DE2234202A1 - Prep. of oxoalkylxanthine - this has e.g. broncholytic and fibrinolytic activity - Google Patents

Prep. of oxoalkylxanthine - this has e.g. broncholytic and fibrinolytic activity

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Publication number
DE2234202A1
DE2234202A1 DE19722234202 DE2234202A DE2234202A1 DE 2234202 A1 DE2234202 A1 DE 2234202A1 DE 19722234202 DE19722234202 DE 19722234202 DE 2234202 A DE2234202 A DE 2234202A DE 2234202 A1 DE2234202 A1 DE 2234202A1
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DE
Germany
Prior art keywords
xanthine
oxo
dimethyl
hydroxy
chromium trioxide
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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.)
Pending
Application number
DE19722234202
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German (de)
Inventor
Alfons Dipl Chem Dr Soeder
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.)
Hoechst AG Werk Kalle Albert
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Chemische Werke Albert
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 Chemische Werke Albert filed Critical Chemische Werke Albert
Priority to DE19722234202 priority Critical patent/DE2234202A1/en
Priority to ES416696A priority patent/ES416696A1/en
Priority to AT611773A priority patent/AT330796B/en
Priority to JP7756073A priority patent/JPS5422517B2/ja
Priority to SE7309835A priority patent/SE400289B/en
Priority to NL7309709A priority patent/NL7309709A/xx
Priority to CH1019873A priority patent/CH588491A5/en
Publication of DE2234202A1 publication Critical patent/DE2234202A1/en
Priority to JP54042101A priority patent/JPS5918394B2/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

Abstract

Title cpds. of formula (I) (where >=1 of R1-R3 = 3-8C oxoalkyl with the CO gp(s) one or more C's removed from the xanthine nucleus, and the others are 1-6C alkyl). may be prepd. from the corresp. hydroxy alkyl cpds. by (a) dehydrogenation with O2 and a Gp VIII metal catalyst. (b) oxidation with Cr(VI), or (c) microbiological dehydrogenation.

Description

Verfahren zur Ilerstellung von Oxoalkylxanthinen Für die erstellung von Xanthinen mit Oxoalkylsubstituenten sind verschiedene Verfahren bekannt geworden, so die Anlagerung von Vinylketonen an Xanthine und die Umsetzung von Xanthinen mit Bromketonen.Process for the preparation of oxoalkylxanthines For the preparation of xanthines with oxoalkyl substituents, various processes have become known, so the addition of vinyl ketones to xanthines and the conversion of xanthines with Bromine ketones.

Durch die Instabilität der benötigten Vinylketone und Bromketone wird die technische~Iterstellung der für therapeutische Zwecke benötigten Oxoalkylxanthine erschwert.Due to the instability of the vinyl ketones and bromine ketones required the technical production of the oxoalkylxanthines required for therapeutic purposes difficult.

Es hat sich nun gezeigt, dass man von den entsprechenden sehr stabilen lIydroxyalkylxanthinen durch Dehydrierung in fast quantitativer Ausbeute zu den gewünschten Oxoalkylxanthinen gelangen kann.It has now been shown that one of the corresponding very stable LIydroxyalkylxanthinen by dehydrogenation in almost quantitative yield to the desired oxoalkylxanthines can arrive.

Gegenstand der Erfindung ist ein Verfahren zur erstellung von Verbindungen der allgemeinen Formel in der R1, 2 und R3 mindestens in einem Fall Oxoalkyl mit 3 - 8 Kohlenstoffatomen und in den restlichen Fällen Alkyl mit 1 - 3 Xohlenstoffatomen bedeuten, wobei jedoch das den Oxosßuerstoff tragende C-Atom nicht endständig ist und durch mindestens ein C-Atom vom Xanthingerüst getrennt ist.Das Verfahren ist dadurch gekennzeichnet, dass man die entsprechenden Hydroxyalkylverbindungen mit einer Chromverbindung der Wertigkeitsstufe IV bis VI dehydriert.The invention relates to a process for the preparation of compounds of the general formula in which R1, 2 and R3 are at least in one case oxoalkyl with 3-8 carbon atoms and in the remaining cases alkyl with 1-3 carbon atoms, but the carbon atom carrying the oxo oxygen is not terminal and is replaced by at least one carbon atom The process is characterized in that the corresponding hydroxyalkyl compounds are dehydrogenated with a chromium compound of valence levels IV to VI.

