DE1302662B - - Google Patents
Info
- Publication number
- DE1302662B DE1302662B DENDAT1302662D DE1302662DA DE1302662B DE 1302662 B DE1302662 B DE 1302662B DE NDAT1302662 D DENDAT1302662 D DE NDAT1302662D DE 1302662D A DE1302662D A DE 1302662DA DE 1302662 B DE1302662 B DE 1302662B
- Authority
- DE
- Germany
- Prior art keywords
- chloromethyl
- methyl
- phenyl
- substance
- per
- 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
- DGTNSSLYPYDJGL-UHFFFAOYSA-N Phenylisocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 150000003949 imides Chemical class 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 230000001773 anti-convulsant Effects 0.000 description 6
- 239000001961 anticonvulsive agent Substances 0.000 description 6
- 230000001225 therapeutic Effects 0.000 description 5
- 206010010904 Convulsion Diseases 0.000 description 3
- 208000005392 Spasm Diseases 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 2
- 206010039911 Seizure Diseases 0.000 description 2
- QMGVPVSNSZLJIA-FVWCLLPLSA-N Strychnine Natural products O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 2
- 241001279009 Strychnos toxifera Species 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- -1 pentamethylene strychnine Chemical compound 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229960005453 strychnine Drugs 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- PCGVPMHGSJFFTI-ZEYGOCRCSA-N (4aR,5aS,8aR,13aS,15aS,15bR)-4a,5,5a,7,8,13a,15,15a,15b,16-decahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinoline-14-one;nitric acid Chemical compound O[N+]([O-])=O.O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 PCGVPMHGSJFFTI-ZEYGOCRCSA-N 0.000 description 1
- WDGCBNTXZHJTHJ-UHFFFAOYSA-N 2H-1,3-oxazol-2-id-4-one Chemical class O=C1CO[C-]=N1 WDGCBNTXZHJTHJ-UHFFFAOYSA-N 0.000 description 1
- 206010034759 Petit mal epilepsy Diseases 0.000 description 1
- QKFJKGMPGYROCL-UHFFFAOYSA-N Phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 1
- 229940059935 Strychnine Nitrate Drugs 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 150000002917 oxazolidines Chemical class 0.000 description 1
- 229940117953 phenylisothiocyanate Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001960 triggered Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/28—Nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Es ist bekannt, 5-Chlormethyi-oxazolidon-(2)-anilinothioformylimid durch Kochen einer alkoholischen Lösung von 5-Chlonnethyl-oxazolidon-(2)-imid mit einer äquivalenten Menge Phenylisothiocyanat unter Rückfluß herzustellen. It is known 5-chloromethyl-oxazolidone- (2) -anilinothioformylimide by boiling an alcoholic solution of 5-Chlonnethyl-oxazolidon- (2) -imid with to prepare an equivalent amount of phenyl isothiocyanate under reflux.
Gegenstand der Erfindung ist das 5-Chlormethyloxazolidon-(2Wanilinoformylimid der Formel und ein Verfahren zu dessen Herstellung, erfindungsgemäß dadurch hergestellt, daß 5-Chlormethyl-oxazolidon-(2-imid mit einer äquimolekularen Menge Phenylisocyanat bei Temperaturen von mehr als 400 C umgesetzt wird Die Reaktion verläuft exotherm unter Seibsterwärmung des Ansatzes auf die erforderliche Temperatur. Um Zersetzung des Phenylisocyanats durch Luftfeuchtigkeit zu vermeiden, wird zweckmäßig in trockener Atmosphäre oder unter Luftausschluß gearbeitet. Die Umsetzung kann auch in inerten Lösungsmitteln vorgenommen werden, deren Siedepunkt oberhalb 400 C liegt. Geeignete Lösungsmittel sind Benzol, Toluol, Chloroform und Tetrachlorkohlenstoff. Aus der erhaltenen Reaktionslösung scheidet sich das 5-Chlormethyl-oxazolidond2)-anilinoformylimid nach dem Erkalten in kristalliner Form ab; es kann aber auch ein Teil des Lösungsmittels abdestilliert werden.The invention relates to 5-chloromethyloxazolidone- (2Wanilinoformylimid of the formula and a process for its production, produced according to the invention by reacting 5-chloromethyl-oxazolidone- (2-imide with an equimolecular amount of phenyl isocyanate at temperatures of more than 400 ° C. The reaction takes place exothermically with self-heating of the batch to the required temperature. Um To avoid decomposition of the phenyl isocyanate by atmospheric moisture, it is expedient to work in a dry atmosphere or with exclusion of air. The reaction can also be carried out in inert solvents whose boiling point is above 400 C. Suitable solvents are benzene, toluene, chloroform and carbon tetrachloride The 5-chloromethyl-oxazolidone2) -anilinoformylimide separates out in crystalline form after cooling; however, part of the solvent can also be distilled off.
