CH518303A - Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters - Google Patents
Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine estersInfo
- Publication number
- CH518303A CH518303A CH1185769A CH1185769A CH518303A CH 518303 A CH518303 A CH 518303A CH 1185769 A CH1185769 A CH 1185769A CH 1185769 A CH1185769 A CH 1185769A CH 518303 A CH518303 A CH 518303A
- Authority
- CH
- Switzerland
- Prior art keywords
- sep
- pyrimidine
- morpholino
- bis
- formula
- Prior art date
Links
- -1 Pyrimidine ester Chemical class 0.000 title description 2
- 239000005554 hypnotics and sedatives Substances 0.000 title 1
- 229940005535 hypnotics and sedatives Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 claims description 3
- 150000003230 pyrimidines Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
- 150000002367 halogens Chemical class 0.000 abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 abstract description 3
- 241001465754 Metazoa Species 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 abstract description 2
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- 230000003533 narcotic effect Effects 0.000 abstract description 2
- 230000000147 hypnotic effect Effects 0.000 abstract 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 abstract 2
- 229960001412 pentobarbital Drugs 0.000 abstract 2
- JTPSPYXENDSWSG-UHFFFAOYSA-N 2-methylpropyl 2,4-dimorpholin-4-ylpyrimidine-5-carboxylate Chemical compound O1CCN(CC1)C1=NC=C(C(=N1)N1CCOCC1)C(=O)OCC(C)C JTPSPYXENDSWSG-UHFFFAOYSA-N 0.000 abstract 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 abstract 1
- 229910052731 fluorine Inorganic materials 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 239000003326 hypnotic agent Substances 0.000 abstract 1
- 239000000932 sedative agent Substances 0.000 abstract 1
- 230000001624 sedative effect Effects 0.000 abstract 1
- 239000011734 sodium Substances 0.000 abstract 1
- 231100001274 therapeutic index Toxicity 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000007858 starting material Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000009835 boiling Methods 0.000 description 4
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229940035893 uracil Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
HYPNOTIC AND SEDATIVE 2,4-BIS-MORPHOLINO- AND THIAMORPHOLINO-5-CARBOXY PYRIMIDINE ESTERS. M3A. are new compounds of formula (I) including their addition salts. (Z = O or S; R = alkyl opt. substd. by 1-4 halogens. esp. F, Cl, Br, alkyl substd. by one or more OH groups, or alkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl (all is not > C9)). Used as narcotic and hypnotics in man and animals with a greater therapeutic index than of pentobarbitone. ED50 i.v. in mice of 4-22 mg/kg compared with 33 mg/kg for sodium pentobarbitone. 2,4-Bis-morpholino-5-isobutoxycarbonyl-pyrimidine has ED50/LD50 of 4/59 compared with 33/80 for Na pentobarbitone. Preferred dose 125-500 mg for adults. Prepared by various methods eg. (X = reactive group).
Description
Verfahren zur Herstellung von Pyrimidin-Derivate
Gegenstand der Erfindung sind neue Pyrimidin-Derivate der allgemeinen Formel:
EMI1.1
worin R gerades oder verzweigtes Alkyl mit höchstens 9 C-Atomen darstellt, in welchem 1 bis 4 Wasserstoffatome durch Halogenatome, insbesondere Brom-, Chloroder Fluoratome, ersetzt sind, oder gerades oder verzweigtes Alkenyl oder Alkoxyalkyl, Cycloalkyl oder Cycloalkylalkyl, mit je höchstens 9 C-Atomen bedeutet, Säure-Additionssalze davon sowie pharmazeutische Zubereitungen davon.
Die genannten Verbindungen zeichnen sich durch ausserordentlich günstige pharmakodynamische Wirkungen aus, insbesondere zeigen sie im Tierversuch, z.B. bei Mäusen, Ratten und Hunden, eine narkotische und hypotische Wirkung.