Uberraschenderweise konnten mit diesem Verfahren quantitative Dehydrierungen innerhalb von 10 Minuten erreicht werden, während zum Beispiel die vergleichbare Dehydrierung von 2-Octanol zu 2-Octanon in 15 bis 22 Stunden nur in 18 %iger Ausbeute erfolgt.Surprisingly, quantitative dehydrogenations could be carried out with this method can be achieved within 10 minutes, while for example the comparable Dehydrogenation of 2-octanol to 2-octanone in 15 to 22 hours only in 18% yield he follows.

Die als geeignete Ausgangsverbindungen dienenden Xanthinderivate tragen Alkylsubstituenten mit einer sekundären Alkoholgruppe in Position 1 und/oder 3 und/oder 7, wie die 1-(2-Hydroxy-propyl)-, 1-(3-Hydroxy-butyl)-, 1-(4-Hydroxy-pentyl)-, l-(5-llydroxy-hexyl)-, l-(6-Hydroxy-heptyl )- und l-(?-Hydroxy-octyl)-3,7-dimethylxanthine, das 3-(2-Hydroxy-propyl)-1,7-dimethylxanthin, die 7-(2-Hydroxy-propyl)-, 7-(3-Hydroxy-butyl)-, 7-(3-Hydroxy-2-methyl-butyl)-, 7- (3-IIydroxy-2-aethyl-butyl )-, 7- (3-Hydroxy-pentyl )-, 7-(4-Hydroxy-pentyl)-, 7-(5-Hydroxy-hexyl)-, 7-(6-Hydroxy-heptyl)-, und 7-(7-ydroxy-octyl)-1,3-dimethylxnthine und das 1,N,7-Tri-(2-hydroxy-propyl )-xanthin.The xanthine derivatives serving as suitable starting compounds carry Alkyl substituents with a secondary alcohol group in position 1 and / or 3 and / or 7, such as 1- (2-hydroxy-propyl) -, 1- (3-hydroxy-butyl) -, 1- (4-hydroxy-pentyl) -, 1- (5-llydroxy-hexyl) -, l- (6-Hydroxy-heptyl) - and l - (? - Hydroxy-octyl) -3,7-dimethylxanthine, 3- (2-Hydroxy-propyl) -1,7-dimethylxanthine, the 7- (2-hydroxy-propyl) -, 7- (3-hydroxy-butyl) -, 7- (3-hydroxy-2-methyl-butyl) -, 7- (3-II-hydroxy-2-ethyl-butyl) -, 7- (3-hydroxy-pentyl) -, 7- (4-hydroxy-pentyl) -, 7- (5-Hydroxy-hexyl) -, 7- (6-Hydroxy-heptyl) -, and 7- (7-Hydroxy-octyl) -1,3-dimethylxnthine and the 1, N, 7-tri- (2-hydroxypropyl) -xanthine.

Zur Dehydrierung der Hydroxyalkylxanthine werden diese in gegenüber den Reaktionsteilnehmern inerten Lösungsmitteln wie ethylenchlorid, Chloroform, Benzol, Essigsäure, Pyridin oder Dimethylformamid mit Chromsäure, Chromtrioxyd oder Chromtrioxyd-Dipyridin-omplex in einem Verhältnis von 2 bis 4 Mol Dehydrierungsmittel je Hydroxyalkyl-Seitenkette, gegebenenfalls in Gegenwart von Wasser und/oder katalytischen Mengen Schwefelsäure umgesetzt. Herstellung und Anwendung des Chromtrioxyd-Dipyridin-Komplexes sind beschrieben von Bauer im Handbuch der präparativen anorganischen Chemie, Band 2, Seite 1212, Ferdinand Enke Verlag, Stuttgart (1962) und von Sisler, Bush und Accountius in Journ. An er. Chem. Soc., Band 70, 3827 (1948). Anstelle der genannten Chromverbindungen können auch andere Verbindungen wie tert.-Butyl-chrmat verwendet werden, d. h. solche, die keine anderen, den Xantllinring angreifenden Gruppen wie Peroxygruppen enthalten. Jedoch hat sich die Dehydrierung mit Chromtrioxyd-Pyridinkomplexen, insbesondere dem Dipyridin-Komplex an besten bewährt.To dehydrate the hydroxyalkylxanthines, these are used in opposite the reactants inert solvents such as ethylene chloride, chloroform, Benzene, acetic acid, pyridine or dimethylformamide with chromic acid, chromium trioxide or Chromium trioxide-dipyridine complex in a ratio of 2 to 4 moles of dehydrating agent per hydroxyalkyl side chain, optionally in the presence of water and / or catalytic amounts Sulfuric acid implemented. Production and application of the chromium trioxide dipyridine complex are described by Bauer in the handbook of preparative inorganic chemistry, volume 2, page 1212, Ferdinand Enke Verlag, Stuttgart (1962) and by Sisler, Bush and Accountius in Journ. To him. Chem. Soc., Vol. 70, 3827 (1948). Instead of the mentioned Chromium compounds can also use other compounds such as tert-butyl chromate be, d. H. those who do not like other groups attacking the xantlline ring Contain peroxy groups. However, the dehydrogenation with chromium trioxide-pyridine complexes, in particular the dipyridine complex has proven its worth.

Die Dehydrierungen werden im allgemeinen bei Temperaturen von 0 bis 500 C, vorzugsweise von 5 bis 250 C durchgeführt. Der Zeitpunkt der vollständigen Dehydrierung lässt sich leicht erkennen, wenn man den Verlauf der Umsetzung chrornatographisch kontrolliert.The dehydrogenations are generally carried out at temperatures from 0 to 500.degree. C., preferably from 5 to 250.degree. The timing of the full Dehydration can easily be recognized if one looks at the course of the reaction by chromatography controlled.

Anschliessend versetzt man das Reaktionsgemisch mit Wasser. Ein eventuell noch vorhandener Überschuss der vier- bis sechswertigen Chromverbindung lässt s sich reduktiv, z. B. durch Zugabe einer aequivalenten Menge einer wässerigen Lösung von Alkalisulfit, Alkalihydrogensulfit oder Oxalsäure, beseitigen. Das Verfahrensprodukt kann in an sich bekannter Weise aus der organischen Phase und/oder aus der wässerigen Phase nach Extraktion, z. B.The reaction mixture is then mixed with water. A possibly any excess of the tetravalent to hexavalent chromium compound can s reductively, e.g. B. by adding an equivalent amount of an aqueous solution of alkali sulphite, alkali hydrogen sulphite or oxalic acid. The process product can in a manner known per se from the organic phase and / or from the aqueous phase Phase after extraction, e.g. B.

mit Methylenchlorid, Chloroform oder Äther nach Umkristallisation in reiner Form gewonnen werden.with methylene chloride, chloroform or ether after recrystallization can be obtained in pure form.

Die erfindungsgemäss erhaltenen Oxoalkylxanthine sind bekannt und zeichnen sich dadurch aus, das sie die Durchblutung fördern B e i s p i e l e : 1) Eine Lösung von 28 g (0,1 Nol) 1-(5-Hydroxy-hexyl)-3,7-dimethylxanthin in 100 ml Essigsäure wird untcr Rühren mit 0,3 Mol Chromtrioxyd-Dipyridin-Komplex, gelöst in 90 ml Essigsäure, versetzt, wobei einc Temperatur von 200 C nicht überschritten wird. Die Reaktion ist nach 10 Minuten beendet (chromatographische Kontrolle). Ein Rest von nicht verbrauchtem Dehydrierungsreagenz lässt sich nach Versetzen des Reaktionsgemisches mit Wasser mit Hilfe einer wässerigen Natriumsulfitlösung reduzieren; dabei tritt ein Farbumschlag nach dunkelgrau bis schwarz ein. Das gebildete 1-(5-Oxohexyl)-3,7-dimethyl xanthin wird durch Extraktion mit Chloroform isoliert. Aus Methanol umkristallisiert schmilzt es bei 103 - 105° C. Ausbeute 26,9 g (96 % der Theorie). IR-Spektrum und Dünnschichtchromatographie, jeweils nach der von W. Kohler und A. Söder, Arzneimittelforschung (Drug Res.) Band 21, 1159 - 1177 (1971) beschriebenen Methode bestätigen die Identität des Verfahrensproduktes.The oxoalkylxanthines obtained according to the invention are known and are characterized by the fact that they promote blood circulation. 1) A solution of 28 g (0.1 mol) 1- (5-hydroxy-hexyl) -3,7-dimethylxanthine in 100 ml of acetic acid is dissolved with 0.3 mol of chromium trioxide-dipyridine complex while stirring in 90 ml of acetic acid, added, whereby a temperature of 200 ° C is not exceeded will. The reaction is over after 10 minutes (chromatographic control). A The rest of unused dehydration reagent can be removed after addition of Reduce the reaction mixture with water using an aqueous sodium sulfite solution; the color changes from dark gray to black. The 1- (5-oxohexyl) -3,7-dimethyl formed xanthine is isolated by extraction with chloroform. Recrystallized from methanol it melts at 103-105 ° C. Yield 26.9 g (96% of theory). IR spectrum and Thin-layer chromatography, in each case according to that of W. Kohler and A. Söder, Arzneimittelforschung (Drug Res.) Vol. 21, 1159-1177 (1971) confirm the identity of the process product.

?-17) Nach der Arbeitsweise des Beispiels 1 werden folgende Oxoalkylxanthin hergestellt und in gleicher Weise wie im Beispiel 1 identifiziert: 2) 3,7-Dimethyl-l-(2-oxo-propyl)-xanthin Schmelzpunkt 167 C 3) 3,7-Dimethyl-1-(3-oxo-butyl)-xanthin ' 144-146 ° 4) 3,7-Dimethyl-1-(2-methyl-3-oxo-butyl)-xanthin " 203-205 ° C + 5) 3,7-Dimethyl-1-(2-aethyl-3-oxo-butyl)-xanthin " 200-205 ° C + 6) 3,7-Dimethyl-l-(4-oxo-pentyl)-xanthin " 111 ° C 7) 3,7-Dimethyl-1-(6-oxo-heptyl)-xanthin " 119-120 ° C 8) 1,3-Dimethyl-7-(2-oxo-propyl)-xanthin 162 ° 9) 1,3-Dimethyl-7-(1-methyl-2-oxo-propyl)-xanthin " 118-120 ° C 10) 1,3-Dimethyl-7-(3-oxo-butyl)-xanthin " It 140-141 ° C 11) 1,3-Dimethyl-7-(2-methyl-3-oxo-butyl)-xanthin " 133-135 ° C 12) 1,3-Dimethyl-7-(2-aethyl-3-oxo-butyl)xanthin " 107-108 ° C 13) 1,3-Dimethyl-7-(3-oxo-pentyl)-xanthin " 126-127 ° C 14) 1,3-Dimethyl-7-(4-oxo-pentyl)-xanthin " 86- 88 C 15) 1,3-Dimethyl-7-(5-oxo-hexyl)-xanthin " 75- 76 ° C 16) 1,3-Dimethyl-7-(6-oxo-heptyl)-xanthin " 69 C 17) 1,3-Dimethyl-7-(7-oxo-octyl)-xanthin " 85 ° C + Schmelzpunkte der 2,4-Dinitrophenylhydrazone ? -17) Following the procedure of Example 1, the following oxoalkylxanthines produced and identified in the same way as in Example 1: 2) 3,7-Dimethyl-1- (2-oxo-propyl) -xanthine Melting point 167 C 3) 3,7-dimethyl-1- (3-oxo-butyl) -xanthine '144-146 ° 4) 3,7-dimethyl-1- (2-methyl-3-oxo-butyl) -xanthine "203-205 ° C + 5) 3,7-Dimethyl-1- (2-aethyl-3-oxo-butyl) -xanthine" 200-205 ° C + 6) 3,7-Dimethyl-1- (4-oxo-pentyl) -xanthine "111 ° C 7) 3,7-Dimethyl-1- (6-oxo-heptyl) -xanthine "119-120 ° C 8) 1,3-dimethyl-7- (2-oxo-propyl) -xanthine 162 ° 9) 1,3-dimethyl-7- (1-methyl-2-oxo-propyl) -xanthine "118-120 ° C 10) 1,3-dimethyl-7- (3-oxo-butyl) -xanthine" It 140-141 ° C 11) 1,3-dimethyl-7- (2-methyl-3-oxo -butyl) -xanthine "133-135 ° C 12) 1,3-Dimethyl-7- (2-aethyl-3-oxo-butyl) xanthine" 107-108 ° C 13) 1,3-Dimethyl-7- (3-oxo-pentyl) -xanthine "126-127 ° C 14) 1,3-Dimethyl-7- (4-oxo-pentyl) -xanthine "86-88 C 15) 1,3-dimethyl-7- (5-oxo-hexyl) -xanthine" 75-76 ° C 16) 1,3-dimethyl-7- (6-oxo-heptyl) -xanthine "69 C 17) 1,3-dimethyl-7- (7-oxo-octyl) -xanthine" 85 ° C + melting points of the 2,4-dinitrophenyl hydrazones

Claims (5)

Patentansprüche 1) Verfahren zur Herstellung von Verbindungen der allgemeinen Formel in der R1, R2 und mindestens in einem Fall Oxoalkyl mit 3 bis 8 Kohlenstoffatomen und in den restlichen Fällen Alkyl mit 1 bis 3 Kohlenstoffatomen bedeuten, wobei jedoch das den Oxosauerstoff tragende C-Atom nicht durch - -endständig ist und/minaesten6 1 C-Atom vom Xanthingerüst getrennt ist, dadurch gekennzeichnet, dass man die entsprechenden Hydroxyalkylverbindungen mit einer Chromverbindung der Wertigkeitsstufe IV bis VI dehydriert.Claims 1) Process for the preparation of compounds of the general formula in which R1, R2 and at least in one case are oxoalkyl with 3 to 8 carbon atoms and in the remaining cases alkyl with 1 to 3 carbon atoms, but the carbon atom carrying the oxo oxygen is not through - -terminals and / or mines6 1 C- Atom is separated from the xanthine skeleton, characterized in that the corresponding hydroxyalkyl compounds are dehydrogenated with a chromium compound of valence levels IV to VI. 2) Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass Chromtrioxyd verwendet wird.2) Method according to claim 1, characterized in that chromium trioxide is used. 3) Verfahren nach Anspruch 2, dadurch gekennzeichnet, dass das Chromtrioxyd als Chromtrioxyd-Dipyridin-Komplex vorliegt.3) Method according to claim 2, characterized in that the chromium trioxide is present as a chromium trioxide dipyridine complex. 4) Verfahren nach Ansprüchen 1 bis 3, dadurch gekennzeichnet, dass man 2 bis 4 Mol Dehydrierungemittel pro Hydroxyalkyl-seitenkette anwendet.4) Process according to claims 1 to 3, characterized in that 2 to 4 moles of dehydrogenating agent are used per hydroxyalkyl side chain. 5) Verfahren nach Ansprüchen 1 bis 4 dadurch gekennzeichnet, dass man die Dehydrierung bei Temperaturen zwischen O und 500 C, bevorzugt zwischen 5 und 250 C durchführt.5) Process according to Claims 1 to 4, characterized in that the dehydrogenation is carried out at temperatures between 0 and 500 ° C., preferably between 5 and 250 C.
DE19722234202 1972-02-12 1972-07-12 Prep. of oxoalkylxanthine - this has e.g. broncholytic and fibrinolytic activity Pending DE2234202A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
DE19722234202 DE2234202A1 (en) 1972-07-12 1972-07-12 Prep. of oxoalkylxanthine - this has e.g. broncholytic and fibrinolytic activity
ES416696A ES416696A1 (en) 1972-07-12 1973-07-07 Procedure for the preparation of oxoalcohylxantinas. (Machine-translation by Google Translate, not legally binding)
AT611773A AT330796B (en) 1972-07-12 1973-07-11 METHOD FOR MANUFACTURING KETOALKYLXANTHINS
JP7756073A JPS5422517B2 (en) 1972-07-12 1973-07-11
SE7309835A SE400289B (en) 1972-07-12 1973-07-12 PROCEDURE FOR THE PREPARATION OF OXOALKYLXANTINES
NL7309709A NL7309709A (en) 1972-07-12 1973-07-12
CH1019873A CH588491A5 (en) 1972-07-12 1973-07-12 Prep. of oxoalkylxanthine - this has e.g. broncholytic and fibrinolytic activity
JP54042101A JPS5918394B2 (en) 1972-02-12 1979-04-09 Method for producing oxoalkylxanthines

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19722234202 DE2234202A1 (en) 1972-07-12 1972-07-12 Prep. of oxoalkylxanthine - this has e.g. broncholytic and fibrinolytic activity

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DE2234202A1 true DE2234202A1 (en) 1974-01-24

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DE19722234202 Pending DE2234202A1 (en) 1972-02-12 1972-07-12 Prep. of oxoalkylxanthine - this has e.g. broncholytic and fibrinolytic activity

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2507555A1 (en) * 1975-02-21 1976-09-02 Wuelfing J A Fa 7- (OXOALKYL) -1,3-DIALKYLXANTHINE, THE METHOD OF MANUFACTURING THEREOF AND MEDICINAL PRODUCTS CONTAINING THIS COMPOUND
US4242345A (en) 1974-01-22 1980-12-30 Johann A. Wulfing 7-(Oxoalkyl)-1,3-dialkyl xanthines, and medicaments containing them
EP0430025A2 (en) * 1989-11-24 1991-06-05 Hokuriku Pharmaceutical Co., Ltd. Xanthine compound, method for preparing thereof, and a pharmaceutical composition comprising the same
EP0570831A2 (en) * 1992-05-20 1993-11-24 Hoechst Aktiengesellschaft Use of Xanthinderivatives for treatment of cerebral nerve dammages after disruption of the blood circulation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0042706B1 (en) * 1980-06-21 1985-12-27 BEECHAM - WUELFING GmbH & Co. KG Xanthine derivatives, pharmaceutical compositions containing them and a process for their preparation

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4242345A (en) 1974-01-22 1980-12-30 Johann A. Wulfing 7-(Oxoalkyl)-1,3-dialkyl xanthines, and medicaments containing them
DE2507555A1 (en) * 1975-02-21 1976-09-02 Wuelfing J A Fa 7- (OXOALKYL) -1,3-DIALKYLXANTHINE, THE METHOD OF MANUFACTURING THEREOF AND MEDICINAL PRODUCTS CONTAINING THIS COMPOUND
EP0430025A2 (en) * 1989-11-24 1991-06-05 Hokuriku Pharmaceutical Co., Ltd. Xanthine compound, method for preparing thereof, and a pharmaceutical composition comprising the same
EP0430025A3 (en) * 1989-11-24 1992-05-06 Hokuriku Pharmaceutical Co., Ltd. Xanthine compound, method for preparing thereof, and a pharmaceutical composition comprising the same
EP0570831A2 (en) * 1992-05-20 1993-11-24 Hoechst Aktiengesellschaft Use of Xanthinderivatives for treatment of cerebral nerve dammages after disruption of the blood circulation
EP0570831A3 (en) * 1992-05-20 1994-03-16 Hoechst Ag

Also Published As

Publication number Publication date
JPS557259A (en) 1980-01-19
JPS5918394B2 (en) 1984-04-26

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