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US2206779A
US2206779A US2206779DA US2206779A US 2206779 A US2206779 A US 2206779A US 2206779D A US2206779D A US 2206779DA US 2206779 A US2206779 A US 2206779A
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methyl
barbituric
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C07D239/62—Barbituric acids

Definitions

  • the present invention relates to new barbituric acid derivatives and to a process of preparing the same.
  • N-alkylated C,C-dialkyl-barb-ituric acid compounds which are free from the said disadvantages of the known N-alkyl-QC-diaikyl-barbituric acids are obtainable by the manufacture of such N-alkylated C,C-dialkylbarbituric acids ,which contain attached to the 5-carbon atom of the barbituric acid as alkyl groups one methyl group and anotheralkyl group of at least 3 carbon atoms.
  • the latter alkyl group may be saturated or unsaturated and may be substituted by alicyclic radicals as,.for in'stance, in the cyclohexylethyl radical, ormay be present in the form of saturated cyclic alkyl groups.
  • the new barbituric acids which, in accordance with the present invention,represent a new group of therapeutically valuable barbituric acids may be defined by the following formula:
  • the new N-mono-or dialk'ylated C-methyl-C-alkylbarbituric acids are obtainable by reacting upon a methylf-alkyl-malonic or cyano acetic acid or derivatives thereof, for instance, the esters, amidesamide-acid esters, chlorides, nitriles with an N-monoor N-dialkylated urea to yield the above characterized N-monoor N-dialkylated C-methyl-C-alkyl-barbituric acids.
  • the alkyl group substituting the malonic or cyan'o acetic acid compounds above referred to is an alkyl, alkenyl, cycloalkyl or cyclo'alkyl substituted alkyl group of atlleast'3carbon*atoms.
  • the reaction is carried out in the presence of a condensing agent, preferably in the presence of alkali metal alcoholates, such as sodium ethylate, and in the presence of a diluent, particularly in the press enoe of an alcohol, such asmethanol and ethanol.
  • N-alkylated ureas themselvesderivatives of N-alkylated ureasmay be employed; for instance, N-alkylate'd guanidines, thioureas and isoureaethers.
  • the primarily ob tained intermediate products, for instance, imino and thiobarbituric acid compounds are subsequently to be transformed into the real barbituric acidin the manner known per se.
  • TheN-monoor dialkylated'barbituric acids being: substituted at the 5'-carb0n atom by a methyl" group and'an alkylgroup' of at least 3 carbon atoms asspecifiedabove are also obtainable by starting with the barbituric acid itself or with suchsub'stitution products of the barbituric acid which contain one ormore of the required substituents. In this case the substituents still missing:- are introduced into the barbituric acid or into its substitution products in themanner known'per se. Instead of-the' b-arb'ituric acid itself or instead of its simple substitution products derivativesthereof may be used as starting materials in which?
  • the intermediate products primarily formed are converted into the N-mon0- or dialkylated C-methy1-C-alkyl-barbituric' acid of the kind above specified in theusual manner.
  • the N mo'noalkylated compounds are advantageously obtained by the alkylationof cyano-imino derivatives or" the barbituri'ci acid, its C-substitu'tion products respcc tively.
  • the N-alkyl-N'cyano imino barbituric acids containing at the 5-carbon' atom a methyl group and an alkyl group of at least3 carbon atoms asabovespecified which are obtained-in this case as: intermediate: products are saponiiiedr: to,
  • Example 1 -20 parts by weight of sodium are dissolved in 400 parts by Weight of ethylalcoihol and 50 parts by weight of methylurea, and parts by weight of butylmethylmalonic acid ethylester are added. The mixture is heated for 8 hours to boiling. Then it is acidified with acetic acid and the alcohol is evaporated. Water is added to the residue, the reaction product is taken up in ether and the solution first shaken with a sodium bicarbonate solution and then with a normal aqueous solution of caustic soda. On acidifying the caustic soda solution the N-methyl- C,C-methyl-butyl-barbituric acid is precipitated. 0n redissolving from cyclohexane it melts at 87 C. The acid may, also be distilled in vacuo. It
  • N-ethyl-C-methyl-C-butylbarbituric acid is obtained in the manner described above.
  • N-methyl-C,C- (n-hexyl) -methylbarbituric acid can be obtained. It distils under 1.5 mm. pressure at 183-185 C., and crystallizes on cooling.
  • N-methyl-C-cyclohexylethyl C methylbarbituricacid is obtained in a similar manner, for instance, when starting with methylurea and cyclohexylethyl-methyl-cyanoacetic acid ester while using sodium ethylate as a condensing agent.