Die Verbindungen gemäss Formel I sowie ihre Säure-Additionssalze sollen in der Human- aber auch in der Veterinärmedizin als Schlaf- und Narkosemittel Verwendung finden.
Die Verbindungen gemäss Formel I sowie ihre Säure-Additionssalze können in Form von pharmazeutischen Zubereitungen, welche neben dem Wirkstoff organische oder anorganische, feste oder flüssige Trägerstoffe enthalten können, enteral oder parenteral verabreicht werden.
Derartige pharmazeutischen Zubereitungen sind z.B. Tabletten, Dragees oder Injektionslösungen.
Die Verbindungen der allgemeinen Formel I werden erhalten, wenn man eine Verbindung der allgemeinen Formel:
EMI1.2
worin R die genannte Bedeutung hat und X eine reaktive, mit Wasserstoff von Morpholin abspaltbare Gruppe bedeutet, mit Morpholin umsetzt, worauf man die erhaltenen Reaktionsprodukte in Form der freien Basen oder geeigneter Additionssalze mit anorganischen oder organischen isoliert.
Als reaktive, mit Wasserstoff von Morpholin abspaltbare Gruppe eignet sich insbesondere ein Halogenatom, vorzugsweise ein Chloratom, die Sulfhydrilgruppe, eine niedrige Alkylthiogruppe, beispielsweise die Methylthiogruppe, oder eine gegebenenfalls durch Substituenten aktivierte Aralkylthiogruppe, z.B. die p-Nitrobenzylthiogruppe.
Die Umsetzung wird vorzugsweise während 3 bis 15 Stunden in einem unter den Reaktionsbedingungen inerten organischen Lösungsmittel, z.B. Benzol oder Toluol oder insbesondere einem Alkohol, z.B. einem niedrigen Alkanol, und bei einer Temperatur zwischen Zimmertemperatur und Siedetemperatur durchgeführt. Als besonders vorteilhaft hat sich erwiesen, wenn das Reaktionsgemisch während ca. 8 Stunden auf Siedetemperatur erhitzt wird.
Die Umsetzung kann unter den obenerwähnten Bedingungen auch ohne Lösungsmittel durchgeführt werden, doch ist es in diesem Falle günstig einen Überschuss an Morpholin zu verwenden.
Falls man von Verbindungen der Formel II ausgeht, worin X Halogen bedeutet, und zu den freien Basen der Formel I gelangen will, soll die Umsetzung in Gegenwart eines säurebindenden Mittels, beispielsweise Triäthylamin oder unter Verwendung eines zumindest 100%gen Überschusses an Morpholin durchgeführt werden.
Falls man von Verbindungen der Formel II ausgeht, worin X Halogen bedeutet, und keine säurebindenden Mittel bzw. kein überschuss an Morpholin zusetzt, erhält man Salze von Verbindungen der Formel I, aus welchen die Basen auf an sich bekannte Weise freigesetzt werden können.
Zu den als Ausgangsmaterialien erwähnten Verbindungen der Formel II, worin X für ein Halogenatom steht, kann man z.B. gelangen, wenn man eine Verbindung der Formel:
EMI2.1
worin Hal Halogen bedeutet, mit einem Alkohol der Formel R-OH, wobei R die genannte Bedeutung hat, umsetzt. Zweckmässigerweise wird die Umsetzung so durchgeführt, dass man die Verbindungen der allgemeinen Formel III mit Verbindungen der allgemeinen Formel R-OH in einem unter den Reaktionsbedingungen inerten organischen Lösungsmittel, wie Toluol, und in Gegenwart säurebindender Mittel, z.B. Triäthylamin, bei einer Temperatur von - 5 bis + 100C zusammenbringt und das Reaktionsgemisch anschliessend während ca. 2 Stunden auf Siedetemperatur erhitzt.
