CH377833A - Method of making a new cough suppressant - Google Patents
Method of making a new cough suppressantInfo
- Publication number
- CH377833A CH377833A CH7575959A CH7575959A CH377833A CH 377833 A CH377833 A CH 377833A CH 7575959 A CH7575959 A CH 7575959A CH 7575959 A CH7575959 A CH 7575959A CH 377833 A CH377833 A CH 377833A
- Authority
- CH
- Switzerland
- Prior art keywords
- sep
- pyridazinone
- methyl
- carboxylic acid
- dihydro
- Prior art date
Links
- 239000003434 antitussive agent Substances 0.000 title description 7
- 229940124584 antitussives Drugs 0.000 title description 7
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000005265 dialkylamine group Chemical group 0.000 claims description 2
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 229940079593 drug Drugs 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 206010011224 Cough Diseases 0.000 description 3
- UZBQIPPOMKBLAS-UHFFFAOYSA-N diethylazanide Chemical compound CC[N-]CC UZBQIPPOMKBLAS-UHFFFAOYSA-N 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 3
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 3
- 230000003533 narcotic effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000007665 chronic toxicity Effects 0.000 description 2
- 231100000160 chronic toxicity Toxicity 0.000 description 2
- 229960004126 codeine Drugs 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- WOSVNRNLAPEKDN-UHFFFAOYSA-N methyl 6-oxo-4,5-dihydro-1h-pyridazine-3-carboxylate Chemical compound COC(=O)C1=NNC(=O)CC1 WOSVNRNLAPEKDN-UHFFFAOYSA-N 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- LXFKHPXXAPOYCC-UHFFFAOYSA-N 1-methyl-6-oxo-4,5-dihydropyridazine-3-carboxamide Chemical compound CN1N=C(C(N)=O)CCC1=O LXFKHPXXAPOYCC-UHFFFAOYSA-N 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-L 2-oxoglutarate(2-) Chemical compound [O-]C(=O)CCC(=O)C([O-])=O KPGXRSRHYNQIFN-UHFFFAOYSA-L 0.000 description 1
- WGKYSFRFMQHMOF-UHFFFAOYSA-N 3-bromo-5-methylpyridine-2-carbonitrile Chemical compound CC1=CN=C(C#N)C(Br)=C1 WGKYSFRFMQHMOF-UHFFFAOYSA-N 0.000 description 1
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 1
- MTJLHSQWYQRXMK-UHFFFAOYSA-N C(CCC)N1N=CCCC1=O Chemical compound C(CCC)N1N=CCCC1=O MTJLHSQWYQRXMK-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- RVCABEYSXYYMSH-UHFFFAOYSA-N methyl 1-methyl-6-oxo-4,5-dihydropyridazine-3-carboxylate Chemical compound COC(=O)C1=NN(C)C(=O)CC1 RVCABEYSXYYMSH-UHFFFAOYSA-N 0.000 description 1
- IHRPJNDVWBJCEH-UHFFFAOYSA-N methyl 4-(butylamino)benzoate Chemical compound CCCCNC1=CC=C(C(=O)OC)C=C1 IHRPJNDVWBJCEH-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229920000847 nonoxynol Polymers 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- CBPYOHALYYGNOE-UHFFFAOYSA-M potassium;3,5-dinitrobenzoate Chemical compound [K+].[O-]C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 CBPYOHALYYGNOE-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung eines neuen Hustenmittels Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung neuer Hustenmittel der Formel
EMI0001.0002
worin Z einen Vinylen- oder Äthylenrest, R einen niedrigen Alkylrest, R' und R" (die gleich oder ver schieden sein können) niedrige Alkylreste oder Wasserstoff bedeuten.
Die erfindungsgemäss erhaltenen Verbindungen können wegen ihres durch pharmakologische Ver suche gezeigten Wirkungsmechanismus unter den zentral wirkenden Hustenmitteln klassifiziert werden. Weiterhin besitzen sie keine narkotische Wirkung und sind in dieser Hinsicht manchen natürlichen oder synthetischen Arzneimitteln überlegen, die ge wöhnlich in der Hustenbehandlung angewendet wer den.
In den letzten Jahren war die Forschung über zentral wirkende, nicht narkotische Hustenmittel ein gehend und führte zur Anwendung einiger therapeu tischer Mittel, die imstande sind, die Schwelle der Empfindlichkeit des Hustenzentrums des verlängerten Marks gegenüber zentripetalen Hustenimpulsen ohne unerwünschte narkotische Wirkung erhöhen zu können.
Man hat jetzt gefunden, dass die erfindungsgemäss erhaltenen Verbindungen eine mit Codein vergleich bare hustenstillende Wirkung zeigen und von den bekannten Nebenwirkungen der gewöhnlich ange wendeten Arzneimittel frei sind. Die folgende Tabelle gibt die durchschnittliche schützende Dosis in mg/kg einiger der neuen Verbindungen gegen Husten, der durch Einatmung von Aerolein als Aerosol in Meer schweinchen verursacht wurde.
EMI0001.0017
Durchschnittliche <SEP> schützende
<tb> Dosis <SEP> in <SEP> mg/kg
<tb> 2-Methyl-4,5-dihydro-3-pyridazinon-6-carbonsäureamid <SEP> 5
<tb> 2-Methyl-3-pyridazinon-6-carbonsäureamid <SEP> 2
<tb> 2-Methyl-3-pyridazinon-6-carbonsäuremethylamid <SEP> 10
<tb> 2-Methyl-3-pyridazinon-6-carbonsäurediäthylamid <SEP> 5
<tb> 2-Butyl-4,5-dihydro-3-pyridazinon-6-carbons:äureamid <SEP> 10
<tb> Codein <SEP> 5 Eine andere günstige Eigenschaft der neuen Ver bindungen ist ihre sehr niedrige akute und chronische Giftigkeit, die die Verabreichung von hohen und häufigen Dosen gestattet. Die folgende Tabelle ver- gleicht die akute Giftigkeit der erfindungsgemäss er haltenen Verbindungen mit derjenigen der gewöhn lich angewendeten Hustenmittel.
EMI0002.0001
Mittlere <SEP> lethale <SEP> Dosis <SEP> in <SEP> Mäusen
<tb> (mg/kg)
<tb> subkutan <SEP> oral
<tb> 2-Methyl-4,5-dihydro-3-pyridazinon-6-carbonsäure.amid <SEP> <B><I>>l500</I></B> <SEP> > <SEP> 1500
<tb> 2-Methyl-3 <SEP> pyridazinon-6-carbonsäureamid <SEP> <B><I>>l500</I></B> <SEP> >l500
<tb> 2-Methyl-3,pyridazinon-6-carbonsäuremethylamid <SEP> 1200 <SEP> >1500
<tb> 2-Methyl-3-pyridazinon-6-carbonsäurediäthylamid <SEP> 840 <SEP> 1220
<tb> 2-Butyl-4,5-dihydro-3-pyridazinon-6-carbonsäureamid <SEP> 1200 <SEP> >1500
<tb> Codein <SEP> 370 <SEP> 250
<tb> Dextromethomorphan <SEP> hydrobromid <SEP> 275 <SEP> 165
<tb> Nonaäthylenglykolmethyl-p-butylaminobenzoat <SEP> 230 <SEP> 700 Auch die chronische Giftigkeit der neuen Ver bindungen ist sehr niedrig:
Dosen bis 300 mg/kg wur den Hunden täglich 3 Monate lang ohne uner wünschte Nebenwirkungen verabreicht. Für thera peutische Zwecke können die Verbindungen der Formel 1 allein oder in Vereinigung mit einem Trä ger angewandt werden. Letzterer kann ein festes Material, eine sterile Flüssigkeit oder ein Sirup sein. Wenn die orale Therapie bevorzugt wird, wie es für diese Art von Arzneimitteln üblich ist, wird die Substanz als Pulver, in Kapseln, Tabletten oder an dern festen Formen verabreicht. Für parenterale An wendung kann man als Lösungsmittel steriles destil liertes Wasser, wo einige Verbindungen sehr löslich sind, verwenden.
Obgleich klinisch schätzbare Effekte bereits mit Dosen von 5-20 mg erreicht wer den, ist die zweckmässige Dosis gewöhnlich höher und kann ohne Gefahr 500 mg und mehr in den hartnäckigen Fällen erreichen. Um das therapeutische Präparat darzustellen, wird die ausgewählte Arznei mitteldosis unmittelbar in die Kapselst allein oder in Vereinigung mit festen inerten Trägern undloder an dern therapeutischen Mitteln gefüllt. Die Tabletten können durch Vereinigung des Arzneimittels mit den gewöhnlich angewendeten Tablettenmaterialien, wie z.
B. Lactose, Talk, Kornstärke, Stearinsäure, Ma- gnesiumstearat, hergestellt werden. Die Ampullen werden durch Auflösung des Arzneimittels in sterilem destilliertem Wasser und Ergiessen der Lösung in die eine genügende Flüssigkeitsmenge enthaltenden Am pullen vorbereitet, um die erwünschte Dosis des Arzneimittels zu erhalten.
Das Präparat kann auch als Sirup hergestellt werden, wobei die Arzneimittel in gewöhnlichem Sirup in einer derart berechneten Konzentration gelöst wird, dass die geeignete Dosis, mit oder ohne Zusatz eines Trägers undjoder eines Geschmacksmittels und'oder anderer Arzneimittel verabreicht wird.
Das erfindungsgemässe Verfahren zur Herstel lung von Verbindungen der Formel 1 ist dadurch gekennzeichnet, dass man Verbindungen der Formel
EMI0002.0018
worin X einen Alkoxy-Rest oder Chlor bedeutet, mit Ammoniak vorzugsweise im überschuss oder mit niederen Alkyl- oder Dialkylaminen vorzugsweise in einem Lösungsmittel umsetzt. Dieses Verfahren hat meistens hochbefriedigende Ergebnisse gegeben.
<I>Beispiel 1</I> Eine Mischung von 10 g 4,5-Dihydro-3-pyrid- azinon 6-carbonsäure und 100 cm3 2%iger Chlor- wasserstofflösung in Methylalkohol wird unter Rückfluss 6 Stunden erhitzt.
Bei Kühlung fällt 6-Carbomethoxy-4,5-dihydro-3-pyridazinon aus, das gesammelt und getrocknet wird. Ausbeute 9 g (85%). Schmp. 136-137 C.
Der entsprechende Methylester kann durch dasselbe Verfahren unter Verwendung von Äthylalkohol anstatt Methylalkohol hergestellt werden. Ausbeute 85%. Schmp. 135-136 C. 10 g des oben erhaltenen 6-Carbomethoxy-4,5-dihydro- 3-pyridazinon werden in einer aus 1,5g Natrium und 100 em3 Methylalkohol vorbereiteten Natriummethy- latlösung gelöst.
10 g Methyljodid werden dann bei Zimmertemperatur zugesetzt und die Mischung 1 Stunde bei Zimmertemperatur und etwa 1 Stunde bei 50-60 , solange das Mittel nicht mehr alkalisch wird, umgerührt. Das dabei als Nebenprodukt gebil dete Dinatrium a-oxo-glutarat wird abfiltriert und das Filtrat zur Trockne eingedampft. Der Rückstand wird mit Chloroform extrahiert.
Das Chloroform wird abdestilliert und der Rückstand aus Methylalkohol umkristallisiert. Ausbeute 6,5 g (600!0) 6-Carbo- methoxy-2-methyl-4,5-dihydro-3-pyridazinon. Schmp. 90-95 C. 10 g der oben erhaltenen Verbindung wer den mit 25 cm-' konzentriertem Ammoniak gemischt; das feste Material Löst sich langsam; dann bildet sich ein Niederschlag. Nach 2 Stunden bei Zimmertempe ratur wird das Produkt gesammelt und aus Äthyl alkohol umkristallisiert. Weitere Mengen des Pro duktes werden nach Konzentrieren der Mutterlaugen erhalten.
Ausbeute 6 g (6611/o) 6-Carbamyl-2-methyl- 4,5-dihydro-3-pyridazinon. Schmp. 170-172 C. <I>Beispiel 2</I> Eine Mischung von 40 g 2-MethyT-3-pyridazinon- 6-carbonsäure und 160 cm?, Thionylchlorid werden unter Rückfluss 3 Stunden erhitzt, dann wird die Lö sung zur Trockne eingedampft und der Rückstand aus Äthyläther umkristallisiert.
Ausbeute 9011/o 2-Me- thyl - 3 - pyridazinon - 6 - carbonsäurechlorid, Schmp. 116 .
Eine Lösung von 15 g 2-Methyl-3-pyridazinon-6- carbonsäurechlorid in 300 cm-' Chloroform wird zu etwa 0 C gekühlt, dann wird eine 25 %ige wässrige Methylaminlösung unter Umrühren langsam zuge setzt.
Die Chloroformschicht wird abgetrennt, die Wasserschicht mit Chloroform extrahiert, die ver einigten Chloroformextrakte zur Trockne einge dampft und der Rückstand aus Propylalkohol um kristallisiert. Ausbeute 921/a 2-Methyl-3-pyridazinon- 6-carbonsäuremethylamid. Schmp. 155-157 C.
<I>Beispiel 3</I> Einer Lösung von 15 g 2-Methyl-3-pyridazinon- 6-carbonsäurechlorid in 500 cm3 Äthyläther wird eine Lösung von 17,5 cm3 Diäthylamin in 150 cm3 Äthyläther zugesetzt. Nach einer halben Stunde wird der kristallisierte Niederschlag, der aus Diäthylamin- hydrochlorid besteht, abfiltriert und das Filtrat zur Trockne eingedampft.
Ein Öl bildet sich, das nach längerem Stehen kristallisiert. Dieses Produkt wird aus Propylalkohol umkristallisiert. Ausbeute 84o/11 2-Methyl-3 -pyridazinon-6-carbonsäurediäthylamid, Schmp. 73-75 C. <I>Beispiel 4</I> Eine Mischung von 20 g 2-Butyl-4,5-dihydro-3- pyridazinon-6-carbonsäuremethylester und 50 cm3 konzentriertem Ammoniak wird 1 Stunde stehen gelassen.
Nach dieser Zeit wird der gebildete Nieder schlag gesammelt und aus Äthylalkohol umkristalli siert. Ausbeute 92o/11 2 - Butyl - 4,5 - dihydro-3- pyridazinon-6-carbonsäureamid, Schmp. 172-174 C.
Process for the preparation of a new cough suppressant The present invention relates to a process for the production of new cough suppressants of the formula
EMI0001.0002
wherein Z is a vinylene or ethylene radical, R a lower alkyl radical, R 'and R "(which may be the same or different) mean lower alkyl radicals or hydrogen.
The compounds obtained according to the invention can be classified under the centrally acting cough suppressants because of their mechanism of action shown by pharmacological tests. Furthermore, they have no narcotic effect and in this respect are superior to some natural or synthetic drugs that are commonly used in cough treatment.
In recent years, research on centrally acting, non-narcotic cough suppressants has resulted in the use of some therapeutic agents capable of raising the threshold of sensitivity of the cough center of the elongated marrow to centripetal cough impulses without undesirable narcotic effects.
It has now been found that the compounds obtained according to the invention show a cough suppressant effect comparable to that of codeine and are free from the known side effects of the drugs commonly used. The table below gives the average protective dose in mg / kg of some of the new compounds against cough caused by inhalation of aerolein as an aerosol in guinea pigs.
EMI0001.0017
Average <SEP> protective
<tb> Dose <SEP> in <SEP> mg / kg
<tb> 2-Methyl-4,5-dihydro-3-pyridazinone-6-carboxamide <SEP> 5
<tb> 2-Methyl-3-pyridazinone-6-carboxamide <SEP> 2
<tb> 2-Methyl-3-pyridazinone-6-carboxylic acid methylamide <SEP> 10
<tb> 2-Methyl-3-pyridazinone-6-carboxylic acid diethylamide <SEP> 5
<tb> 2-Butyl-4,5-dihydro-3-pyridazinone-6-carboxylic: acid amide <SEP> 10
<tb> Codeine <SEP> 5 Another beneficial property of the new compounds is their very low acute and chronic toxicity, which allows the administration of high and frequent doses. The following table compares the acute toxicity of the compounds obtained according to the invention with that of the commonly used cough suppressants.
EMI0002.0001
Mean <SEP> lethal <SEP> dose <SEP> in <SEP> mice
<tb> (mg / kg)
<tb> subcutaneous <SEP> oral
<tb> 2-Methyl-4,5-dihydro-3-pyridazinone-6-carboxylic acid.amide <SEP> <B><I>>l500</I> </B> <SEP>> <SEP> 1500
<tb> 2-Methyl-3 <SEP> pyridazinone-6-carboxamide <SEP> <B><I>>l500</I> </B> <SEP>> 1500
<tb> 2-Methyl-3, pyridazinone-6-carboxylic acid methylamide <SEP> 1200 <SEP>> 1500
<tb> 2-Methyl-3-pyridazinone-6-carboxylic acid diethylamide <SEP> 840 <SEP> 1220
<tb> 2-Butyl-4,5-dihydro-3-pyridazinone-6-carboxamide <SEP> 1200 <SEP>> 1500
<tb> Codein <SEP> 370 <SEP> 250
<tb> Dextromethomorphan <SEP> hydrobromide <SEP> 275 <SEP> 165
<tb> Nonaethylene glycol methyl p-butylaminobenzoate <SEP> 230 <SEP> 700 The chronic toxicity of the new compounds is also very low:
Doses up to 300 mg / kg were administered to the dogs daily for 3 months without undesirable side effects. For therapeutic purposes, the compounds of formula 1 can be used alone or in combination with a carrier. The latter can be a solid material, a sterile liquid or a syrup. If oral therapy is preferred, as is customary for this type of drug, the substance is administered as a powder, in capsules, tablets, or other solid forms. For parenteral use, the solvent used can be sterile, distilled water, where some compounds are very soluble.
Although clinically estimable effects are achieved with doses of 5-20 mg, the appropriate dose is usually higher and can safely reach 500 mg and more in stubborn cases. In order to present the therapeutic preparation, the selected drug dose is filled directly into the capsule alone or in association with solid inert carriers and / or other therapeutic agents. The tablets can be prepared by combining the drug with the commonly used tablet materials, such as.
B. lactose, talc, corn starch, stearic acid, magnesium stearate can be produced. The ampoules are prepared by dissolving the drug in sterile distilled water and pouring the solution into the ampoules containing sufficient liquid to obtain the desired dose of the drug.
The preparation can also be produced as a syrup, the medicament being dissolved in ordinary syrup in a concentration calculated in such a way that the appropriate dose is administered with or without the addition of a carrier and / or a flavoring agent and / or other medicaments.
The process according to the invention for the preparation of compounds of the formula 1 is characterized in that compounds of the formula
EMI0002.0018
where X is an alkoxy radical or chlorine, is reacted with ammonia, preferably in excess, or with lower alkyl or dialkyl amines, preferably in a solvent. This procedure has mostly given highly satisfactory results.
<I> Example 1 </I> A mixture of 10 g of 4,5-dihydro-3-pyrid-azinone 6-carboxylic acid and 100 cm3 of 2% strength hydrogen chloride solution in methyl alcohol is heated under reflux for 6 hours.
On cooling, 6-carbomethoxy-4,5-dihydro-3-pyridazinone precipitates, which is collected and dried. Yield 9g (85%). M.p. 136-137 C.
