US3663564A - Urazoles and their production - Google Patents

Urazoles and their production Download PDF

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US3663564A
US3663564A US742994A US3663564DA US3663564A US 3663564 A US3663564 A US 3663564A US 742994 A US742994 A US 742994A US 3663564D A US3663564D A US 3663564DA US 3663564 A US3663564 A US 3663564A
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urazole
phenyl
urazoles
hydrazine
yield
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Charles R Jacobson
Anthony D Adamo
Charlotte E Cosgrove
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Knoll Pharmaceutical Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

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  • the present invention relates to urazole compounds and more particularly to urazole compounds of noteworthytherapeutic value, to processes of making such urazole compounds, and to methods of using same in human and veterinary medicine.
  • the present invention relates to the new and useful therapeutic process for the amelioration or elimination of convulsions or seizures and other manifestations of epilepsy, either idiopathic or of traumatic or exogenous origin including those found in arteriosclerosis and those that are induced by drugs, by the administration of known and new chemical compounds of the urazole series, i.e., to derivatives of lH-1,2,4-triazole-3,5- (2 H,4H).-dione, commonly and hereafter referred to as urazoles.
  • urazole derivatives useful in this process are 1,2-disubstituted or 1,2,4-trisubstituted urazoles which are represented by, the general Formula I,
  • R represents a phenyl radical either unsubstituted or substituted by lower alkyl radicals and/ or lower alkoxy groups and /or halogen
  • R represents a straight-chain or branched-chain alkyl radical, preferably those containing 1 to 12 carbon atoms which may be substituted by halogen, hydroxyl, or alkoxy groups, an alkenyl radical, preferably containing 2 to 5 carbon atoms, a cycloalkyl radical of 5 to 7 carbon atoms which may be substituted by lower alkyl radicals or lower alkoxy groups, a phenyl substituted lower alkyl radical, and a phenyl radical which may be substituted by lower alkyl, lower alkoxy, hydroxyl, amino, or substituted amino.groups, or halogen, and
  • 1 R represents hydrogen,'a straight-chain or branched-chain alkyl radical preferably containing 1 to 6'carbon atoms which may be substituted .by hydroxyl, lower carbalkoxy or carboxamido groups, or halogen, an alkenyl radical preferably of 2 to 5 carbon atoms, a phenyl substituted lower alkyl radical, a phenyl radical, an a lower alkoxy carbonyl group.
  • the new and therapeutically useful process of the present invention involves the administration of the above described urazole derivatives to humans afilicted with convulsions or seizures such as are characteristic of the epileptic syndrome or other diseases.
  • Administration of these therapeutic agents to humans can be accomplished either orally or parenterally.
  • the pure compounds may be administered or they may be combined with conventional pharmaceutical excipients, diluents, and binders and converted into conventional dry dosage forms such as tablets, pills, capsules, powders and the like.
  • Suspensions in appropriate agents, gels, or similar vehicles may be used for either oral or parenteral dosage forms.
  • the disubstituted urazole derivatives are converted into their water soluble salts with ammonia, alkali metal hydroxides, carbonates, bicarbonates, and the like, or with organic bases such as alkyl amines, alkanol amines, and the like to provide a convenient water soluble dosage form.
  • the salts of the disubstituted urazoles with bases may also be prepared for oral administration in conventional pharmaceutical vehicles, such as syrups and elixirs suitably flavored and colored.
  • Water insoluble types of the urazoles of the present invention such as the 1,2,4-trisubstituted urazoles may be compounded with solubilizing or lyophilizing agents to make liquid preparations suitable for oral administration.
  • Rectal administration of the ureazole derivatives of the present invention can be accomplished by admixture or solution of these therapeutic agents with cacao butter, glycerinated gelatin, polyethylene glycol bases and other conventional pharmaceutical suppository bases.
  • the urazole derivatives useful in this therapeutic process have never previously been employed as therapeutic agents. These compounds have been evaluated and classified pharmacologically on the basis of their relative effectiveness in preventing the convulsions induced by pentamethylene tetrazole, electroshock, and strychnine, according to the test methods described by Elizabeth H. Jenney and Carl C. Pfeitfer Ann. NY. Acad. Sci.” vol. 64, page 679 (1956). They have been found to be highly effective and therapeutically useful anticonvulsant agents which possess among the series varying degrees of potency and toxicity. However, the compounds of the present invention are generally associated with relatively low toxicity, thus providing a high therapeutic index and an excellent margin of safety for use as effective and reliable anticonvulsant agents.
  • R is phenyl
  • R is lower alkyl
  • R is hydrogen
  • Trisubstituted derivatives of these disubstituted urazoles of Formula I in which R is lower alkyl also show useful and effective anticonvulsant activity.
  • New and useful 1,2-disubstituted urazoles of value in the therapeutic process of the present invention are represented by the general Formula I wherein R represents aphenyl radical either unsubstituted or substituted by lower alkyl radicals, lower alkoxy groups, or halogen, wherein R represents a lower alkyl radical of 4 to 5 carbon atoms branched on the carbon atom attached to the urazole ring nitrogen atom, such as Z-butyl, 3-phenyl and the like radicals, a higher straight-chain or branched-chain alkyl radical of at least six carbon atoms and preferably with 6 to 12 carbon atoms, an alkyl radical preferably of 1 to 12 carbon atoms substituted by halogen, hydroxyl, or alkoxy groups, an alkenyl radical, a cycloalkyl radical of 5 to 7 carbon atoms either unsubstituted or substituted by lower alkyl radicals or alkoxy groups, a phenyl substituted lower
  • R represents a phenyl radical further substituted by a lower alkyl radical, a lower alkoxy group, or halogen, wherein R represents a lower straight-chain or branched-chain alkyl radical preferably of 1 to 5 carbon atoms, and wherein R represents hydrogen.
  • R represents a phenyl radical either unsubstituted or substituted by lower alkyl radicals, lower alkoxy groups, or halogen
  • R represents a straight-chain or branched-chain alkyl radical, preferably of 3 to 6 carbon atoms, a lower alkyl radical substituted by halogen, hydroxyl, or alkoxy groups, a lower alkenyl radical, a cycloalkyl radical of 5 to 7 carbon atoms, a phenyl substituted lower alkyl radical, and a phenyl radical, either unsubstituted or substituted by lower alkyl radicals, lower alkoxy, hydroxyl, amino, or substituted amino groups, or halogen, and wherein R represents a straightchain or branched-chain alkyl radical preferably
  • the above described new and novel compounds of the present invention represent an extension of the field of therapeutic agents useful and desirable in the new therapeutic process of the present invention beyond those substances previously described in the literature. They also possess a desirable range of potency as anticonvulsant or antiepileptic agents and can effectively be used in the therapeutic process of the present invention with advantage over known practice.
  • Extremely useful compounds among the new and novel therapeutic agents are 1,2-disubstituted urazoles of the general Formula I wherein R is aryl, and R is 2-butyl, 3-pentyl, 4-heptyl, allyl, a cycloalkyl radical, or an aryl radical, such specific compounds as l-phenyl-Z-cyclohexyl urazole and 1,2-diphenyl urazole being particularly potent anticonvulsant agents with extremely low toxicity, neurotoxicity as determined according to the method of Swinyard et al., J. Pharm. Exptl. Therap.,'vol. 106, page 319 (1952), and central nervous system depressant effects.
  • urazoles of the general Formula I specific examples of useful and effective anticonvulsant agents with extremely low toxicity are 1-phenyl-2-isopropyl-4-methyl urazole, 1-phenyl-2-npropyl-4-methyl urazole, 1-phenyl-2-n-propyl-4-ethyl urazole, l-phenyl-2-n-propyl-4-(,B-hydroxy ethyl) urazole, 1- phenyl-2,4-di-n-propyl urazole, and l-phenyl-2-benzyl-4- (fl-hydroxyethyl) urazole.
  • Muscle relaxant properties of therapeutic usefulness are also exhibited by certain of urazoles included within the scope of this invention, a specific example of a compound with such properties being l-phenyl-2-methyl urazole.
  • Potent sedative-hypnotic action of the barbiturate type is exhibited by certain of these urazole derivatives, thus providing new and novel non-barbiturate sedative-hypnotic agents.
  • Particularly useful in this respect are such compounds as l-phenyl-Z-n-amyl urazole, l-phenyl-2-isobarbital, i.e. "sodium '5- (I-cyclohexene-l-yl)-l,5 dimethyl barbiturate.
  • R represents a phenyl radical or a lower carbalkoxy radical
  • R represents hydrogenan aralkyl radical, a lower carbalkoxy, carboxamido, carboxanilido, lower dialkyl carboxamido group, or a phenyl radical
  • R represents hydrogen, a lower alkyl, cyclohexyl, aralkyl, or phenyl radical, but wherein only one of said substituents R and R is hydrogen.
  • urazole derivatives possess useful and valuable therapeutic properties as analgesic and antiinfiammatory agents which can be employed in therapy in conditions such as, for instance, rheumatic disorders and arthritis.
  • 1,2-disubstituted urazoles and 1,2,4- trisubstituted urazoles represented by the general Formula I, wherein R and R represent like or different lower alkyl radicals either unsubstituted or substituted by halogen, hydroxyl, or lower alkoxy groups, cycloalkyl radicals of 5 to 7 carbon atoms, and phenyl substituted lower alkyl radicals, and wherein R represents hydrogen, a lower alkyl radical, a hydroxy alkyl group, or an aralkyl radical.
  • R and R represent like or different lower alkyl radicals either unsubstituted or substituted by halogen, hydroxyl, or lower alkoxy groups, cycloalkyl radicals of 5 to 7 carbon atoms, and phenyl substituted lower alkyl radicals, and wherein R represents hydrogen, a lower alkyl radical, a hydroxy alkyl group, or an aralkyl radical.
  • the disubstituted urazoles of the present invention possess an acidic hydrogen atom on the unsubstituted urazole ring nitrogen atom and, therefore, these compounds are capable of forming salts with alkali metals such as sodium or potassium and with organic bases.
  • the salts of these urazoles are, in general, stable and readily water soluble and they provide a convenient means of preparing aqueous solutions of these novel and therapeutically useful compounds. It is to be understood, therefore, that the salts of the disubstituted urazoles of the present invention, obtainable by treating the urazoles wih alkali metal hydroxide, bicarbonate, or carbonate solutions or with organic bases are within the scope of the present invention.
  • a preferred method (Process A) of manufacture of a wide' variety of l-monosubstituted and 1,2-disubstituted urazoles in good to excellent yields consists in'the condensation of l-monosubstituted or 1,2-disubstituted hydrazines with lower alkyl esters of allophanic acid in an inert solvent at temperatures above 100 C. and preferably but notnecessarily below 140 C.
  • l l, R represents preferably a lower alkyl radical
  • R and R represent hydrogen, straight-chain or branchedchain alkyl radicals, preferably those containing 1 to 12 carbon atoms, alkenyl radicals, preferably those containing 2 to Scarbon atoms, cycloalkyl radicals of v 5 to '7 carbon atoms, aralkyl radicals, and aryl radicals, said alkyl,- alkenyl, cycloalkyl, aralkyl, and aryl radicals being either unsubstituted-,- or substituted by alkyl radicals, alkoxy, hydroxyl,"-aac'y1oxy, .mercapto, alkyl .mercapto, carbalkoxy, carboxamido, sulfonamido, nitro, amino or substituted amino. groups, halogen, or R and R together forming aIsaturated-or unsaturated polyrnethylene chain, whereby
  • the temperature. of the reaction isbeshbutnot neces sarily controlled by the boiling pointof the solvent em: ployedf Solvents from which lower alkanols. can: be readily separated by distillationand inwhichammonia is not readily soluble at the temperature of the reaction are to be preferred.
  • Xylene has been found to be an especially suitable solvent for this reaction while other aromatic hydrocarbons, such as toluene, methylene, and others, aromatic and high boiling aliphatic esters such as anisole, phenetole, -di-n-butyl ether, and others, high boiling petroleum fractions,'and high boiling aliphatic hydroxylic solvents such as amyl alcohol, glycerol, propylene glycol, and others maybe used.
  • aromatic hydrocarbons such as toluene, methylene, and others
  • aromatic and high boiling aliphatic esters such as anisole, phenetole, -di-n-butyl ether, and others
  • high boiling petroleum fractions such as amyl alcohol, glycerol, propylene glycol, and others
  • I ln' general, Process A involves combining the appropriately substituted hydrazine with the allophanic acid ester in the solvent either before'or after heating to the reaction-temperature above 100 C.
  • the evolved alcohol and ammonia, lay-products of the condensation are removed from the reaction zone as they form.
  • the urazole isdsolated by separation' from the solvent and recrystallization, distillation, or other appropriate means of purification. 1
  • process A allows both l-monosubstituted and l,2 disubstituted urazoles to 1 be obtained through a single reaction from the starting hydrazine.
  • an appropriate inert solvent generally lower reaction temperatures are employed than have previously been possible and reactions are easier to control providing generally higher yields of purer products.
  • Another preferred process, B, for the manufacture of l-monosubstituted and 1,2-disubstituted urazoles has been found which process involves the condensation of l-monosubstituted or 1,2-disubstituted hydrazines with imido dicarboxylic acid esters (aza malonic acid esters) at temperatures above 100 C. and preferably but not necessarily below 140.
  • R and R represent the same substituents as described above for R and R in Process A, While R and R preferably represent lower alkyl radicals.
  • dimethyl or diethyl esters of imido dicarboxylic acid are preferred for use in this process but any lower alkyl esters in which the two alkyl radicals are alike or different may be used.
  • the condensation will proceed merely upon heating a mixture of the reactants, the use of an inert solvent is desirable.
  • the condensation may be conveniently controlled by the choice of a solvent of appropriate boiling point.
  • the by-products of the condensation are alcohols corresponding to the esters employed, the use of solvents from which these lower alkanols can readily be separated by distillation is desirable, as removal and collection of the alcohol from the reaction zone as it forms, provides a convenient measure of the progress of the condensation.
  • xylene has been employed as the solvent, the condensation has been found generally to proceed rapidly and in excellent yield.
  • Other suitable inert solvents include aromatic hydrocarbons, high boiling aliphatic and aromatic ethers, high boiling petroleum fractions, and high boiling aliphatic hydroxylic solvents as they havebeen mentioned hereinabove.
  • Process B comprises, generally, the admixture of the appropriately substituted hydrazine and imido dicarboxylic acid ester and xylene or some suitable solvent either before or after heating to the reaction temperature above 190 C.
  • the reaction mixture is kept at a temperature preferably in the range of 100-140 C. until alcohol evolution ceases. Isolation of the product is accomplished by separation from the solvent followed by recrystallization, distillation, or other appropriate means of purification.
  • Process B provides all of the advantages of the previously described Process A employing allophanic acid esters and, in addition, it generally proceeds more rapidly at the same temperature and eliminates evolution of gaseous lay-products while providing a better means of following the progress of the reaction.
  • 1,2-disubstituted urazoles of this invention can also be prepared by alkylation of l-monosubstituted urazoles by known procedures. Similarly, monoalkylation of 1,2-disubstituted urazoles or dialkylation of l-monosubstituted urazoles provides many of the 1,2,4-tri- 1 substituted urazoles of this invention.
  • urazole derivatives useful as intermediates or final products of this invention which cannot be synthesized by the preferred processes or by alkylation of lmonosubstituted or 1,2-disubstituted urazoles can be prepared by other methods known in the literature.
  • 1,4-disubstituted urazoles can readily be prepared by treatment of 2,4-disubstituted-l-carbalkoxy semicarbazides with hot alkali hydroxide solutions.
  • 1,4- diphenyl urazole can be prepared from 2,4-diphenyl-1-carbethoxy semicarbazide.
  • the 1-aryl-4-alkyl urazoles, '1-aryl-4-cycloalkyl urazoles, 1-aryl-4-ara1kyl urazoles, and 1,4-diaryl urazoles can be synthesized from the appropriately substituted semicarbazides.
  • ethyl carbethoxythiocarbamate reacts with mono-substi- 2-carbethoxy-4-n-butyl urazole.
  • Many of the other urazoles of this invention can also be prepared by the known methods described above through choice of the appropriate reagents, as will be apparent to those skilled in the art.
  • PROCESS A Example 1 pressure. The residual solid is dissolved in dilute sodium hydroxide solution and the solution is filtered to remove insoluble materials. Addition of concentrated hydrochloric acid precipitates a solid that is recrystallized from heptane to yield 83 g. of 1,2-di-isopropyl urazole, a colorless crystalline solid melting at 13914l C. Yield: 75%.
  • Example 4 l-phenyl-Z-ethyl urazole.To a stirred refluxing suspension of 53 g. of ethyl allophanate in 400 cc. of xylene, there are added 54 g. of 1-phenyl-2-ethyl hydrazine dissolved in 100 cc. of xylene within 30 minutes. Ethanol and ammonia are evolved and are allowed to escape. The clear yellow solution obtained after one hour is refluxed at 130140 C. for 18 hours and then the xylene is distilled off under reduced pressure.
  • Example 2 l-phenyl urazole.In the apparatus described in Example 1 there are placed 57 g. of methyl allophanate, 52 g. of phenyl hydrazine, and 600 cc. of xylene. The stirred reaction mixture is heated to 125 C. where evolution of ammonia and methanol is observed. Heating is continued at 125 -l40 C. for 24 hours during which time an essentially clear solution briefly forms followed by separation of a colorless solid. The precipitate is filtered from the cooled solution, washed with ether, and dried. Recrystallization from dilute acetic acid yields 72 g. of pure 1- phenyl urazole, a colorless crystalline solid which melts at 268270 C. with decomposition. The yield is 85%.
  • Example 3 1,2-di-isopropyl urazole.A stirred suspension of 79 g. of ethyl allophanate in 500cc. of xylene is heated to 120 C. and 70 g. of 1,2-di-isopropyl hydrazine are slowly added thereto. Maintaining the temperature of the reaction mixture at 120 C. for five hours, the evolved ethanol is distilled off and the evolved ammonia is allowed to escape. The resulting clear solution is heated an additional eight hours and is concentrated to dryness under reduced colorless crystals melting at 120-121" C. Yield: 77%.
  • Example 5 dilute sodium hydroxide solution.
  • the basic solution is extracted with ether to remove colored by-products and then is acidified with concentrated hydrochloric acid.
  • the separated orange oil is extracted into ether, the ether solution is dried over anhydrous sodium sulfate, and the ether is distilled from the dried extract. Distillation of the residue under reduced pressure yields 38 g. of l-phenyl-Z-nheptyl urazole, a viscous yellow oil that solidifies upon standing. Boiling point: 205-206 C./0.3 mm.; n 1.5362. Yield: 69%.
  • Example 6 l-p-tolyl-Z-cyclohexyl urazole-Crude cyclohexanone p-tolyl' hydrazone, prepared by condensing cyclohexanone with p-tolyl hydrazine in the presence of a trace of glacial aceticacid according to the method of Carlin and Fisher [1. Am. Chem..Soc., vol.
  • 1,2-diphenyl urazole-A mixture of 132g. of ethyl allophanate, 184 g. of hydrazo benzene and'1200 cc. of xylene is stirred and refluxed for 30 hours. During this time ethanol andammonia are evolved. A clear solution forms brieflyand then a colorless crystalline precipitate separates from the solution.
  • the 1,2-diphenyl urazole is filtered from the cooled solution, Washed with ether, and purified by dissolution in 10% sodium hydroxide solution, reprecipitation with acid, and recrystallization from isopropanol to'yield 180 g. of colorless crystals or needles inelting at 228.-'2-3'0 C.
  • Example 10 tion is'acidified.
  • the precipitated white solid is recrysf:
  • Example 11 p ;l,-2-dicy clohexyl'ureazole.-A mixture of 4 8 g. of diethyl imido dicarboxylate and 59 g. of 1,2-dicyclohexyl hydrazine in 500 cc. of xylene isreacted at 120-140 C. as described in the above examples until one hour after ethanol distillation has ceased. Concentration of the solution and purification of the solid residue by dissolving it as the sodium salt, reprecipitating the free acid, and recrystallizing said acid from a mixture of isopropanol and heptane (1:10) yields 61 g. of 1,2-dicyclohexy1 urazole in the form of colorless platelets melting at 205-207 C. with decomposition.
  • Example 12 I l-phenyl-Z-isopropyl urazole-161 g. of diethyl imido dicarbo'xylate and 150 g. of l-phenyl-Z-isopropyl hydrazine in 1000 cc. of xylene are reacted at 120-138 C. for five hours as described in the above examples. Most of the product is isolated by'filtration of the cooled reaction mixture while additional small amounts are recov ered by concentration of the filtrate. Recrystallization of the crude material from dilute isopropanol yields 180 g. of l-phenyl-2-isopropyl urazole in the form of colorless crystals melting at 162-1 64 C. Yield:
  • 1-phenyl-2-(3-pentyl) urazole A solution of 48 g. of diethyl imido'dicarboxylate and 53 g. of l-phenyl-Z- (3-pentyl) hydrazine in 500 cc. of xylene is reacted at l20-l40 C. until one hour after ethanol evolution ceased. Concentration of the resulting solution under reduced pressure yields a solid residue which after the usual purificationgives 64 g. of l-phenyl-2-(3-pentyl) urazole in the form of cream-colored crystals melting at 120-122 C. Yield: 87%.
  • l-ethyl urazole may be prepared from ethyl hydrazine; l-n-butyl urazole may be prepared from nbutyl hydrazine; l-n-hexyl urazole may be prepared from n-hexyl hydrazine; l-benzyl urazole may be prepared from benzyl hydrazine; 1-(2-hydroxy ethyl) urazole may be prepared from 1-(2-hydroxy ethyl) hydrazine; 1-(3-hydroxy-2-butyl) urazole may be prepared from 1-(3-hydroxy-2-butyl) hydrazine; 1,2-di-n-propyl urazole may be prepared from 1,2-di-n-propyl hydrazine; 1,2-di-n-butyl urazole may be prepared from 1,2-di-n-butyl hydrazine; 1,2-di-n-buty
  • ALKYLATION Example 17 l-phenyl-Z-ethyl urazole.A mixture of 18 g. of 1- phenyl urazole and 5.7 g. of potassium hydroxide in 500 cc. of 75% isopropanol is stirred and heated to reflux. Thereby, a clear solution of the sodium salt. is formed. After slow addition of 16 g. of ethyl iodide, the solution is refluxed for 18 hours and then evaporated to dryness under reduced pressure. Extraction of the solid residue with chloroform yields an insoluble solid from which 5.4 g. of unreacted l-phenyl urazole are recovered.
  • Example 18 1-phenyl-2-methallyl urazole.9 g. of methallyl chloride are slowly added to a refluxing solution of the sodium salt of l-phenyl urazole, prepared from 18 g. of l-phenyl urazole and 4 g. of sodium hydroxide in 400 cc. of methanol. The resulting solution is stirred and refluxed for hours. The solid residue obtained by evaporation of the solution to dryness is extracted with benzene; 2 g. ofunreacted l-phenyl urazole remain as the insoluble portion. The solid obtained by evaporation of the benzene extract is dissolved in dilute sodium hydroxide solution and the resulting basic solution is extracted with ether. Acidification of the basic solution with acid precipitates 18 g. of 1- phenyl-Z-methallyl urazole which, after one recrystallization from xylene melts at 128129 C.
  • Example 19 l-phenyl-Z-benzhydryl urazole.--A mixture of 15 g. of the sodium salt of l-phenyl urazole and 15 g. of chloro diphenyl methane in 300' cc. of dry benzene is refluxed for 24 hours. After evaporating the mixture to dryness under reduced pressure, the residue is dissolved in a large volume of dilute sodium hydroxide solution. The basic solution is filtered to remove insoluble material, extracted with ether, and acidified with concentrated hydrochloric acid. The precipitated solid is separated, dried, and extracted with chloroform leaving insoluble l-phenyl urazole as residue. By evaporating the chloroform solution and twice recrystallizing the residue from xylene, 11 g. of lphenyl-2.benzhydryl urazole melting at 209-211 C. are obtained. Yield: 43%
  • Example 20 1-p-bromo-phenyl-2-methyl urazole.
  • a mixture of 13 g. of l-p-bromo phenyl urazole and 2 g. of sodium hydroxide in 350 cc. of methanol is refluxed for 30 minutes. Thereafter, 8 g. of methyl iodide are slowly added. After one hour of refluxing, a clear yellow solution is formed which is refluxed for an additional seven hours and then is evaporated to dryness under reduced pressure. The residue is treated with dilute sodium hydroxide solution and the resulting basic solution is extracted with ether. Acidification of the basic solution precipitates a solid that is recrystallized from xylene to yield 9 g. of l-p-bromo phenyl-2-methyl urazole in the form of colorless crystals melting at l86188 C. Yield: 67%.
  • Example 21 1-phenyl-2,4-di-n-propyl urazole.--A mixture of 18 g. of l-phenyl urazole and 12 g. of potassium hydroxide in 300 cc. of isopropanol is heated to reflux. 25 g. of n-propyl bromide are slowly added to the solution and refluxing is continued for 18 hours. An additional 5 g. of potassium hydroxide and 12 g. of n-propyl bromide are added and heating is continued for eight hours. After evaporating the solution to dryness, dilute sodium hydroxide solution is added to the residue and the separated insoluble oil is extracted with ether. 2 g.
  • Example 22 1-phenyl-2,4-dibenzyl urazole. To a hot suspension of 24 g. of the potassium salt of l-phenyl urazole, prepared by adding the free urazole to a refluxing solution of 13.5
  • 1,2,4-triisopropyl urazole may be prepared from l-isopropyl urazole and isopropyl
  • Example 23 1,2-diisopropyl-4-n-propyl urazole.-A mixture of 37 g. of 1,2 diisopropyl urazole and 8 g. of sodium hydroxide in 300 cc. of 99% isopropanol is refluxed for 30 minutes. Thereafter, 25 g. of n-propyl bromide are [added to the solution. After 18 hours of refluxing the precipitated sodium bromide is filtered oif and the filtrate is concentrated under reduced pressure.
  • Dilute sodium hydroxide solution is added to the residue and the precipitated insoluble oil is extracted with ether.
  • My acidification of the basic solution unreacted 1,2- diisopropyl urazole (5 g.) is recovered.
  • Evaporation of the dried ether extracts and distillation of the residue under reduced pressure yields 26 g. of 1,2-diisopropyl-4-n-propyl and evaporated to dryness under reduced pressure. Recrystallization of the residue from isopropanol and then from a mixture of heptane and isopropanol .(2:1) and decolorizing with charcoal, yields 20 g. of 1,2-diphenyl-4- (2-chloro ethyl) urazole'in the form of colorless needles melting at 111-l13 C. with decomposition.
  • Example 26 Ethyl 1,2-diphenyl-4-urazolyl acetate.To a stirred, refluxing solution of g. of the sodium salt of 1,2-diphenyl urazole in 300 cc. of dry benzene there are slowly added 34 g. of ethylbromo acetate and the resulting solution is refluxed for six hours. Wateris added to the cooled reaction mixture and, after separating the benzene layer, the aqueous phase is extracted with benzene. The combined benzene layer and extracts are dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization of the residue from methanol yields 44 g. of colorless, crystalline ethyl 1,2-diphenyl-4-urazolyl acetate melting at l13-115 C. Yield: 64%.
  • Example 27 1,2-diphenyl-4-urazolyl acetic acid.Saponification of the ester obtained according to Example 26 by means of potassium hydroxide yields 98% of the free acid in the form of the monohydrate. Melting point: 161-1-63 C.
  • Example 28 1,2-diphenyl-4-urazolyl acetamide.-Treatment of the above acid with thionyl chloride in refluxing benzene yields a solid acid chloride. On reaction thereof with gaseous ammonia in cold chloroform solution 1,2-diphenyl-4- urazolyl acetamide is obtained in the form of colorless platelets melting at 234-236 C. after recrystallization urazole in the form of a pale yellow oil, boiling point:
  • Example 24 1,2-diphenyl-4-.(2-hydroxy ethyl) urazole.-To a refluxing solution of 54 -g. of 1,2-diphenyl urazole and 12 g. of potassium hydroxide in 350 cc. of water there are slowly from dilute isopropanol. The yield is 89%.
  • 1,2diphenyl urazole (5 g.) is recovered by acidification.
  • the base insoluble product is recrystallized from dilute isopropanol to yield 45 g. of 1,2-diphenyl-4-(2-hydroxy ethyl) urazole in the form of colorless needles melting at 130132 C. with decomposition. Yield: 71%.
  • Example 25 4-urazolyl acetate; l-phenyl-Z-benzhydryl urazole and 3- bromo propanol yield l-phenyl-2-benzhydryl-4-(3-hydroxy propyl) urazole; l-phenyl-Z-(l-phenyl ethyl) urazole and ethyl iodide yield l-phenyl-Z-(l-phenyl ethyl)-4- ethyl urazole; -1-p-tolyl-2-methyl urazole and ethylene bromohydrin yield 1-p-tolyl-2-methyl-4-(2-hydroxy ethyl) urazole; l-p-ethoxy phenyl-Z-methyl urazole and l-bromo- 2-propanol yield l-p-ethoxy phenyl-2-methyl-4-(2-hydroxy propyl) urazole; l-p-toly
  • 1,2-diphenyl urazole and n-hexyl bromide yield 1,2-diphenyl-4-n-hexyl urazole; l-phenyl-2-o-tolyl urazole and methyl iodide yield 1-phenyl-2-o-tolyl-4-methyl urazole; 1- phenyl-Z-p-methoxy phenyl urazole and allyl bromide yield l-phenyl-Z-p-methoxy phenyl-4-allyl urazole.
  • Example 104 l-phenyl urazole from phenyl hydrazine and ethyl carbethoxy thiocarbamate.5.4 g. of phenyl hydrazine are slowly added to 8.9 g. of ethyl carbethoxy thiocarbamate, accompanied by some spontaneous warming and evolution of hydrogen sulfide. The resulting mixture is warmed on a steam bath for two hours until evolution of hydrogen sulfide ceases. The precipitated solid is filtered oil? and recrystallized from ethanol to give 2 g. of 1-phenyl-3- ethoxy-1,2,4-triazol--one.
  • Example 105 I-phenyl-Z-cyclohexyl urazole from l-phenyl-Z-cyclohexyl semicarbazide and urea.--To a stirred solution of 38 g. of 1-phenyl-2-cyclohexyl hydrazine in 150 cc. of glacial acetic acid, 20 g. of potassium cyanate are added in small portions during one hour. The temperature of the reaction mixture rises to about 40 C. and a yellow slurry forms. After heating the reaction mixture at 60 C. for an additional 30 minutes, during which time most of the solid dissolves, it is poured into 500 cc. of ice and water.
  • a mixture of 12 g. of 1-phenyl-2-cyclohexyl semicarbazide and 3.7 g. of urea is heated at 230-240 C. for two hours, ammonia being evolved.
  • the cooled melt is taken up in dilute sodium hydroxide solution and the solution is filtered to remove some insoluble matter. Acidification of the basic solution with concentrated hydrochloric acid precipitates a tan solid that after recrystallization from dilute isopropanol and decolorization with charcoal gives 9.3 g. of 1-phenyl-2-cyclohexyl urazole melting at 138-140" C.
  • Example 106 1,4-diphenyl urazole.-Refluxing 6 g. of 1-carbethoxy 2,4-diphenyl semi-carbazide with 50 cc. of 10% sodium hydroxide solution for minutes, cooling the solution, and acidifying it with concentrated hydrochloric acid gives a tan solid. Recrystallization from acetic acid gives colorless crystals of 1,4-diphenyl urazole melting at 164- 165 C. The yield is 4.4 g.
  • Example 107 Sodium salt of 1,2-diphenyl urazole.-Mixing hot isopropanol solutions containing equimolecular quantities of 1,2-diphenyl urazole and sodium hydroxide produces, after cooling, a colorless crystalline deposit of the sodium salt that is filtered off, washed with cold isopropanol, and dried. Melting point: 344 C. with decomposition.
  • Example 108 Ethylene diamine salt of 1 phenyl 2 cyclohexyl urazole.--To a warm solution of 104 g. of 1-phenyl-2- cyclohexyl urazole in 450 cc. of isopropanol there is added a solution of 25 g. of ethylene diamine in 50 cc. of isopropanol. The cream colored crystalline deposit formed upon cooling and standing is filtered off, washed with cold isopropanol, and dried. The yield of the water soluble ethylene diamine salt, melting at 131l36 C.
  • a 10% aqueous solution of the salt has a pH of 9.5.
  • organic bases may be prepared in a similar manner employing such organic bases as, for instance, ethylamine, diethylamine, isopropylamine, di-n-butylamine, cyclohexylamine, ethanolamine, diethanolamine, diethylamino ethanolamine and the like.
  • Example 109 750 mg. of l-phenyl-Z-cyclohexyl urazole are thoroughly mixed with 3.0 g. of lactose.
  • the mixture is filled into ten capsules, to be administered orally.
  • the usual dose is one capsule repeated three to five times daily, preferably after meals.
  • the ratio of 1-phenyl-2-cyclohexyl urazole to lactose or other diluent such as sucrose, dextrose, calcium carbonate, and other inert substances, may be varied to adjust the individual dosage.
  • a range of 25 mg. to 300 mg. is the preferred dosage range.
  • the mixed powder may also be administered orally without the capsules, in appropriate divided doses.
  • Example 110 A mixture of 7.5 g. of 1-phenyl-2-isopropyl-4-methyl urazole, 5.0 g. of talc, 10.0 g. of starch, and 7.5 g. of lactose is carefully prepared in finely ground form. The mixture is prepared in granular form using water, syrup, gelatin paste, starch paste, or other binder, in accordance with known pharmaceutical practice. The mass is dried and the granules are pressed on a tablet machine using a small quantity of talc, magnesium stearate, mineral oil, or other lubricant. A total of 100 tablets each containing 75 mg. of active medicament is produced.
  • diluents binders, and lubricants
  • inert substances such as pectin, dextrose, calcium carbonate, and kaolin.
  • the usual dose is one to three tablets, two to five times daily. Appropriate adjustment in dosage or tablet strength may be made.
  • Example 111 A solution is prepared by dissolving 0.5 g. of the sodium salt of 1-phenyl-2-cyclohexyl urazole in 10 cc. of water for injection. The solution is filled into ten ampules of 1.0 cc. each, which are sealed and sterilized. The drug is administered by injection. The injection solution may also be filled into multiple dose sterile vials with perforable stoppers.
  • Example 112 Five g. of the sodium salt of 1-phenyl-2-isopropyl urazole are dissolved in sufficient distilled water to make 100 cc. of solution. The usual dose is 1 cc., administered orally, two to five times daily.
  • Example 1 13 To 1.5 g. of 1-phenyl-2-cyclohexyl urazole contained in a mortar there are added 0.35 g. of ethylene diamine. Syrup of raspberry is slowly admixed thereto whereby the amine salt of the urazole compound is dissolved. The final volume is adjusted to 100 cc. with syrup of raspberry. The usual dose is /2 to 4 teaspoonfuls.
  • Example 114 8.0 g. of 1-phenyl-2-n-propyl-4-ethyl urazole are mixed with 12.0 g. of olive oil or other bland fixed oil such as, for instance, corn oil, cottonseed oil, or rapeseed oil. The oily mixture is then emulsified with water using acacia, tragacanth, or other emulsifying agents. The volume is adjusted to 100 cc. The usual dose is /2 to 4 teaspoonfuls.
  • Example 115 1.5 g. of l-phenyl-Z-ethyl urazole are dissolved in aromatic elixir to make a volume of '100 cc. The usual dose is /2 to 4 teaspoonfuls.
  • Example 116 To 1.5 g. of finely ground 1,2-diphenyl urazole contained in a mortar or other suitable mixing vessel, there is slowly added a 1% tragacanth solution with intensive mixing. The volume is finally adjusted to 100 cc. The resulting suspension is suitable for oral administration in the usual dosage range of A to 2 teaspoonfuls.
  • Other suspending and thixotropic agents such as, for example, bentonite, acacia, karaya, iceland moss, pectin, gelatin, methocel and the like may be used.
  • Mechanical methods for dispersion involving homogenizers and intensive mixers may also be used to improve the stability of the suspension.
  • Example 117 Suppositories for rectal administration are prepared by mixing 100 mg. of 1-phenyl-2-n-propyl urazole with 1.8 g. of cocoa butter per suppository. The usual dose is one suppository.
  • Other suppository bases such as, for example, glycerinated gelatin, polyoxy ethylene glycols, and their derivatives may be used.
  • the doses may be adjusted to the age and condition of the patient by varying the proportions of the diluents and inert substances. Further dose variation may be accomplished by varying the number of units administered, i.e., the number of tablets, teaspoonfuls, ampoules, and the like.
  • the vehicle may be varied to manufacture products of varying color, taste, consistency, texture, and the like. Tablets may be coated, flavored, colored, and otherwise varied in accordance with the usual methods of pharmaceutical manufacture.
  • the urazoles having an anticonvulsant action find therapeutic application in the treatment of convulsions, seizures and other manifestations of genuine, arteriosclerotic, or drug-induced epilepsy.
  • the muscle relaxant urazoles are of use in the treatment of musculo-skeletal disorders and neurological diseases involving skeletal muscle spasm including rheumatic disorders, bursitis, strains, sprains, cerebral palsy, multiple sclerosis, and Parkinsons disease.
  • the analgesic and anti-inflammatory urazoles are useful in the treatment of rheumatic, arthritic and allied disorders and generalized inflammatory disorders of acute, subacute, and chronic nature including, for example, acute rheumatic arthritis, gouty arthritis, rheumatoid arthritis, muscular rheumatism, osteo-arthritis, bursitis and neuritis.
  • the urazoles having a central nervous system stimulating effect are useful in the treatment of a wide variety of depressed and fatigued states such as those brought on by illness, drugs, and old age.
  • the dosage administered varies with the urazole employed, the respective disease, condition and age of the patient. In general, a minimum dose of at least about 0.5 mg. to 1.0 mg. per dosage unit is required.
  • ethyl urazole exerts a stimulating elfect upon the central nervous system.
  • mice Oral administration in mice shows that this material possesses an extremely low order of toxicity.
  • Table V The very A few examples of the variety of compounds of this invention which exhibit useful anticonvulsant action in mice when tested against electro-shock by the above mentioned standard procedures are given in Table V.
  • the listed compounds all provide protection for at least Illustrative of the potent sedative-hypnotic action possessed by certain of the urazole derivatives are the results of pharmacological tests measuring the mean sleeping time of mice administered 300 mg./ kg. orally of the urazole derivative in comparison with the wellknown and highly effective hexobarbital also administered orally in the same dose as shown in Table VI.