Falls man jedoch Verbindungen der Formel III mit dem Alkohol R-OH bei Siedetemperatur umsetzt, erhält man eine leicht isolierbare und kristallisierbare Verbindung der Formel:
EMI2.2
worin R die genannte Bedeutung hat, welche durch Halogenieren, z.B. mit Hilfe von Thionylchlorid, zu Verbindungen der Formel II überführt werden kann.
Zu Verbindungen der allgemeinen Formel IV kann man jedoch auch gelangen, indem man Uracil(5)carbonsäure 60 Stunden mit Thionylchlorid in Gegenwart katalytischer Mengen von Dimethylformamid und anschliessendes kurzes Erhitzen auf Rückfluss reagieren lässt und das erhaltene Reaktionsprodukt mit einem Alkohol der allgemeinen Formel R-OH umsetzt.
Die Verbindung der Formel III und die Uracil(5)carbonsäure sind bekannt oder können auf an sich bekannte Weise hergestellt werden.
Ausgangsverbindungen der Formel II, worin X die Sulfhydrilgruppe bedeutet. erhält man z.B. durch Umsetzen von Uracil(5)carbonsäure mit Phosphorpentasulfid und Verestern der erhaltenen Verbindung bzw. eines reaktionsfähigen Säurederivates davon, insbesondere eines Halogenides, mit einem Alkohol der Formel R-OH.
Durch Alkylierung oder entsprechende Aralkylierung des so erhaltenen Produktes kann man zu den Ausgangsmaterialien der Formel II, worin X eine Alkylthio- oder eine gegebenenfalls aktivierte Aralkylthiogruppe bedeutet, gelangen.
Diejenigen Ausgangsverbindungen der Formel II, worin der Rest X eine andere Bedeutung besitzt die eines Halogenatoms, der Sulfhydrilgruppe, einer Alkylthiogruppe oder einer gegebenenfalls aktivierten Aralkylthiogruppe können in analoger Weise hergestellt werden.
Die nach den beschriebenen Verfahren erhaltenen Verbindungen, welche auf an sich bekannte Weise isoliert und gereinigt werden, sind bei Zimmertemperatur teils feste, gegebenenfalls kristalline, teils flüssige basische Verbindungen, die durch Umsetzen mit geeigneten anorganischen oder organischen Säuren in ihre Säure-Additionssalze übergeführt werden können. Hierfür haben sich als anorganische Säuren z.B. Halogenwasserstoffsäuren, Salpetersäure, Phosphorsäure und als organische Säuren z.B. Methansulfonsäure und Pikrinsäure als geeignet erwiesen.
In den nachfolgenden Beispielen, die die Erfindung näher erläutem, ihren Umfang aber in keiner Weise einschränken sollen, erfolgen alle Temperaturangaben in Celsiusgraden und sind nicht korrigiert.
Beispiel I
11,2 g 2,4-Dichlor-5-carballyloxy-pyrimidin werden in 100 ml Isobutanol gelöst und mit 11 g Triäthylamin und 8,8 g Morpholin versetzt. Das Gemisch wird während 8 Stunden am Rückfluss erhitzt und hierauf zur Trockne eingedampft. Der Rückstand wird in Chloroform gelöst und mit Wasser unter Zusatz von Eis gewaschen, mit Natriumsulfat getrocknet und zur Trockne eingedampft. Der Rückstand wird in Hexan gelöst und durch Aluminiumoxyd filtriert. Nach Abdampfen des Lösungsmittels erhält man 2,4-bis-Morpholino-5-carballyloxy-pyrimidin in Form eines Öles, welches nach längerem Stehenlassen Kristalle vom Schmelzpunkt 81,5-83 ,50C liefert.
