US3242174A

US3242174A - 1-(tertiary aminosulfonyl)-3-(hydrocarbon) ureas

Info

Publication number: US3242174A
Application number: US171337A
Authority: US
Inventors: James M Mcmanus; William M Mclamore; Gerald D Laubach
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1962-02-06
Filing date: 1962-02-06
Publication date: 1966-03-22
Anticipated expiration: 1983-03-22

Description

United States This invention relates to new and useful sulfamylureas which are effective in lowering the amount of sugar in the blood. More particularly, it is concerned with various N,N-disu-bstituted sulfamylureas and with the acid and base salts thereof, as well as with the method of reducing the blood sugars in a diabetic subject by the oral administration thereto of said sul-famylureas or of one of their pharmaceutically acceptable salts. The present application is a continuation-in-part of our copending application Serial No. 88,033, tiled February 9, 1961, now abandoned.

The novel compounds which are included within the scope of the present invention are all selected from the class of sulfamylureas having one of the following general structural formulae:

z iv-soiNinc oNna" wherein R is lower alkyl, and R is a member chosen from the group consisting of lower alkyl, lower alkenyl, aryl (e.g., phenyl), cycloalkyl having from three to eight carbon atoms, cycloalkenyl, aralkyl, pyridylalkyl, thienylalkyl and furylalkyl in which each alkyl moiety is lower alkyl, and ring-substituted derivatives thereof in which each ring substituent is chosen from the group consisting 'of chlorine, bromine and methyl (as well as amino and alkoxyl in the case of aralkyl and pyridylalkyl); Z represents the atoms completing a radical chosen from the group consisting of 'pyrrolidino, tetrahydropyridino, piperidino, C-aminopiperidino, C-(lower alkyl)piperidin'0, 4,4-di(lower alkyl)piperidino, 4,4 tetramethylenepiperidino, 4,4 pentamethylenepiperidino, homopi-peridino, piperazino, N-alkylpiperazino, N-arylpiperazino, morpholino, C-(lower alkyl)morpholino, thiamorpholino, C-(lower aIkyD-thiamorpholino, and 1,2,3,'4-tetra hydrois-oquinolino; and R is a member chosen from the group consisting of alkyl having from two to eight carbon atoms, lower polyfluoroalkyl, cycloalkylalkyl having from four to nine carbon atoms, cycloalkyl (including terpene-like radicals) having from three to nine carbon atoms, as well as ring-substituted derivatives thereof in which each ring substituent is either lower alkyl or gem-dimethyl, aralkyl having from seven to thirteen carbon atoms, pyridylal-kyl, thienylalkyl, furylalkyl, morpholinoalkyl in which each alkyl moiety is lower alkyl, p-toly'l, p-chl'orophenyl, p-di- (lower alkyl)amino-phenyl and S-(lower alkyl)mercaptophenyl. There is also intended to include within the purview of this invention all the various non-toxic acid addition, alkali metal, alkaline-earth metal, ammonium and watersoluble amine addition salts which the compounds of the present invention will form. Among the typical member compounds of this series are such novel, N,N-diswbstituted sulfamylureas as [N-methyl-N- o -chlorobenzyl aminosulfonyl] -3- (n-propyl)u-rea, 1- (N-methyl-N-cyclohexylaminosulfonyl -3 atent 3,242,174 Patented Mar. 22, I966 and the like. Additionally, compounds which are disubstituted on the 3-amino group of the molecule are also contemplated as being within the scope of this invention, as are those compounds having for their a-mino moiety fused bicyclic nitrogen-containing heterocyclic ring system such as those of the tropane type.

In accordance with .the present invention, various N,=N- disubstituted sulfamyl-ureas of the foregoing type and certain salts thereof have been found to the especially valuable and useful as agents for lowering blood sugar levels when administered orally to an animal subject, including man. Moreover, the advantages offered by the pharmacologically acceptable compounds of this invention are manifold: for instance, (.1) they may be administered orally as aforesaid, thereby eliminating parenteral administration which is often very 'painful and irritating; (2) they are extremely effective in lowering blood sugar levels in animals, including humans, to a very high degree and for a sustained period of time; (3) toxic side efiects have been found to be either minimal or else completely absent; (4) pharmacological investigation reveals no evidence of kidney damage or crystalluria; (5) they may be easily prepared in good yield from readily available starting materials by any number of synthetic organic methods which are rather convenient and economical to operate; and lastly, (6) these compounds readily lend them-selves to the preparation of suitable oral dosage formulations.

