DE1135915B - Process for the production of new, anticonvulsant spirohydantoins - Google Patents
Process for the production of new, anticonvulsant spirohydantoinsInfo
- Publication number
- DE1135915B DE1135915B DEA37763A DEA0037763A DE1135915B DE 1135915 B DE1135915 B DE 1135915B DE A37763 A DEA37763 A DE A37763A DE A0037763 A DEA0037763 A DE A0037763A DE 1135915 B DE1135915 B DE 1135915B
- Authority
- DE
- Germany
- Prior art keywords
- hydantoin
- spiro
- methyl
- chloro
- alkali metal
- 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
- 230000001773 anti-convulsant effect Effects 0.000 title claims description 6
- 239000001961 anticonvulsive agent Substances 0.000 title claims description 4
- 229960003965 antiepileptics Drugs 0.000 title claims description 4
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 238000000034 method Methods 0.000 title claims description 3
- 229940091173 hydantoin Drugs 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 6
- -1 alkali metal salts Chemical class 0.000 claims description 6
- 239000001099 ammonium carbonate Substances 0.000 claims description 6
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical compound C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 150000001339 alkali metal compounds Chemical class 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000000243 solution Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 150000001469 hydantoins Chemical class 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 208000005392 Spasm Diseases 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000001256 tonic effect Effects 0.000 description 3
- YKDLXGGXGDKKLB-UHFFFAOYSA-N 3-methyl-1-phenylimidazolidine-2,4-dione Chemical compound O=C1N(C)C(=O)CN1C1=CC=CC=C1 YKDLXGGXGDKKLB-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- JNGWGQUYLVSFND-UHFFFAOYSA-N 5-methyl-5-phenylimidazolidine-2,4-dione Chemical compound C=1C=CC=CC=1C1(C)NC(=O)NC1=O JNGWGQUYLVSFND-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940053195 antiepileptics hydantoin derivative Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
Verfahren zur Herstellung neuer, antikonvulsiv wirksamer Spirohydantoine Es ist bekannt, daß Hydantoine, die am Kohlenstoff 5 zweifach durch aromatische oder aliphatische Reste substituiert sind, wie z. B. das 5, 5-Diphenylhydantoin oder 5-Phenyl-5-methyl-hydantoin, eine antikonvulsive Wirkung besitzen. Process for the production of new, anticonvulsant spirohydantoins It is known that hydantoins, which at carbon 5 are twofold by aromatic or aliphatic radicals are substituted, such as. B. the 5,5-diphenylhydantoin or 5-phenyl-5-methyl-hydantoin, have an anticonvulsant effect.
Es wurde nun gefunden, daß die Hydantoinabkömmlinge der nachfolgenden allgemeinen Formel worin der aromatische Ring durch ein oder mehrere Halogenatome und/oder durch einen Methyl-oder Äthylrest substituiert sein kann, X für Sauerstoff oder Schwefel steht und die Größe des Heteroringes durch n = 2 oder 3 bestimmt ist, sowie deren Alkalimetallsalze und die durch Substitution in der 3'-Stellung erhaltenen niederen Alkyl-Derivate bei guter antikonvulsiver Wirkung eine große therapeutische Breite besitzen, d. h. die therapeutische Dosis ist mit einer geringen Toxizität belastet.It has now been found that the hydantoin derivatives of the following general formula wherein the aromatic ring can be substituted by one or more halogen atoms and / or by a methyl or ethyl radical, X is oxygen or sulfur and the size of the hetero ring is determined by n = 2 or 3, as well as their alkali metal salts and those by substitution in the lower alkyl derivatives obtained in the 3'-position have a large therapeutic range with good anticonvulsant action, ie the therapeutic dose is burdened with low toxicity.