Den in diesem Beispiel verwendeten Ausgangsstoff erhielt man wie folgt:
Eine Lösung von 10 g 2,4-Dichlor-uracil-5-carbonsäu- rechlorid in 100 ml absolutem Toluol wird unter Rühren und Eiskühlung zu einem Gemisch von 2,9 g Allylalkohol, 8 g Triäthylamin und 120 ml absolutem Toluol getropft, worauf man während 2 Stunden am Rückfluss erhitzt. Das Reaktionsgemisch wird hierauf mit Wasser und 2N Kaliumbicarbonatlösung gewaschen, mit Natriumsulfat getrocknet und am Vakuum eingedampft. Man erhält 2,4-Dichlor-5-carballyloxypyrimidin, welches ohne weitere Reinigung in die vorstehende Reaktion eingesetzt wird.
Bei analogem Vorgehen wie in Beispiel 1, jedoch unter Verwendung entsprechender Ausgangsstoffe, erhält man die in der folgenden Tabelle aufgeführten Produkte: TABELLE
EMI3.1
<tb> Beispiel <SEP> R <SEP> Schmelz
<tb> Nr. <SEP> punkt
<tb> <SEP> 2 <SEP> -CH3-C(CH3)=CH2 <SEP> Base:
<tb> <SEP> 68-700C
<tb> <SEP> 3 <SEP> -CH2-C(CH3 <SEP> - <SEP> Br)-CH2Br <SEP> Base:
<tb> <SEP> 102-1 <SEP> 100C
<tb> <SEP> CH2CH2
<tb> <SEP> \cH;Base:
<tb> <SEP> 4 <SEP> -cH <SEP> CH2 <SEP> Base:
<tb> <SEP> \ <SEP> / <SEP> 91-96 C
<tb> <SEP> CH2CH2
<tb> <SEP> CH2CH2
<tb> <SEP> sulfonat:
<tb> <SEP> 5 <SEP> -CH <SEP> sulfonat:
<tb> <SEP> CH2-CH2 <SEP> 167-1680C
<tb> <SEP> CH2
<tb> <SEP> CH2 <SEP> CH3
<tb> <SEP> 6 <SEP> -CH <SEP> Base:
<tb> <SEP> 90-940C
<tb> <SEP> CH2 <SEP> CH2
<tb> <SEP> CH2
<tb> <SEP> 3
<tb> <SEP> CH2CH2
<tb> <SEP> 7 <SEP> -CH2-CH <SEP> CH2 <SEP> Base:
:
<tb> <SEP> 95-990C
<tb> <SEP> CH3-CH3
<tb> <SEP> 8 <SEP> -CH2-CH=CHCH3 <SEP> Base:
<tb> <SEP> Öl
<tb> <SEP> 9 <SEP> -CH3-C(CH3 <SEP> - <SEP> Br)CH3 <SEP> Base:
<tb> <SEP> 86-940C
<tb> <SEP> CH3Cl
<tb> 10 <SEP> -CH <SEP> Base:
<tb> <SEP> öl
<tb> <SEP> CH2Cl
<tb>
Process for the preparation of pyrimidine derivatives
The invention relates to new pyrimidine derivatives of the general formula:
EMI1.1
where R represents straight or branched alkyl with a maximum of 9 carbon atoms, in which 1 to 4 hydrogen atoms have been replaced by halogen atoms, in particular bromine, chlorine or fluorine atoms, or straight or branched alkenyl or alkoxyalkyl, cycloalkyl or cycloalkylalkyl, each with a maximum of 9 carbon atoms -Atoms means acid addition salts thereof and pharmaceutical preparations thereof.
The compounds mentioned are distinguished by extremely favorable pharmacodynamic effects, in particular they show in animal experiments, e.g. in mice, rats and dogs, a narcotic and hypotic effect.
The compounds according to formula I and their acid addition salts are intended to be used as sleeping and anesthetic agents in human but also in veterinary medicine.
The compounds according to formula I and their acid addition salts can be administered enterally or parenterally in the form of pharmaceutical preparations which, in addition to the active ingredient, can contain organic or inorganic, solid or liquid carriers.
