nützlich. Feste Gemische ähnlicher Art können auch als Füllstoffe für weiche und harte gefüllte Gelatinekapseln verwendet werden. Bevorzugte Materialien in dieser Hinsicht enthalten ferner Laktose oder Milchzucker sowie hochmolekulare Polyäthylenglycole.
Wenn wässrige Suspensionen und/oder Elixiere für die orale Verabreichung gewünscht werden, kann der wesentliche wirksame Bestandteil mit verschiedenen Süss- oder Geschmacksstoffen, färbenden bzw. Farbstoffen und, falls erwünscht, Emulgier- und / oder Suspendiermitteln sowie mit Verdünnungsmitteln, wie Wasser, Äthanol, Propylenglycol, Glycerin, und deren Kombinationen vermischt werden.
Für die parenterale Verabreichung können Lösungen der l-Phenoxymethyl-3,4-dihydroisochinolinbase in Sesam- oder Erdnussöl, in wässrigem Propylenglycol oder in N,N-Dimethylformamid verwendet werden, ferner sterile wässrige Lösungen der entsprechenden wasserlöslichen, nicht-toxischen, oben genannten Salze. Die wässrigen Lösungen sollten, falls notwendig, entsprechend gepuffert und das flüssige Verdünnungsmittel mit ausreichend Kochsalz oder Glucose isotonisch gemacht sein.
Diese wässrigen Lösungen sind insbesondere für die intravenöse, intramuskuläre und intraperitoneale Verabreichung geeignet.
Es ist klar, dass bei der Herstellung der injizierbaren Lösungen Vorsorge getroffen werden muss, dass die Endprodukte in steriler Form erhalten werden.
Die folgenden Beispiele erläutern das erfindungsgemässe Verfahren.
Beispiel I
Zu einer warmen Lösung (800C) aus 56 g (0,193 Mol) von N-(p-Chlorphenoxyacetyl)-p - phenyläthyl-amin in 600 ccm trockenem Toluol wurden 165 g (1,162 Mol) Phosphorpentoxyd gegeben, und zwar in Anteilen über einen Zeitraum von 30 Minuten, wobei man heftig rührte.
Nach Beendigung der Zugabe wurde das Reaktionsgemisch unter Rühren 3 Stunden unter Rückfluss erhitzt und dann auf Raumtemperatur gekühlt. Dann wurde das überschüssige Toluol vom festen Material abdekantiert und letzteres unter Rühren zu einem Liter Eiswasser gegeben. Die erhaltene wässrige Lösung, die das rohe 1-(p- -Chlorphenoxymethyl) -3,4- dihydroisochinolin enthielt, wurde mit 200 ccm Diäthyläther extrahiert, um das restliche Toluol zu entfernen, und dann mit 500 ccm konzentrierter Chlorwasserstoffsäure behandelt, worauf man das Hydrochlorid der Dihydroisochinolinverbindung erhielt.
Das gewünschte Produkt fiel fast unmittelbar aus der Mischung aus, und nach 2stündigem Stehen wurde es abgesaugt und anschliessend aus Methanol-Chlorwasserstoffsäure (Volumenverhältnis 1: 4) umkristallisiert. Man erhielt 37 g (62%) 1 -(p-Chlorphenoxymethyl)-3,4-dihydroisochinolinhydrochlorid in Form farbloser Nadeln vom Schmelzpunkt 205 bis 2070C.
Analyse für ClGHl6Cl2NO:
Berechnet: C 62,33 H 4,91 N 4,54
Gefunden: C 62,60 H 5,00 N 4,47 Durch Behandlung des Hydrochlorids mit 5n NaOH erhielt man die freie Base 1-(p-Chlorphenoxymethyl)-3,4 -dihydroisochinolin.
Beispiel 2
Nach dem Verfahren des Beispiels 1 erhielt man unter Verwendung von N-(p-Fluorphenoxyacetyl)-8-phenyl- äthylamin als Ausgangsstoff 1-( Fluorphenoxymethyl)- -3,4-dihydroisochinolin als Endprodukt. Das Hydrochlorid schmolz bei 201 bis 2030C.
Analyse für Cl6Hl5CIFNO:
Berechnet: F 6,51 Gefunden: F 6,53 Die Umwandlung des Hydrochlorids in die freie Base.
1 -(p-Fluorphenoxymethyl)-3,4-dihydroisochinolin, erfolgte wie in Beispiel 1.
Beispiel 3
Die nachfolgend mit ihren Schmelzpunkten aufgeführten Produkte wurden nach dem Verfahren des Beispiels 1 aus der entsprechenden N-Phenoxyacetyl-j3-phe- nyläthylaminbase und Phosphorpentoxyd hergestellt. In denjenigen Fällen, in denen das Hydrochlorid zu löslich war, um aus der Lösung auszufallen, wie es beim Hydrochlorid des 1 -(p-Methoxyphenoxymethyl)-3,4-dihydroiso- chinolins der Fall war, wurde die Lösung mit 50%igem wässrigem Natriumhydroxyd basisch gemacht und dann zur Gewinnung der Base mit Diäthyläther extrahiert. Bei Zugabe von ätherischem Chlorwasserstoff zum Extrakt fiel das gewünschte Hydrochlorid als kristalliner Niederschlag aus.
1-Phenoxymethyl-3,4-dihydroisochinolin Hydrochlorid, F = 210-2120C, l-(p-Methylphenoxymethyl)-3,4-dihydroisochinolin Hydrochlorid, F = 188-1890C, 1-(1 -Phenoxyäthyl)-3,4-dihydroisochinolin Hydrochlorid, F = l60-1620C, I-Phenoxymethyl-3-methyl-3,4-dihydroisochinolin Hydrochlorid, F = 159-1610C, 1-Phenoxymethyl-4-methyl-3,4-dihydroisochinolin Hydrochlorid, F = 207-2080C,
1 -(m-Methylphenoxymethyl)-3,4-dihydroisochinolin Hydrochlorid, F = 186-1880C, 1 -(m-Chlorphenoxymethyl)-3,4-dihydroisochinolin Hydrochlorid, F = l92-1930C, 1 -(o-Fluorphenoxymethyl)-3,4-dihydroisochinolin Hydrochlorid (Monohydrat), F = 147-1490C, 1-(m-Fluorphenoxymethyl)-3,4-dihydroisochinolin Hydrochlorid (Monohydrat), F = 190-1950C, 1 -[p-(n-Butoxy)phenoxymethyl]-3,4-dihydroisochinolin Hydrochlorid, F = 172-1730C, 1 -(p-tert-Butylphenoxymethyl)-3,4-dihydroisochinolin Hydrochlorid, F = 213-215 C, I-(p-Bromphenoxymethyl)-3,4-dihydroisochinolin Hydrochlorid,
F = 2070C, 1 -[1 -(p-Chlorphenoxy)äthyl]-3,4-dihydroisochinolin Hydrochlorid (Monohydrat), F = 850C, 1 -(p-Methoxyphenoxymethyl)-3,4-dihydroisochinolin Hydrochlorid, F = 1870C.
Die Behandlung der oben genannten Hydrochloride mit 5 n NaOH ergibt die entsprechenden freien 1-Phenoxy- methyl-3,4-dihydroisochinolinbasen in reiner Form.
Beispiel 4
Die in der nachfolgenden Tabelle aufgeführten Verbindungen wurden aus dem entsprechenden N-Phenoxy acetyl-r-phenyläthylamin und Phosphorpentoxyd nach dem Verfahren des Beispiels 1 erhalten.
EMI3.1
R2 R3 RJ X H H H 3-Br H H H 2-OCH3 CH3 H H 2-C1 H C2H5 H 2-F H H C2115 H CH3 CH3 CH3 2-CH5 C2H. H H H H H H 3-C2H H H C2H2 4-Br H H H 4-(n-C2H11) H n-C3H7 H H n-C4H!,
H H 3-C1 H H n-C4Hn 3-OC3H7(i) iso-C3H7 H H 2-Br H iso-C4H9 CH3 H H H iso-CsH, H H H H 3-C2H5 R1 R CH3 CH2 H 3-F H C H5 CM5 4-C1 H H CH3 2-OC4H9 CH3 H CH2 3-Br n-C4H0 H H H H CH3 H 3-(iso-C4Hs) H H H 4-OC5H,
Beispiel 5
Das Hydrobromid des 1-(p-Chlorphenoxymethyl)-3,4 -dihydroisochinolins wird durch Lösen der freien Base in einer wässrigen Lösung erhalten, die die moläquivalente Menge in Bromwasserstoffsäure enthält.