  • the imino-N-methyl-C-cyclohexylethyl-C-methylbarbituric acid first formed is subsequently boiled for about 6-8 hours with 20% aqueous sulfuric acid.
  • Example 2.9.5 parts by weight of sodium are dissolved in 200 parts by weight of dry ethyl alcohol and mixed with 42 parts by weight of methyl-allylmalonic ester and 20 parts by weight of methylurea while stirring. The mixture is heated for 6 to 8 hours under reflux. After cooling the salt which crystallizes out is filtered off, dissolved in water and the free acid is precipitated with acetic acid. On recrystallizing from water the N-methyl-C,C-methyl-allyl-barbituric acid melts at 135 C.
  • N-methyl- C,C-bromoallylmethylbarbituric acid can be obtained. It distils under 1.5 mm. pressure at 136- From allyl urea and methyl-isoamyl-malonic acid ester in an analogous manner the N-allyl-C- methyl-C isoamylbarbituric acid is obtained which boils at 150 C. under 1 mm. pressure and melts at 68-69 C.
  • Example 346 parts by weight of sodium metal are dissolved in 500 parts by weight of methanol, 92 parts by weight of dicyandiamide and 256 parts by weight of cyclohexyl-methyl-malonic acid diethylester (boiling at 137-138" C. under 1 mm. pressure) are added and the mixture is heated for 10 hours under reflux to 70-80 C.
  • N-methyl-C-cyclopentyl-C-methylbarbituric acid is obtained in the form of white crystals.
  • N-methyl-C,C-beta-ethy1hexyl-methylbarbituric acid forms an oily product.
  • R1 stands for a cyclohexyl group
  • alkyl stands for a radical selected from the group consisting of saturated and unsaturated alkyl groups
  • X stands for a 'substituent selected from the group consisting .of hydrogen and alkali and alkaline earth metals, which compounds are whitish crystalline products, insoluble in water in the form of the free acid but soluble in the form of the alkali metal salts.
  • R1 stands for a cyclohexyl group
  • X stands for a substituent selected from the group consisting of hydrogen and alkali and alkaline earth metals, which compounds are whitish crystalline products, insoluble in water in the form of the free acid but soluble in the form of the alkali metal salts.
  • Ristands fora cyclohexyl group which compounds 'are whitish crystalline products, insoluble in water in the form of the free acid but soluble in the form of the alkali metal salts.
  • R1 stands for a radical selected from the group consisting of cyclopentyl, cyclohexyl, and cyclohexyalkyl groups
  • alkyl stands for a radical selected from the group consisting of saturated and unsaturated alkyl groups
  • X stands for a substituent selected from the group consisting of hydrogen, alkali and alkalineeearth metals, which compounds are whitish crystalline products, insoluble in Water in the form of the free acid but soluble in the form of the alkalimetal salts.
  • R1 stands for a radical selected from the group consisting of cyclopentyl, cyclohexyl, and cyclohexylalkyl groups
  • X stands for a substituent selected from the group consisting of hydrogen, alkali and alkaline-earth metals, which compounds are whitish crystalline products, insoluble in Water in the form of the free acid but soluble in the form of the alkali metal salts.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Patented July 2, 1940 N-ALKYL-G-METHYL-BARBITURIC a ACID COMPOUNDS Walter Kropp and Ludwig Taub; wuppertal- Elberfeld, Germany, ,Chemical Company, In corporation of New Yor assignors to Winthrop c., New York, N; Y., a
No Drawing. Application March 17, 1934, Serial No. 716,223. In GermanyMarch 25, 1933 Claims. I (O1. 260+257) The present invention relates to new barbituric acid derivatives and to a process of preparing the same.
It is known that alkylation of the nitrogen atoms of barbituric acids which are twice substituted at the 5-carbon atom has various effects as to the therapeutic properties of such barbituric acid derivatives, substantially depending on the w particular substituentsi which are present at the,
S-carbon atom of the barbituric acid. For instance, vby the N-methylation or the N-ethylation of C-aryl-C-alkyl barbituric acids therapeutically active compounds have been obtained which display a prolonged activity as compared with the corresponding non-.N-alkylated products. Otherwise the N-alkylated '(l-cyclopentenyl-and C-cyclohexenyl-C-alkyl-barbituric acids display an action which relativelyquickly sets in and relatively quickly ceases, which properties render the said barbi-turic acid suitable for specific therapeutic purposes. Contrary thereto it is known that certain N alkylated C,C-dialkylbarbituric acids are very toxic and cannot be used therapeutically in view of their undesired secondary effects.
In, accordance with the present invention new N-alkylated C,C-dialkyl-barb-ituric acid compounds which are free from the said disadvantages of the known N-alkyl-QC-diaikyl-barbituric acids are obtainable by the manufacture of such N-alkylated C,C-dialkylbarbituric acids ,which contain attached to the 5-carbon atom of the barbituric acid as alkyl groups one methyl group and anotheralkyl group of at least 3 carbon atoms. The latter alkyl group may be saturated or unsaturated and may be substituted by alicyclic radicals as,.for in'stance, in the cyclohexylethyl radical, ormay be present in the form of saturated cyclic alkyl groups. Accordingly the new barbituric acids which, in accordance with the present invention,represent a new group of therapeutically valuable barbituric acids may be defined by the following formula:
in general, render them suitable particularly for the short narcosis Without showing any secondary effects,
In accordance with the present invention the new N-mono-or dialk'ylated C-methyl-C-alkylbarbituric acids are obtainable by reacting upon a methylf-alkyl-malonic or cyano acetic acid or derivatives thereof, for instance, the esters, amidesamide-acid esters, chlorides, nitriles with an N-monoor N-dialkylated urea to yield the above characterized N-monoor N-dialkylated C-methyl-C-alkyl-barbituric acids. The alkyl group substituting the malonic or cyan'o acetic acid compounds above referred to is an alkyl, alkenyl, cycloalkyl or cyclo'alkyl substituted alkyl group of atlleast'3carbon*atoms. The reaction is carried out in the presence of a condensing agent, preferably in the presence of alkali metal alcoholates, such as sodium ethylate, and in the presence of a diluent, particularly in the press enoe of an alcohol, such asmethanol and ethanol. Instead of the alkylated ureas themselvesderivatives of N-alkylated ureasmay be employed; for instance, N-alkylate'd guanidines, thioureas and isoureaethers. In suchcases the primarily ob tained intermediate products, for instance, imino and thiobarbituric acid compounds are subsequently to be transformed into the real barbituric acidin the manner known per se.
TheN-monoor dialkylated'barbituric acids being: substituted at the 5'-carb0n atom by a methyl" group and'an alkylgroup' of at least 3 carbon atoms asspecifiedabove are also obtainable by starting with the barbituric acid itself or with suchsub'stitution products of the barbituric acid which contain one ormore of the required substituents. In this case the substituents still missing:- are introduced into the barbituric acid or into its substitution products in themanner known'per se. Instead of-the' b-arb'ituric acid itself or instead of its simple substitution products derivativesthereof may be used as starting materials in which? case the intermediate products primarily formed are converted into the N-mon0- or dialkylated C-methy1-C-alkyl-barbituric' acid of the kind above specified in theusual manner. Thus; for instance, the N mo'noalkylated compounds are advantageously obtained by the alkylationof cyano-imino derivatives or" the barbituri'ci acid, its C-substitu'tion products respcc tively. The N-alkyl-N'cyano imino barbituric acids containing at the 5-carbon' atom a methyl group and an alkyl group of at least3 carbon atoms asabovespecified which are obtained-in this case as: intermediate: products are saponiiiedr: to,
Example 1.-20 parts by weight of sodium are dissolved in 400 parts by Weight of ethylalcoihol and 50 parts by weight of methylurea, and parts by weight of butylmethylmalonic acid ethylester are added. The mixture is heated for 8 hours to boiling. Then it is acidified with acetic acid and the alcohol is evaporated. Water is added to the residue, the reaction product is taken up in ether and the solution first shaken with a sodium bicarbonate solution and then with a normal aqueous solution of caustic soda. On acidifying the caustic soda solution the N-methyl- C,C-methyl-butyl-barbituric acid is precipitated. 0n redissolving from cyclohexane it melts at 87 C. The acid may, also be distilled in vacuo. It
boils at 133-135 C. under 1 mm. pressure.
With sodium alcoholate it can be readily transformed into the sodium salt which is readily soluble in water.
When starting with ethylurea N-ethyl-C-methyl-C-butylbarbituric acid is obtained in the manner described above.
In an analogous manner the N-methyl-C,C- (n-hexyl) -methylbarbituric acid can be obtained. It distils under 1.5 mm. pressure at 183-185 C., and crystallizes on cooling.
The N-methyl-C-cyclohexylethyl C methylbarbituricacid is obtained in a similar manner, for instance, when starting with methylurea and cyclohexylethyl-methyl-cyanoacetic acid ester while using sodium ethylate as a condensing agent. In this case the imino-N-methyl-C-cyclohexylethyl-C-methylbarbituric acid first formed is subsequently boiled for about 6-8 hours with 20% aqueous sulfuric acid. 1
Example 2.9.5 parts by weight of sodium are dissolved in 200 parts by weight of dry ethyl alcohol and mixed with 42 parts by weight of methyl-allylmalonic ester and 20 parts by weight of methylurea while stirring. The mixture is heated for 6 to 8 hours under reflux. After cooling the salt which crystallizes out is filtered off, dissolved in water and the free acid is precipitated with acetic acid. On recrystallizing from water the N-methyl-C,C-methyl-allyl-barbituric acid melts at 135 C.
In an analogous manner also the N-methyl- C,C-bromoallylmethylbarbituric acid can be obtained. It distils under 1.5 mm. pressure at 136- From allyl urea and methyl-isoamyl-malonic acid ester in an analogous manner the N-allyl-C- methyl-C isoamylbarbituric acid is obtained which boils at 150 C. under 1 mm. pressure and melts at 68-69 C.
Example 3.46 parts by weight of sodium metal are dissolved in 500 parts by weight of methanol, 92 parts by weight of dicyandiamide and 256 parts by weight of cyclohexyl-methyl-malonic acid diethylester (boiling at 137-138" C. under 1 mm. pressure) are added and the mixture is heated for 10 hours under reflux to 70-80 C. The
mixture is then cooledand parts by weight of dimethylsulfate are added drop by drop while stirring, care being taken that the temperature does not exceed 50 C. After the reaction temperature has gone down the methylalcohol is distilled ofi, the residue is treated with the 6- fold quantity of its weight of a 20% aqueous solution of sulfuric acid and boiled for 6 hours under reflux while stirring. After cooling the N-methyl-C,C-cyclohexyl methylbarbituric acid separated is sucked off and redissolved from dilute alcohol. Thus colorless needles melting at 157 C., are obtained. The sodium salt forms a white product which is readily soluble in water.
When'using allyl or crotylbromide instead of dimethylsulfate as the alkylating agent, N-allyland N-crotyl-C-methyl C cyclohexylbarbituric acid are obtained. j
' When starting with cyclopentyl-methylmalonic acid ester, N-methyl-C-cyclopentyl-C-methylbarbituric acid is obtained in the form of white crystals.-
- The. N-methyl-C,C-beta-ethy1hexyl-methylbarbituric acid forms an oily product.
Weclaim: 1. Barbituric acid derivatives of the formula:
1 0CNalkyl HaO\ /o 00 R. I
OCNX
wherein R1 stands for a cyclohexyl group, alkyl stands for a radical selected from the group consisting of saturated and unsaturated alkyl groups and X stands for a 'substituent selected from the group consisting .of hydrogen and alkali and alkaline earth metals, which compounds are whitish crystalline products, insoluble in water in the form of the free acid but soluble in the form of the alkali metal salts.
2. Barbituric acid derivatives of the formula:
wherein R1 stands for a cyclohexyl group, X stands for a substituent selected from the group consisting of hydrogen and alkali and alkaline earth metals, which compounds are whitish crystalline products, insoluble in water in the form of the free acid but soluble in the form of the alkali metal salts.
3. Barbituric acid derivatives of the formula:
0 C-N-CH:
wherein Ristands fora cyclohexyl group, which compounds 'are whitish crystalline products, insoluble in water in the form of the free acid but soluble in the form of the alkali metal salts.
4. Barbituric acid derivatives of the formula:
wherein R1 stands for a radical selected from the group consisting of cyclopentyl, cyclohexyl, and cyclohexyalkyl groups, alkyl stands for a radical selected from the group consisting of saturated and unsaturated alkyl groups and X stands for a substituent selected from the group consisting of hydrogen, alkali and alkalineeearth metals, which compounds are whitish crystalline products, insoluble in Water in the form of the free acid but soluble in the form of the alkalimetal salts.
5. Barbituric acid derivatives of the formula:
OG-NOH3 H:C\| l o 00 BK I I wherein R1 stands for a radical selected from the group consisting of cyclopentyl, cyclohexyl, and cyclohexylalkyl groups, and X stands for a substituent selected from the group consisting of hydrogen, alkali and alkaline-earth metals, which compounds are whitish crystalline products, insoluble in Water in the form of the free acid but soluble in the form of the alkali metal salts.
WALTER KRO-PP.
LUDWIG TAUB.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3324125A (en) * 1965-02-23 1967-06-06 Takeda Chemical Industries Ltd Barbituric acid derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3324125A (en) * 1965-02-23 1967-06-06 Takeda Chemical Industries Ltd Barbituric acid derivatives

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