DE4003262A1 - Use of naphth:oxazine derivs. - Google Patents

Use of naphth:oxazine derivs.

Info

Publication number
DE4003262A1
DE4003262A1 DE19904003262 DE4003262A DE4003262A1 DE 4003262 A1 DE4003262 A1 DE 4003262A1 DE 19904003262 DE19904003262 DE 19904003262 DE 4003262 A DE4003262 A DE 4003262A DE 4003262 A1 DE4003262 A1 DE 4003262A1
Authority
DE
Germany
Prior art keywords
naphth
oxazine
hexahydro
methoxy
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
DE19904003262
Other languages
German (de)
Inventor
Joachim Dr Nozulak
Andre Dr Sauter
Jean-Marie Vigouret
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AG
Sandoz Patent GmbH
Original Assignee
Sandoz AG
Sandoz Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sandoz AG, Sandoz Patent GmbH filed Critical Sandoz AG
Priority to DE19904003262 priority Critical patent/DE4003262A1/en
Priority to HU908017A priority patent/HU214591B/en
Priority to EP90810968A priority patent/EP0433239B1/en
Priority to DE69013476T priority patent/DE69013476T2/en
Priority to DK90810968.9T priority patent/DK0433239T3/en
Priority to AT90810968T priority patent/ATE113040T1/en
Priority to ES90810968T priority patent/ES2063328T3/en
Priority to MYPI90002168A priority patent/MY108782A/en
Priority to CA002032132A priority patent/CA2032132A1/en
Priority to US07/626,352 priority patent/US5190941A/en
Priority to AU67975/90A priority patent/AU639512B2/en
Priority to KR1019900020463A priority patent/KR0182276B1/en
Priority to IE449790A priority patent/IE66143B1/en
Priority to JP2410720A priority patent/JPH0825880B2/en
Priority to PT96178A priority patent/PT96178B/en
Publication of DE4003262A1 publication Critical patent/DE4003262A1/en
Priority to HK97101777A priority patent/HK1000244A1/en
Priority to CY9802065A priority patent/CY2065B1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings

Abstract

The use of naphthoxazines of formula (I) in pharmaceutical compsns. for the treatment of conditions associated with cerebral ischaemia, e.g. stroke, is new. R1 and R2 independently are H or 1-4C alkyl. R3 = OH or 1-4C alkoxy. R4 = 1-4C alkylthio, 1-4C alkylsulphoxide, 1-4C alkylsulphone, Ckl, Br, I or CF3. Also claimed is (-)-(4aR,10aR)-3,4,4a,5,10,10a-hexahydro-6-methoxy-4-methyl-9-methylth io-2H-naphth(2,3-b)-1,4-oxazine hydrogen malonate, its use in pharmaceutical compsns., and a process for its prodn. which includes the step of reacting the corresponding free base (II) with malonic acid.

Description

Die Erfindung betrifft das (-)-(4aR,10aR)-3,4,4a,5,10,10a- Hexahydro-6-methoxy-4-methyl-9-methylthio-2H-naphth[2,3-b]- 1,4-oxazin-hydrogenmalonat der Formel I.The invention relates to (-) - (4aR, 10aR) -3,4,4a, 5,10,10a- Hexahydro-6-methoxy-4-methyl-9-methylthio-2H-naphth [2,3-b] - 1,4-oxazine hydrogen malonate of formula I.

Die freie Base und das Hydrochlorid des (-)-(4aR,10aR)- 3,4,4a,5,10,10a-Hexahydro-6-methoxy-4-methyl-9-methylthio-2H- naphth[2,3-b]-1,4-oxazins sind aus der deutschen Offenlegungsschrift 35 20 104 bekannt.The free base and the hydrochloride of (-) - (4aR, 10aR) - 3,4,4a, 5,10,10a-hexahydro-6-methoxy-4-methyl-9-methylthio-2H- naphth [2,3-b] -1,4-oxazine are from the German published application 35 20 104 known.

Gemäß Beispiel 2 dieser Veröffentlichung wird die freie Base als Öl erhalten. Betreffend das Hydrochlorid wurde gezeigt, daß dieses Salz Polymorphorismus aufweist. Weitere, von der Anmelderin ebenfalls hergestellte Salze, wie z. B. das Hydrogenmaleinat und das Hydrogenfumarat, weisen den gleichen Nachteil auf. Es ist z. B. bekannt, daß polymorphe Salze nach peroraler Verabreichung eine nicht homogene Resorption verursachen.According to example 2 of this publication, the free base is as Get oil. Regarding the hydrochloride, it was shown that this salt has polymorphorism. Further, by the applicant also prepared salts, such as. B. the hydrogen maleate and the hydrogen fumarate have the same disadvantage. It is e.g. B. known that polymorphic salts after oral administration cause a non-homogeneous absorption.

Es wurde nun überraschenderweise gefunden, daß das Hydrogenmalonat der Formel I keinen Polymorphismus zeigt.It has now surprisingly been found that the hydrogen malonate of formula I shows no polymorphism.

Die Verbindung der Formel I ist in der Literatur bisher noch nicht beschrieben worden. Sie kann aus der freien Base durch Umsetzung mit Malonsäure hergestellt werden, z. B. wie im nachfolgenden Beispiel beschrieben.The compound of formula I is still in the literature has not been described. You can go through from the free base Reaction can be prepared with malonic acid, e.g. B. as in the following Example described.

Die Verbindung der Formel I weist im Tierversuch interessante pharmakologische Eigenschaften auf, wie in der oben erwähnten deutschen Offenlegungsschrift beschrieben, und kann aufgrund dieser Wirkungen als Psychostimulans und Antidepressivum Anwendung finden.The compound of the formula I has interesting results in animal experiments pharmacological properties as mentioned in the above German published specification, and may be due to these effects as psychostimulant and antidepressant application Find.

Für die oben genannten Anwendungen variiert die zu verwendende Dosis selbstverständlich je nach verwendeter Substanz, Art der Administration und der gewünschten Behandlung. Im allgemeinen werden aber befriedigende Resultate mit Dosen von ungefähr 0,5 bis 50 mg/kg Körpergewicht erreicht; die Administration kann mit einer Dosis täglich vorgenommen werden oder nötigenfalls in mehreren Teildosen erfolgen. Für größere Säugetiere liegt die Tagesdosis im Bereich von etwa 1 bis 50 mg der Substanz, geeignete Dosierungsformen enthalten im allgemeinen ungefähr 0,3 bis 50 mg wirksame Substanz neben festen oder flüssigen Trägersubstanzen oder Verdünnungsmitteln.The one to be used varies for the above applications Dose of course depending on the substance used, type of Administration and the desired treatment. In general but will have satisfactory results with doses of approximately Reached 0.5 to 50 mg / kg body weight; the administration can with one dose daily or, if necessary, in several partial doses. For larger mammals, that is Daily dose in the range of about 1 to 50 mg of the substance, suitable Dosage forms generally contain approximately 0.3 to 50 mg of active substance in addition to solid or liquid Carriers or diluents.

Als Heilmittel können die erfindungsgemäßen Verbindungen allein oder in geeigneter Arzneiform mit pharmakologisch indifferenten Stoffen verabreicht werden.The compounds according to the invention alone can be used as medicines or in a suitable pharmaceutical form with pharmacologically indifferent Substances are administered.

Das nachfolgende Beispiel erläutert die Erfindung. Temperaturangaben erfolgen in Celsiusgraden und sind unkorrigiert.The following example explains the invention. Temperature information are in degrees Celsius and are uncorrected.

Beispielexample (-)-(4aR,10aR)-3,4,4a,5,10,10a-Hexahydro-6-methoxy- 4-methyl-9-methylthio-2H-naphth[2,3-b]-1,4-oxazin- hydrogenmalonat(-) - (4aR, 10aR) -3,4,4a, 5,10,10a-hexahydro-6-methoxy- 4-methyl-9-methylthio-2H-naphth [2,3-b] -1,4-oxazin- hydrogen malonate

Zu 2,00 g (7,2 mmol) (-)-(4aR,10aR)-3,4,4a,5,10,10a-Hexahydro- 6-methoxy-4-methyl-9-methylthio-2H-naphth[2,3-b]-1,4-oxazin in Aceton gibt man eine Lösung von 0,75 g (7,2 mmol) Malonsäure in Aceton. Das auskristallisierende Produkt wird abgesaugt, mit Essigester und Ether gewaschen und getrocknet. Man erhält nach Umkristallisation aus Aceton/Essigester/Ether (-)-(4aR,10aR)- 3,4,4a,5,10,10a-Hexahydro-6-methoxy-4-methyl-9-methylthio-2H- naphth[2,3-b]-1,4-oxazin-hydrogenmalonat mit dem Schmelzpunkt 127° und dem Drehwert [α]=-102,5° (c=0,5, Methylenchlorid: Methanol, 1 : 1).To 2.00 g (7.2 mmol) (-) - (4aR, 10aR) -3,4,4a, 5,10,10a-hexahydro- 6-methoxy-4-methyl-9-methylthio-2H-naphth [2,3-b] -1,4-oxazine in Acetone is added to a solution of 0.75 g (7.2 mmol) malonic acid Acetone. The product which crystallizes out is filtered off with Washed ethyl acetate and ether and dried. You get after Recrystallization from acetone / ethyl acetate / ether (-) - (4aR, 10aR) - 3,4,4a, 5,10,10a-hexahydro-6-methoxy-4-methyl-9-methylthio-2H- naphth [2,3-b] -1,4-oxazine hydrogen malonate with the melting point 127 ° and the rotation value [α] = - 102.5 ° (c = 0.5, methylene chloride: Methanol, 1: 1).

Claims (4)

1. Das (-)-(4aR,10aR)-3,4,4a,5,10,10a-Hexahydro-6-methoxy- 4-methyl-9-methylthio-2H-naphth[2,3-b]-1,4-oxazin-hydrogenmalonat der Formel I. 1. The (-) - (4aR, 10aR) -3,4,4a, 5,10,10a-hexahydro-6-methoxy-4-methyl-9-methylthio-2H-naphth [2,3-b] - 1,4-oxazine hydrogen malonate of formula I. 2. Verfahren zur Herstellung von (-)-(4aR,10aR)-3,4,4a,5,10,10a- Hexahydro-6-methoxy-4-methyl-9-methylthio-2H-naphth[2,3-b]- 1,4-oxazin-hydrogenmalonat, dadurch gekennzeichnet, daß man (-)-(4aR,10aR)-3,4,4a,5,10,10a-Hexahydro-6-methoxy-4-methyl- 9-methylthio-2H-naphth[2,3-b]-1,4-oxazin mit Malonsäure umsetzt.2. Process for the preparation of (-) - (4aR, 10aR) -3,4,4a, 5,10,10a- Hexahydro-6-methoxy-4-methyl-9-methylthio-2H-naphth [2,3-b] - 1,4-oxazine hydrogen malonate, characterized in that (-) - (4aR, 10aR) -3,4,4a, 5,10,10a-hexahydro-6-methoxy-4-methyl- 9-methylthio-2H-naphth [2,3-b] -1,4-oxazine is reacted with malonic acid. 3. Eine pharmazeutische Zusammensetzung, enthaltend die Verbindung der Formel I gemäß Anspruch 1, zusammen mit pharmakologisch indifferenten Stoffen.3. A pharmaceutical composition containing the compound of formula I according to claim 1, together with pharmacologically indifferent substances. 4. Die Verbindung der Formel I gemäß Anspruch 1 zur Anwendung als Pharmazeutikum.4. The compound of formula I according to claim 1 for use as a pharmaceutical.
DE19904003262 1989-12-14 1990-02-03 Use of naphth:oxazine derivs. Withdrawn DE4003262A1 (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
DE19904003262 DE4003262A1 (en) 1990-02-03 1990-02-03 Use of naphth:oxazine derivs.
HU908017A HU214591B (en) 1989-12-14 1990-11-30 Process for preparing the malonate salt of a naphthoxazine derivative and pharmaceutical compns. contg. the said compnd. as active ingredient
EP90810968A EP0433239B1 (en) 1989-12-14 1990-12-11 Use of naphthoxazines
DE69013476T DE69013476T2 (en) 1989-12-14 1990-12-11 Use of naphthoxazines.
DK90810968.9T DK0433239T3 (en) 1989-12-14 1990-12-11 Use of naphthoxazines
AT90810968T ATE113040T1 (en) 1989-12-14 1990-12-11 APPLICATION OF NAPHTHOXAZINES.
ES90810968T ES2063328T3 (en) 1989-12-14 1990-12-11 NEW USE OF NAFTOXAZINES.
US07/626,352 US5190941A (en) 1989-12-14 1990-12-12 Use of naphthoxazines for the treatment of conditions associated with cerebral ischaemia
CA002032132A CA2032132A1 (en) 1989-12-14 1990-12-12 Use of naphthoxazines
MYPI90002168A MY108782A (en) 1989-12-14 1990-12-12 New use of naphthoxazines.
AU67975/90A AU639512B2 (en) 1989-12-14 1990-12-12 Improvements in or relating to organic compounds
KR1019900020463A KR0182276B1 (en) 1989-12-14 1990-12-13 Pharmaceutical use of naphthoxazines
IE449790A IE66143B1 (en) 1989-12-14 1990-12-13 Use of naphthoxazines
JP2410720A JPH0825880B2 (en) 1989-12-14 1990-12-13 New uses of naphthoxazines
PT96178A PT96178B (en) 1989-12-14 1990-12-13 METHOD FOR THE USE OF NAFTOXAZINS IN THE TREATMENT OF CONDITIONS ASSOCIATED WITH CEREBRAL SCHEME
HK97101777A HK1000244A1 (en) 1989-12-14 1997-09-15 Use of naphthoxazines
CY9802065A CY2065B1 (en) 1989-12-14 1998-06-12 Use of naphthoxazines

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19904003262 DE4003262A1 (en) 1990-02-03 1990-02-03 Use of naphth:oxazine derivs.

Publications (1)

Publication Number Publication Date
DE4003262A1 true DE4003262A1 (en) 1991-08-08

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ID=6399397

Family Applications (1)

Application Number Title Priority Date Filing Date
DE19904003262 Withdrawn DE4003262A1 (en) 1989-12-14 1990-02-03 Use of naphth:oxazine derivs.

Country Status (1)

Country Link
DE (1) DE4003262A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3520104A1 (en) * 1984-06-12 1985-12-12 Sandoz-Patent-GmbH, 7850 Lörrach Naphthoxazines, their preparation and use

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3520104A1 (en) * 1984-06-12 1985-12-12 Sandoz-Patent-GmbH, 7850 Lörrach Naphthoxazines, their preparation and use

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