Die erhaltene Lösung wird unter vermindertem Druck zur Trockne eingedampft, worauf man reines kristallines 1-(p-Chlorphenoxymethyl)-3,4-dihydroisochinolin Hydrobromid erhält.
Beispiel 6
Andere Säureanlagerungssalze der neuen l-Phenoxy- methyl-3,4-dihydroisochinoline werden nach dem Verfahren des Beispiels 5 unter Verwendung der geeigneten freien Basen nach Beispiel 1-4 und Chlorwasserstoff-, Bromwasserstoff- und Jodwasserstoffsäure, Salpetersäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Äthansulfonsäure, Benzolsulfonsäure, p-Toluolsulfonsäure, Essigsäure, Milchsäure, Zitronensäure, Weinsäure, Oxalsäure, Benzoesäure, Bernsteinsäure und Maleinsäure hergestellt.
Process for the preparation of 1-phenoxymethyl-3,4-dihydroisoquinolines and their acid addition salts
The invention relates to a process for the manufacture of 1-phenoxymethyl-3,4-dihydroisoquinolinei of the formula
EMI1.1
in which R1, R and R3 are hydrogen or alkyl radicals having 1 to 4 carbon atoms and X is hydrogen
Alkyl radical with 1 to 5 carbon atoms or alkoxy radical with 1 to 5 carbon atoms, fluorine, chlorine or bromine.
Representative compounds of this type are e.g. 1 - (p-Chlorophenoxymethyl) - 3,4-dihydroisoquinoline, 1- (p- - Fluorophenoxymethyl) - 3,4-dihydroisoquinoline and 1- (p- -Methoxyphenoxymethyl) -3,4 - dihydroisoquinoline and their non-toxic, pharmaceutical suitable acid storage salts, such as the hydrohalides. These connec tions have excellent activity against viruses, especially against the influenza virus.
The process according to the invention is characterized in that a corresponding N-phenoxyacetyl-p-phenylethylamine, preferably in an inert organic solvent, is brought into contact with a strongly acidic dehydrating agent. These are mainly dehydrating agents such as those used in the Bischler-Napieralski reaction.
The cyclization of the amide according to the invention occurs according to the following equation:
EMI1.2
In this scheme, R1, R and R3 and X have the meaning given above. Preferred acidic, cyclizing dehydrating agents in the process according to the invention are e.g. Phosphorus pentoxide, 85% polyphosphoric acid, polyphosphonic acid, phosphorus pentachloride, aluminum chloride, zinc chloride, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride and the like. The reaction is normally carried out in the above-mentioned solvent at temperatures between about 150 and about 130 ° C. for about 1 to 12 hours. In the process of the present invention, aromatic hydrocarbon solvents such as benzene, toluene, xylene and nitrobenzene can be used.
These solvents are preferred, but halogenated hydrocarbon solvents such as methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride and s-tetrachloroethane are also useful. It is also possible to use an excess of the dehydrating agent, e.g. 85% polyphosphoric or polyphosphonic acid to be used as the reaction medium, and the addition of an organic solvent is then omitted. In both cases, after the reaction has ended, the desired dihydroisoquinoline base can either be isolated as such from the reaction mixture or first converted into an acid storage salt which is then obtained from the mixture by customary methods.
The acid addition salt can then be purified and, if pharmaceutically acceptable, used as such, or it can be converted to the free base or to a pharmaceutically acceptable acid addition salt if so desired.
The N-phenoxyacetyl-1 (3-phenylethylamine, which is used as starting material, can easily be prepared by customary methods, either from the corresponding p-phenylethylamine base and a corresponding phenoxyacetyl halide or from a corresponding phenoxyacetic acid ester Phenoxyacetyl halide (e.g. p -chlorophenoxyacetyl chloride) is preferred because in this process only the two reactants need to be refluxed in an aromatic hydrocarbon solvent such as benzene, an excess of (3-phenylethylamine being used to remove the hydrogen halide by-product.
In preparing the new pharmaceutically acceptable acid addition salts, acids can be used which form non-toxic salts, i. Acids with pharmacologically suitable anions. Preferred acids are hydrochloric, hydrobromic and hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, succinic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and the like.
p-toluenesulfonic acid.
As previously indicated, the new 1-phenoxymethyl-3,4-dihydroisoquinolines are effective against viruses, especially the influenza virus. E.g. it was found that the typical and preferred compound 1 - (p-chlorophenoxymethyl) -3,4-dihydroisoquinoline hydrochloride caused a substantial increase in the mean survival time in mice infected with the influenza virus PR8 without any undesirable side effects being observed. In addition, the compounds which can be prepared according to the invention can be administered both orally and parenterally as agents effective against viruses. In general, they are used in doses of about 1 mg to about 25 mg / kg body weight / day, although variations are of course possible and depend on the weight of the human or animal treated and the route of administration chosen.
The products of the process can be administered either alone or together with pharmaceutically suitable carriers in the manner indicated above. Administration can take place in single or multiple doses. In other words, the products of the process can be used in a variety of different dosage forms; they can be mixed with various pharmaceutically suitable inert carriers in the form of tablets, capsules, lozenges, powders, sprays (for the upper respiratory tract), aqueous suspensions, injectable solutions, elixirs, syrups and the like.
to be brought. Such carriers include above all solid diluents or bulking agents, sterile aqueous media and various non-toxic organic solvents, etc. In addition, the preparations to be administered orally can be suitably sweetened and / or smelled and flavored. Means for this purpose are well known. In the above-mentioned preparations, the new, therapeutically active compounds are generally present in a concentration of about 0.5 to about 90% by weight of the total preparation, i.e. in amounts sufficient to provide the desired unit dose noted above.
For oral administration tablets are suitable which contain various carriers, such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various agents which cause the disintegration of the tablets, such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates and binders such as polyvinylpyrrolidone , Sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful in tableting. Solid mixtures of a similar type can also be used as fillers for soft and hard filled gelatin capsules. Preferred materials in this regard also contain lactose or milk sugar and high molecular weight polyethylene glycols.
If aqueous suspensions and / or elixirs for oral administration are desired, the essential active ingredient can be mixed with various sweeteners or flavorings, coloring agents and, if desired, emulsifying and / or suspending agents and with diluents such as water, ethanol, Propylene glycol, glycerin, and their combinations are mixed.
For parenteral administration, solutions of the l-phenoxymethyl-3,4-dihydroisoquinoline base in sesame or peanut oil, in aqueous propylene glycol or in N, N-dimethylformamide can be used, as well as sterile aqueous solutions of the corresponding water-soluble, non-toxic salts mentioned above . The aqueous solutions should, if necessary, be appropriately buffered and the liquid diluent should be made isotonic with sufficient common salt or glucose.
These aqueous solutions are particularly suitable for intravenous, intramuscular and intraperitoneal administration.
It is clear that when preparing the injectable solutions, care must be taken to ensure that the final products are obtained in sterile form.
The following examples explain the process according to the invention.
Example I.
To a warm solution (800C) of 56 g (0.193 mol) of N- (p-chlorophenoxyacetyl) -p-phenylethylamine in 600 ccm of dry toluene, 165 g (1.162 mol) of phosphorus pentoxide were added, in portions over a period of time of 30 minutes, stirring vigorously.
After the addition was complete, the reaction mixture was refluxed with stirring for 3 hours and then cooled to room temperature. The excess toluene was then decanted off from the solid material and the latter was added to one liter of ice water with stirring. The resulting aqueous solution containing the crude 1- (p- -chlorophenoxymethyl) -3,4-dihydroisoquinoline was extracted with 200 cc of diethyl ether to remove the remaining toluene, and then treated with 500 cc of concentrated hydrochloric acid, whereupon the Hydrochloride of dihydroisoquinoline compound was obtained.
The desired product precipitated out of the mixture almost immediately, and after standing for 2 hours it was filtered off with suction and then recrystallized from methanol-hydrochloric acid (volume ratio 1: 4). 37 g (62%) of 1 - (p-chlorophenoxymethyl) -3,4-dihydroisoquinoline hydrochloride were obtained in the form of colorless needles with a melting point of 205 ° to 2070 ° C.
Analysis for ClGHl6Cl2NO:
Calculated: C 62.33 H 4.91 N 4.54
Found: C 62.60 H 5.00 N 4.47 Treatment of the hydrochloride with 5N NaOH gave the free base 1- (p-chlorophenoxymethyl) -3,4-dihydroisoquinoline.
Example 2
Following the procedure of Example 1, using N- (p-fluorophenoxyacetyl) -8-phenylethylamine as the starting material, 1- (fluorophenoxymethyl) -3,4-dihydroisoquinoline was obtained as the end product. The hydrochloride melted at 201 to 2030C.
Analysis for Cl6Hl5CIFNO:
Calculated: F 6.51 Found: F 6.53 The conversion of the hydrochloride to the free base.
1 - (p-Fluorophenoxymethyl) -3,4-dihydroisoquinoline was carried out as in Example 1.
Example 3
The products listed below with their melting points were prepared by the method of Example 1 from the corresponding N-phenoxyacetyl-j3-phenylethylamine base and phosphorus pentoxide. In those cases in which the hydrochloride was too soluble to precipitate out of solution, as was the case with the hydrochloride of 1 - (p-methoxyphenoxymethyl) -3,4-dihydroisoquinoline, the solution was made with 50% aqueous Sodium hydroxide made basic and then extracted with diethyl ether to obtain the base. When ethereal hydrogen chloride was added to the extract, the desired hydrochloride precipitated out as a crystalline precipitate.
1-phenoxymethyl-3,4-dihydroisoquinoline hydrochloride, F = 210-2120C, l- (p-methylphenoxymethyl) -3,4-dihydroisoquinoline hydrochloride, F = 188-1890C, 1- (1-phenoxyethyl) -3,4- dihydroisoquinoline hydrochloride, F = 160-1620C, I-phenoxymethyl-3-methyl-3,4-dihydroisoquinoline hydrochloride, F = 159-1610C, 1-phenoxymethyl-4-methyl-3,4-dihydroisoquinoline hydrochloride, F = 207-2080C ,
1 - (m-methylphenoxymethyl) -3,4-dihydroisoquinoline hydrochloride, F = 186-1880C, 1 - (m-chlorophenoxymethyl) -3,4-dihydroisoquinoline hydrochloride, F = 192-1930C, 1 - (o-fluorophenoxymethyl) - 3,4-dihydroisoquinoline hydrochloride (monohydrate), F = 147-1490C, 1- (m-fluorophenoxymethyl) -3,4-dihydroisoquinoline hydrochloride (monohydrate), F = 190-1950C, 1 - [p- (n-butoxy) phenoxymethyl] -3,4-dihydroisoquinoline hydrochloride, F = 172-1730C, 1 - (p-tert-butylphenoxymethyl) -3,4-dihydroisoquinoline hydrochloride, F = 213-215 C, I- (p-bromophenoxymethyl) -3, 4-dihydroisoquinoline hydrochloride,
F = 2070C, 1 - [1 - (p-chlorophenoxy) ethyl] -3,4-dihydroisoquinoline hydrochloride (monohydrate), F = 850C, 1 - (p-methoxyphenoxymethyl) -3,4-dihydroisoquinoline hydrochloride, F = 1870C.
Treatment of the above-mentioned hydrochlorides with 5N NaOH gives the corresponding free 1-phenoxymethyl-3,4-dihydroisoquinoline bases in pure form.
Example 4
The compounds listed in the table below were obtained from the corresponding N-phenoxy acetyl-r-phenylethylamine and phosphorus pentoxide by the method of Example 1.
EMI3.1
R2 R3 RJ X H H H 3-Br H H H 2 -OCH3 CH3 H H 2-C1 H C2H5 H 2-F H H C2115 H CH3 CH3 CH3 2-CH5 C2H. H H H H H H 3-C2H H H C2H2 4-Br H H H 4- (n-C2H11) H n-C3H7 H H n-C4H !,
HH 3-C1 HH n-C4Hn 3-OC3H7 (i) iso-C3H7 HH 2-Br H iso-C4H9 CH3 HHH iso-CsH, HHHH 3-C2H5 R1 R CH3 CH2 H 3-FHC H5 CM5 4-C1 HH CH3 2-OC4H9 CH3 H CH2 3-Br n-C4H0 HHHH CH3 H 3- (iso-C4Hs) HHH 4-OC5H,
Example 5
The hydrobromide of 1- (p-chlorophenoxymethyl) -3,4-dihydroisoquinoline is obtained by dissolving the free base in an aqueous solution which contains the molar equivalent amount in hydrobromic acid.
The resulting solution is evaporated to dryness under reduced pressure, whereupon pure crystalline 1- (p-chlorophenoxymethyl) -3,4-dihydroisoquinoline hydrobromide is obtained.
Example 6
Other acid addition salts of the new l-phenoxymethyl-3,4-dihydroisoquinolines are prepared according to the procedure of Example 5 using the suitable free bases according to Example 1-4 and hydrochloric, hydrobromic and hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, methanesulfonic acid Ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, succinic acid and maleic acid.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB5154564A GB1077089A (en) | 1964-12-18 | 1964-12-18 | 1-substituted-3,4-dihydroisoquinolines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH493520A true CH493520A (en) | 1970-07-15 |
Family
ID=10460432
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1738465A CH493520A (en) | 1964-12-18 | 1965-12-16 | Antiviral isoquinoline derivs esp 1-phenoxymethyl-3 4 |
Country Status (11)
| Country | Link |
|---|---|
| AT (2) | AT264525B (en) |
| BE (1) | BE673952A (en) |
| CH (1) | CH493520A (en) |
| DE (1) | DE1620122A1 (en) |
| DK (1) | DK114694B (en) |
| ES (1) | ES320801A1 (en) |
| FI (1) | FI45757C (en) |
| FR (1) | FR4911M (en) |
| GB (1) | GB1077089A (en) |
| NL (1) | NL6516328A (en) |
| SE (1) | SE342623B (en) |
-
1964
- 1964-12-18 GB GB5154564A patent/GB1077089A/en not_active Expired
-
1965
- 1965-12-15 NL NL6516328A patent/NL6516328A/xx unknown
- 1965-12-15 DE DE19651620122 patent/DE1620122A1/en active Pending
- 1965-12-16 FI FI301865A patent/FI45757C/en active
- 1965-12-16 CH CH1738465A patent/CH493520A/en not_active IP Right Cessation
- 1965-12-16 ES ES0320801A patent/ES320801A1/en not_active Expired
- 1965-12-17 AT AT1136665A patent/AT264525B/en active
- 1965-12-17 BE BE673952D patent/BE673952A/xx unknown
- 1965-12-17 FR FR42726A patent/FR4911M/fr not_active Expired
- 1965-12-17 DK DK648165A patent/DK114694B/en unknown
- 1965-12-17 AT AT650867A patent/AT271478B/en active
- 1965-12-17 SE SE1642265A patent/SE342623B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SE342623B (en) | 1972-02-14 |
| DE1620122A1 (en) | 1970-04-09 |
| ES320801A1 (en) | 1967-03-01 |
| BE673952A (en) | 1966-04-15 |
| FR4911M (en) | 1967-03-13 |
| DK114694B (en) | 1969-07-28 |
| GB1077089A (en) | 1967-07-26 |
| AT271478B (en) | 1969-06-10 |
| FI45757B (en) | 1972-05-31 |
| FI45757C (en) | 1972-09-11 |
| AT264525B (en) | 1968-09-10 |
| NL6516328A (en) | 1966-06-20 |
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| Date | Code | Title | Description |
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| PL | Patent ceased |