DE2622981A1 - (N)-Haloalkyl nitrogen-contg. heterocyclics prodn. - by reacting (N)-heterocyclics e.g. barbiturates with bis-haloalkyl sulphates, e.g. bis-chloroethyl sulphate - Google Patents
(N)-Haloalkyl nitrogen-contg. heterocyclics prodn. - by reacting (N)-heterocyclics e.g. barbiturates with bis-haloalkyl sulphates, e.g. bis-chloroethyl sulphateInfo
- Publication number
- DE2622981A1 DE2622981A1 DE19762622981 DE2622981A DE2622981A1 DE 2622981 A1 DE2622981 A1 DE 2622981A1 DE 19762622981 DE19762622981 DE 19762622981 DE 2622981 A DE2622981 A DE 2622981A DE 2622981 A1 DE2622981 A1 DE 2622981A1
- Authority
- DE
- Germany
- Prior art keywords
- bis
- chloroethyl
- haloalkyl
- heterocyclics
- phenobarbital
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
- C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
- C07D233/72—Two oxygen atoms, e.g. hydantoin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
Abstract
Description
Verfahren zur Herstellung von halogen- Process for the production of halogen
alkylierten Verbindungen. alkylated compounds.
Die Erfindung betrifft ein Verfahren zur Herstellung von N-halogenalkylierten Verbindungen, die dabei erhaltenen Verbindungen und sie enthaltende Arzneimittel.The invention relates to a process for the preparation of N-haloalkylated compounds Compounds, the compounds obtained thereby and medicaments containing them.
Die Erfindung betrifft insbesondere ein Verfahren zur Herstellung von N-halogenaikylierten, stickstoffhaltigen heterocyclischen Verbindungen durch Umsetzen eines Alkalimetallsalzes einer stickstoffhaltigen heterocyclischen Verbindung mit einem Bis(halogenalkyl)-sulfat. Die Reinigung des erhaltenen Bis(halogenalkyl)-derivats erfolgt in Abhängigkeit von dem besonderen Derivat oder den vorliegenden Anforderungen in üblicher Weise, beispielsweise durch Umkristallisation oder durch Chromatographie.In particular, the invention relates to a method of manufacture of N-haloalkylated, nitrogen-containing heterocyclic compounds Reacting an alkali metal salt of a nitrogen-containing heterocyclic compound with a bis (haloalkyl) sulfate. Purification of the bis (haloalkyl) derivative obtained takes place depending on the particular derivative or the existing requirements in customary manner, for example by recrystallization or by Chromatography.
Das erfindungsgemäße Verfahren ist besonders geeignet zur Herstellung von Bis(halogenalkyl)-barbiturat-derivaten. Es ist bekannt, daß Barbiturate, wie Phenobarbital (Phenobarbiton oder 5-Äthyl-5-phenyl-barbitursäure) narkotische Eigenschaften besitzen, aufgrund derer sie seit vielen Jahren therapeutisch genutzt werden. Phenobarbital wird als antikonvulsives Mittel für Warmblütler eingesetzt und wurde auch zur Behandlung der Epilepsie verwendet. Es leidet jedoch an dem Nachteil, daß es sowohl eine hypnotische Wirkung als auch eine antikonvulsive Wirkung entfaltet. Es wurde gefunden (US-PS 3 635 980), daß N,N'-Bis(halogenmethyl)-phenobarbital-Verbindungen wirksame antikonvulsive Mittel darstellen, die aus pharmakologischer Sicht Phenobarbital insofern überlegen sind, als sie keine hypnotischen Wirkungen besitzen.The method according to the invention is particularly suitable for production of bis (haloalkyl) barbiturate derivatives. It is known that barbiturates such as Phenobarbital (phenobarbitone or 5-ethyl-5-phenyl-barbituric acid) has narcotic properties because of which they have been used therapeutically for many years. phenobarbital is used as an anticonvulsant for warm-blooded animals and has also been used for treatment used in epilepsy. However, it suffers from the disadvantage that it is both hypnotic Effect as well as an anticonvulsant effect unfolds. It was found (U.S. PS 3,635,980) that N, N'-bis (halomethyl) phenobarbital compounds are effective anticonvulsant Represent agents that are superior to phenobarbital from a pharmacological point of view are when they have no hypnotic effects.
Die in dieser US-Patentschrift angegebenen Syntheseverfahren sind jedoch aufwendig und langwierig, da sie 5 bis 7 Tage erfordern. Andererseits ist das oben beschriebene und im folgenden anhand der bevorzugten Ausführungsformen zur Synthese von Bis(chloräthyl)-barbitursäurederivaten erläuterte erfindungsgemäße Verfahren relativ sehr einfach und erfordert nicht mehr als eine einstufige Umsetzung. Die Verbindungen erhält man durch die direkte Umsetzung des Alkalimetallsalzes des freien Barbitursäurederivates mit Bis(chloräthyl)-sulfat.The synthetic methods given in this US patent are however, time-consuming and tedious, since they take 5 to 7 days. On the other hand is that described above and below with reference to the preferred embodiments for the synthesis of bis (chloroethyl) barbituric acid derivatives explained according to the invention Procedure relatively very simple and does not require more than a one-step implementation. The compounds are obtained by direct reaction of the alkali metal salt of free barbituric acid derivative with bis (chloroethyl) sulfate.
Das erfindungsgemäße Verfahren ist mit besonderem Vorteil anwendbar auf: 1. Barbiturate, beispielsweise Phenobarbital, Amylobarbital, Pentobarbital, Hexobarbital, Butobarbital, Barbital, Secobarbital, Cyclobarbital, Mephobarbital und Secbutobarbital, zur Herstellung der entsprechenden Bis(chloräthyl)-derivate und 2. auf andere antikonvulsive Arzneimittel, einschließlich Ethosuximid in Form seines N-Chloräthyl-derivats, Peganon (3-Äthyl-5-phenylhydantoin) in Form seines N-Chloräthyl-derivats, Mephenytoin in Form seines N-Chloräthyl-derivats, Glutethimid in Form seines N-Chloräthyl-derivats und Diphenylhydantoin in Form seines N-Chloräthyl-derivats und in Form seines N,N'-Bis(chloräthyl)-derivats.The method according to the invention can be used with particular advantage on: 1. Barbiturates, for example phenobarbital, amylobarbital, pentobarbital, Hexobarbital, butobarbital, barbital, secobarbital, cyclobarbital, mephobarbital and secbutobarbital, for the preparation of the corresponding bis (chloroethyl) derivatives and 2. to other anticonvulsant drugs, including Ethosuximide in the form of its N-chloroethyl derivative, peganone (3-ethyl-5-phenylhydantoin) in the form its N-chloroethyl derivative, mephenytoin in the form of its N-chloroethyl derivative, Glutethimide in the form of its N-chloroethyl derivative and diphenylhydantoin in the form of its N-chloroethyl derivative and in the form of its N, N'-bis (chloroethyl) derivative.
Das erfindungsgemäße Verfahren erlaubt, wenn möglich, auch die Herstellung der monoalkylierten Derivate, das heißt sowohl des N-Chloräthyl-derivats als auch des N,N'-Bis(chloräthyl)-derivats.If possible, the process according to the invention also allows production the monoalkylated derivatives, that is, both the N-chloroethyl derivative and of the N, N'-bis (chloroethyl) derivative.
Die folgenden Beispiele dienen der weiteren Erläuterung der Erfindung.The following examples serve to further illustrate the invention.
Beispiel 1 N,N'-Bis(chloräthyl)-phenobarbital.Example 1 N, N'-bis (chloroethyl) phenobarbital.
Man erhitzt eine Mischung, die 0,35 g Phenobarbital, 1,5 g Kaliumcarbonat, 15 ml absolutes Äthanol und 1,6 ml Bis(chloräthyl)-sulfat enthält, während 1 Stunde zum Sieden am Rückfluß.A mixture is heated containing 0.35 g of phenobarbital, 1.5 g of potassium carbonate, Contains 15 ml of absolute ethanol and 1.6 ml of bis (chloroethyl) sulfate for 1 hour to reflux.
Dann zieht man das restliche Äthanol im Vakuum ab und behandelt das zurückbleibende öl mit 25 ml Wasser und dann mit 25 ml Äther. Die isolierte wässrige Phase extrahiert man ein zweites Mal mit 25 ml Äther und wäscht die vereinigten Ätherphasen mit verdünnter Säure und anschließend mit Wasser. Durch Entfernen des Äthers erhält man ein viskoses gelbes öl (0,36 g), das eine gewisse Menge überschüssigen Bis(chloräthyl)-sulfats enthält.Then you pull off the remaining ethanol in vacuo and treat it residual oil with 25 ml of water and then with 25 ml of ether. The isolated aqueous Phase is extracted a second time with 25 ml of ether and washed the combined Ether phases with dilute acid and then with water. By removing the Ether gives a viscous yellow oil (0.36 g), which has a certain amount of excess Contains bis (chloroethyl) sulfate.
Man löst das öl in Hexan und trägt es auf eine mit aktiviertem Aluminiumoxid (115 g in Hexan) beschickte Säule auf. Die Entwicklung erfolgt mit 285 ml Hexan, dann mit 270 ml einer 1%igen (Volumen/Volumen) Lösung von Äther in Hexan und schließmit mit 95 ml einer 10%igen Lösung (Volumen/Volumen) Äther in Hexan. In dieser Weise wird das gewünschte Derivat durch die eingesetzten Lösungsmittel eluiert, während das überschüssige Bis(chloräthyl)-sulfat von der Säule zurückgehalten wird. Durch Abziehen des Lösungsmittels erhält man 0,22 g (Ausbeute = 39%) eines weißen Feststoffs mit einem Schmelzpunkt von 79 bis 800C.Dissolve the oil in hexane and apply it to an activated aluminum oxide (115 g in hexane) loaded column. The development takes place with 285 ml of hexane, then with 270 ml of a 1% (volume / volume) solution of ether in hexane and finally with 95 ml of a 10% solution (volume / volume) ether in hexane. That way the desired derivative is eluted by the solvent used while the excess Bis (chloroethyl) sulfate retained by the column will. By stripping off the solvent, 0.22 g (yield = 39%) of one is obtained white solid with a melting point of 79 to 800C.
Analyse: C H N ber. 53,80 5,08 7,84 % gef. 54,10 5,01 7,55 % Beispiel 2 N, N' -Bis (chloräthyl) -pentobarbital.Analysis: C H N calc. 53.80 5.08 7.84% found. 54.10 5.01 7.55% Example 2 N, N '-bis (chloroethyl) pentobarbital.
Man erhitzt eine Mischung aus 0,23 g Pentobarbital, 1 g Kaliumcarbonat, 1,6 ml Bis(chloräthyl)-sulfat und 12 ml absolutem Äthanol während 1 Stunde zum Sieden am Rückfluß.A mixture of 0.23 g of pentobarbital, 1 g of potassium carbonate, 1.6 ml of bis (chloroethyl) sulfate and 12 ml of absolute ethanol for 1 hour to the boil at reflux.
Das restliche Äthanol wird im Vakuumiabgezogen, wonach man das zurückbleibende Öl mit 25 ml Wasser und 25 ml Äther behandelt. Die isolierte wässrige Phase wird ein zweites Mal mit 25 ml Äther extrahiert, worauf man die vereinigten Ätherphasen mit verdünnter Säure und schließlich mit Wasser wäscht.The remaining ethanol is removed in vacuo, after which the remaining Oil treated with 25 ml of water and 25 ml of ether. The isolated aqueous phase is extracted a second time with 25 ml of ether, whereupon the combined ether phases washes with dilute acid and finally with water.
Durch Abziehen des Äthers erhält man ein viskoses gelbes Öl.A viscous yellow oil is obtained by stripping off the ether.
Man trägt das Öl auf eine mit aktiviertem Aluminiumoxid (64 g in Hexan) beschickte Säule auf und eluiert das gewünschte Derivat mit 320 ml Hexan, worauf man aus dem Eluat nach dem Abtrennen des Lösungsmittels 0,15 g (Ausbeute = 43%j des gewünschten Produktes in Form eines farblosen Öles erhält.The oil is applied to an activated aluminum oxide (64 g in hexane) loaded column and eluted the desired derivative with 320 ml of hexane, whereupon one from the eluate after separating off the solvent 0.15 g (yield = 43% j of the desired product in the form of a colorless oil.
Analyse: C H N ber.: 51,6 6,94 7,46 % gef.: 51,29 6,89 7,98 % Beispiel 3 N,N'-Bis(chloräthyl)-amylobarbital.Analysis: C H N calc .: 51.6 6.94 7.46% found: 51.29 6.89 7.98% example 3 N, N'-bis (chloroethyl) amylobarbital.
Man erhitzt eine Mischung aus 0,23 g Amylobarbital 1 g Kaliumcarbonat, 12 ml absolutem Äthanol und 1,6 ml Bis(chloräthyl)-sulfat während 15 Minuten zum Sieden am Rückfluß.A mixture of 0.23 g of amylobarbital 1 g of potassium carbonate is heated, 12 ml of absolute ethanol and 1.6 ml of bis (chloroethyl) sulfate for 15 minutes Reflux.
Dann zieht man das Lösungsmittel ab, versetzt den Rückstand mit 25 mol Wasser und extrahiert zweimal mit 25 ml Äther. Man wäscht die vereinigten Ätherphasen mit verdünnter Säure und schließlich mit Wasser. Nach dem Abziehen des Äthers erhält man 0,24 g eines Rückstandes in Form eines viskosen gelben Öls.The solvent is then drawn off, and 25 is added to the residue mol of water and extracted twice with 25 ml of ether. The combined ether phases are washed with dilute acid and finally with water. Receives after removing the ether 0.24 g of a residue in the form of a viscous yellow oil.
Das Öl trägt man auf eine mit aktiviertem Aluminiumoxid (115 g in Hexan) beschickte Säule auf und entwickelt mit 130 ml Hexan. Das Derivat wird mit 140 ml einer 196igen Lösung von Äther in Hexan eluiert. Nach dem Abziehen des Lösungsmittels erhält man 0,14 g (Ausbeute = 40%) des Produktes in Form- eines farblosen Öls.The oil is applied to an activated alumina (115 g in Hexane) charged column and developed with 130 ml of hexane. The derivative is with 140 ml of a 196igen solution of ether in hexane eluted. After removing the solvent 0.14 g (yield = 40%) of the product is obtained in the form of a colorless oil.
Analyse: C H N ber.: 51,46 7,04 7,45 % gef.: 51,29 6,89 7,45 % Beispiel 4 N-Chloräthyl-ethosuximid.Analysis: C H N calc .: 51.46 7.04 7.45% found: 51.29 6.89 7.45% Example 4 N-chloroethyl-ethosuximide.
Man erhitzt eine Mischung aus 0,28 g Ethosuximid, 1,6 mol Bis(chloräthyl)-sulfat, 1,0 g Kaliumcarbonat und 15 ml absolutem Äthanol während 10 Minuten zum Sieden am Rückfluß.A mixture of 0.28 g of ethosuximide, 1.6 mol of bis (chloroethyl) sulfate is heated, 1.0 g of potassium carbonate and 15 ml of absolute ethanol for 10 minutes to the boiling point Reflux.
Den Rückstand behandelt man nach dem Abziehen des Lösungsmittels mit 25 ml Wasser und 25 ml Äthylacetat. Man wäscht die Äthylacetatschicht mit dreimal 15 ml Wasser, trocknet sie und engt sie durch Abziehen des Lösungsmittels zu einem Öl ein.After the solvent has been stripped off, the residue is treated with 25 ml of water and 25 ml of ethyl acetate. The ethyl acetate layer is washed three times 15 ml of water, dry them and concentrate them by stripping off the solvent Oil a.
Das Reinigen erfolgt mit Hilfe einer mit Aluminiumoxid (115 g) beschickten Säule durch Elution des Derivats mit 220 ml einer 5%igen Lösung (Volumen/Volumen) von Äthylacetat in Hexan, wobei man 0,29 g (Ausbeute = 72%) des gewünschten Produkts in Form eines farblosen Öls erhält.The cleaning is carried out with the aid of a loaded with aluminum oxide (115 g) Column by eluting the derivative with 220 ml of a 5% solution (volume / volume) of ethyl acetate in hexane, 0.29 g (yield = 72%) of the desired product in the form of a colorless oil.
Analyse: CgH14ClN02 C H N ber. : 53,1 6,9 6,9 96 gef.: 52,9 6,9 6,6 % Beispiel 5 N-Chloräthyl-glutethimid.Analysis: CgH14ClN02 C H N calc .: 53.1 6.9 6.9 96 found: 52.9 6.9 6.6 % Example 5 N-chloroethyl glutethimide.
Man erhitzt eine Mischung aus 0,44 g Glutethimid, 1,6 ml Bis(chloräthyl)-sulfat, 1,8 g Kaliumcarbonat und 25 ml absolutem Äthanol während 25 Minuten zum Sieden am Rückfluß.A mixture of 0.44 g of glutethimide, 1.6 ml of bis (chloroethyl) sulfate is heated, 1.8 g of potassium carbonate and 25 ml of absolute ethanol for 25 minutes to the boiling point Reflux.
Den alkoholfreien Rückstand behandelt man auf einer mit 75 g Aluminiumoxid beschickten Säule, indem man das Eluat mit 210 ml einer 3%igen (Volumen/Volumen) Lösung von Äthylacetat in Hexan eluiert. Man erhält 0,30 g (Ausbeute = 71%) des gewünschten Produkts in Form eines farblosen Öls.The alcohol-free residue is treated on one with 75 g of aluminum oxide loaded column by mixing the eluate with 210 ml of a 3% (volume / volume) Eluted solution of ethyl acetate in hexane. 0.30 g (yield = 71%) of des desired product in the form of a colorless oil.
Analyse: C15H 18ClN02 C H N ber.: 64,4 6,5 5,0 % gef.: 64,1 6,3 4,9 % Beispiel 6 N-Chloräthyl-diphenylhydantoin und N,N'-Bis(chloräthyl)-diphenylhydantoin.Analysis: C15H 18ClN02 C H N calc .: 64.4 6.5 5.0% found: 64.1 6.3 4.9 % Example 6 N-chloroethyl-diphenylhydantoin and N, N'-bis (chloroethyl) -diphenylhydantoin.
Man vermischt eine Mischung aus 0,40 g Diphenylhydantoin, 2,5 ml Bis(chloräthyl)-sulfat, 1,5 g Kaliumcarbonat und 25 ml absolutem Äthanol während 1 Stunde. Den alkoholfreien Rückstand behandelt man mit 25 ml Wasser und 25 ml Äthylacetat, wonach man das durch Verdampfen des Äthylacetats gewonnene Öl auf eine mit Aluminiumoxid (110 g in Hexan)-beschickte Säule aufträgt.A mixture of 0.40 g of diphenylhydantoin, 2.5 ml of bis (chloroethyl) sulfate is mixed, 1.5 g of potassium carbonate and 25 ml of absolute ethanol for 1 hour. The alcohol-free Residue it is treated with 25 ml of water and 25 ml of ethyl acetate, which is then evaporated The oil recovered from the ethyl acetate is loaded onto an alumina (110 g in hexane) Column.
Das Bis(chloräthyl)-derivat gewinnt man mit 140 ml einer 5%igen (Volumen/Volumen)
Lösung von Äthylacetat in Hexan, während man das überschüssige Bis(chloräthyl)-sulfat
mit 120 mol einer 6%igen (Volumen/Volumen) Lösung von Äthylacetat in Hexan eluiert.
Schließlich eluiert man das N-Chloräthylderivat mit 120 ml einer 30%igen (Volumen/Volumen)
Äthylacetatlösung. Durch Abziehen der Lösungsmittel und Umkristallisieren aus wässrigem
Äthanol erhält man 0,15 g (Ausbeute = 30%) N-Chloräthyl-diphenylhydantoin (Schmelzpunkt
= 153 bis 154 0C) und 0,06 g (Ausbeute = 15%) N,N'-Bis(2-chloräthyl)-diphenylhydantoin
(Schmelzpunkt = 107 bis 1080C) jeweils in Form von weißen Feststoffen. Die Verbindungen
besitzen die folgenden Analysenwerte:
Claims (12)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762622981 DE2622981A1 (en) | 1976-05-21 | 1976-05-21 | (N)-Haloalkyl nitrogen-contg. heterocyclics prodn. - by reacting (N)-heterocyclics e.g. barbiturates with bis-haloalkyl sulphates, e.g. bis-chloroethyl sulphate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762622981 DE2622981A1 (en) | 1976-05-21 | 1976-05-21 | (N)-Haloalkyl nitrogen-contg. heterocyclics prodn. - by reacting (N)-heterocyclics e.g. barbiturates with bis-haloalkyl sulphates, e.g. bis-chloroethyl sulphate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2622981A1 true DE2622981A1 (en) | 1977-12-08 |
Family
ID=5978740
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19762622981 Pending DE2622981A1 (en) | 1976-05-21 | 1976-05-21 | (N)-Haloalkyl nitrogen-contg. heterocyclics prodn. - by reacting (N)-heterocyclics e.g. barbiturates with bis-haloalkyl sulphates, e.g. bis-chloroethyl sulphate |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE2622981A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999018084A1 (en) * | 1997-10-02 | 1999-04-15 | Taro Pharmaceutical Industries Ltd. | Method and reagents for n-alkylating ureides |
| US6756379B2 (en) | 2001-07-26 | 2004-06-29 | Taro Pharmaceutical Industries Ltd. | Non-sedating barbiturate compounds as neuroprotective agents |
| US6939873B2 (en) | 2000-07-26 | 2005-09-06 | Taro Pharmaceuticals Industries Limited | Non-sedating barbituric acid derivatives |
| US7683071B2 (en) | 2000-07-26 | 2010-03-23 | Taro Pharmaceuticals Industries Ltd. | Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid |
| US7776871B2 (en) | 2002-12-11 | 2010-08-17 | Taro Pharmaceutical Industries Ltd. | Method of treating movement disorders using barbituric acid derivatives |
-
1976
- 1976-05-21 DE DE19762622981 patent/DE2622981A1/en active Pending
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6093820A (en) * | 1997-10-02 | 2000-07-25 | Taro Pharmaceutical Industries Ltd. | Method and reagents for N-alkylating ureides |
| US6664262B2 (en) | 1997-10-02 | 2003-12-16 | Taro Pharmaceuticals Industries Ltd. | N-methoxymethyl-5,5-diphenylbarbituric acid |
| WO1999018084A1 (en) * | 1997-10-02 | 1999-04-15 | Taro Pharmaceutical Industries Ltd. | Method and reagents for n-alkylating ureides |
| US6906079B2 (en) | 1997-10-02 | 2005-06-14 | Taro Pharmaceutical Industries Limited | Method and reagents for N-alkylating ureides |
| USRE38934E1 (en) | 1997-10-02 | 2006-01-10 | Taro Pharmaceutical Industries Ltd. | Method and reagents for N-alkylating ureides |
| US8076346B2 (en) | 2000-07-26 | 2011-12-13 | Taro Pharamaceutical Industries Ltd. | Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid |
| US6939873B2 (en) | 2000-07-26 | 2005-09-06 | Taro Pharmaceuticals Industries Limited | Non-sedating barbituric acid derivatives |
| US7683071B2 (en) | 2000-07-26 | 2010-03-23 | Taro Pharmaceuticals Industries Ltd. | Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid |
| US7723346B2 (en) | 2000-07-26 | 2010-05-25 | Taro Pharmaceutical Industries Ltd. | Non-sedating barbiturate compounds as neuroprotective agents |
| US8158639B2 (en) | 2000-07-26 | 2012-04-17 | Taro Pharmaceutical Industries Ltd. | Non-sedating barbiturate compounds as neuroprotective agents |
| US6756379B2 (en) | 2001-07-26 | 2004-06-29 | Taro Pharmaceutical Industries Ltd. | Non-sedating barbiturate compounds as neuroprotective agents |
| US7776871B2 (en) | 2002-12-11 | 2010-08-17 | Taro Pharmaceutical Industries Ltd. | Method of treating movement disorders using barbituric acid derivatives |
| US8314115B2 (en) | 2002-12-11 | 2012-11-20 | Taro Pharmaceutical Industries Limited | Method of treating movement disorders using barbituric acid derivatives |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE3250034C2 (en) | ||
| DE2516025A1 (en) | NEW PYRIDINE DERIVATIVES, THEIR PRODUCTION AND USE | |
| DE1493579B1 (en) | Process for the preparation of new pharmaceutically valuable compounds | |
| DE3009071C2 (en) | 2-isopropylamino-hydroxypyrimidine compounds, processes for their preparation and pharmaceuticals containing these compounds | |
| DE2622981A1 (en) | (N)-Haloalkyl nitrogen-contg. heterocyclics prodn. - by reacting (N)-heterocyclics e.g. barbiturates with bis-haloalkyl sulphates, e.g. bis-chloroethyl sulphate | |
| DE2154245C3 (en) | 3-hydrazino-6- (2-hydroxypropylamino) pyridazine derivatives, process for their preparation and pharmaceutical preparation containing them | |
| DE1620727A1 (en) | Dithiosemicarbazones with coccidiostatic activity | |
| DE2726820A1 (en) | IMIDAZOTHIAZINE | |
| DE3438244C2 (en) | ||
| DE2603046C2 (en) | 4'α- and 4'β-amino-4'-deoxy-oleandrins, processes for their preparation and pharmaceutical preparations containing them | |
| AT391470B (en) | METHOD FOR PRODUCING 1- (2- (5HU850111104 / 85 | |
| DE1593145A1 (en) | New 0- (2-guanidino-ethyl) -oximes | |
| DD211554A5 (en) | PROCESS FOR PREPARING NEW DIHYDROPYRIDINES | |
| EP0068259A1 (en) | Derivatives of substituted 2-amino-pyridine, process for their preparation, their use in medicaments and preparation thereof | |
| DE2828487A1 (en) | PROCESS FOR THE PRODUCTION OF 3-ACYLAMINO-4-HOMOISOTWISTAN | |
| DE2950235C2 (en) | ||
| DE2609574C3 (en) | 1 - ^ - Fluoro-S-trifluoromethylthiophenyD-piperazine, its salts, process for its preparation and pharmaceuticals | |
| DE2324993C3 (en) | 4'-DEHYDRO-OLEANDRIN, THE METHOD FOR MANUFACTURING THE SAME, AND A PHARMACEUTICAL PREPARATION CONTAINING THIS COMPOUND | |
| DE3012190A1 (en) | PHARMACEUTICAL AGENT BASED ON 1,3,5-SUBSTITUTED BIURET COMPOUNDS | |
| DE2438462C3 (en) | Process for the preparation of n-ethynylbenzhydrol and its ring-substituted derivatives and ring-substituted α-ethynylbenzhydrol derivatives and pharmaceuticals containing them | |
| EP0066303B1 (en) | 2-azidomethyl-1,4-benzodiazepines, their salts, process for preparing them and pharmaceutical compositions containing them | |
| DE1545634A1 (en) | Process for the production of adenosine ketals | |
| DE2748794C2 (en) | Malonylurea complexes, processes for their preparation and pharmaceutical compositions containing them | |
| DE1443376C3 (en) | Process for the preparation of 2-amino-alpha-substituted benzylideneamines, as well as new 2-amino-alpha-substituted benzylideneamines as such | |
| DE1914507C (en) | 6 alpha, 7 alpha or 6 beta, 7 beta methylene 20 spirox 4 en 3 on compounds and processes for their manufacture |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| OHJ | Non-payment of the annual fee |