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DD220311A1 - PROCESS FOR SYNTHESIS OF 1-PHENYL-2- (N-METHYL-N- (6H-1,3,4-THIADIAZIN-2-YL) -AMINO) -PROPAN-1-OLENE - Google Patents

PROCESS FOR SYNTHESIS OF 1-PHENYL-2- (N-METHYL-N- (6H-1,3,4-THIADIAZIN-2-YL) -AMINO) -PROPAN-1-OLENE Download PDF

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DD220311A1
DD220311A1 DD25884683A DD25884683A DD220311A1 DD 220311 A1 DD220311 A1 DD 220311A1 DD 25884683 A DD25884683 A DD 25884683A DD 25884683 A DD25884683 A DD 25884683A DD 220311 A1 DD220311 A1 DD 220311A1
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German Democratic Republic
Prior art keywords
phenyl
methyl
amino
thiadiazin
propan
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DD25884683A
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German (de)
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Pfeiffer
Bulka
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Univ Ernst Moritz Arndt
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  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

DIE ERFINDUNG BETRIFFT EIN VERFAHREN ZUR DARSTELLUNG DES BISHER UNBEKANNTEN BIOCHEMISCH INTERESSANTEN VERBINDUNGSTYPS DER 1-PHENYL-2(N-METHYL-N-(6H-1,3,4-THIADIAZIN-2-YL)-AMINO)-PROPAN-1-OLE.DIE TITELVERBINDUNGEN KOENNEN ALS PHARMAKA MITSPASMOLYTISCHER WIRKSAMKEIT UND ZUR SYNTHESE WEITERER HETEROCYCLEN VERWENDET WERDEN. SIE LASSEN SICH ERFINDUNGSGEMAESS DURCH UMSETZUNG VON 4-METHYL-4-((1RS:2SR)-1-HYDROXY-1-PHENYL-PROP-2-YL)-THIOSEMICARBAZID UND ALPHA-HALOGENKETONEN IN ALKOHOLEN BZW. DMF SYNTHETISIEREN.The invention relates to a method for illustrating the hitherto unprecedented BIOCHEMICALLY INTERESTING CONNECTION TYPE OF 1-PHENYL-2 (N-METHYL-N- (6H-1,3,4-THIADIAZIN-2-YL) -AMINO) -PROPAN-1-OLE .TITLE COMPOUNDS CAN BE USED AS A PHARMAKA OF MITSPASMOLYTIC EFFICACY AND FOR THE SYNTHESIS OF OTHER HETEROCYCLES. They can be obtained by the reaction of 4-methyl-4 - ((1RS: 2SR) -1-hydroxy-1-phenyl-prop-2-yl) -thiosemicarbazide and alpha-halo ketones in alcohols or, respectively, by the present invention. SYNTHETIZE DMF.

Description

Anwendungsgebiet der ErfindungField of application of the invention

Die Erfindung betrifft ein Verfahren zur Herstellung von 1-Phenyl-2-[N-methyl-N-(6H-1,3,4-thiadiazin-2-yl)-amino]-propan-1-olen, die als Pharmaka mit spasmolytischer Wirkung und als organische Zwischenprodukte verwendet werden können.The invention relates to a process for the preparation of 1-phenyl-2- [N-methyl-N- (6H-1,3,4-thiadiazin-2-yl) -amino] -propan-1-ols, which are used as pharmaceuticals with Spasmolytischer effect and can be used as organic intermediates.

Charakteristik der bekannten technischen LösungenCharacteristic of the known technical solutions

Der biochemisch interessante Verbindungstyp der 1-Phenyl-2-[N-methyl-N-(6H-1,3,4-thiadiazin-2-yl)-amino]-propan-1-ole ist nicht bekannt. Angaben über die Synthese von 6H-1,3,4-Thiadiazinen liegen bereits in der Literatur vor: R.C. Elderfield, Heterocyclic Compounds, Vol._7,826; J. Wiley and Sons, Inc. New York, London 1961; H. Beyer, Z.Chem.jjj 361 (1969); W.D.Pfeiffer, E.DiIk und E.Bulka, Wiss. Zeitschrift der Ernst-Moritz-Arndt-Universität Greifswald XXVII, 135 (1978). 6H-1,3,4-Thiadiazine zeigten bei der Testung eine gute spasmolytische Wirkung. Durch Einführung des 6H-1,3,4-Thiadiazin-2-ylrestes in das bekannte Arzneimittel Ephedrin sollte die Wirksamkeit dieser Substanz verändert werden. ,The biochemically interesting compound type of 1-phenyl-2- [N-methyl-N- (6H-1,3,4-thiadiazin-2-yl) -amino] -propan-1-ols is not known. Information about the synthesis of 6H-1,3,4-thiadiazines is already available in the literature: R.C. Elderfield, Heterocyclic Compounds, Vol._7,826; J. Wiley and Sons, Inc. New York, London 1961; H. Beyer, Z. Chem., 361 (1969); W.D.Pfeiffer, E.DiIk and E.Bulka, Wiss. Journal of the Ernst Moritz Arndt University Greifswald XXVII, 135 (1978). 6H-1,3,4-thiadiazines showed good spasmolytic activity during testing. By introducing the 6H-1,3,4-thiadiazin-2-yl residue into the known drug ephedrine, the efficacy of this substance should be changed. .

«Ziel der Erfindung«Object of the invention

Ziel der Erfindung ist die Bereitstellung neuer Verbindungen mit spasmolytischer Wirkung. Darlegung des Wesens und der Merkmale der ErfindungThe aim of the invention is to provide novel compounds with spasmolytic action. Explanation of the nature and features of the invention

Erfindungsgemäß werden 1-Phenyl-2-[N-methyl-N-(6H-1,3,4-thiadiazin-2-yl)-amino]-propan-1-ple der allgemeinen Formel dargestellt, , ,According to the invention 1-phenyl-2- [N-methyl-N- (6H-1,3,4-thiadiazin-2-yl) amino] propane-1-ple represented the general formula,,

CH3 OH ICH 3 OH I

C6H5 C 6 H 5

wobei R1 und R2 eine Arylgruppe, einen niederen geradkettigen oder verzweigten Alkylrest bzw. ein Η-Atom bedeuten, indem man äquimolare Mengen von4-Methyl-4-[(1RS:2SR)-1-hydroxy-1-phenyl-prop-2-ylJ-thiosemicarbazid unda-Halogen-ketone in Alkoholen bzw. DMF auf 40-15O0C erhitzt. Nach dem Abkühlen bzw. beim Versetzen mit Ether fallen die Hydrohalogenide aus. Als Lösungsmittel für die Reaktionskomponenten dienen Alkohole, vorzugsweise mit Siedetemperaturen unter 1500C bzw. DMF. Die freien Basen erhält man aus den Hydrohalogeniden durch Lösen in Ethanol und Versetzen mit Ammoniak.where R 1 and R 2 denote an aryl group, a lower straight-chain or branched alkyl radical or a Η-atom by equimolar amounts of 4-methyl-4 - [(1RS: 2SR) -1-hydroxy-1-phenylpropyl 2-ylJ-thiosemicarbazid unda-halo-ketones in alcohols or DMF to 40-15O 0 C heated. After cooling or when mixed with ether, the hydrohalides precipitate. The solvents used for the reaction components are alcohols, preferably with boiling temperatures below 150 ° C. or DMF. The free bases are obtained from the hydrohalides by dissolving in ethanol and adding ammonia.

Ausführungsbeispiele Beispiel 1:Exemplary embodiments Example 1

(1RS:2SR)-1-Phenyl-2-[N-methyl-N-(5-phenyl-6H-1,3,4-thiadiazin-2-yl)-amino]-propan-1-ol Hydrobromid: 2,39g (lOmmol) 4-Methyl-4-[(1RS:2SR)-1-hydroxy-1-phenyl-prop-2-yl]-thiosemicärbazid und 1,99g (lOmmol) ω-Brom-acetophenon werden in 60ml Ethanol 30Min. unter Rückfluß erhitzt. Nach dem Abkühlen fügt man 10ml Ether hinzu, wobei ein farbloser Niederschlag ausfällt.(1RS: 2SR) -1-phenyl-2- [N -methyl-N- (5-phenyl-6H-1,3,4-thiadiazin-2-yl) -amino] -propan-1-ol hydrobromide: 2 , 39 g (10 mmol) of 4-methyl-4 - [(1RS: 2SR) -1-hydroxy-1-phenyl-prop-2-yl] -thiosemicarbazide and 1.99 g (10 mmol) of ω-bromo-acetophenone are dissolved in 60 ml of ethanol 30 min. heated to reflux. After cooling, add 10 ml of ether, whereby a colorless precipitate precipitates.

Ausb. 3,1g (74%). Farblose Blättchen (aus Ethanol), F. 182-1830C.Y. 3.1g (74%). Colorless flake (from ethanol), m.p. 182-183 0 C.

Freie Base: Ausderethanolischen Lösung des Hydrobromids durch Zugabe von Ammoniak. Gelbe Prismen (aus Ethanol), F.125-126°C.Free base: Ausderethanolic solution of the hydrobromide by addition of ammonia. Yellow prisms (from ethanol), F.125-126 ° C.

Beispiel 2:Example 2:

(IRS^SRi-i-Phenyl^-IN-methyl-N-fS-p-chlor-phenyl-eH-I.S^-thiadiazin^-yD-aminoJ-propan-i-ol· Hydrochlorid: 2,39g (tOmmol) 4-Methyl-4-[(1RS:2SR)-1-hydroxy-1-phenyl-prop-2-yl]-thiosemicarbazid und 1,89g (lOmmol) p-(IRS 1, 2Si-1-Phenyl) -IN-methyl-N-f S -p -chloro-phenyl-eH-IS 3 -thiadiazine 1-yl-amino-J-propan-i-ol hydrochloride: 2.39 g (tOmmol) 4-Methyl-4 - [(1RS: 2SR) -1-hydroxy-1-phenyl-prop-2-yl] thiosemicarbazide and 1.89 g (10 mmol) p-

ω-Dichlor-acetophenon werden in 50ml Isopropanol 15Min. unter Rückfluß erhitzt. Nach dem Abkühlen scheidet sich ein Kristallbrei ab. Ausb. 3,0g (73%). Farblose Stäbchen (aus Ethanol), F. 172-173X.ω-dichloro-acetophenone are dissolved in 50 ml of isopropanol 15min. heated to reflux. After cooling, a crystal slurry separates. Y. 3.0g (73%). Colorless rods (made of ethanol), mp 172-173X.

Freie Base: Aus der ethanolischen Lösung des Hydrochlorids durch Zugabe von Ammoniak. Zur Reinigung löst man in warmem Trichlorethylen und läßt in Petrolether eintropfen. Gelbe Prismen, F.66°C.Free Base: From the ethanolic solution of the hydrochloride by adding ammonia. For purification, dissolve in warm trichlorethylene and allowed to drip into petroleum ether. Yellow prisms, F.66 ° C.

Hydrabromid: 2,39g (lOmmol) 4-Methyl-44(1RS:2SR)-1-hydroxy-1-phenyl-propr2-yl]-thiosemicarbazid und 2,8g (lO.mmol) p-ω-Dibrom-acetophehon werden in 50ml Dimethylformamid 15Min. auf 900C erwärmt. Bei EtherZugabe fällt ein Niederschlag aus. Ausb. 3,5g (70%). Farblose Prismen (aus Ethanol), F. 181-182°C.Hydrabromide: 2.39g (10mmol) of 4-methyl-44 (1RS: 2SR) -1-hydroxy-1-phenyl-propr-2-yl] -thiosemicarbazide and 2.8g (10mmol) of p-ω-dibromo-acetophehone in 50ml dimethylformamide 15min. heated to 90 0 C. Ether addition drops a precipitate. Y. 3.5g (70%). Colorless prisms (from ethanol), mp 181-182 ° C.

Hydrochloric^: Aus2,39g (lOmmol)^Methyl-^-HIRS^SRJ-i-hydroxy-i-phenyl-prop^-yll-thiosemicarbazid und 2,45g (lOmmol) p-Brom-w-chlor-acetophenpn wie beim Hydrobromid beschrieben. Ausb. 3,32g (73%). Farblose Stäbchen (ausHydrochloric ^: from 2.39g (10mmol) ^ methyl - ^ - HIRS ^ SRJ-i-hydroxy-i-phenyl-propyl-1-thiosemicarbazide and 2,45g (10mmol) p-bromo-w-chloro-acetophenpn as indicated Hydrobromide described. Y. 3.32g (73%). Colorless chopsticks (out of

Ethanol), F. 177 bis 1780C. Ethanol), m.p. 177-178 0 C.

Freie Base: Aus der ethanölischen Lösung der Hydrohalogenide durch Zugabe von Ammoniak. Gelbe Prismen (äus-Ethanol),Free Base: From the ethanolic solution of hydrohalides by adding ammonia. Yellow prisms (äus-ethanol),

F.82°C. - ' ' , ; ' . '-: '.' ' ' . ' ' ... ", / , ' .- ; jF.82 ° C. - '',; '. '-:'. ' ''. '' ... ", /, '.-; j

Hydrachlorid: Aus 2,39g '(1.0mm'ol) 4-Methyl-4-[(lRS:2SR)-1-hydroxy-1-phenyl-pröp-2-yl]-thiosemiCarbazid und 1,69g (IOmmoi) p-Methyl-w-chlor-acetophenon analog Beispiel 1. Ausb. 2,9g (75%). Farblose Prismen (aus Ethanol), F. 161 bisHydrachloride: From 2.39 g (1.0 mmol) of 4-methyl-4 - [(1RS: 2SR) -1-hydroxy-1-phenyl-2-propyl-1-thiosemiarbazide and 1.69 g (10 mmol) of p -Methyl w-chloro-acetophenone analogous to Example 1. Ausb. 2,9g (75%). Colorless prisms (from ethanol), F. 161 to

i62°e. . ; ·; . -.· ' ' . ; " ' ..':. ' ' ; " ' .' ' ·"·. :-. . · . Freie Base: Aus der ethanölischen Lösung des Hydrochlorids durch Zugabe von Ammoniak. Gelbe Prismen (aus Ethanol), F.76°C. ' '. '. · . ' - / .; . :·; ' " ' "' ; · : ' ' ' ;' ' ' ' '. ' .': . . V ~i62 ° e. , ; ·; , -. '''.;"'..' :. '';'''.'. · "· - · Free base: From ethanölischen solution of the hydrochloride by addition of ammonia Yellow prisms (from ethanol), F.76 ° C.....''-/;.' ·.. '. . ·; '''''·''';'''''.'.':"V ~

Beispiels:example:

(1RS:2SR)-1-Phenyl-2-[N-methyl-N-(5-p-methoxy-phenyl-6H-1,3/4-thiadiaziri-2-yl)-amino]-propan-iOl Hydrochloric!: Aus 2,39g (10mmol)4-Methyl-4-{(1RS:2SR)-1-hydroxy-1-phenyl-prop-2-yl]-thiosemicarbazid und 1,85g dOmmol) p-Methoxy-fti-chlor-acetophenon analog Beispiel 1. Ausb. 2,94g (72%). Farblose Prismen (aus Ethanol/Ether), F.138(1RS: 2SR) -1-phenyl-2- [N -methyl-N- (5-p-methoxyphenyl-6H-1,3 / 4-thiadiaziri-2-yl) -amino] -propane-i-ol Hydrochloric !: From 2.39 g (10 mmol) of 4-methyl-4 - {(1RS: 2SR) -1-hydroxy-1-phenyl-prop-2-yl] -thiosemicarbazide and 1.85 g of dOmmol) p-methoxy-tetrahydrofuran Chloro-acetophenone analogous to Example 1. Ausb. 2,94g (72%). Colorless prisms (from ethanol / ether), F.138

Freie Base: Aus der ethanölischen Lösung des Hydrochlorids durch Zugabe von Ammoniak. Gelbe Prismen (aus Ethanol),Free Base: From the ethanolic solution of the hydrochloride by adding ammonia. Yellow prisms (from ethanol),

Beispiele:Examples:

(1RS:2SR)-1-Phenyl-2-lN-methyl-N-(5-p-nitro^phenyl-6H-1,3,4-thiädiazin-2ryl)-amino]-propan-1-ol Hydrobromid: 2,39g (IOmmoi) 4-Methy|-4-[(1RS:2SR)-1-hydroxy-1-phenyl-prop-2-yl]-thiosemicarbazid und 2,44g (IQmmol) p-Nitro-w-brom-acetophenon werden in 60ml tert. Butanol zunächst 1 Std. bei Raumtemperatur gerührt und anschließend 20 Min.(1RS: 2SR) -1-phenyl-2-lN-methyl-N- (5-p-nitro-phenyl-6H-1,3,4-thiadiazin-2-ryl) -amino] -propan-1-ol hydrobromide: 2.39g (10mmol) of 4-methyl-4 - [(1RS: 2SR) -1-hydroxy-1-phenyl-prop-2-yl] thiosemicarbazide and 2.44g (Immol) p-nitro-w-bromo acetophenone are tert in 60ml. Butanol first for 1 hr. At room temperature and then stirred for 20 min.

unter Rückfluß erhitzt. Nach dem Abkühlen versetzt man mit 30ml Ether, wobei ein gelblicher Niederschlag ausfällt. Ausb.heated to reflux. After cooling, it is mixed with 30 ml of ether, whereby a yellowish precipitate precipitates. Y.

3,24g (70%). Gelbliche Prismen (aus Ethanol). F. 177 bis 1786C.3.24g (70%). Yellowish prisms (from ethanol). F. 177 to 178 6C .

Freie Base: Aus der ethanölischen Lösung des Hydrobromids durch Zugabe von Ammoniak. Gelbe Prismen (aus Ethanol),Free Base: From the ethanolic solution of the hydrobromide by adding ammonia. Yellow prisms (from ethanol),

F.65,5°C. / .. · ' : '· ' .. · ·. ;: ' ' ' ' . . .'. ;'F.65,5 ° C. / .. · ':' · '.. · ·. ;: ''''. , . '. ; ' Beispiel:Example:

(1RS:2SR)-1-Phenyl-2-[N-methyl-N-(5,6-diphenyl-6H-1,3,4-thiadiazin-2-yl)-amino]-propan-1-ol Hydrobromid: 2,39g (IOmmoi) 4-Methyl-4-[(1RS:2SR)-1-hydroxy-1-phenyl-prop-2-yli-thiosemicarbazid und 2>75g (IOmmoi) Desylbromid werden in 20ml Ethanol 1,5Std. unter Kühlung mit Eis gerührt und anschließend 5Min. auf 5O0C erhitzt. Die Reaktionslösung gibt man tropfenweise in Ether, wobei ein Niederschlag ausfällt. Ausb. 3,52g (71 %). Farblose Prismen (aus Ethanol/Ether), F. 136X.(1RS: 2SR) -1-phenyl-2- [N -methyl-N- (5,6-diphenyl-6H-1,3,4-thiadiazin-2-yl) -amino] -propan-1-ol hydrobromide : 2.39 g (10 mmol) of 4-methyl-4 - [(1RS: 2SR) -1-hydroxy-1-phenyl-prop-2-yl-thiosemicarbazide and 2> 75 g (10 mmol) of desylbromide are dissolved in 20 ml of ethanol for 1.5 hr , stirred under cooling with ice and then 5Min. heated to 5O 0 C. The reaction solution is added dropwise to ether, precipitate being precipitated. Y. 3.52g (71%). Colorless prisms (from ethanol / ether), F. 136X.

Beispiele:Examples:

(1RS:2SR)-1-Phenyl-2-[N-methyl-N-(5-phenyl-6-methyl-6H-1,3,4-thiadiazin-2-Yl)-amino]-propan-1-ol Hydrobromid: 2,39g (IOmmoi) 4-Methyl-4-[(1RS:2SR)-1-hydroxy-1-phenyl-prop-2-yl]-thiosemicarbazid und 2,13g (IOmmoi) a-Brom-propiophenon werden in 30ml Ethanol 30Min. unter Rückfluß erhitzt. Anschließend tropft man die Reaktionslösung in Ether, wobei ein farbloser Niederschlag ausfällt. Ausb. 4,12g (95%). Farblose Prismen (aus Ethanol/Ether), F. 1140C.(1RS: 2SR) -1-phenyl-2- [N-methyl-N- (5-phenyl-6-methyl-6H-1,3,4-thiadiazin-2-yl) -amino] -propan-1- Hydrobromide: 2.39 g (10 mmol) of 4-methyl-4 - [(1RS: 2SR) -1-hydroxy-1-phenyl-prop-2-yl] thiosemicarbazide and 2.13 g (10 mmol) of a-bromo-propiophenone be in 30ml of ethanol 30min. heated to reflux. The reaction solution is then added dropwise to ether, whereby a colorless precipitate precipitates. Y. 4.12g (95%). Colorless prisms (from ethanol / ether), mp 114 ° C.

Claims (1)

Erfindungsanspruch:Invention claim: Verfahren zur Synthese von 1-Phenyl-2-[N-methyl-N-(6H-1,3,4-thiadiazin-2-yl)-amino]-propan-1-olen der allgemeinen Formel,Process for the synthesis of 1-phenyl-2- [N-methyl-N- (6H-1,3,4-thiadiazin-2-yl) -amino] -propan-1-ols of the general formula /CH3 OH '/ CH 3 OH ' ^CH-CH-C6H5
CH3
^ CH-CH-C 6 H 5
CH 3
gekennzeichnet dadurch, daß man äquimolare Mengen von 4-Methyl-4-[(1RS:2SR)-1-hydroxy-1-phenyl-prop-2-yl]-thiosemicarbazid mit a-Halogen-ketonen in Alkoholen oder DMF auf 40-1500C erwärmt und dann aufarbeitet. ,characterized by equimolar amounts of 4-methyl-4 - [(1RS: 2SR) -1-hydroxy-1-phenyl-prop-2-yl] thiosemicarbazide with α-halo ketones in alcohols or DMF at 40 ° C. 150 0 C heated and then worked up. .
DD25884683A 1983-12-29 1983-12-29 PROCESS FOR SYNTHESIS OF 1-PHENYL-2- (N-METHYL-N- (6H-1,3,4-THIADIAZIN-2-YL) -AMINO) -PROPAN-1-OLENE DD220311A1 (en)

Priority Applications (1)

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DD25884683A DD220311A1 (en) 1983-12-29 1983-12-29 PROCESS FOR SYNTHESIS OF 1-PHENYL-2- (N-METHYL-N- (6H-1,3,4-THIADIAZIN-2-YL) -AMINO) -PROPAN-1-OLENE

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DD25884683A DD220311A1 (en) 1983-12-29 1983-12-29 PROCESS FOR SYNTHESIS OF 1-PHENYL-2- (N-METHYL-N- (6H-1,3,4-THIADIAZIN-2-YL) -AMINO) -PROPAN-1-OLENE

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6028068A (en) * 1995-12-28 2000-02-22 The Procter & Gamble Company Substituted 6H-1,3,4-thiadiazine-2-amines, the use thereof as anaesthetising, cardiovascular and hypometabolic agents, and a pharmaceutical composition containing them
US6313111B1 (en) 1995-12-28 2001-11-06 The Procter & Gamble Company Substituted 6H-1,3,4-thiadiazine-2-amines, the use thereof as anaesthetising, cardiovascular and hypometabolic agents, and pharmaceutical composition containing them

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6028068A (en) * 1995-12-28 2000-02-22 The Procter & Gamble Company Substituted 6H-1,3,4-thiadiazine-2-amines, the use thereof as anaesthetising, cardiovascular and hypometabolic agents, and a pharmaceutical composition containing them
US6313111B1 (en) 1995-12-28 2001-11-06 The Procter & Gamble Company Substituted 6H-1,3,4-thiadiazine-2-amines, the use thereof as anaesthetising, cardiovascular and hypometabolic agents, and pharmaceutical composition containing them

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