Such pharmaceutical preparations are e.g. Tablets, coated tablets or injection solutions.
The compounds of the general formula I are obtained when a compound of the general formula:
EMI1.2
wherein R has the meaning mentioned and X is a reactive group which can be split off from morpholine with hydrogen, is reacted with morpholine, whereupon the reaction products obtained are isolated in the form of the free bases or suitable addition salts with inorganic or organic compounds.
A particularly suitable reactive group which can be split off from morpholine with hydrogen is a halogen atom, preferably a chlorine atom, the sulfhydril group, a lower alkylthio group, for example the methylthio group, or an aralkylthio group which is optionally activated by substituents, e.g. the p-nitrobenzylthio group.
The reaction is preferably carried out for 3 to 15 hours in an organic solvent which is inert under the reaction conditions, e.g. Benzene or toluene or especially an alcohol e.g. a lower alkanol, and carried out at a temperature between room temperature and boiling temperature. It has proven to be particularly advantageous if the reaction mixture is heated to the boiling point for about 8 hours.
The reaction can also be carried out without a solvent under the abovementioned conditions, but in this case it is advantageous to use an excess of morpholine.
If you start from compounds of the formula II in which X is halogen, and want to get to the free bases of the formula I, the reaction should be carried out in the presence of an acid-binding agent, for example triethylamine, or using an at least 100% excess of morpholine.
If one starts from compounds of the formula II in which X is halogen and no acid-binding agents or no excess of morpholine are added, salts of compounds of the formula I from which the bases can be released in a manner known per se are obtained.
The compounds of formula II, in which X stands for a halogen atom, mentioned as starting materials can be e.g. get when you get a compound of the formula:
EMI2.1
in which Hal is halogen, with an alcohol of the formula R-OH, where R has the meaning mentioned. The reaction is expediently carried out in such a way that the compounds of the general formula III are mixed with compounds of the general formula R-OH in an organic solvent which is inert under the reaction conditions, such as toluene, and in the presence of acid-binding agents, e.g. Triethylamine, brings together at a temperature of -5 to + 100C and the reaction mixture is then heated to boiling temperature for about 2 hours.
If, however, compounds of the formula III are reacted with the alcohol R-OH at the boiling point, an easily isolatable and crystallizable compound of the formula is obtained:
EMI2.2
wherein R is as defined which can be obtained by halogenation, e.g. with the aid of thionyl chloride, can be converted to compounds of the formula II.
Compounds of the general formula IV can also be obtained by reacting uracil (5) carboxylic acid for 60 hours with thionyl chloride in the presence of catalytic amounts of dimethylformamide and then briefly heating to reflux and the reaction product obtained with an alcohol of the general formula R-OH implements.
The compound of the formula III and the uracil (5) carboxylic acid are known or can be prepared in a manner known per se.
Starting compounds of the formula II in which X is the sulfhydryl group. one obtains e.g. by reacting uracil (5) carboxylic acid with phosphorus pentasulfide and esterifying the compound obtained or a reactive acid derivative thereof, in particular a halide, with an alcohol of the formula R-OH.
The starting materials of the formula II in which X is an alkylthio group or an optionally activated aralkylthio group can be obtained by alkylation or corresponding aralkylation of the product thus obtained.
Those starting compounds of the formula II in which the radical X has a different meaning: that of a halogen atom, the sulfhydryl group, an alkylthio group or an optionally activated aralkylthio group can be prepared in an analogous manner.
The compounds obtained by the processes described, which are isolated and purified in a manner known per se, are partly solid, optionally crystalline, partly liquid basic compounds at room temperature, which can be converted into their acid addition salts by reaction with suitable inorganic or organic acids . For this purpose, inorganic acids have e.g. Hydrohalic acids, nitric acid, phosphoric acid and as organic acids e.g. Methanesulfonic acid and picric acid proved to be suitable.