Die Herstellung dieser Verbindungen erfolgt in an sich bekannter Weise durch Umsetzung von gegebenenfalls im aromatischen Kern entsprechend substituierten Chromanonen oder Homochromanonen bzw. ihrer Thioanalogen bei erhöhter Temperatur und erhöhtem Druck mit einem Cyanid, z. B. Kaliumcyanid, und Ammoniumcarbonat in einem mit Wasser gemischten Lösungsmittel im Sinne der folgenden Gleichung Die Alkalimetallsalze werden in an sich bekannter Weise durch Umsetzung der neuen Spirohydantoine mit z. B. Alkalimetallhydroxyden oder Alkalimetallalkoholatlösungen erhalten. Die in der 3-Stellung durch eine niedere Alkylgruppe substituierten Derivate der neuen Spirohydantoine werden durch Umsetzung der Spirohydantoine mit Alkylierungsmitteln in alkalischer Lösung erhalten.These compounds are prepared in a manner known per se by reacting chromanones or homochromanones or their thioanalogues, optionally substituted in the aromatic nucleus, with a cyanide, e.g. B. potassium cyanide, and ammonium carbonate in a solvent mixed with water in the sense of the following equation The alkali metal salts are known in a manner by reacting the new spirohydantoins with z. B. obtained alkali metal hydroxides or alkali metal alcoholate solutions. The derivatives of the new spirohydantoins substituted in the 3-position by a lower alkyl group are obtained by reacting the spirohydantoins with alkylating agents in an alkaline solution.
Die in der beschriebenen Weise hergestellten neuen Spirohydantoine zeigen, wie aus den in der Tabelle zusammengestellten Ergebnissen der nachstehend angegebenen pharmakologischen Prüfung hervorgeht, überraschende, andern Hydantoinen gegenüber überlegene therapeutische Eigenschaften. The new spirohydantoins produced in the manner described show how from the results compiled in the table below indicated pharmacological test shows surprising, different hydantoins versus superior therapeutic properties.
Die in der Tabelle angegebenen DE5O-Werte sowie der Dgo-Index wurden durch Studium der effektiven Wirkung beim maximalen Elektrokrampf bei Ratten erhalten. The DE5O values and the Dgo index given in the table were obtained by studying the effective effect on maximal electroconvulsions in rats.
Reizgerät : Medeor in Verbindung mit der Hirsch-Zeituhr. Stimulator: Medeor in conjunction with the Hirsch time clock.
Reizdaten : Impuls-Frequenz (100 hz), Impuls-Dauer : 4, 64 ms, Impuls-Stärke : 82, 5 mA. Stimulus data: pulse frequency (100 hz), pulse duration: 4, 64 ms, pulse strength : 82.5 mA.
Reizzeit : 0, 215s. Stimulation time: 0, 215s.
Ohrenelektroden : eine Elektrode enthält zwei Edelmetallbügel, die durch gehärtete, elastische Kunststoffmasse zusammengehalten werden. Die aus der Masse herausragenden parabolförmigefi Bleche sind mit Wildleder überzogen. Ear electrodes: one electrode contains two precious metal clips that are held together by hardened, elastic plastic compound. The ones from the Mass protruding parabolic sheets are covered with suede.
Kriterium : Tonischer Streckkrampf der Hinterextremitäten. Als geschützt werden die Tiere bezeichnet, bei denen der tonische Streckkrampf unterdrückt wird. Criterion: tonic stretching spasm of the hind limbs. As protected are the animals in which the tonic stretching spasm is suppressed.
Die DEso bezeichnet also die Dosis, bei der mit einer Wahrscheinlichkeit von 50°/0 Ratten gegenüber dem tonischen Streckkrampf nach Elektroreizung geschützt sind. The DEso describes the dose at which there is a probability Protected by 50% rats against the tonic stretching spasm after electrical stimulation are.
Als Standardsubstanzen wurden das Diphenylhydantoin (a) sowie das Methylphenylhydantoin (b) verwendet. Prüfsubstanzen sind gemäß der Erfindung hergestellte Spirohydantoine. Vergleicht man die neu entwickelten Produkte mit den beiden Standard- substanzen a und b (Tabelle), die von den vorbekannten Hydantoinen die größte therapeutische Breite besitzen, so erkennt man, daß die Steigerung der therapeutischen Breite insbesondere bei Verbindung 4, aber auch bei Verbindung 2, 3 und 5 ein überraschend großes Ausmaß besitzt. Der D5o-Index, der bei den beiden Standardsubstanzen bei einem Wert von etwa 25 liegt, steigt bei der wirksamsten Substanz 4 auf einen Wert von 287 an. Von besonderem Interesse ist auch der Vergleich der molaren effektiven Konzentrationen für die antikonvulsive Wirkkomponente. Im Vergleich zur Substanz a sieht man eine Verstärkung um mehr als das lOfache, im Vergleich zum Methylphenylhydantoin (b) eine Verstärkung um rund das Doppelte. Diphenylhydantoin (a) and Methylphenylhydantoin (b) is used. Test substances are prepared according to the invention Spirohydantoins. If you compare the newly developed products with the two standard substances a and b (table), which of the previously known hydantoins is the greatest therapeutic Having breadth, one recognizes that the increase in therapeutic breadth in particular with connection 4, but also with connection 2, 3 and 5 a surprisingly large extent owns. The D5o index, which for the two standard substances has a value of is around 25, the most effective substance 4 increases to a value of 287. The comparison of the effective molar concentrations is also of particular interest for the anticonvulsant active component. Compared to substance a you can see one Reinforcement by more than 10 times compared to methylphenylhydantoin (b) a gain around twice as much.
Von besonderer Bedeutung ist die Tatsache, daß die effektive Wirkkomponente bei oraler Applikation bestimmt wurde, so daß also auch für den Menschen bei oraler Applikation eine gute Wirkung in der Therapie der Krampfleiden zu erwarten ist.Of particular importance is the fact that the effective active component was determined in the case of oral administration, so that also for humans in the case of oral administration Application is expected to have a good effect in the therapy of convulsive disorders.
Tabelle
Fp. 236 bis 242°C ; Ausbeute : 66 g = 60°/o der Theorie. Mp 236 to 242 ° C; Yield: 66 g = 60% of theory.
Analog Beispiel 1 wurden folgende Substanzen hergestellt : 6-Methyl-chroman-spiro- (4, 5')-hydantoin .................... Fp. 242 bis 246°C 6-Äthyl-chroman-spiro-(4,5')-hydantoin................... Fp. 211 bis 215°C 6-Chlor-chroman-spiro-(4,5')-hydantoin .................... Fp. 267 bis 270°C 8-Chlor-chroman-spiro- (4, 5')-hydantoin................... Fp. 231 bis 235°C 6-Brom-chroman-spiro- (4, 5')-hydantoin Fp. 264 bis 269°C 6-Chlor-7-methyl-chroman-spiro-(4, 5')-hydantoin............. Fp. 232 bis 237°C 8-Chlor-5-methyl-chroman-spiro-(4, 5')-hydantoin............. Fp. 262 bis 265°C 7-Methyl-homochromanspiro- (5, 5')-hydantoin........ Fp. 231 bis 238°C 9-Methyl-homochromanspiro- (5, 5')-hydantoin....... Fp. 225 bis 229°C 8-Methyl-homochromanspiro- (5, 5')-hydantoin........ Fp. 213 bis 217°C 7-Äthyl-homochroman-spiro- (5, 5')-hydantoin................. Fp. 225 bis 229°C 7, 8-Dichlor-homochromanspiro- (5, 5')-hydantoin........ Fp. 237 bis 241'C 9-Chlor-homochromanspiro- (5, 5')-hydantoin........ Fp. 251 bis 256°C 8-Chlor-homochromanspiro- (5, 5')-hydantoin........ Fp. 218 bis 222°C 7-Chlor-homochromanspiro- (5, 5')-hydantoin........ Fp. 240 bis 245'C 7-Fluor-homochronanspiro- (5, 5')-hydantoin........ Fp. 253 bis 257°C 7-Brom-homochromanspiro- (5, 5')-hydantoin........ Fp. 249 bis 259°C 7-Chlor-8-methyl-homochromanspiro- (5, 5')-hydantoin........ Fp. 260 bis 263°C 7-Chlor-9-methyl-homochromanspiro- (5, 5')-hydantoin........ Fp. 257 bis 263°C Thio-chroman-spiro- (4, 5')-hydantoin................... Fp. 222 bis 227°C Thio-homochromanspiro- (5, 5')-hydantoin........ Fp. 288 bis 290°C Beispiel 2 Homochroman-spiro- (5, 5')-hydantoin 162 g Homochroman- (5), 82 g Kaliumcyanid, 164 g Ammoniumcarbonat, 700 ml Alkohol und 350 ml Wasser werden in einem Rührautoklav 8 Stunden bei 80° C und 35 atü CO2-Druck erhitzt. Aufarbeitung wie im Beispiel 1. The following substances were prepared analogously to Example 1: 6-methyl-chroman-spiro- (4, 5 ') - hydantoin .................... Mp. 242 to 246 ° C 6-ethyl-chroman-spiro- (4.5') - hydantoin ................... Mp. 211 to 215 ° C 6-chloro-chroman-spiro- (4.5 ') - hydantoin .................... Mp. 267 to 270 ° C 8-chloro-chroman-spiro- (4, 5 ') - hydantoin ................... m.p. 231 up to 235 ° C 6-bromo-chroman-spiro- (4, 5 ') - hydantoin M.p. 264 to 269 ° C 6-chloro-7-methyl-chroman-spiro- (4, 5 ') - hydantoin ............. Mp. 232 to 237 ° C 8-chloro-5-methyl-chroman-spiro- (4, 5 ') - hydantoin ............. Mp. 262 to 265 ° C 7-methyl-homochromanspiro- (5, 5') - hydantoin ........ Mp. 231 to 238 ° C 9-methyl-homochromanspiro- (5, 5 ') - hydantoin ........ Mp. 225 to 229 ° C 8-methyl-homochroman-spiro- (5, 5 ') - hydantoin ........ Mp. 213 to 217 ° C 7-ethyl-homochroman-spiro- (5, 5 ') - hydantoin ................. Mp. 225 to 229 ° C 7, 8-dichloro-homochromanspiro- (5, 5 ') - hydantoin ........ Mp. 237 to 241'C 9-chloro-homochromanspiro- (5, 5') - hydantoin ........ Mp. 251 to 256 ° C 8-chloro-homochromanspiro- (5, 5 ') - hydantoin ........ Mp. 218 to 222 ° C 7-chloro-homochromanspiro- (5, 5 ') - hydantoin ........ Mp. 240 to 245'C 7-fluoro-homochromanspiro- (5, 5 ') - hydantoin ........ Mp. 253 to 257 ° C 7-bromo-homochromanspiro- (5, 5') - hydantoin ........ Mp. 249 to 259 ° C 7-chloro-8-methyl-homochromanspiro- (5, 5 ') - hydantoin ........ Mp. 260 to 263 ° C 7-chloro-9-methyl-homochromanspiro- (5, 5 ') -hydantoin ........ Mp. 257 up to 263 ° C thio-chroman-spiro- (4, 5 ') - hydantoin ................... m.p. 222 to 227 ° C Thio-homochromanspiro- (5, 5 ') - hydantoin ........ Mp. 288 to 290 ° C Example 2 Homochroman-spiro- (5, 5 ') - hydantoin 162 g homochroman- (5), 82 g potassium cyanide, 164 g ammonium carbonate, 700 ml of alcohol and 350 ml of water are in a stirred autoclave for 8 hours at 80 ° C and 35 atü CO2 pressure heated. Work-up as in Example 1.
Fp. 245 bis 248°C ; Ausbeute : 152g=65°/o der Theorie. M.p. 245 to 248 ° C; Yield: 152 g = 65% of theory.
Beispiel 3 9-Chlor-homochroman-spiro- (5, 5')-hydantoin In einem 2-Liter-Rührautoklav werden 84 g 9-Chlorhomochroman- (5), 53 g Kaliumcyanid, 119 g Ammoniumcarbonat, 490 ml Alkohol und 490 ml konz. Example 3 9-chloro-homochroman-spiro- (5, 5 ') -hydantoin in one 84 g of 9-chlorohomochroman- (5), 53 g of potassium cyanide, 119 g ammonium carbonate, 490 ml alcohol and 490 ml conc.
Ammoniak 16 Stunden auf 110°C erhitzt. Nach dem Erkalten wird mit verdünnter Salzsäure angesäuert, die ausgefallene Substanz abgesaugt und mit Äther gewaschen. Zur Reinigung wird das Hydantoin in verdünnter Natronlauge gelöst und mit CO2 gefällt.Ammonia heated to 110 ° C for 16 hours. After cooling down, with dilute hydrochloric acid acidified, the precipitated substance sucked off and with ether washed. For cleaning, the hydantoin is dissolved in dilute sodium hydroxide solution and like with CO2.
Nach dem Absaugen wird aus Alkohol umkristallisiert.After suctioning off, it is recrystallized from alcohol.
Fp. 251 bis 256'C ; Ausbeute : 60g = 53°/0 der Theorie. M.p. 251 to 256'C; Yield: 60 g = 53% of theory.
Analog Beispiel 3 wurden folgende Verbindungen hergestellt : 6, 8-Dimethyl-homochromanspiro- (5, 5')-hydantoin........ Fp. 148 bis 152°C 6-Methyl-8-äthyl-homochromanspiro- (5, 5')-hydantoin........ Fp. 203 bis 207°C 6, 8-Dimethyl-7-chlor-homochroman-spiro- (5, 5')-hydantoin.... Fp. 218 bis 223°C Beispiel 4 8, 9-Dichlor-homocliroman-spiro- (5, 5')-hydantoin Das Produkt wurde aus 74 g 8, 9-Dichlor-homochromanon- (5), 19, 5 g Natriumcyanid, 52 g Ammoniumcarbonat, 220ml Alkohol und 110 ml Wasser durch 8 Stunden langes Erhitzen in einem Rührautoklav bei 80°C und 35 atü CO2-Druck hergestellt.The following compounds were prepared analogously to Example 3: 6, 8-Dimethyl-homochromanspiro- (5, 5 ') - hydantoin ........ Mp. 148 to 152 ° C 6-methyl-8-ethyl-homochromanspiro- (5, 5 ') - hydantoin ........ Mp. 203 to 207 ° C 6, 8-dimethyl-7-chloro-homochroman-spiro- (5, 5 ') - hydantoin .... m.p. 218-223 ° C Example 4 8, 9-dichloro-homocliroman-spiro- (5, 5 ') - hydantoin The product was made from 74 g of 8, 9-dichloro-homochromanone- (5), 19, 5 g sodium cyanide, 52 g ammonium carbonate, 220 ml alcohol and 110 ml water 8 hours of heating in a stirred autoclave at 80 ° C and 35 atmospheric CO2 pressure.
Die Aufarbeitung erfolgte wie im Beispiel 2.The work-up was carried out as in Example 2.
Fp. 273 bis 279°C ; Ausbeute : 51 g = 53°/0 der Theorie. Mp 273-279 ° C; Yield: 51 g = 53% of theory.
Beispiel 5 Homochroman-spiro- (5, 5')-hydantoin-Natrium 11, 6 g Homochroman-spiro- (5, 5')-hydantoin werden in einer Lösung von 2 g Natriumhydroxyd in 50 ml Wasser gelöst und die Lösung dann im Vakuum bei 30 bis 40°C zur Trockne eingedampft. Der Rückstand wird im Vakuum über Phosphorpentoxyd getrocknet, Fp. 204 bis 207°C. Example 5 Homochroman-spiro- (5, 5 ') - hydantoin sodium 11, 6 g Homochroman-spiro- (5, 5 ') - hydantoin are in a solution of 2 g of sodium hydroxide in 50 ml of water dissolved and the solution then evaporated to dryness in vacuo at 30 to 40 ° C. Of the The residue is dried over phosphorus pentoxide in vacuo, melting point 204 to 207.degree.
Beispiel 6 9-Chlor-homochroman-spiro- (5, 5')-hydantoin-Natrium In einer alkoholischen Natronlauge von 2 g Natriumhydroxyd in 200 ml Alkohol werden 13, 3 g 9-Chlorhomochroman-spiro- (5, 5')-hydantoin gelöst. Die Lösung wird bis zur Kristallisation eingedampft und dann abgesaugt. Das Natriumsalz wird über Phosphorpentoxyd getrocknet. Es zeigt bis 350° C keinen Schmelzpunkt. Example 6 9-chloro-homochroman-spiro- (5, 5 ') -hydantoin-sodium In an alcoholic sodium hydroxide solution of 2 g of sodium hydroxide in 200 ml of alcohol 13.3 g of 9-chlorohomochroman-spiro- (5, 5 ') - hydantoin dissolved. The solution will be up evaporated to crystallization and then filtered off with suction. The sodium salt is over phosphorus pentoxide dried. It shows no melting point up to 350 ° C.
Beispiel 7 6-Chlor-chroman-spiro- (4, 5')-hydantoin-Natrium Zu einer Natriumalkoholatlösung aus 1, 15 g Natrium in 100 ml absol. Alkohol werden 12, 6 g 6-Chlorchroman-spiro- (4, 5')-hydantoin gegeben. Die Lösung wird im Vakuum bis zur Trockne eingedampft, Fp. 70 bis 73°C. Example 7 6-chloro-chroman-spiro- (4, 5 ') -hydantoin-sodium To a Sodium alcoholate solution from 1, 15 g sodium in 100 ml absol. Alcohol turn 12, 6 g 6-chlorochroman-spiro- (4, 5 ') - hydantoin given. The solution is in vacuo up evaporated to dryness, m.p. 70 to 73 ° C.
Beispiel 8 Homochroman-spiro- (5, 5')-3'-methyl-hydantoin Zu einer Lösung von 5, 2 g Natriumhydroxyd in 200ml Wasser werden 30 g Homochroman-spiro- (5, 5')-hydantoin gegeben. Nachdem sich das Hydantoin gelöst hat, werden 13, 6g Dimethylsulfat zugegeben und 11/2 Stunden im Wasserbad auf 90 bis 100° C erhitzt. Nach dem Erkalten werden die Kristalle abgesaugt, mit Wasser gewaschen und aus Alkohol umkristallisiert, Fp. 200 bis 207°C. Example 8 Homochroman-spiro- (5, 5 ') - 3'-methyl-hydantoin To a Solution of 5.2 g of sodium hydroxide in 200 ml of water, 30 g of homochroman-spiro- (5, 5 ') - given hydantoin. After the hydantoin has dissolved, 13.6g Dimethyl sulfate was added and the mixture was heated to 90 to 100 ° C. in a water bath for 11/2 hours. After cooling, the crystals are suctioned off, washed with water and made from alcohol recrystallized, m.p. 200-207 ° C.
Beispiel 9 9-Chlor-homochroman-spiro- (5, 5')-3'-methyl-hydantoin Das Produkt wird aus 30 g 9-Chlor-homochromanspiro- (5, 5')-hydantoin, 4, 5 g Natriumhydroxyd und 14 g Dimethylsulfat in Wasser hergestellt, Fp. 190 bis 207° C. Example 9 9-chloro-homochroman-spiro- (5, 5 ') -3'-methyl-hydantoin The product is made from 30 g of 9-chloro-homochromanspiro- (5, 5 ') -hydantoin, 4.5 g of sodium hydroxide and 14 g of dimethyl sulfate prepared in water, m.p. 190 to 207 ° C.
Beispiel 10 8-Chlor-homochroman-spiro- (5, 5')-3'-methyl-hydantoin Das Produkt wurde analog zu Beispiel 8 hergestellt, Fp. 170 bis 174°C. Example 10 8-chloro-homochroman-spiro- (5, 5 ') -3'-methyl-hydantoin The product was prepared analogously to Example 8, melting point 170 to 174.degree.
Beispiel 11 6-Chlor-chroman-spiro- (4, 5')-3'-äthyl-hydantoin 6, 7 g Kaliumhydroxyd werden unter Rühren in 250 ml Alkohol gelöst und mit 25, 3 g 6-Chlor-chromanspiro- (4, 5')-hydantoin versetzt. Nach Zugabe von 18, 7 g Äthyljodid wird 1 Stunde zum Sieden erhitzt. Example 11 6-chloro-chroman-spiro- (4, 5 ') -3'-ethyl-hydantoin 6, 7 g of potassium hydroxide are dissolved in 250 ml of alcohol with stirring and with 25.3 g 6-chloro-chromanspiro- (4, 5 ') - hydantoin added. After adding 18.7 g of ethyl iodide is heated to the boil for 1 hour.
Der Alkohol wird dann im Vakuum abgezogen, der Rückstand mit Wasser versetzt und die ausgefallene Substanz abgesaugt. Das erhaltene 6-Chlor-chromanspiro- (4, 5')-3'-äthyl-hydantoin wird aus Alkohol umkristallisiert, Fp. 131 bis 134°C.The alcohol is then stripped off in vacuo, the residue with water added and the precipitated substance sucked off. The 6-chloro-chromanspiro- (4, 5 ') -3'-ethyl-hydantoin is recrystallized from alcohol, melting point 131 ° to 134 ° C.
Beispiel 12 6-Chlor-chroman-spiro- (4, 5')-3'-butyl-hydantoin Das Produkt wird aus 25, 3 g 6-Chlor-chromanspiro- (4, 5')-hydantoin, 6, 7 g Kaliumhydroxyd und 16, 5 g Butylbromid in Alkohol hergestellt, Fp. 155 bis 159°C. Example 12 6-chloro-chroman-spiro- (4, 5 ') -3'-butyl-hydantoin Das The product is made from 25.3 g of 6-chloro-chromanspiro- (4, 5 ') -hydantoin, 6.7 g of potassium hydroxide and 16.5 g of butyl bromide in alcohol, m.p. 155-159 ° C.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEA37763A DE1135915B (en) | 1961-06-29 | 1961-06-29 | Process for the production of new, anticonvulsant spirohydantoins |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEA37763A DE1135915B (en) | 1961-06-29 | 1961-06-29 | Process for the production of new, anticonvulsant spirohydantoins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1135915B true DE1135915B (en) | 1962-09-06 |
Family
ID=6930404
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEA37763A Pending DE1135915B (en) | 1961-06-29 | 1961-06-29 | Process for the production of new, anticonvulsant spirohydantoins |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1135915B (en) |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2746244A1 (en) * | 1976-10-18 | 1978-04-20 | Pfizer | SPIRO-HYDANTOIN COMPOUNDS AND THEIR USE |
| US4117230A (en) * | 1976-10-18 | 1978-09-26 | Pfizer Inc. | Hydantoin derivatives as therapeutic agents |
| US4127665A (en) * | 1978-01-18 | 1978-11-28 | Pfizer Inc. | Thienohydantoin derivatives |
| US4130714A (en) * | 1977-05-23 | 1978-12-19 | Pfizer Inc. | Hydantoin therapeutic agents |
| US4147795A (en) * | 1977-02-11 | 1979-04-03 | Pfizer Inc. | Hydantoin derivatives as therapeutic agents |
| US4147797A (en) * | 1978-08-11 | 1979-04-03 | Pfizer Inc. | Spiro-furanohydantoin derivatives |
| US4176185A (en) * | 1979-01-22 | 1979-11-27 | Pfizer Inc. | Spiro-quinolylhydantoins |
| US4177282A (en) * | 1977-05-23 | 1979-12-04 | Pfizer Inc. | Hydantoin therapeutic agents |
| US4181729A (en) * | 1979-03-21 | 1980-01-01 | Pfizer Inc. | Phenyl or phenoxy substituted spiro-imidazolidinedione derivatives |
| US4248882A (en) * | 1980-02-12 | 1981-02-03 | Pfizer Inc. | Treating diabetes-associated complications with hydantoin amines |
| US4281009A (en) * | 1978-06-13 | 1981-07-28 | Nippon Zoki Pharmaceutical Co., Ltd. | Hydantoin derivatives |
| EP0037672A2 (en) * | 1980-03-28 | 1981-10-14 | Pfizer Inc. | Process for the preparation of chiral hydantoins, and a novel hydantoin produced by said process and a pharmaceutical composition containing it |
| US4436745A (en) | 1982-04-15 | 1984-03-13 | Alcon Laboratories, Inc. | Method of inhibiting aldose reductase activity |
| US4438272A (en) | 1982-04-15 | 1984-03-20 | Alcon Laboratories, Inc. | Spiro-(fluoren-9,4'-imidazolidine)-2',5'-diones |
| US4464385A (en) * | 1982-04-15 | 1984-08-07 | Alcon Laboratories, Inc. | Treatment of diabetic complications with hydantoins |
-
1961
- 1961-06-29 DE DEA37763A patent/DE1135915B/en active Pending
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2367754A1 (en) * | 1976-10-18 | 1978-05-12 | Pfizer | NEW HYDANTOIN DERIVATIVES AND PHARMACEUTICAL COMPOSITION CONTAINING THEM |
| US4117230A (en) * | 1976-10-18 | 1978-09-26 | Pfizer Inc. | Hydantoin derivatives as therapeutic agents |
| DE2746244A1 (en) * | 1976-10-18 | 1978-04-20 | Pfizer | SPIRO-HYDANTOIN COMPOUNDS AND THEIR USE |
| US4147795A (en) * | 1977-02-11 | 1979-04-03 | Pfizer Inc. | Hydantoin derivatives as therapeutic agents |
| US4130714A (en) * | 1977-05-23 | 1978-12-19 | Pfizer Inc. | Hydantoin therapeutic agents |
| FR2392024A1 (en) * | 1977-05-23 | 1978-12-22 | Pfizer | NEW DEXTROGYRE ISOMERS OF ASYMETRIC SPIRO-HYDANTOINS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US4177282A (en) * | 1977-05-23 | 1979-12-04 | Pfizer Inc. | Hydantoin therapeutic agents |
| US4127665A (en) * | 1978-01-18 | 1978-11-28 | Pfizer Inc. | Thienohydantoin derivatives |
| US4281009A (en) * | 1978-06-13 | 1981-07-28 | Nippon Zoki Pharmaceutical Co., Ltd. | Hydantoin derivatives |
| US4147797A (en) * | 1978-08-11 | 1979-04-03 | Pfizer Inc. | Spiro-furanohydantoin derivatives |
| US4176185A (en) * | 1979-01-22 | 1979-11-27 | Pfizer Inc. | Spiro-quinolylhydantoins |
| EP0014079A1 (en) * | 1979-01-22 | 1980-08-06 | Pfizer Inc. | Spiro-quinolylhydantoins, process for their preparation and pharmaceutical compositions thereof |
| US4181729A (en) * | 1979-03-21 | 1980-01-01 | Pfizer Inc. | Phenyl or phenoxy substituted spiro-imidazolidinedione derivatives |
| US4248882A (en) * | 1980-02-12 | 1981-02-03 | Pfizer Inc. | Treating diabetes-associated complications with hydantoin amines |
| EP0037672A2 (en) * | 1980-03-28 | 1981-10-14 | Pfizer Inc. | Process for the preparation of chiral hydantoins, and a novel hydantoin produced by said process and a pharmaceutical composition containing it |
| EP0037672A3 (en) * | 1980-03-28 | 1983-08-24 | Pfizer Inc. | Process for the preparation of chiral hydantoins, novel intermediates useful therein, and a novel hydantoin produced by said process and a pharmaceutical composition containing it |
| US4436745A (en) | 1982-04-15 | 1984-03-13 | Alcon Laboratories, Inc. | Method of inhibiting aldose reductase activity |
| US4438272A (en) | 1982-04-15 | 1984-03-20 | Alcon Laboratories, Inc. | Spiro-(fluoren-9,4'-imidazolidine)-2',5'-diones |
| US4464385A (en) * | 1982-04-15 | 1984-08-07 | Alcon Laboratories, Inc. | Treatment of diabetic complications with hydantoins |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE1135915B (en) | Process for the production of new, anticonvulsant spirohydantoins | |
| DE1445186B2 (en) | 3,3'-di-2-imidazolin-2-yl-carbanilide | |
| DE2237632A1 (en) | METHOD FOR PREPARING 1- (4-METHYL-6-METHOXY-2-PYRIMIDINYL) -3-METHYL-5METHOXYPYRAZOLE | |
| DE1518452C3 (en) | 4 substituted 2 benzhydryl 2 butanol derivatives and process for their preparation | |
| DE2534962C3 (en) | cis-3,4-ureylenethiophane-l, l-dioxide and process for its preparation | |
| DE1470284B1 (en) | Beta- {1-methyl-4- [1-methyl-4- (1-methyl-4-formylamino-pyrrole-2-carboxamido) -pyrrole-2-carboxamido] -pyrrole-2-carboxamido} -propionamidine and its acid addition salts | |
| DE2530398A1 (en) | ORGANIC CONNECTION | |
| EP0029117B1 (en) | 10-bromosandwicine and 10-bromoisosandwicine, as well as their additions salts with pharmacolical acceptable acids process for their preparation and their use | |
| DE1670143C3 (en) | ||
| DE2832977C2 (en) | ||
| DE737931C (en) | Process for the preparation of 2,4-diaminochinazoline | |
| DE1542826C (en) | Sulphonium compounds and their uses | |
| DE1618310C3 (en) | ||
| AT373588B (en) | METHOD FOR PRODUCING NEW SUBSTITUTED 1-BENZOYL-2-PHENYLIMINO IMIDAZOLIDINES AND THEIR SALTS | |
| DE1017172B (en) | Process for the preparation of 5- (p-bromophenyl) -5-ethylhydantoin or its 3-methyl- and 3-oxymethyl-substituted derivatives | |
| DE1695580C (en) | Quaternary compounds of benzil acid beta piperidino ethyl ester and a process for their preparation | |
| DE1768787C3 (en) | (o-Carboxy-phenyl) -acetamidine, process for their preparation and (o-CarboxyphenyO-acetamidine-containing preparations | |
| DE1670456C3 (en) | Process for the preparation of vitamin B deep 1-tetrahydrofurfuryl disulfide | |
| DE1670378C (en) | Process for the preparation of the salt from 4-n-butyl-3,5-dioxo-1,2-diphenylpyrazolidine and the beta-diethylamino-ethylamide of p-chlorophenoxyacetic acid | |
| DE1122070C2 (en) | Process for the preparation of diuretically active disulfamylaniline compounds | |
| DE842064C (en) | Process for the preparation of 2-diphenylmethoxymethyl-imidazoline | |
| AT231445B (en) | Process for the preparation of new 1, 2, 4-triazolonen- (5) | |
| DE1668199C3 (en) | Benzenesulfonyl-3- (2-hydroxycyclohexyl) ureas | |
| AT219605B (en) | Process for the preparation of new thioxanthene derivatives | |
| DE2218248C3 (en) | Picolinic acid dithiocarbamates |