Das 5-Chlormethyl-oxaxolidon-(2)-anilinoformylimid besitzt eine gute antikonvulsive Wirkung bei. geringer Toxizität. The 5-chloromethyl-oxaxolidone- (2) -anilinoformylimide has a good one anticonvulsant effect. low toxicity.
Es ist zwar bekannt, daß 2-Oxazolidone der allgemeinen Formel in denen R einen gesättigten aliphatischen Substituenten bedeutet, antikonvulsiv wirken. Es ist auch bekannt, daß bestimmte Oxazolidine, nämlich solche, die in 5-Stellung Aryloxymethylreste oder in 4-Stellung oder 5-Stellung aromatische Substituenten enthalten, antikonvulsiv wirksam sind (Journal American Chemical Soc., Bd. 82 [1960], S. 1166 bis 1171, und Bd. 73 [1951], S. 95 bis 98). Die gute antikonvulsive Wirkung der erfindungsgemäß erhaltenen Verbindung ist jedoch deswegen besonders überraschend, weil an der letztgenannten Stelle (Seite 96) angegeben wird, daß Verbindungen, die in 4- und/oder 5-Stellung aliphatische Substituenten enthalten, z. B. den 5-Chlormethylrest, entweder inaktiv oder sehr wenig wirksam sind.It is known that 2-oxazolidones of the general formula in which R is a saturated aliphatic substituent, have an anticonvulsant effect. It is also known that certain oxazolidines, namely those which contain aryloxymethyl radicals in the 5-position or aromatic substituents in the 4-position or 5-position, have an anticonvulsant effect (Journal American Chemical Soc., Vol. 82 [1960], p. 1166 to 1171, and vol. 73 [1951], pp. 95 to 98). The good anticonvulsant effect of the compound obtained according to the invention is particularly surprising because at the last-mentioned point (page 96) it is stated that compounds which contain aliphatic substituents in the 4- and / or 5-position, e.g. B. the 5-chloromethyl radical, are either inactive or very little effective.
Beispiel Zu einer Suspension von 10 g 5-Chlormethyloxazolidong2)-imid in 200 ml Toluol wird unter gutem Rühren eine Lösung von 8, 85 g Phenyl-isocyanat in 50 mol Toluol hinzugetropft, anschließend wird 40 Minuten am siedenden Wasserbad erwärmt. Example For a suspension of 10 g of 5-chloromethyloxazolidong2) imide in 200 ml of toluene, a solution of 8.85 g of phenyl isocyanate is obtained with thorough stirring in 50 mol of toluene is added dropwise, followed by 40 minutes on a boiling water bath warmed up.
Dabei beginnt bereits das Reaktionsprodukt in feinen, weißen Nadeln auszufallen; eine weitere Anreicherung tritt beim Abkühlen ein. Umkristallisiert wird aus Toluol. Schmelzpunkt: 165°C, Ausbeute 92% der Theone.The reaction product begins in fine, white needles to fail; a further enrichment occurs on cooling. Recrystallized is made from toluene. Melting point: 165 ° C, yield 92% of the Theone.
Versuchsbericht Die krampflösende Wirkung der erfindungsgemäßen Verbindung wurde mit derjenigen von N-Methyl-a-methyl-a-phenyl-succinimid der Formel verglichen. Dabei wurde einmal der Krampf mit 100 bis 120 mg/kg Pentamethylentetrazol und einmal mit 1,5 mg/kg Strychninnitrat ausgelöst. Die Prüfsubstanzen wurden bei intraperitonealer Gabe 15 Minuten vor Pentamethylentetrazol und bei oraler Gabe 60 Minuten vorher gegeben. Beurteilt wird die vollkommene Unterdrückung des Krampfes innerhalb einer Beobachtungszeit von 30 Minuten.Test report The anticonvulsant effect of the compound according to the invention was compared with that of N-methyl-a-methyl-a-phenyl-succinimide of the formula compared. The spasm was triggered once with 100 to 120 mg / kg pentamethylenetetrazole and once with 1.5 mg / kg strychnine nitrate. The test substances were given 15 minutes before pentamethylenetetrazole for intraperitoneal administration and 60 minutes before for oral administration. The complete suppression of the spasm is assessed within an observation time of 30 minutes.