In the following examples, which explain the invention in more detail but are not intended to restrict its scope in any way, all temperatures are given in degrees Celsius and are not corrected.
Example I.
11.2 g of 2,4-dichloro-5-carballyloxypyrimidine are dissolved in 100 ml of isobutanol, and 11 g of triethylamine and 8.8 g of morpholine are added. The mixture is refluxed for 8 hours and then evaporated to dryness. The residue is dissolved in chloroform and washed with water with the addition of ice, dried with sodium sulfate and evaporated to dryness. The residue is dissolved in hexane and filtered through aluminum oxide. After evaporation of the solvent, 2,4-bis-morpholino-5-carballyloxypyrimidine is obtained in the form of an oil which, after prolonged standing, gives crystals with a melting point of 81.5-83.50 ° C.
The starting material used in this example was obtained as follows:
A solution of 10 g of 2,4-dichloro-uracil-5-carboxylic acid chloride in 100 ml of absolute toluene is added dropwise with stirring and ice-cooling to a mixture of 2.9 g of allyl alcohol, 8 g of triethylamine and 120 ml of absolute toluene, whereupon heated to reflux for 2 hours. The reaction mixture is then washed with water and 2N potassium bicarbonate solution, dried with sodium sulfate and evaporated in vacuo. 2,4-dichloro-5-carballyloxypyrimidine is obtained, which is used in the above reaction without further purification.
If the procedure is analogous to that in Example 1, but using appropriate starting materials, the products listed in the following table are obtained: TABLE
EMI3.1
<tb> Example <SEP> R <SEP> enamel
<tb> No. <SEP> dot
<tb> <SEP> 2 <SEP> -CH3-C (CH3) = CH2 <SEP> Base:
<tb> <SEP> 68-700C
<tb> <SEP> 3 <SEP> -CH2-C (CH3 <SEP> - <SEP> Br) -CH2Br <SEP> Base:
<tb> <SEP> 102-1 <SEP> 100C
<tb> <SEP> CH2CH2
<tb> <SEP> \ cH; Base:
<tb> <SEP> 4 <SEP> -cH <SEP> CH2 <SEP> Base:
<tb> <SEP> \ <SEP> / <SEP> 91-96 C
<tb> <SEP> CH2CH2
<tb> <SEP> CH2CH2
<tb> <SEP> sulfonate:
<tb> <SEP> 5 <SEP> -CH <SEP> sulfonate:
<tb> <SEP> CH2-CH2 <SEP> 167-1680C
<tb> <SEP> CH2
<tb> <SEP> CH2 <SEP> CH3
<tb> <SEP> 6 <SEP> -CH <SEP> Base:
<tb> <SEP> 90-940C
<tb> <SEP> CH2 <SEP> CH2
<tb> <SEP> CH2
<tb> <SEP> 3
<tb> <SEP> CH2CH2
<tb> <SEP> 7 <SEP> -CH2-CH <SEP> CH2 <SEP> Base:
:
<tb> <SEP> 95-990C
<tb> <SEP> CH3-CH3
<tb> <SEP> 8 <SEP> -CH2-CH = CHCH3 <SEP> Base:
<tb> <SEP> oil
<tb> <SEP> 9 <SEP> -CH3-C (CH3 <SEP> - <SEP> Br) CH3 <SEP> Base:
<tb> <SEP> 86-940C
<tb> <SEP> CH3Cl
<tb> 10 <SEP> -CH <SEP> Base:
<tb> <SEP> oil
<tb> <SEP> CH2Cl
<tb>
Claims (1)
Priority Applications (37)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BG015084A BG17589A3 (en) | 1969-08-05 | 1969-07-02 | METHOD FOR OBTAINING NEW PYRIMIDINE DERIVATIVES |
| CH1177771A CH535782A (en) | 1969-08-05 | 1969-08-05 | Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters |
| CH1185769A CH518303A (en) | 1969-08-05 | 1969-08-05 | Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters |
| CH1177971A CH535784A (en) | 1969-08-05 | 1969-08-05 | Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters |
| CH1177871A CH535783A (en) | 1969-08-05 | 1969-08-05 | Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters |
| GB50806/69A GB1270120A (en) | 1968-11-08 | 1969-10-16 | Pyrimidine carboxylic acid ester derivatives |
| NL6916269A NL6916269A (en) | 1968-11-08 | 1969-10-29 | |
| US873646A US3635962A (en) | 1968-11-08 | 1969-11-03 | 4 - bis-morpholino- and 2 |
| DE19691955318 DE1955318A1 (en) | 1968-11-08 | 1969-11-04 | New pyrimidine derivatives and processes for their preparation |
| RO66816A RO57597A (en) | 1968-11-08 | 1969-11-06 | |
| RO66813A RO57208A (en) | 1968-11-08 | 1969-11-06 | |
| BG015083A BG17586A3 (en) | 1969-08-05 | 1969-11-06 | METHOD FOR OBTAINING NEW PYRIMIDINE DERIVATIVES |
| BG013309A BG17587A3 (en) | 1969-02-28 | 1969-11-06 | METHOD FOR OBTAINING NEW PYRIMIDINE DERIVATIVES |
| SU1375163D SU407450A3 (en) | 1968-11-08 | 1969-11-06 | |
| AT735371A AT307435B (en) | 1969-08-05 | 1969-11-06 | Process for the preparation of new pyrimidine derivatives and their salts |
| RO61486A RO55872A (en) | 1968-11-08 | 1969-11-06 | |
| IE1515/69A IE33364B1 (en) | 1968-11-08 | 1969-11-06 | Pyrimidine carboxylic acid ester derivatives |
| IL33321A IL33321A (en) | 1968-11-08 | 1969-11-06 | Pyrimidine derivatives,their preparation and pharmaceutical compositions containing them |
| OA53776A OA03165A (en) | 1968-11-08 | 1969-11-06 | New pyrimidine derivatives and their preparation. |
| RO66814A RO57209A (en) | 1968-11-08 | 1969-11-06 | |
| AT735571A AT307437B (en) | 1969-08-05 | 1969-11-06 | Process for the preparation of new pyrimidine derivatives and their salts |
| BE741376D BE741376A (en) | 1968-11-08 | 1969-11-06 | |
| SU1615151A SU394969A3 (en) | 1969-08-05 | 1969-11-06 | |
| ES373237A ES373237A1 (en) | 1968-11-08 | 1969-11-06 | 4 - bis-morpholino- and 2 |
| RO66815A RO57210A (en) | 1968-11-08 | 1969-11-06 | |
| AT735271A AT307434B (en) | 1969-02-28 | 1969-11-06 | Process for the preparation of new pyrimidine derivatives and their salts |
| AT1044569A AT307433B (en) | 1968-11-08 | 1969-11-06 | Process for the preparation of new pyrimidine derivatives and their salts |
| AT735471A AT307436B (en) | 1969-08-05 | 1969-11-06 | Process for the preparation of new pyrimidine derivatives and their salts |
| FR6938186A FR2024819B1 (en) | 1968-11-08 | 1969-11-06 | |
| DK591669AA DK121440B (en) | 1968-11-08 | 1969-11-07 | Analogous process for the preparation of 2,4-bis-morpholino- or-thiomorpholino-5-carbalkoxy-pyrimidines. |
| NO4422/69A NO124209B (en) | 1968-11-08 | 1969-11-07 | |
| BG015082A BG17588A3 (en) | 1969-08-05 | 1970-07-02 | METHOD FOR OBTAINING NEW PYRIMIDINE DERIVATIVES |
| BG015085A BG17590A3 (en) | 1969-08-05 | 1970-07-02 | METHOD FOR OBTAINING NEW PYRIMIDINE DERIVATIVES |
| ES383801A ES383801A1 (en) | 1969-08-05 | 1970-09-19 | Procedure for the obtaining of pyrimidine derivatives. (Machine-translation by Google Translate, not legally binding) |
| ES383799A ES383799A1 (en) | 1969-02-28 | 1970-09-19 | Procedure for the obtaining of pyrimidine derivatives. (Machine-translation by Google Translate, not legally binding) |
| ES383800A ES383800A1 (en) | 1969-08-05 | 1970-09-19 | Procedure for the obtaining of pyrimidine derivatives. (Machine-translation by Google Translate, not legally binding) |
| ES383802A ES383802A1 (en) | 1969-08-05 | 1970-09-19 | Procedure for the obtaining of pyrimidine derivatives. (Machine-translation by Google Translate, not legally binding) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1185769A CH518303A (en) | 1969-08-05 | 1969-08-05 | Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH518303A true CH518303A (en) | 1972-01-31 |
Family
ID=4377571
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1185769A CH518303A (en) | 1968-11-08 | 1969-08-05 | Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters |
| CH1177871A CH535783A (en) | 1969-08-05 | 1969-08-05 | Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters |
| CH1177771A CH535782A (en) | 1969-08-05 | 1969-08-05 | Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters |
| CH1177971A CH535784A (en) | 1969-08-05 | 1969-08-05 | Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters |
Family Applications After (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1177871A CH535783A (en) | 1969-08-05 | 1969-08-05 | Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters |
| CH1177771A CH535782A (en) | 1969-08-05 | 1969-08-05 | Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters |
| CH1177971A CH535784A (en) | 1969-08-05 | 1969-08-05 | Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters |
Country Status (5)
| Country | Link |
|---|---|
| AT (3) | AT307437B (en) |
| BG (3) | BG17589A3 (en) |
| CH (4) | CH518303A (en) |
| ES (3) | ES383802A1 (en) |
| SU (1) | SU394969A3 (en) |
-
1969
- 1969-07-02 BG BG015084A patent/BG17589A3/en unknown
- 1969-08-05 CH CH1185769A patent/CH518303A/en not_active IP Right Cessation
- 1969-08-05 CH CH1177871A patent/CH535783A/en not_active IP Right Cessation
- 1969-08-05 CH CH1177771A patent/CH535782A/en not_active IP Right Cessation
- 1969-08-05 CH CH1177971A patent/CH535784A/en not_active IP Right Cessation
- 1969-11-06 AT AT735571A patent/AT307437B/en not_active IP Right Cessation
- 1969-11-06 SU SU1615151A patent/SU394969A3/ru active
- 1969-11-06 BG BG015083A patent/BG17586A3/en unknown
- 1969-11-06 AT AT735371A patent/AT307435B/en not_active IP Right Cessation
- 1969-11-06 AT AT735471A patent/AT307436B/en not_active IP Right Cessation
-
1970
- 1970-07-02 BG BG015082A patent/BG17588A3/en unknown
- 1970-09-19 ES ES383802A patent/ES383802A1/en not_active Expired
- 1970-09-19 ES ES383800A patent/ES383800A1/en not_active Expired
- 1970-09-19 ES ES383801A patent/ES383801A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| AT307435B (en) | 1973-05-25 |
| BG17589A3 (en) | 1973-11-10 |
| CH535784A (en) | 1973-04-15 |
| BG17588A3 (en) | 1973-11-10 |
| ES383802A1 (en) | 1973-06-01 |
| BG17586A3 (en) | 1973-11-10 |
| AT307436B (en) | 1973-05-25 |
| SU394969A3 (en) | 1973-08-22 |
| CH535783A (en) | 1973-04-15 |
| AT307437B (en) | 1973-05-25 |
| ES383801A1 (en) | 1973-06-01 |
| ES383800A1 (en) | 1973-06-01 |
| CH535782A (en) | 1973-04-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |