US3663564A - Urazoles and their production - Google Patents

Abstract

A PHENYL-SUBSTITUTED URAZOLE AND A METHOD OF MAKING URAZOLES. THE URAZOLES ARE DRUGS, ESPECIALLY ANTICONVULSANTS.

Description

United States Patent Ofice 3,663,564 Patented May 16, 1972 US. Cl. 260-308 C 19 Claims ABSTRACT OF THE DISCLOSURE A phenyl-substituted urazole and a method of making urazoles. The urazoles are drugs, especially anticonvulsants.

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.

More particularly, 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.

It has been found that the urazole derivatives useful in this process are 1,2-disubstituted or 1,2,4-trisubstituted urazoles which are represented by, the general Formula I,

wherein 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

wherein 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. For oral therapy 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. As the pure compounds are generally not appreciably water soluble, where aqueous solutions are to be preferred, 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.

Especially marked anticonvulsant action is shown by compounds of Formula I where R is phenyl, R is lower alkyl, and R is hydrogen, such as 1-phenyl-2-methyl urazole, l-phenyl 2 ethyl urazole, l-phenyl-Z-n-propyl urazole, l-phenyl-Z-isopropyl urazole, 1-phenyl-2-n-butyl urazole, and 1-phenyl-2-isobutyl urazole. 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 alkyl radical, and a phenyl radical either unsubstituted or substituted by a lower alkyl radical, lower alkoxy,

hydroxy], amino, or substituted amino groups, or halogen, and wherein R represents hydrogen.

Another group of new and useful 1,2-substituted urazoles with valuable therapeutic properties according to the present invention is represented by the general Formula I wherein 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.

Still another group of new and useful 1,2,4-trisubstituted urazoles of value in the therapeutic process according to the present invention and included in the scope" of the present invention are represented by the general Formula I wherein R represents a phenyl radical either unsubstituted or substituted by lower alkyl radicals, lower alkoxy groups, or halogen, wherein 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 containing 1 to 6 carbon atoms either unsubstituted or substituted by hydroxyl, lower carbalkoxy, or carboxarnido groups, or halogen, an alkenyl radical, preferably of 2 to 5 carbon atoms, a phenyl substituted lower alkyl radical, a phenyl radical, and a lower alkoxy carbonyl group.

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.

Similarly, among the new 1,2,4-trisubstituted 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.

In addition to the therapeutically useful anticonvulsant action possessed by these known and new urazole derivatives as described within the scope of the present invention, some of these novel compounds have been found to possess other useful therapeutic properties.

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.

Additional useful therapeutic properties are exhibited by other diand trisubstituted urazoles included within the scope of the present invention and represented by the general Formula I wherein 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 and wherein R represents hydrogen, a lower alkyl, cyclohexyl, aralkyl, or phenyl radical, but wherein only one of said substituents R and R is hydrogen.

The above described 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.

Further compounds included within the scope of the present invention are 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. The above described urazole derivatives exhibit useful central nervous system stimulatory properties.

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.

The chemical literature reveals that all generally applicable known syntheses of urazoles initiate from hydrazine or its suitably substituted derivatives. Only 1- monosubstituted aryl urazoles have been synthesized di rectly from a monosubstituted hydrazine or its acid additron salt by a one-step condensation-cyclization reaction where reagents containing the N-CO linkage and capable of condensing with a hydrazine such as urea and biuret have been most frequently used. Hydrazo dicarbonamide, ethyl carbethoxy thiocarbamate, and the like compounds have also been employed for this purpose. Subsequently, the same general procedure was employed to prepare l-phenyl urazole by heating together phenyl hydrazine and allophanic acid esters at temperatures above C.

To accomplish these condensation-cyclization reactions the reactants have usually been heated in the absence of solvents to temperatures in the range of C. to 230 C. Low yields are frequently obtained and considerable quantities of other products are often encountered making isolation and purification of the desired products difficult.

The literature reports that ethyl carbethoxythiocarba mate, a reagent not readily prepared, condenses with phenylhydrazine at temperatures not exceeding 100 C. However, the product of the reaction is not l-phenylurazole, but is rather the O-ethyl derivative which must be hydrolyzed to l-phenylurazole In the prior art, all other syntheses of l-monosubstituted urazoles or 1,2-disubstituted urazoles prepared from noncyclic starting materials have required the prep aration of the monocarboxamide derivatives of the hydrazines such as semi-carbazides which derivatives either are condensed and cyclized to urazoles by the above described process or are further substituted with carboxyl, carbalkoxy, or carboxamido groups followed by cyclization to urazoles. All these known processes require several steps to obtain the desired products.

' .The above described processes for the synthesis of 1- monosubstituted and 1,2-disubstituted urazoles suffer from a variety of disadvantages among which are lack of wide adaptability, multi-step reaction sequences, highreaction temperatures, and low yields with resulting .difiiculties in isolation and purification of the products.

According to a specific valuable embodiment of th 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.

: R1- I I--l &Rg

In Process A, l l, R represents preferably a lower alkyl radical, and 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, however, R and R shall not simultaneously.represent hydrogen;

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. 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. When alcohol andammonia evolution are complete, the urazole isdsolated by separation' from the solvent and recrystallization, distillation, or other appropriate means of purification. 1

Use of process A allows both l-monosubstituted and l,2 disubstituted urazoles to 1 be obtained through a single reaction from the starting hydrazine. By use of 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. r

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.

The 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.

While 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. As 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. When 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.

- Many of the 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.

Other 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. For example, 1,4-disubstituted urazoles can readily be prepared by treatment of 2,4-disubstituted-l-carbalkoxy semicarbazides with hot alkali hydroxide solutions. In this way, 1,4- diphenyl urazole can be prepared from 2,4-diphenyl-1-carbethoxy semicarbazide. Similarly, 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. Alternatively, 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.

The following examples will illustrate in greater detail the processes for preparing the compounds of this invention. The examples are illustrative of the processes and of the novel compounds of this invention and are not to be construed as imposing any limitations on the invention as defined by the claims.

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%.

Analysis.-'-Calcd. for C H N (percent): C, 51.87; H, 8.16; N, 22.69.Found (percent): C, 51.97; H, 8.15; N, 22.76.

, 7 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. The residue is dissolved in dilute sodium hydroxide solution and the basic solution is decolorized with charcoal, filtered, and acidified with concentrated hydrochloric acid to precipitate a crystalline solid. Recrystallization of the solid from carbon tetrachloride yields 63 g. of l-phenyl-2-ethyl urazole as l-benzhydryl urazole.A two-liter flask equipped with a mechanical stirrer, thermometer, and distilling column topped by a distilling head and condenser is charged with 39 g. of ethyl allophanate, 50 g. of benzhydryl hydrazine, and 600 cc. of xylene. The stirred mixture is heated to 130 C. where ethanol and ammonia are evolved and a clear solution is formed. After heating for ten hours at 130 C. to 140 C., ethanol and ammonia evolution ceases and the solution is cooled. The solid that separates is filtered off, dried, and dissolved in dilute sodium hydroxide solution. After filtering the solution of the sodium salt to remove insoluble matter, acidification with concentrated hydrochloric acid precipitates 36 g. of l-benzhydryl urazole which melts at 280 C. with decomposition after recrystallization from glacial acetic acid. The yield is 45%.

AnaIysis.-Calcd. for C H N O (percent): C, 67.40; H, 4.90; N, 15.72. Found (percent): C, 67.45; H, 4.97; N. 15.54. 1

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%.

When this reaction is conducted in the same manner using 66 g. of ethyl allophanate and 54 g. of phenyl hydrazine in 750 cc. of toluene, isoamyl alcohol, di-n-butyl ether, phenetol, or glycerol, 6070% yields of l-phenyl urazole are obtained.

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%.

.Analysis.,Calc. for C H N O (percent): C, 65.43; H, 7.69; N, 15.26. Found (percent): C, 65.35; H, 7.71; N, 15.06.

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. '70, page 3421 (1948)], is reduced in a 35% overall yield by using an excess of lithium aluminum hydride and refluxing the mixture in ether to give l-p-tolyl-Z-cyclohexyl hydrazine in the form of colorless needles melting at -97 C.-The hydrochloride salt decomposes at 198 C.

A mixture of 32 g. of ethyl allophanate, 49 g. of the above hydrazine, and 500. cc. of xylene is heated at 138 C. for eight hours accompanied by ethanol and ammonia evolution. The solution is concentrated under reduced pressure, the residue is dissolved in dilute sodium hydroxide solution, and the resulting basic solution is extracted with ether and decolorized with charcoal. Acidification of the basic solutionwith concentrated hydrochloric acid precipitates a cream-colored solid that is filtered 01f, washed with water, and dried. Recrystallization from dilute isopropanol yields 52 g. of l-p-tolyl-Z- cyclohexyl urazole as cream-colored crystals melting at 183-185 C.

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. Yield: 71%. -Analysis.-Calc. for C H' 1'N O (percent): C, 66.39; H," 4.38; N,16.59.' Found (percent): C, 66.52; H, 4.62; N, 16.90. i

'PROCESSB Example 9 l-isopropyl urazole.'--In a one-liter round-bottomed flaskaequipped'with a'mechanical stirrer, a thermometer, and a short distilling column surmounted by a distilling I head with attaehed condenser and receiver there are placed 32 g. of diethyl imido dicarboxylate, 15 g. of iso: propyl hydrazine, and 400 cc. of xylene. The reaction mixture is stirred and heated at 110-140 C. until no further ethanol distills overrThereaf ter the xylene is distilled off under reduced 'pressureJThe darlg residue is taken up in' a small "quantity of ammonium hydroxide solution and, after decolorizing'theresultingbasic solu; tion with charcoal and filtering'fit, acidi'ficationwith acid precipitates 14 g. of l-isopropyl urazole melting at 188- 190fC on recrystallization from water.

Example 10 tion is'acidified. The precipitated white solid is recrysf:

tallized from water to give 34, g. of 1-(2 ,5-dichlorophenyl) urazole in the form of colorless needles melting at 209- 211 C. Yield: 92%.

Ahal-ysis-Calcd. for C H N O Cl (percent): C, 39105; H, 2.05; N, 17.08. Found (percent): C, 39.21; H; 2.16; N, 17.02." f

. 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.

Amzlysis.-Calcd. for C' H N O (percent): C, 63.36; H, 8.74; N, 15.84. Found (percent): C, 63.45; H, 8.91; N, 15.88.

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:

"The use of toluene at 107-111 C. for 24 hours, of isoamyl alcohol at 125 -131 C. for three hours, of di-nbutyl ether at 135-140 C. for two hours, and of anisole at 145 -150 C. for two hours as solvents in the above reaction gives yields of 75-80% of I-phenyl- 2-isopropyl urazole. v

Example 13,.

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%.

Analysis.-Calcd. for C H N O (percent): C, 63.14; H, 6.93; N, 16.99. Found (percent): C, 63.20; H, 6.99; N, 16.87.

" v Example 14 1-phenyl-2-cyclohexyl urazole.--A mixture of 80 g. of diethyl imido dicarboxylate and g. of l-phenyl-2-cyclohexyl hydrazine in 750 cc. of xylene is refluxed at 140 C. while allowingthe ethanol formed in the reaction to distill off. The theoretical quantity of ethanol is collected within two hours and, after an additional hour, the solution is evaporated to dryness underv reduced pressure. The resulting solid residue is dissolved in dilute sodium hydroxide solution and the basic solution is extracted with ether, decolorized with-charcoal, and acidified with hydrochloric acid to precipitate g. of l-phenyl- 2-cyclohexyl urazole. Recrystallization from dilute isopropanol gives 116 g. of colorless crystals melting at 142" C. Yield: 90%.

Analysis.Calc. for C H N O (percent): C, 64.84; H, 6.61; N, 16.21. Found (percent): C, 64.95; H, 6.92; N, 16.34. 1

- Example 15 1-phenyl-2-allyl urazole-16 g. of diethyl imido dicar- -b0xylate and 14 g. of l-phenyl-Z-allyl hydrazine in 200 1-phenyl-2-(1-phenyl ethyl) urazole-46 g. of diethyl imido dicarboxylate and 21 g. of 1-phenyl-2-(1-phenyl 11 ethyl) hydrazine in 200 cc. of xylene are reacted as described in the above examples. After purification and recrystallization from carbon tetrachloride, 24 g. of l-phenyl-2-(l-phenyl ethyl) urazole are obtained as colorless crystals melting at 122124 C.

Analysis.Calcd. for C H N O (percent): C, 68.31; H, 5.38; N, 14.94. Found (percent): C, 68.35; H, 5.42; N, 14.84.

In the same manner, employing either Process A or Process B, 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-amyl urazole may be prepared from 1,2-di-n-amyl hydrazine; 1,2-di-(l-phenyl ethyl) urazole may be prepared from 1,2-di-(1-phenyl ethyl) hydrazine; l-isopropyl- 2-methyl urazole may be prepared from 1-isopropyl-2- methyl hydrazine; l-phenyl-Z-dodecyl urazole may be prepared from l-phenyl-2-dodecyl hydrazine; 1-phenyl-2-otolyl urazole may be prepared from 1-phenyl-2-o-tolyl hydrazine; l-phenyl-Z-p-tolyl urazole may be prepared from 1-phenyl-2-p-tolyl hydrazine; 1-phenyl-2-p-methoxy phenyl urazole may be prepared from l-phenyl-Z-p-methoxyphenyl hydrazine; 1-phenyl-2-p-hydroxy phenyl urazole may be prepared from l-phenyl-2-p-hydroxy phenyl hydrazine; l-phenyl-2-p-bromo phenyl urazole may be prepared from l-phenyl-Z-p-bromo phenyl hydrazine; l-phenyl-2-p-amino phenyl urazole may be prepared from 1- phenyl-2-p-amino phenyl hydrazine; l-phenyl-2-p-dimethylamino phenyl urazole may be prepared from l-phenyl- Z-p-dimethylamino phenyl hydrazine; 1,2-di-m-tolyl urazole may be prepared from 1,2-di-m-tolyl hydrazine and l-o-tolyl-2-(3-methyl-4-amino phenyl) urazole may be prepared from 1-o-tolyl-2-(3-methyl-4-amino phenyl) hydrazine.

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. From the chloroform extract there is isolated a solid that is recrystallized once from 2% hydrochloric acid and then from carbon tetrachloride to give g. of l-pheny1-2-ethyl urazole in the form of long, colorless needles melting at 120-l2l C. Yield: 49%.

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.

12 Atnalysis.calcd. for C H N O (percent): C, 62.32; H, 5.67; N, 18.17. Found (percent): C, 62.28; H, 5.87; N, 18.21. t

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%

Anulysis.Calcd. for C H N O (percent): C, 73.45; H, 4.99; N, 12.24. Found (percent): C, 73.25; H, 4.96; N, 12.21.

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%.

Analysis.Calcd. for C H N 0 Br (percent): C, 40.01; H, 2.99; N, 15.56. Found (percent): C, 40.02; H, 3.12; N, 15.44.

In .the same way l-isopropyl urazole and methyl iodide yield 1-isopropyl-2-methyl urazole; l-benzhydryl urazole and methyl iodide yield 1-benzhydry1-2-methyl urazole; 1- cyclohexyl urazole and ethyl iodide yield 1-cycl0hexyl-2- ethyl urazole; l-o-ethyl phenyl urazole and methyl iodide yield l-o-ethyl phenyl-2-methyl urazole; l-p-ethoxy phenyl urazole and allyl chloride yield l-p-ethoxyphenyl-Z-allyl urazole; l-o-chloro phenyl urazole and isoamyl bromide yield l-o-chloro phenyl-2-isoamyl urazole; 1-(2,5-dichloro phenyl) urazole and benzyl chloride yield l(2,5-dichlorophenyl)-2-benzyl urazole.

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. of unreacted lphenyl urazole are recovered by acidification of .the basic aqueous phase. The dried ether extract is concentrated and the residue is distilled under reduced pressure to give 21 g. of 1-phenyl-2,4,-di-n-propyl urazole, a slightly viscous, pale yellow oil. Boiling point: 133136 C./0.3. mm., n =l.5298, Yield:

Analysis.-Calcd. for C H N O (percent): C, 64.35; H, 7.33; N, 16.08. Found (percent): C, 64.45; H, 7.44; N, 16.19.

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

13 g. of potassium hydroxide in 500 cc. of 99% isopropanol, there are slowly added 28 g. of benzyl chloride. The resulting mixture is refluxed for 24 hours.

After evaporating the reaction mixture to dryness under reduced pressure, the residue is boiled for a short time with 10% sodium hydroxide solution, the mixture is cooled, and the solid is filtered off and washed thoroughly with water. Recrystallization of the solid from isopropanol and then from heptane yields 32 g. of 1-phenyl-2,4-dibenzyl urazole in the form of colorless crystals melting at l-l02 C. Yield: 75%.

Analysis.Calcd. for C H N O (percent): C, 73.93; H, 5.36; N, 11.76. Found (percent) C, 73.88; H, 5.35; N, 11.76.

By the above procedure 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.

-Analysis.Calcd. for C H N O- Cl (percent): C, 60.86; H, 4.47; N, 13.31. Found (percent): C, 61.05; H, 4.54; N, 13.20.

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%.

Analysis.-Calcd. for C18H17N3O4 (percent): C, 63.71; H, 5.05; N, 12.38. Found (percent): C, 63.73; H, 5.18; N, 12.41. r

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.

Analysis.--Calcd. for C H N O (percent): C, 58.36; H, 4.59; N, 12.76. Found (percent): C, 58.42; H, 4.36; N, 13.01.

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:

7677 C./0.3 min'., n =1.4609. Yield. 57%.

Analysis.-Calcd. for C H N O (percent): C, 58.17;

H, 9.31; N, 18.49. Found (percent): C, 57.98; H, 9.45;

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%.

Analysis.Calcd. for C H N O (percent): C, 61.93; H, 4.55; N, 18.06. Found (percent): C, 62.00; H, 4.50; N, 18.02.

In the same manner 1,2-diisopropyl urazole and methyl iodide yield 1,2-diisopropyl-4-methyl uraZole ;1,2- di-n-y amyl urazole and ethylene bromohydrin yield 1,2-di-namyl-4-(2-hydroxy ethyl) urazole; 1,2-dicyclohexyl urazole and methyl iodide yield 1,2-dicyclohexyl-4-methyl urazole; l-phenyl-Z-methyl urazole and allyl bromide yield added 27 g. of ethylene bromohydrin. An oil soonseparates from the refluxing solution to which an additional 3 12 g. of potassium hydroxide and 27 g. of ethylene bromohydrin are added after four hours. After 24 hours the 1-phenyl-2-methyl-4-allyl urazole; 1-phenyl-2-isopropyl urazole and ethyl chloroformate yield 1-phenyl-2-isopropyl-4carbethoxy urazole; 1-phenyl-2-cyclohexyl urazole and ethyl bromo acetate yield ethyl 1-phenyl-2-cyclohexylreaction mixture is cooled and the solidified oil is filtered off and washed with hot concentrated ammonium hydroxide and water. From the basic filtrate 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%. V

Analysis.-Calcd. for C H N O (percent): C, 64.63; H, 5.09; N, 14.14. Found (percent): C, 64.77; H, 5.37; N. 13.91.

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-tolyl-Z-cyclohexyl urazole and methyl iodide yield 1-p-tolyl-2-cyclohexyl-4-methyl urazole; 1-

(2,5-dichloro phenyl)-Z-benzyl urazole and methyl iodide vyield 1-(2,5-dichloro phenyl)-2-benzyl-4-methyl urazole;

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.

It will be evident to those skilled in the art that other substituted urazoles can readily be prepared in the manner 16 Example 103' 15 described in the above examples by use of either Process A or Process B and by alkylation of urazoles with appropriate alkylating reagents. For example, in addition to the examples of preparing urazole compounds given hereinabove, thefollowing compounds have been prepared by employing one or the other of the above described methl-phenyl urazole from phenyl hydrazine hydrochloride and urea.A stirred mixture of 29 g. of phenyl hydrazine 5 hydrochloride and 24 g. of urea is heated at 160-170 C. for ten hours. During this time, ammonia is continually ods: evolved. 400 cc. of water are added to the cooled sol1d General formula l a :0 0:0

R1NNR1 TABLEI Melting point (boiling point) Example R1 R2 R3 (mm.) degrees, C.

(cycl0)C6H11 H H 2711272 (0) CH3-C5H4 H 11 174-176 (p) 01 13-05114 II H 285 (due) (0) C2H5-C5H4 H H 178-180 (p) 0211 0-0 11, H H 266 (666.) (0) 01-0 11 H H 161-193 (m) 010 11. H H 228-230 (p) 017C6114 H H 268 (666.) (p) Bl-C5H4 H H 300 ((180,) (D) O2N-C5H4 H H 264 ((100) C6H5 OH; H 184-186 C5115 I1C3H1 H 128-130 0111 1-C4Hv H 129-131 06115 150-0411 H 155 (4100.) CBH5 CH(CH3)CH2CH:1 H 142-14 C6H5 11-C5H11 H -77 CsH 150-C5H11 H -98 C5H5 CH(n-C 1 7)2 H 117-118 C5115 H'CWHZ H 51-52 C5H5 (cyclo) 05H H 146-148 06115 (0) CH (cycl0)C5 11 H 132-134 0 11 (p) GHQ-(W010) 01H" H 161-163 (36H; p- Hs0 (cyclo) eHn H 1 0-155 C5115 (cyclo) 0 111; H 151-152 (1 CH3-C6H4 1 H 195-200 (p) BrC H C 5 H 186-188 (0) C1'CBH4 5 H 213-214 as-(cng-c m O H 207-208 (1)) 011150-0111; H 204-206 (0) 01-0 11, y )C6 11 H 192-193 0611 CH4cH=oH-cH3 H 145-147 CQH CH2 OH2C5H5 H 158-154 06115 H 227-228 ((180.) (3511 H 4115 176-178 0 H, H -05 11 -122 0 11, H HzCGH 232-234 0111 H 4H1 151-153 0411 H 1 5 165-167 CH3 CH1 9 1 64-66 156-0 11 iso-CaH-y ISO-05H" 106-109 (0.9) (CYC10)C5H11 (W 0) 011111 7 1 56-58 00115 a 04-96 CGHS on 01143112011 140141 0411 CH3 s 7 81-82 C111 CH1 0-C5Hn 176-178 C1115 1 o s 133-135 C111 C1115 1 118-120, 52-53 (0. 3 c n CzH Q2115 128-130 (0.4) (3H5 C2H5 6H5 126-128 11-0 11 H; 134-138 (0 3) 0 m n-C4H1 C2H4 -126 (0 3) CH5 {PC3117 CH2CH2OH 172-175 (0, 3) 0611 1so-C:H7 5 67-66 g g -01111 CHzCH OH -173, 5456 (0.1) C4115 1s5-C5H1 5 -01111 119-121 (0.15) C5H5 1s0-CsH7 lso-CaHv 88-90 0611 5 n -CQH1 144-148 (0. 3) CaH; (W810) C5H11 CH5 117-118 c 11,, (cyclo)C H CHz-CHz-OH 197-198, 82-84 (0.15) 0611 YclrDCs 11 -61 1 169-170 (0.5 0 ,11 Orb-C611 C 115-117 11 0111-0711 CH2,CHz-OH 86-87 C6115 CHz-CsHs a 7 181183 (0. 6) 0011 00102115 102115 139-141 CaH CBH5 CH1 140-141 (dec.) C111 C4H5 1 CH5 135-137 C6H5 (W010) u n CHZOH 118-120 04115 a s 3 7 74-75 C511 C511 CH2CH(OH)CHZOH 156-158 (666.) C4H C6H5 4H1 85-86 0 ,11 C1H5 {1-C5H11 72-74 C5115 C5115 ISO-051111 110-111 C6115 C4115 (31120 11 166-168 102 CsHs ce s CO2C2H5 143-144 The new urazole compounds according to the present invention can, of course, also be produced according to known processes as they have been mentioned hereinabove. The following examples serve to illustrate the preparation of valuable new urazole compounds according to the present invention without, however, limiting the same thereto.

mass, the mixture is heated to boiling, and the insoluble 70 brown solid is filtered off and dried. Yield: 20 g. An additional 4 g. of crude product is obtained by chilling the filtrate. The combined crops of crude product are dissolved in dilute sodium hydroxide solution and tarry insoluble impurities are removed by filtration. Acidification 75 of the red filtrate with concentrated hydrochloride acid 17 gives a pink solid that is recrystallized once from methanol and once from dilute acetic acid, decolorizing with charcoal, to yield 18 g. of l-phenyl urazole as colorless crystals melting at 265-267 C. The yield is 51%.

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.

By refluxing 2 g. of 1-phenyl-3-ethoxy-1,2,4-triazol-5- one for 30 minutes with dilute hydrochloric acid, cooling the mixture, and filtering off the precipitated solid, 1.7 g. of l-phenyl urazole are obtained.

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. The resulting yellow precipitate is recrystallized twice from dilute methanol, decolorizing with charcoal, to give 37 'g. of l-phenyl-2-cyclohexyl semicarbazide as flutfy needles melting at 190192 C.

Analysis.-Calcd. for C H N 0 (percent): C, 66.92; H, 8.21; N, 18.01. Found (percent): C, 67.20; H, 8.33; N, 18.01.

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.

is 115 g., corresponding to a yield of A 10% aqueous solution of the salt has a pH of 9.5.

Other salts of the urazole derivatives of this invention with 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. Other ratios of the diluents, binders, and lubricants may be used as well as other 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.

19 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.

T he above examples are intended for illustration only and are not to be construed as limiting the scope of this invention. 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.

250 mg. of the active compound per tablet have proved to be especially suitable in the case of certain of the urazole derivatives. 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.

Pharmacological tests with the urazole compounds according to the present invention produced the following results:

The generally low neurotoxicity of the urazole derivatives as determined in pharmacological tests on mice according to the method of Swinyard et al. is illustrated by the representative examples in Table II.

TABLE II.--NEUROTOXICITY OF URAZOLE DERIVATIVES The content of active compounds in such preparations used in therapy may, of course, vary. It is necessary that the active compound be present in such an amount that a suitable dosage per dosage unit will be ensured. Tablets containing, for instance, between about 10 mg. and 500 To indicate the eflicacy of the compounds of this invention, Table III provides a comparison of the neurotoxicity, potency and protective indices of a few of the urazole derivatives with corresponding values for the well-known and clinically useful anticonvulsant, trimethmg. and preferably between about 30 mg. and about adione, when tested in mice against pentamethylene tet- 21 razole convulsions according to the method described by Elizabeth H. Jenney and Carl C. 'Pfeifier, mentioned hereinabove.

22 It is interesting to notethat, while the lphenyl-2-benzyl urazole has a sedative effect, the l-phenyl-2-(2-phenyl In addition Table IV lists some examples of other compounds of this invention that have exhibited useful anticonvulsant action when tested in mice against pentamethylene tetrazole convulsions by the same standard procedures described above. The dose which protects 50% of the animals from convulsion (ED is 500 mg./kg. or less for all of the listed compounds.

ethyl) urazole exerts a stimulating elfect upon the central nervous system.

Other pharmacological properties of the urazole derivatives of this invention are represented by the results of more detailed studies on l-phenyl-Z-cyclohexyl urazole.

Oral administration in mice shows that this material possesses an extremely low order of toxicity. 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.

TABLE VI Mean sleeping Example time, No. Drug minutes 44 l-phenyl-Z-n-amyl urazole 94 45 {1- henyl-2-isoamyl urazole. 47 exobarhital.-. r 59 high dose required to kill 50% of the animals tested (LD is 3.1 gm./kg. Thus for therapeutic use in humans the drug is considered to be essentially non-toxic.

After oral administration of 1-phenyl-2-cyclohexyl urazole to mice, complete protection against pentamethylene tetrazole convulsions mg./kg., subcutaneously) is provided for 50% of the animals tested at a dose of 260 mg./kg. (ED

In rabbits after oral administration of the drug fol lowed by 40 mg./kg. of pentamethylene tetrazole, intravenously, the ED mg./kg. Oral doses of up to 500 mg./ kg. of the drug to rabbits produced no observable symptoms.

After a 21-day subacute toxicity experiment in rats receiving 2 gm./kg./day of l-phenyl-Z-cyclohexyl urazole, autopsy of all animals revealed no gross pathologic changes. At this very high dose level no obvious signs of neurotoxicity were noted following drug administration. There was a slight appetite depressant effect and some depression of body weights was noted.

Metabolism studies indicate that 1-phenyl-2-cyclohexyl urazole is completely metabolized in the body, liver degradation being a factor.

Experiments in dogs have also shown that the drug has no curate-like properties and is neither cholinergic nor anticholinergic in :action. Rapid intravenous injection into dogs produces hypotension.

We claim:

1. In a process of producing urazole compounds, the steps which comprise heating a lower alkyl ester of allo phanic acid with a hydrazine compound of the formula R -NHNHR wherein 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,

in the presence of an inert organic solvent at a temperature exceeding 100 C. until evolution of the lower alka- 1101 and ammonia split 01f during the reaction ceases, and isolating the resulting urazole compound from the reaction mixture.

2. The process according to claim 1 wherein the 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.

3. In a process producing urazole compounds, 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, only one of said R and R representing hydrogen, at a temperature exceeding 100 C. until evolution of the lower alkanol split 01? during the reaction ceases, and isolating the resulting urazole compound from the reaction mixture.

4. The process according to claim 3, wherein the 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.

5. The process according to claim 4, wherein 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.

6. 1-phenyl-2-cyclohexyl urazole.

7. 1,2-diphenyl urazole.

8. 1-phenyl-2-benzyl urazole.

9. 1-phenyl-2-alkyl-4-hydroxy alkyl urazoles, the alkyl radicals of said compounds having 1 to 5 carbon atoms.

10. 1-phenyl-2-(2'-phenylethy1) urazole.

11. l-phenyl-2-(1'-phenylethyl) urazole.

12. l-phenyl-Z-dodecyl urazole.

13. A urazole of the formula tiL-L wherein R is phenyl, R is allyl, methallyl or alkyl of 1 to 3 carbon atoms substituted by phenyl, and R is hydrogen, and the salts of said urazole compounds with a base selected from the group consisting of an alkali metal hydroxide and a pharmaceutically acceptable organic base.

14. A urazole of the formula of claim 13 wherein R is phenyl, R is methallyl or allyl, and R is hydrogen.

15. 1 phenyl-Z-methallyl urazole.

16. l-phenyl-Z-allyl urazole.

17. 1-p-tolyl-2-methylurazole.

18. l-p-bromophenyl 2-methylurazole.

19. The process of claim 3 wherein non of R or R is hydrogen.

References Cited UNITED STATES PATENTS 7/1960 Close et a1. 260308 OTHER REFERENCES Chemical Abstracts: vol. 18, 1924, p. 18267; vol. 20, 1926, p. 16044; vol. 24, 1930, pp. 4765-4766; vol. 42, 1948, pp. 8190-8191; vol. 50 ,1956, pp. 7783-7784.

Boagault, Bull. Soc. Chim. (4), vol. 47, pp. 594-605 (1930) obtained three Chem. Abs., vol. 24, 1930, pp. 4765- 4766.

Harris, J. Applied Physiology, July 1954, pp. 84-88.

Batterman, J.: A.M.A., vol. 155, No. 11, July 10, 1954, pp. 965-968.

J., A.M.A., vol. 165, No. 7, Oct. 19,1957, p. 780.

Laurence, B. M. J., Mar. 22, 1958, pp. 700-702. B.M.J., Apr. 19, 1958, pp. 938-939.

Dains et al., J. A. C. S., 42, pp. 2303-2309 (1920).

ALTON D. ROLLINS, Primary Examiner US. Cl. X.R.