The corresponding methyl ester can be prepared by the same procedure using ethyl alcohol instead of methyl alcohol. Yield 85%. Melting point 135-136 ° C. 10 g of the 6-carbomethoxy-4,5-dihydro-3-pyridazinone obtained above are dissolved in a sodium methylate solution prepared from 1.5 g of sodium and 100 cubic meters of methyl alcohol.
10 g of methyl iodide are then added at room temperature and the mixture is stirred for 1 hour at room temperature and for about 1 hour at 50-60, as long as the agent no longer becomes alkaline. The disodium α-oxo-glutarate formed as a by-product is filtered off and the filtrate is evaporated to dryness. The residue is extracted with chloroform.
The chloroform is distilled off and the residue is recrystallized from methyl alcohol. Yield 6.5 g (600! 0) of 6-carbomethoxy-2-methyl-4,5-dihydro-3-pyridazinone. Mp. 90-95 C. 10 g of the compound obtained above who mixed the with 25 cm- 'concentrated ammonia; the solid material slowly dissolves; then a precipitate forms. After 2 hours at room temperature, the product is collected and recrystallized from ethyl alcohol. Further amounts of the product are obtained after concentrating the mother liquors.
Yield 6 g (6611 / o) 6-carbamyl-2-methyl-4,5-dihydro-3-pyridazinone. Melting point 170-172 C. <I> Example 2 </I> A mixture of 40 g of 2-methyl-3-pyridazinone-6-carboxylic acid and 160 cm ?, thionyl chloride are heated under reflux for 3 hours, then the solution becomes evaporated to dryness and the residue recrystallized from ethyl ether.
Yield 9011 / o 2-methyl-3-pyridazinone-6-carboxylic acid chloride, melting point 116.
A solution of 15 g of 2-methyl-3-pyridazinone-6-carboxylic acid chloride in 300 cm- 'chloroform is cooled to about 0 C, then a 25% aqueous methylamine solution is slowly added with stirring.
The chloroform layer is separated off, the water layer is extracted with chloroform, the combined chloroform extracts are evaporated to dryness and the residue is recrystallized from propyl alcohol. Yield 921 / a of 2-methyl-3-pyridazinone-6-carboxylic acid methylamide. 155-157 C.
<I> Example 3 </I> A solution of 17.5 cm3 diethylamine in 150 cm3 ethyl ether is added to a solution of 15 g of 2-methyl-3-pyridazinone-6-carboxylic acid chloride in 500 cm3 of ethyl ether. After half an hour, the crystallized precipitate, which consists of diethylamine hydrochloride, is filtered off and the filtrate is evaporated to dryness.
An oil forms, which crystallizes after standing for a long time. This product is recrystallized from propyl alcohol. Yield 84o / 11 of 2-methyl-3-pyridazinone-6-carboxylic acid diethylamide, melting point 73-75 C. <I> Example 4 </I> A mixture of 20 g of 2-butyl-4,5-dihydro-3-pyridazinone -6-carboxylic acid methyl ester and 50 cm3 concentrated ammonia is left to stand for 1 hour.
After this time, the precipitate formed is collected and recrystallized from ethyl alcohol. Yield 92o / 11 2-butyl-4,5-dihydro-3-pyridazinone-6-carboxamide, m.p. 172-174 C.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB22991/58A GB893278A (en) | 1958-07-17 | 1958-07-17 | Pyridazone amide derivatives |
| GB3931158 | 1958-12-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH377833A true CH377833A (en) | 1964-05-31 |
Family
ID=26256225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH7575959A CH377833A (en) | 1958-07-17 | 1959-07-14 | Method of making a new cough suppressant |
Country Status (2)
| Country | Link |
|---|---|
| CH (1) | CH377833A (en) |
| FR (1) | FR148M (en) |
-
1959
- 1959-07-14 CH CH7575959A patent/CH377833A/en unknown
-
1960
- 1960-08-08 FR FR835250A patent/FR148M/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR148M (en) | 1961-02-06 |
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