CH535782A - Pyrimidine ester derivs - hypnotics and sedatives esp 2,4-bis morpholino-and thiamorpholino-5-carboxy pyrimidine esters - Google Patents

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

  

  
 



   The invention relates to a process for the preparation of 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 up to 4 hydrogen atoms are replaced by halogen atoms, in particular bromine, chlorine or fluorine atoms, or straight or branched alkenyl or cycloalkyl or cycloalkyl-alkyl, each with a maximum of 9 carbon atoms -Atoms means, or of acid, addition salts 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 hypnotic 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 2,4-bis-morpholino-5-carboxy-pyrimidine of the formula:
EMI1.2
 or a reactive functional acid derivative thereof is esterified with the introduction of the radical R, whereupon the reaction products obtained are isolated in the form of the free bases or suitable addition salts with inorganic or organic acids.



   The esterification can e.g. take place by adding 2,4-bis-morpholino-5-carboxy-pyrimidine of formula II or a reactive functional acid derivative, e.g. a halide, in particular chloride or a metal salt, is reacted with an alcohol of the formula R-OH, in which R has the meaning mentioned. A preferred embodiment consists in allowing the acid chloride to react with the alcohol in the presence of a suitable inert organic solvent, such as benzene, chloroform, toluene, for one to several hours while heating to the boiling point. It has proven particularly advantageous if the reaction mixture is heated to reflux for 3 hours.



   Under the specified conditions, the reaction can also take place without a solvent, but in this case it is advantageous to use an excess of alcohol of the formula R — OH.



   The esterification can also be accomplished by reacting an acid halide, in particular the acid chloride, of the compound of the formula II with a metal derivative, in particular an alkali metal derivative, such as sodium alcoholate, of the alcohol of the formula R-OH.



   Another variant consists in reacting a metal salt, in particular a silver salt, of the acid of the formula II with a compound of the formula R-Y. Y here denotes a reactive group which can be split off with the metal. e.g. a halogen, in particular chlorine atom, or a tosyl radical. R has the meaning mentioned.



   The 2,4-bis-morpholino-5-carboxy-pyrimidine of the formula II used as the starting compound is obtained e.g. by reacting 2,4-dichloro-5-carboxy-pyrimidine with morpholine. 2,4-Dichloro-5-carboxy-pyrimidine is in turn obtained by treating 2,4-dichloro-uracil-5-carboxylic acid chloride with wet ether.



   The compounds obtained by the process 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. all temperatures are given in degrees Celsius and are not corrected.



   Example I.
10 g of 2,4-bis-morpholino-5-carboxy-pyrimidine hydrochloride are boiled with 80 ml of thionyl chloride for 21/2 hours. After distilling off the thionyl chloride, 40 ml of dry benzene u. evaporates to dryness every time. The residue is taken up in a mixture of 16 ml of allyl alcohol and 50 ml of absolute chloroform and heated to reflux for 3 hours. The residue obtained after evaporation of the solvent is dissolved in a little water, made neutral with 5N sodium hydroxide solution with cooling and extracted exhaustively with chloroform. The chloroform phase is dried with sodium sulfate and evaporated in vacuo. The residue is crystallized from petroleum ether, 2,4-bis-morpholino-S-carballyloxypyrimidine having a melting point of 81.5-83.50C.



   The starting material used in this example was obtained as follows:
20 g of 2,4-dichloro-uracil-5-carboxylic acid chloride are dissolved in 120 ml of ether and mixed with 20 ml of water.



  The reaction mixture is stirred at 30-350C for 1 hour, whereupon the ether phase is separated off, dried with sodium sulfate, filtered and evaporated at 400C in vacuo. The oily residue obtained becomes crystalline on cooling and melts at 97-1010C. 17.3 g of the 2,4-dichloro-5-carboxy-pyrimidine hydrochloride obtained in this way are suspended in a mixture of 100 ml of benzene and 20 ml of ether and, while stirring and ice-cooling, are added dropwise to a mixture of 18.2 g of morpho lin and 18.8 g of triethylamine are added. The reaction mixture is left to stand for 15 hours at room temperature, heated to 8 ° C. for 1 hour and filtered hot. The solid residue is briefly boiled with 70 ml of butanol each time. The combined filtrates are evaporated at 50 ° C. in vacuo.

  The oily residue is dissolved in 30 ml of methanol and ethereal hydrochloric acid is added while cooling with ice. The 2,4-bis-morpholino-5-carboxy-pyrimidine hydrochloride which crystallizes out on cooling is filtered off and crystallized from a mixture of methanol and a little ether. The product obtained shows a double melting point of 165-170 / 2252300C.



   With an analogous procedure as in Example 1, but using appropriate starting materials, the products listed in the table below are obtained.



  TABLE
EMI2.1


<tb> Example <SEP> No. <SEP> R <SEP> Melting point
<tb> Example <SEP> No.
<tb>



   <SEP> 2 <SEP> -CH2-C (CHs) = CH2 <SEP> Base: <SEP> 68- <SEP> 700C
<tb> <SEP> 3 <SEP> -CH2-C {CHs <SEP> Br) -CH2Br <SEP> Base: <SEP> 102-1 <SEP> 100C
<tb> <SEP> - <SEP> OH
<tb> <SEP> RAW
<tb> <SEP> 4 <SEP> - <SEP> CH <SEP> CH2 <SEP> 2 <SEP> Base: <SEP> 91- <SEP> 96 C
<tb> <SEP> 2
<tb> <SEP> 5 <SEP> -CH <SEP> CH- <SEP> CH,
<tb> <SEP> 5 <SEP> -OH <SEP> OH2 <SEP> raw2 <SEP> methanesulfonate: <SEP> 167-1 <SEP> 680C
<tb> <SEP> aH <SEP> OH2
<tb> <SEP> CHCH2¯CH <SEP> Base: <SEP> 90- <SEP> 94 C
<tb> <SEP> 2CH2CH2
<tb> <SEP> oH2
<tb> <SEP> 2
<tb> <SEP> CH <SEP> CH
<tb> <SEP> 7 <SEP> - <SEP> Base: <SEP> OH <SEP> - <SEP> OH
<tb> <SEP> OH <SEP> Base: <SEP> 95- <SEP> 99 C
<tb> <SEP> 2 <SEP> OH
<tb> <SEP> 2 <SEP> OH2
<tb> <SEP> 8 <SEP> -CH2-CH = CH-CH3 <SEP> Base: <SEP> oil
<tb> <SEP> 9 <SEP> -CH2-C (CHs <SEP> Br) -CH5 <SEP> Base:

  <SEP> 86- <SEP> 940C
<tb> <SEP> 10 <SEP> - <SEP> CH2O1 <SEP> Base: <SEP> oil
<tb> <SEP> Base: <SEP> Ol
<tb> <SEP> 2
<tb>

 

Claims (1)

PATENT CLAIM Process for the preparation of pyrimidine derivatives of the general formula: EMI2.2 where R is straight or branched alkyl with at most 9 carbon atoms, in which up to 4 hydrogen atoms are replaced by halogen atoms, or straight or branched alkenyl is cycloalkyl or cycloalkylalkyl with at most 9 carbon atoms each, as well as acid addition salts thereof, characterized in that 2,4-bis morpholino-5-carboxy-pyrimidine of the formula: EMI3.1 or a reactive functional acid derivative thereof is esterified with the introduction of the radical R, whereupon the reaction products obtained are isolated in the form of the free bases or suitable addition salts with inorganic acids.