Es wurden folgende Werte ermittelt:
Wie die Versuchsergebnisse zeigen, liegt der therapeutische Index der erfindungsgemäßen Substanz nach oraler Verabreichung wesentlich höher als derjenige von N-Methyl-a-methyl-a-phenyl-succinimid, nämlich bei über 71 gegenüber 14,8 und bei über 114 gegenüber weniger als 5,9 Da es sich bei der Indikation der antikonvulsiven Mittel um eine langfristige Therapie handelt, hat die parenterale Therapie praktisch keine Bedeutung, so daß die Ergebnisse der peroralen Behandlung tatsächlich für die Beurteilung stärker zu berücksichtigen sind. As the test results show, the therapeutic index lies of the substance according to the invention after oral administration is significantly higher than that of N-methyl-a-methyl-a-phenyl-succinimide, namely over 71 compared to 14.8 and at over 114 compared to less than 5.9 Since it is the indication of the anticonvulsant As a means of long-term therapy, parenteral therapy is practical no meaning, so the results of the oral treatment actually apply for the assessment should be given greater consideration.
Die Ergebnisse zeigen ferner, daß die Toxizität der erfindungsgemäßen Substanz bei oraler Verabreichung so günstig ist, daß man sie praktisch als untoxisch bezeichnen kann. Dementsprechend erhält man eine sehr große therapeutische Breite. Der technische Effekt gegenüber der bekannten Vergleichssubstanz liegt somit in der geringeren Toxizität der erhöhten Wirkung bei peroraler Verabreichung und der größeren therapeutischen Breite der erfindungsgemäßen Substanz, die sich speziell zur Behandlung von Petit-mal-Epilepsien eignet. The results also show that the toxicity of the invention Substance when administered orally is so cheap that it is practically as non-toxic can denote. Accordingly, one obtains a very wide therapeutic range. The technical effect compared to the known reference substance is thus in the lower toxicity, the increased effect with oral administration and the greater therapeutic breadth of the substance according to the invention, which is specifically suitable for the treatment of petit mal epilepsy.
Claims (1)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1302662B true DE1302662B (en) | 1971-02-04 |
Family
ID=621399
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DENDAT1302662D Pending DE1302662B (en) |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1302662B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2630107A1 (en) * | 1975-07-04 | 1977-01-27 | Nippon Chemiphar Co | 5-BENZYL-2-OXAZOLIDONE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
| DE2538424A1 (en) * | 1975-08-29 | 1977-03-03 | Nordmark Werke Gmbh | NEW OXAZOLIDINONE, METHOD OF PREPARATION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| FR2533923A1 (en) * | 1982-10-05 | 1984-04-06 | Cortial | New N-(5-aminomethyl-2-oxazolin-2-yl)-N'-phenylureas, method for preparing them and their therapeutic application |
| EP0105821A1 (en) * | 1982-10-05 | 1984-04-18 | Cortial S.A. | N-(aminomethyl-5-oxazolin-2-yl-2)-N'-phenyl ureas |
| WO1999015526A2 (en) * | 1997-09-19 | 1999-04-01 | Smithkline Beecham Plc | N-5,6,7,8-tetrahydro(1,6)naphthyridine-n'-phenylurea derivatives |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2844590A (en) * | 1956-10-01 | 1958-07-22 | Monsanto Chemicals | 4-alkylidene-2-oxazolidones and process |
-
0
- DE DENDAT1302662D patent/DE1302662B/de active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2844590A (en) * | 1956-10-01 | 1958-07-22 | Monsanto Chemicals | 4-alkylidene-2-oxazolidones and process |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2630107A1 (en) * | 1975-07-04 | 1977-01-27 | Nippon Chemiphar Co | 5-BENZYL-2-OXAZOLIDONE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
| DE2538424A1 (en) * | 1975-08-29 | 1977-03-03 | Nordmark Werke Gmbh | NEW OXAZOLIDINONE, METHOD OF PREPARATION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| FR2533923A1 (en) * | 1982-10-05 | 1984-04-06 | Cortial | New N-(5-aminomethyl-2-oxazolin-2-yl)-N'-phenylureas, method for preparing them and their therapeutic application |
| EP0105821A1 (en) * | 1982-10-05 | 1984-04-18 | Cortial S.A. | N-(aminomethyl-5-oxazolin-2-yl-2)-N'-phenyl ureas |
| WO1999015526A2 (en) * | 1997-09-19 | 1999-04-01 | Smithkline Beecham Plc | N-5,6,7,8-tetrahydro(1,6)naphthyridine-n'-phenylurea derivatives |
| WO1999015526A3 (en) * | 1997-09-19 | 1999-05-20 | Smithkline Beecham Plc | N-5,6,7,8-tetrahydro(1,6)naphthyridine-n'-phenylurea derivatives |
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