  • Metabolism studies indicate that 1-phenyl-2-cyclohexyl urazole is completely metabolized in the body, liver degradation being a factor.
  • R and R indicate members selected from the group consisting of hydrogen, alkyl radicals, alkenyl radicals, said alkyl having 1 to 12 carbon atoms, said alkenyl having 2 to 5 carbon atoms, cycloalkyl radicals with 5 to 7 carbon atoms, aryl-lower-alkyl wherein the aryl has 6 or 12 carbon atoms, phenyl radical, such alkyl, alkenyl, cycloalkyl, and phenyl radicals that are substituted by a lower alkyl radicals, hydroxyl, lower alkoxy, acyloxy, mercapto, nitro, amino or lower alkyl substituted amino groups, and halogen, R and R together forming a polymethylene chain, only one of said R and R representing hydrogen,
  • reaction temperature is between about 100 C. and about 140 C. and the inert organic solvent is a solvent boiling above 100 C. and being selected from the group consisting of aromatic hydrocarbons, aromatic and aliphatic ethers, petroleum hydrocarbons, and aliphatic solvents containing hydroxyl groups.
  • the steps which comprise heating a di-lower alkyl ester of imido dicarboxylic acid with a hydrazine compound of the formula R and R indicate members selected from the group consisting of hydrogen, alkyl radicals, alkenyl radicals, alkenyl radicals, said alkyl having 1 to 12 carbon atoms, said alkenyl having 2 to 5 carbon atoms, cycloalkyl radicals with 5 to 7 carbon atoms, aryllower alkyl wherein the aryl has 6 or 12 carbon atoms, phenyl radicals, such alkyl, alkenyl, cycloalkyl, aryl-lower-alkyl and phenyl radicals that are substituted "by alkyl radicals, hydroxyl, lower alkoxy, acyloxy, mercapto, nitro, amino or lower alkyl substituted amino groups, and halogen, R and R together forming a polymethylene chain,
  • reaction temperature is between about 100 C. and about 140 C. and the reaction is carried out in the presence of an inert organic solvent boiling above 100 C.
  • the inert organic solvent is a solvent from the group consisting of aromatic hydrocarbons, aromatic and aliphatic ethers, petroleum hydrocarbons, and aliphatic solvents containing hydroxyl groups.

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4088767A (en) * 1974-12-06 1978-05-09 Mitsubishi Chemical Industries Limited 4-Dichlorophenylurazole compounds and use in agricultural fungicidal compositions
US4276420A (en) * 1978-05-24 1981-06-30 Chevron Research Company Herbicidal and plant-growth-regulating 1,2,4-trisubstituted-1,2,4-triazolidin-3-one-5-thione
EP0024309A3 (de) * 1979-07-23 1981-07-22 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Triazolopyridazinderivate, Verfahren und Zwischenprodukte zu ihrer Herstellung und diese enthaltende Arzneimittel
EP0044421A1 (de) * 1980-07-21 1982-01-27 Bayer Ag Di- und Oligo-1,2,4-triazolidin-3,5-dione und Verfahren zu ihrer Herstellung
US4326878A (en) * 1979-02-09 1982-04-27 Chevron Research Herbicidal and plant-growth-regulating 1,2,4-trisubstituted-1,2,4-triazolidin-3,5-dithiones
US5034528A (en) * 1988-07-27 1991-07-23 North Carolina Central University Compositions for the control of hyperlipidemia
US5192761A (en) * 1988-07-27 1993-03-09 North Carolina Central Univ. 1,2,4-triazolidine-3,5-diones and 1,3,5-triazine-2,4(1-H,3H)-diones, pharmaceutical compositions
WO2014202505A1 (de) 2013-06-20 2014-12-24 Bayer Cropscience Ag Arylsulfid- und arylsulfoxid-derivate als akarizide und insektizide

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4088767A (en) * 1974-12-06 1978-05-09 Mitsubishi Chemical Industries Limited 4-Dichlorophenylurazole compounds and use in agricultural fungicidal compositions
US4276420A (en) * 1978-05-24 1981-06-30 Chevron Research Company Herbicidal and plant-growth-regulating 1,2,4-trisubstituted-1,2,4-triazolidin-3-one-5-thione
US4326878A (en) * 1979-02-09 1982-04-27 Chevron Research Herbicidal and plant-growth-regulating 1,2,4-trisubstituted-1,2,4-triazolidin-3,5-dithiones
EP0024309A3 (de) * 1979-07-23 1981-07-22 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Triazolopyridazinderivate, Verfahren und Zwischenprodukte zu ihrer Herstellung und diese enthaltende Arzneimittel
US4307094A (en) * 1979-07-23 1981-12-22 Hoffmann-La Roche Inc. Triazolopyridazine derivatives
EP0044421A1 (de) * 1980-07-21 1982-01-27 Bayer Ag Di- und Oligo-1,2,4-triazolidin-3,5-dione und Verfahren zu ihrer Herstellung
US4386213A (en) * 1980-07-21 1983-05-31 Bayer Aktiengesellschaft Di- and Oligo-1,2,4-triazolidine-3,5-diones and processes for their production
US5034528A (en) * 1988-07-27 1991-07-23 North Carolina Central University Compositions for the control of hyperlipidemia
US5192761A (en) * 1988-07-27 1993-03-09 North Carolina Central Univ. 1,2,4-triazolidine-3,5-diones and 1,3,5-triazine-2,4(1-H,3H)-diones, pharmaceutical compositions
WO2014202505A1 (de) 2013-06-20 2014-12-24 Bayer Cropscience Ag Arylsulfid- und arylsulfoxid-derivate als akarizide und insektizide

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