As previously indicated, these compounds can all be readily synthesized by those having skill in the art to which it pertains. For instance, general preparative methods which are applicable for such a purpose include those synthetic rout-es which involve the reaction of an N,N- disubstituted aminosulfonyl isocyanate with the appro- :priate amine or conversely, the reaction of an N,N- dis ubstituted aminosulfonamide with the appropriate isocyanate or with compounds which can be converted into such an isocyanate during the course of the reaction; or the reaction of "an N,N-disubstituted aminosulfonylurethane with the appropriate amine or conversely, the reaction of an N,N-disubstituted aminosulfonamide with an appropriate urethane; or the reaction of an N,N-disubstitwted aminosulfonamide with the appropriate N-monosubstituted carbamyl chloride or the conversion of an N,N- disubstituted aminosulfonylurea to the desired 3-substituted compound by means of the appropriate amine; or the reaction of an N,N-disubstituted amin-osul fonamide with the appropriate l,3-(disubstituted)urea; or the reaction of an N,N-disubstituted iaminosulfonyl chloride with the corresponding isourea in the form of a suitable salt, followed by acid hydrolysis of the resulting intermediate; or the reaction of an N,N-disubstituted aminosulfonylurea with the appropriate 1,3-(disubstituted)thio urea or the corresponding substituted guanidine by either first desulfurizing or hydrolyzing these reagents or. by.

3 employing them as such, followed by respective desulfurization or hydrolyzation to the desired N,N-disubstituted sulfamylurea compound.

Preferred synthetic routes in this connection include the reaction of the N,N-disubstituted aminosulfonamide with the appropriate isocyanate in accordance with a modifict tion of the procedure of F. Kurzer [Journal of the Chemical Society (London), 1951, p. 1258], employing a strongly basic organic amine such as triethyl amine as a catalyst. Another preferred method of synthesis, which is even more desirable from the standpoint of yields, involves the reaction of an alkali metal or alkaline-earth metal salt of the N,N-disubstituted aminosulfonamide with either a 1,1,3-trisubstituted urea such as or with an aryl N-monosubstituted carbamate or a corresponding thiocarbamate such as R"XCONHR", where X is either oxygen or sulfur and R' is an aryl group such as phenyl, p-clorophenyl, p-bromophenyl, p-nitrophenyl, piacetylaiminophenyl, p-tolyl, p-anisyl, a-naphthyl, enaphthyl, and the like.

In accordance with a more specific embodiment of the present invention with respect to the preferred method of synthesis, an N,N-dilsubsti-mted aminosulfon'aimide salt of the foregoing type is reacted with a 1,1-diaryl-3(monosubstituted)urea or with an aryl N-monosubstituted carbamate or thiolcarbamate of the type previously referred to, as is illustrated below by the following two equations wherein M represents the cation of an alkali metal salt and X is either oxygen or sulfur as aforesaid:

This reaction is preferably conducted in the presence of a reaction-inert polar organic solvent. Typical organic solvents useful in this connection include the N,N-di(lower alkyl) substituted derivatives of lower aliphatic hydrocarbon carboxamides such as dimethylformamide, dimethylacetamide, diethylformamide, diethylacetamide, and so forth, as Well as lower dialkyl sulfoxides and sulfones such as dimethyl sulfoxide, diethyl sulfoxide, diisopropyl sulfoxide, di-n-propyl sulfoxide, dimethyl sulfone, diethyl sulfone, diisopropyl sulfoxide, dimethyl sulfone, diethyl sulfone, diisopropyl sulfone, di-n-propyl sulfone, and the like. It is desirable that the aforementioned solvent be present in sufficient amount to dissolve each of the previously referred to starting materials. In general, the reaction is carried out at a temperature that is in the range of from about C. to about 150 C. for a period of about one-half to about ten hours. Recovery of the desired product is most conveniently accomplished by first diluting the reaction solution with water and then adjusting the resulting aqueous solution to a pH that is at least above pH 8.0, followed by subsequent extraction of the basic aqueous solution with any water-immiscible solvent in order to remove minor amounts of unreacted or excess organic reagent that might possibly be present. Isolation of the desired N,N-disubstituted sulfamylurea from the basic aqueous layer is then effected by the addition thereto of a dilute aqueous acid solution, wherein the acid is present in sufficient amount to cause precipitation of the said sulfamylurea from solution.

In connection with a more detailed consideration of this preferred method of synthesis, the relative amounts of the agents employed is such that the molar ratio of the N,N- disubstituted aminosulfonamide salt to either the 1,1- diaryl-3-(monosubstituted)urea or aryl N-monosubstituted carbamate or thiolcarbamate is desirably in the preferred range of from about 1:1 to about 3:1, although substantially equimolar ratios will afford satisfactory results in this reaction. Nevertheless, an excess of the trisubstituted urea or aryl N-monosubstituted carbamate or thiolcarbamate is usually employed inasmuch as this not only aids in shifting the reaction equilibrium to the product side of the equation, but it is also advantageous in that the excess reagent is easily removed after completion of the reaction by means of the solvent extraction step previously referred to. Moreover, it is to be noted that the formation of the phenolic or aryl mercaptan byproducts is greatly enhanced by the overall basic character of the reaction mixture.

The starting materials necessary for the process of this invention are compounds which are either commercially available and/ or well-known in the prior art or else they are easily prepared in accordance with standard organic procedures previously described in the chemical literature. For instance, the N,N-disubstituted aminosulfonamides can either be commercially obtained or else they can be readily prepared by means of amm-onolysis of the corresponding sulfonyl chlorides. A compound of the latter type can, in turn, be either synthesized directly from the corresponding N,N-disubstituted amine by treatment of this compound with chlorosulfonic acid or it can be pre pared from the readily available N,N-disubstituted sulfamic acid sodium salt by the use of phosphorus pentachloride. The N,N-dibustituted aminosulfonamide so obtained is easily converted to the corresponding salts employed in this reaction by any number of standard and convenient procedures. For instance, the N,N-disubstituted aminosulfonamlde salt may be prepared by dissolving the corresponding sulfonamide in a solution or an aqueous suspension of an alkali metal or alkaline-earth metal base, such as sodium hydroxide, potassium hydroxide or calcium hydroxide or with a strong basic salt such as sodium carbonate, and then evaporating the resulting mixture to dryness. Alternatively, the N,N-disubstituted aminosulfonamide may be treated in an anhydrous alcoholicsolv nt medium at room temperature with at least an equival nt amount in moles of the desired alkali metal or alkalineearth metal alkoxide. The N,N-disubstituted aminosulfonamide salts so produced in this particular case are obtained in almost quantitative yields, and they can easily be isolated from the reaction solution by means of precipitation with a suitable anti-solvent, such as any relatively nonpolar organic solvent like diethyl ether, chloroform, and so forth. Incidentally, it is even possible to employ the free N,N-disubstituted aminosulfonamide as such by placing this compound in the usual solvent medium together with an alkali metal or alkaline-earth metal base and the 1,1- diaryl-3-(monosubstituted)urea or aryl N-monosubstitut ed carbamate or thiolcarbamate; in this case, the N,N-di substituted aminosulfonamide salt is first formed in situ and then reacts with one of the aforementioned starting materials.

The other major starting materials required for this re action, viz, the 1,1-diaryl-3-(monosubstituted)ureas and the aryl N-monosubstituted carbamates or thiolcarbamates, are all readily prepared from common organic reagents by employing standard procedures well-known in the art. For instance, the desired trisubstituted urea may be prepared in accordance with the general procedure described by Reudel in the Recueil des Travaux Chimiques des Pays-Bas, vol. 33, p, 64 (1914), which is illustrated below by the following equation wherein R' is the aryl group previously defined:

The two reactants stated in the above equation can easily be prepared by those skilled in the art from readily available starting materials in accordance with classical organic, procedures, such as those presented by Houben-Weyl in Die Methoden der Organischen Chemie, fourth edition, Verlag Georg Thieme (1952), vol. VIII, p. 117. In the; case of the aryl N-monosubstituted carbamate or thiolcarbamate type compounds, application of the well-known Schotten-Baumann technique is extremely suitable. his;

approach is illustrated below by means of the following equation wherein R is the aforementioned aryl group:

In connection with the synthesis of the above aryl chlorocarbonate, it is well known in the art that the chlorocarbonates in general are prepared by reacting the appropriate alcohol (phenol) with an equimolar amount of phosgene. In like manner, the corresponding chlorothiocarbonates are obtained by merely employing an appropriate aryl mercaptan (thiophenol) in place of the aforementioned hydroxy compound in this same reaction step.

Insofar as many of the N,N-disubstituted sulfamylureas of this invention are amphoteric compounds, they are capable of forming a wide variety of salts with various acids and bases. In practice, it is preferable to employ a strong acid or base for such purposes in view of the nature of the compound which is to be reacted. Although such salts must be pharmaceutically acceptable as the final products are solely intended for oral human consumption, it is possible to first isolate the desired sulfamylurea from the reaction mixture in the form of a pharmaceutically unacceptable salt and then subsequently convert the latter salt to the free amphoteric compound by treatment with either acid or base as the case may be; the free N,N-disubstituted sulfamylureas so obtained are then converted to a pharmaceutically acceptable salt thereof in the manner hereinafter indicated.

For instance, the acid and base salts of the sulfamylureas of this invention may be prepared by treating the amphoteric compound with a substantially equimolar amount of the chosen acid or base. The salt-formation step can be carried out in aqueous solution or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the solid salt is obtained. Alternatively, other recovery techniques are also applicable, such as freeze-drying when the solvent is water or the use of an anti-solvent in the case of an organic solution, e.g., the addition of diethylether to a methanolic solution of the product will cause precipitation of the salt from said solution to occur.

The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the N,N-disubstituted sulfamylureas of this invention which are basic in character are those which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroi-odide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, oxalate, succinate and maleate salts.

The bases which are used to prepare the pharmaceutically acceptable base salts of the N,N-disubstituted sulfamylureas of this invention are those which form nontoxic salts containing pharmaceutically acceptable cations, such as the alkali metal, alkaline-earth metal, am- ITIOIllH'ITL or water-soluble amine addition salts like the lower alkanolammonium and other base salts with organic amines which are compatible with the human system. Preferred members of this group include the sodium, potassium, magnesium, calcium and ethanolammonium salts. Some of these salts such as the sodium, magnesium and ethanolammonium salts are especially valuable in view of their water-solubility.

As previously mentioned, the N,N-disubstituted sulfamylurea compounds of this invention are all readily adapted to therapeutic use as oral diabetic agents. Fur- 'thermore, the toxicity of all these compounds has been found to be quite low, as aforesaid, when they are orally administered to mice in amounts which are sufiicient to achieve the desired therapeutic effects. Moreover, no other harmful pharmacological side eifects, such as crystalluria or kidney damage, have been observed to occur as a result of their administration. The hypoglycemic activity of these particular sulfamylureas is well illustrated by the series of tests hereinafter described, wherein intact male albino rats, each weighing approximately 150 grams are the experimental test animals employed for such purposes. The test animals are fasted approximately 20-24 hours prior to oral administration of the drug, and food is also withheld from them throughout the entire test period. Blood sugar levels are then determined as glucose on tail blood samples at two and four 'hour intervals in accordance with the micro method of Folin-Malmros, and groups of control and treated rats are sacrificed after each determination. The treated animals are given the sulfamylurea to be tested .at the mg./kg. dosage level; in each instance, the drug is suspended in a 1% carboxymethyl cellulose solution and the doses are administered in a volume of 4 Ink/kg. In each and every case, the control rats are given the vehicle alone, and the results obtained are expressed in terms of the percentage decrease in the fasting blood glucose value from the control pre-treatment value. In this connection, it is significant to note that the results obtained show that the compounds of the present invention exhibit a hypoglycemic effect which is comparable to that afforded by the known clinically useful antidiabetics in this field. Data illustrating the results of acute toxicity tests performed in conjunction with clinical testing program indicate that the herein described N,N-disubstituted sulfamylureas can all be considered to be relatively non-toxic in nature. Incidentally, microscopic examination of urine samples collected five and twenty-five hours after oral administration to such animals reveals the absence of any crystalluria or kidney damage as aforementioned.

In accordance with a method of treatment of the present invention, the hypoglycemically-active N,N-disubstituted sulfamylureas or one of their aforementioned pharmaceutically acceptable salts can be administered to the diabetically-afliicted subject via the oral route as previously indicated. In general, these compounds are most satisfactorily administered at a dosage level that is in the range of from about 75 mg. to about 2125 g. per day in the order of about one to .about five doses, although variations will necessarily occur depending upon the'weight of the subject being treated. However, a dosage level that is in the range of from about 1.0 mg. to about 30 mg. per kg. of body weight per day is most desirably employed in order to achieve effective results. Nevertheless, it is to be appreciated that still other variations may also occur in this respect, depending upon the severity of the patients condition and on its individual response to said hypoglycemic agent, as well as on the particular oral formulation and/ or compound chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful or deleterious side effects to ensue as a result of such administration, provided that such higher levels are first divided into several smaller doses that are to be administered throughout the day.

In connection with the use of the herein described N,N-disubstituted sulfamylureas or one of their aforementioned pharmaceutically acceptable salts in the oral treatment of diabetes, it is to be noted that they may be administered either alone or, and preferably, in combination with a pharmaceutically acceptable carrier, and that such administration can be carried out in single or multiple doses. More particularly, the orally-effective, hypoglycemically-active compounds of this invention may be administered in suitable dosage forms providing a unit dosage of the essential active ingredient in an amount that is preferably at least 1.0 mg. per dosage unit, although concentration levels in the range of from about 1.0 mg. to about 30 mg. per unit dosage per day may be employed to advantage. "For instance, dosage forms containing as high as 30 mg. of the active ingredient have been found to be particularly useful in combatting the hyperglycemia. caused by this disease in extremely severe cases. When larger doses of these hypoglycemic agents are to be used, it is preferable to administer two or more unit doses at various time intervals, adjusting, if necessary, the content of the antidiabetic agent per unit dosage form accordingly. Moreover, multiple dose treatment has indicated the feasibility, in some instances, of administering the sulfamylurea-containing compositions at periodic time intervals, e.g., by orally administering the hypoglycemic agent to an afllicted subject at a dosage level that is in the range of approximately 0.250-1.0 g. per day divided into about two to about five doses of equal strength that are to be administered throughout the day. Furthermore, optimum results can often be obtained in such cases by administering a higher dose initially, followed by the administration of a maintenance dose of therapy at a lower dosage level, e.g., 1.0 g. the first day, 0.6 g. the second day, 0.4 g. the third day, and 0.2 g. per day thereafter.

It is apparent from the foregoing that the hypoglycemically-active compounds of this invention can be administered in a wide variety of different oral dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of capsules, tablets, lozenges, troches, hard candies, aqueous suspensions, elixirs, etc. Such carriers include solid diluents or fillers, aqueous media, various non-toxic organic solvents, and the like. Moreover, these oral pharmaceutical compositions may be sweetened and/ or flavored by means of various agents of the type commonly employed for such a purpose. In general, the sulfamylureas of this invention are present in such oral dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage previously indicated.

For purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as alignic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, gelatin and acacia; in addition, lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft elastic and hard-shelled gelatin capsules; preferred materials in this connection would also include polyethylene glycol, propylene glycol and glycerin as they not only may be used in this particular type of pharmaceutical dosage form as diluents, but also as plasticizing agents serving to protect the capsule against any leakage that might possibly occur due to denaturation of the gelatin protein. When aqueous suspensions and/ or elixirs are desired for oral administration, the hypoglycemically-active ingredient may be combined with various sweetening and flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

This invention is further illustrated by the following examples, which are not to be construed as imposing any limitations on the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications and equivalents thereof which readily suggest themselves to those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.

EXAMPLE I A suspension consisting of 2.42 g. (0.013 mole) of the monosodiurn salt of N-piperidinesulfonamide and 5.07 g. (0.016 mole) of 1,1-diphenyl-3-(p-dimethylaminophenyl) urea in 20 ml, of anhydrous dimethylformamide was heated on a steam bath for approximately 16 hours. At

the end of this period, the reaction mixture was cooled to room temperature and diluted with ml. of water. The resulting aqueous solution was then made strongly alkaline with 10% aqueous sodium hydroxide, washed by means of extraction with several portions of diethyl ether and filtered. The filtrate so obtained was then slowly poured into a chilled aqueous solution containing an excess of hydrochloric acid with constant agitation being maintained throughout this step. The crystalline material which precipitated at this point was recovered by means of filtration, washed well with cold water and subsequently air-dried. In this manner, there was obtained l-(N- piperidinesulfonyl) 3 (p dimethylaminophenyl)urea, which after one recrystallization from benzene melted at 157-158 C.

Analysis.-Calcd. for C H N O S: C, 51.51; H, 6.80; N, 17.17. Found: C, 52.84; H, 6.93; N, 17.90.

EXAMPLE II A solution consisting of 3.06 g. (0.036 mole) of npropylisocyanate dissolved in 12 ml. of anhydrous dimethylformamide was added to a chilled suspension of 4.92 g. (0.03 mole) of N-piperidinesulfonamide in 18 ml. of anhydrous triethylamine. The reaction mixture was then stirred at room temperature for approximately 16 hours and finally poured slowly into 500 ml. of chilled 50% aqueous acetic acid during the course of about a one-half hour period with constant agitation being maintained throughout this step. The solid material which precipitated from the solution at this point was recovered by means of filtration and subsequently washed with cold water. The product so obtained was then dissolved in 5% aqueous sodium carbonate and the resulting solution was immediately filtered. Isolation of the desired compound was then effected by slowly pouring the filtrate into 500 ml. of chilled 20% aqueous acetic acid, whereupon precipitation of the crystalline material occurred. The precipitate was then filtered, washed well with cold water and subsequently air-dried to constant weight. In this manner, there was obtained l-(N-piperidinesulfonyl)-3- (n-propyl)urea, M.P. 144-145" C.

Analysis.-Calcd. for C H N O S: C, 43.36; H, 7.68; N, 16.90. Found: C, 43.19; H, 7.56; N, 16.74.

EXAMPLE III The procedures described in Examples I (Method A) and II (Method B) are repeated using other starting materials and reagents in place of those specifically mentioned therein. For the sake of time and convenience and in order to avoid any unnecessary repetition of experimental detail, these two general procedures are outlined below as follows:

Method A.To 0.013 mole of the sodium salt of the N,N-disubstituted aminosulfonamide suspended in 20 ml. of anhydrous dimethylformamide there is added 0.016 mole of the appropriate N,N-diphenylurea derivative. The reaction mixture is then heated on a steam bath overnight for approximately 16 hours, cooled to room temperature and diluted with 125 ml. of water. After extraction of the resulting solution with diethyl ether and subsequent acidification of the aqueous layer, there is obtained the desired N,N-disubstituted sulfamylurea in the form of a crystalline precipitate.

Method B.-To 0.03 mole of the N,N-disubstituted aminosulfonamide dissolved in 18 ml. of anhydrous triethylamine there is added 0.036 mole of the appropriate isocyanate dissolved in 12 ml. of anhydrous dimethylformamide. The reaction mixture is allowed to stir at room temperature for approximately 16 hours (overnight) and then diluted with ml. of water. Isolation of the desired product from said aqueous solution is then achieved in the same manner as that described in Method A. A1- ternatively, the product may also be isolated from the stirred reaction mixture by employing the procedure described in Example 11, wherein it is first slowly poured l- ['N- (2-met-hyl-2-n-propylmorpholine) sulfonyl1- 3-cyclopentylurea l- [N- 2,2-diethyl-morpholine sulfonyl] -3- (n-hexyl urea l- [N- (Z-ethylthiamonpholine sulfonyl] -3 cyclobutylurea l-[N (Sn-prOpylthiamorpholine) sulfonyl1-3 (n-hep-tyl urea l- [N- 2,2- 'iethyl-thiamorpholine )sulfonyl] -3- (pdimethyla-minophenyl urea l- [N-2-methyl-2- n-propyl) thiamorpholine) sulfonyl] 3 cyclop entylu-rea l- [N-2,2-dimethylthiamohpholine sulfonyl] 3-cyclohexylurea l- [N ,N-dimethylaminosulfonyl -3-cyclooctylurea l- N-rnethyl-N-cyclhexylaminosulfonyl] -3- cyclopentylurea EXAMPLE V The non-toxic acid additon salts of the atmospheric N,N-di-substitu-ted sulfa-mylureas of this invention are prepared by either one of .two general methods. In the case of the hydrohalide salts, such as the hydrochloride, hyd'robromide and hydriodide, thus is accomplished by first dissolving the am'photeric sulfamylurea compound in absolute ether followed by the introduction of the appropriate hydrogen halide gas into the solution until saturation of said solution with respect to the gas is complete, whereupon the desired salt precipitates from solution. The crystalline product so obtained is then recrystallized from acetone to yield the pure hydrohalide salt. In this manner, equimolar amounts of l-(N-piperidinesultonyh- 3(p-di-methylaminophenyl)urea and hydrogen chloride react to form the corresponding acid addition salt.

In the case of the corresponding nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, oxalate, succinate, maleate, glu-conate and saccharate salts, the respective acid and the amphoteric sulfamylurea are both separately dissolved in ethanol and the two solutions are then mixed, followed by the addition of diethyl ether to the resulting reaction mixture in order to effect precipitation of the desired acid addition salt from said solution.

EXAMPLE VI An N,N-disubstituted sulfamylurea is dissolved in an equim-olar amount of a aqueous sodium hydroxide solution at a temperature of approximately 40 C. The resulting solution is then adjusted to a pH of 7.5 by the addition of small amounts of either the sulfamylurea or 15% aqueous sodium hydroxide solution as the case may be. The so-adjust-ed solution is then filtered and allowed to stand for some time in an ice-box until crystallization of the desired salt occurs, e.g., the sodium salt of l-(N- piperidinesulfonyl)-3-(n-propyl)urea if the latter compound is the particular sulfonylurea employed as starting material in this example.

In like manner, the use of lithium hydroxide in place of the sodium hydroxide employed above afiords the corresponding lithium salts.

EXAMPLE VII The procedure described in Example VI is initially followed except that the concentration of the aqueous sodium hydroxide employed is such that it is sufficient to afford a solution of the sulfonylurea compound. This solution is then heated to 80 C. and filtered, and the resulting filtrate treated with twice the equimolar amount of a 15% aqueous potassium carbonate solution at this same temperature. After cooling the resultant reaction mixture to room temperature, crystallization of the so prepared potassium salt of the particular sulfamylurea employed as starting material soon occurs.

14 EXAMPLE VIII An N,N-disubstituted sulfamylurea prepared as described in Examples I-IV is dissolved in an equimolar amount of triethanolamine and suflicient water to aiford a 50% solution of said sulfamylurea. This solution is then heated to approximately 60 C., filtered while hot and the resulting filtrate poured into an aqueous calcium chloride solution containing g. of calcium chloride dissolved in 100 ml. of water and whose temperature is also at 60 C. On cooling to room temperature and further standing for several hours, the calcium salt of the particular sulfamylurea employed as starting material crystallizes from solution. In this way, the calcium salt of l-(N-morpholine-sulfonyl)-3-cyclohexylurea is obtained when the latter sulfamylurea is the particular compound employed as starting material.

In like manner, the strontium and barium salts of each of the N,N-disubstituted sulfamylureas of this invention are also each individually obtained in accordance with this very same reaction procedure by merely substituting the appropriate alkaline-earth metal chloride, i.e., either strontium chloride or barium chloride as the case may be in place of the calcium chloride used above.

EXAMPLE IX An N,N-disubstituted sulfamylurea prepared as described in Examples I-IV is dissolved in 2 ml. of 10 N ammonium hydroxide at 50 C. The resulting solution is filtered immediately, and then allowed to cool to room temperature and to further stand at this point for several hours until crystallization occurs. In this manner, white crystals of the ammonium salt of 1-(N,N-diethylaminosulfonyl)-3 (p-dimethylaminophenyl)urea are obtained from solution as a crystalline precipitate when said sulfamylurea is the particular starting material employed in this example.

EXAMPLE X Equimolar amounts of an N,N-disubsti'tuted sulfamylurea such as that used in Example IX and monoethanolamine are dissolved in a sufficient amount of water at 58 C. to aiford a 20% solution of the free sulfonylurea compound. Upon evaporation of the so prepared aqueous solution under reduced pressure at 40 C., there is obtained a solid residual material which is the monoethanolammonium salt of the desired compound.

In like manner, each of the other N,N-disubstituted sulfamylureas of this invention individually form salts with diethanolamine, triethanolamine, ethylene diamine, diethylamine, triethylamine and pyridine by contacting one of the aforesaid sulfonylureas with the appropriate lower alkanolamine or lower alkylamine as the case may be in accordance with this very same reaction procedure.

'EXAMPLE XI A dry solid pharmaceutical composition is prepared by blending the following materials in the proportions by Weight specified below:

l-(N-piperidinesulfonyl) -3-(p-dimethylaminophenyl) urea 50 Sodium citrate 25 Alginic acid 10 Polyvinylpyrrolidone l0 Magnesium stearate 5 After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such size that it contains 100 mg. of the active ingredient.

EXAMPLE XII A dry solid pharmaceutical composition is prepared by combining the following materials in the proportions by weight specified below:

1-( N-piperidinesulfonyl)-'3-( n-propyl)urea 50 Calcium carbonate 20 Polyethylene glycol (average molecular weight,

The dried solid mixture so prepared is thoroughly agitated so as to obtain a powdered product that is completely uniform. Soft elastic and hard-shelled gelatin capsules containing this pharmaceutical composition are then prepared, employing a suflicient quantity of material so as to furnish 250 mg. of the active ingredient in each capsule.

EXAMPLE XIII A dilute aqueous-levulose solution of the calcium salt of 1-(N-morpholino-sulfonyl)-3-cyclohexylurea is prepared by dissolving said salt in a 50% aqueous levulose solution in such amount that each ml. of solution contains 75 mg. of the sulfonylurea calculated on the basis of its free sulfonylurea form. The so obtained solution can then be sweetened and/ or flavored as desired in order to mask the taste of the essential active ingredient, and rendered more viscous by the addition of the appropriate amount of methyl cellulose.

EXAMPLE XIV A dry solid pharmaceutical composition is prepared by blending the following materials in the proportions by weight specified below:

1-[N-(4,4-dimethylpiperidine)-sulfony1]-3-cycloheptylurea Sodium citrate 25 Alginic acid 10 Polyvinylpyrrolidone 10 Magnesium stearate 5 After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being the pharmaceutical acceptable alkali metal salts, alkaline earth-metal salts, ammonium salts and water-soluble amine addition salts thereof; the pharmaceutically acceptable acid addition salts of those compounds wherein R" is p-di(lower aIkyD-aminophenyl; and the pharmaceutically acceptable acid addition salts of those compounds wherein Z represents the atoms completing the piperazino radical and the N'-methyl derivative thereof wherein Z represents the atoms completing a radical chosen from the group consisting of pyrroidino, tetrahydropyridino, piperidino, C-(lower a1kyl)-piperidino, 4,4-di(lower a1ky1)piperidino, 4,4-tetramethylenepiperidino, 4,4-pentamethylenepiperidino, homopiperidino, piperazino, N-methylpiperazino, morpholino, C-(lower alky1)morpholino, thiamorpholino, C-(lower alkyl)-thiamorpholino, and 1,2,3,4-tetraphydroisoquinolino; and R" is a member selected from the group consisting of alkyl having from two to five carbon atoms, cyclopropylmethyl, cycloalkyl having from five to eight carbon atoms and p-dimethylaminophenyl.

6. 1-(N-piperidinesulfonyl)-3-(n-propyl)urea.

7. 1-(N-morpholinesulfonyl)-3-cyclooctylurea.

8. 1 [N (4,4-pentamethylenepiperidine)sulfonyl]-3- cycloheptylurea.

9. 1 [N (4-methylpiperidine)sulfonyl1-3-cycoperityl urea.

10. l-(N-piperidinesulfonyl)-3-cyclohexylurea.

11. 1 [N (4,4-dimethylpiperidine)sulfonyl]-3-cycloheptylurea. v

12. 1 (N piperidinesulfonyl)-3-(p-dimethylaminophenyl) urea.

References Cited by the Examiner UNITED STATES PATENTS 3,108,098 10/ 1963 McManus 260-247.1

FOREIGN PATENTS 993,465 7/1951 France.

OTHER REFERENCES Petersen: Deutsche Chemische Gesellschaft (Berichte), vol. 83: pages 552558 (1950).

NICHOLAS S. RIZZO, Primary Examiner.

WALTER A. MODANCE, Examiner.

JOSEPH W. MOLASKY, JOSE TOVAR,

Assistant Examiners.

Claims

5. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE STRUCTURAL FORMULA: