US3245982A

US3245982A - Sulfamylsemicarbazides

Info

Publication number: US3245982A
Application number: US182972A
Authority: US
Inventors: James M Mcmanus
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1962-03-27
Filing date: 1962-03-27
Publication date: 1966-04-12
Anticipated expiration: 1983-04-12

Description

United States Patent ()filice M 3,245,982 Patented Apr. .12, 1966 3,245,982 SULFAMYLSEMECARBAZIDES James M. MclVianus, Uncasviile, Comm, assignor to Chas. Pfizer 8: C0., lire, New York, N.Y., a corporation of Delaware No Drawing. Filed Mar. 27, 1962, Ser. No. 182,972 13 Claims. (Cl. 260-239) This application is a continuation-in-part of Serial No. 133,340, filed August 23, 1961, now abandoned.

T his invention relates to new and useful sulfamylsemicarbazides which are orally eiiective hypoglycemic agents. More particularly, it is concerned with various substituted sulfamylsemicarbazides 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 of said sultamylsemicarbazides or one of their pharmaceutically acceptable salts. There is also included within the scope of this invention pharmaceutical compositions containing these sulfa-mylsemicarbazides as the essential active ingredient together with diluent amounts of pharmaceutically acceptable inert carriers.

The compounds of this invention comprise:

and the pharmaceutically acceptable salts thereof; wherein R andR when considered separately are selected from the group consisting of (1) Hydrogen provided that when one of said R and R substituents is hydrogen, the other is a member selected from the group consisting of lower alkyl, lower alkenyl, trifiuoromethyl-lower alkyl, trifiuorornethyl-lower alkenyl, lower alkoxy-lower alkyl and lower alkoxylower alkenyl;

(2) Lower alkyl;

(3) Lower alkenyl;

(4) T rifiuoromethyl-lower alkyl;

(5) Trifiuoromethyl-lower alkenyl;

(6) Lower alkoxy-lower alkyl;

(7) Lower alkoxy-lower alkenyl;

(8) Cycloalkyl having from 4 to 8 carbon atoms;

(9) Bicycloalkyl having from 7 to 9 carbon atoms;

R, and R when taken together with the nitrogen atom to which they are attached form a nitrogen heterocycl-ic ring selected from the group consisting of (1) Pyrrolidino,

(2 Tetrahydropyridino,

(3) Piperidino,

(4) 4-lower alkyl piperidino,

(5) 4-lower alkoxy piperidino,

(6) C-mono-lower alkyl piperidino,

(7) 4,4-di-lower alkyl piperidino,

(8) 4-lower alkyl-4-lower alkoxy piperidino,

(9) 4,4-tetramethylene piperidino,

(l0) 4,4-pentamethylene piperidino,

(1 1 4,4-tetramethylene oxypipe-ridino,

(l2) 4,4-pentamethylene oxypiperidino,

(13) Homopiperidino,

(l4) Piperazino,

(15) N-lower alkylpiperazino,

(l6) N'-lower acyl piperazino,

(17) Morpholino,

( 18) Thiamorpholino, and

(19) C-mono-lower alkyl thiamorpholino;

R and R when considered separately are selected from the group consisting of (1) Hydrogen provided when one of said R and R substituents is hydrogen, the other is selected from the group consisting of lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, phenyl, lower alkyl phenyl, lower alkoxy phenyl, chlorophenyl, bromophenyl and trifiuoromethylphenyl,

(2) Phenyl, l

(3) Lower alkyl phenyl,

(4) Lower alkoxy phenyl,

(5) Chlorophenyl,

(6) Bromophenyl,

.(7) Trifluoromethylphenyl,

(8) Lower alkyl,

(9) Lower alkenyl,

(10) Lower alkoxy lower alkyl,

(11) Lower alkoxy lower alkenyl,

(12 Cycloalkyl having from 4 to 7 carbon atoms and R and R when taken together with the nitrogen atom to which they are attached form a ring selected from the group consisting of 1) Piperidino,

(2) Homopiperidino,

(3) Morpholino,

(4) Thiamorpholino In the above, lower alkyl, lower alkenyl and lower alkoxy contain from one to four carbon atoms.

' It is also intended to include within the scope of this invention non-toxic acid addition, alkali metal, alkalineearth metal, and water-soluble amine addition salts of the compounds of the present invention.

Among the typical member compounds of this series are such novel substituted sulfamylsemicarbazides as 4-(4- morpholinosulfonyl)-1,1-hexamethylene"semicarbazide, 4- (4,4 tetramethylene 1 piperidinosulfonyl) 1,1 pentamethylene semicarbazide; 4 (N methyl N ethylaminosulfonyl) 1 methyl 1 (n propyl)semicarbazide; 4 (4,4 pentamethylene 1 piperidinosulfonyl)-1,1-hexamethylene semicarbazide; and 4-'(4-morpholinosulfonyl) -"1 (p' trifiuoromethylphenyl) 1- ethyl semicarbazide.

The advantages aitorded by the sulfamylsemicarbazides of this invention are manifold; they may be administered orally, thus eliminating the parenteral route which is often painful and irritating, and they lower blood sugar levels to an effective degree in animals, including humans, for .a sustained period of time.

General preparative methods which are applicable to the synthesis of these compounds involve the'reac'tion of aryl-N,N-disubstituted carbazate wi'th'an alkali metal or an alkaline-earth metal salt of the appropriate N,N-disubstituted amino sulfonamide; the reaction of an:N,N- disubstituted aminosulfonyliso'cyanate with the appropriate N,N-disubstituted hydrazine, or the reaction of N,N- disubstituted aminosulfonyl carbamate with the appropriate N,N-disubstituted-hydrazine. Still another .method of preparing these compounds is the reaction of a 4,4-(diphenyl)-1,l-disubstituted semicarbazidewith an alkali metal or alkaline earth metal salt of the appropriate aminosulfonarnide. I t I One of the preferred synthetic routes, involves the reaction of a 4,4-(diphenyl)-l,1-disubstituted semicarbazide with the appropriate aminosulfonamide. This reaction can be represented by the following equation:

I 2NSOzNHM NCONHNR R wherein R R R and R are defined as aforementioned; and M represents the cation of alkali metal or alkaline earth metal.

This reaction is preferably conducted in the presence of an inert polar organic solvent. Typical organic solvents which may be employed are the N,N-di(lower alkyl) substituted derivatives of lower aliphatic hydrocarbon carboxamides such as dimethylformamide, diniethylacetamide, diethylformamide, and so forth, as well as lower dialkyl sulfoxides and sulfones such as dimethyl sulfoxide, diethyl sulfoxide and the like.

It is desirable that the aforementioned solvent be present in sufiicient amounts to dissolve ach of the previously cited starting materials which are present in substantially equimolar ratios. In general, the reaction is preferably carried out within .the temperature range of about 20 C. to 150 C. for a period of about one-half to thirty 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 between 6 and 7,,with a dilute aqueous solution of a mineral acid, such as hydrochloric, phosphoric or sulfuric acid. When a suflicient amount of acid is added, precipitation occurs, and separation of the filtrate may be effected by filtration or decantation. Alternatively, if the reaction product is not precipitated by acid, it is extracted from the acidic aqueous solution with a non-polar solvent. After filtration to remove und-issolved material, the solvent is removed by evaporation and the resulting product obtained.

Another preferred method for the synthesis of certain compounds of this invention involves the reaction of an alkali metal salt of an N,N-disubstituted aminosulfonamide with the appropriate 1,1-(disubstituted)-3-substituted carbazate. This reaction can be represented by the following equation:

wherein R R and M are defined as aforesaid; R is phenyl or p-nitrophenyl; and R and R when considered separately are selected from the group consisting of (1) Hydrogen provided that when one of said R and R substituents is hydrogen, the other is selected from the group consisting of phenyl, lower alkylpheny-l, lower alkoxyphenyl, chlorophenyl, bromophenyl, and trifluoromethylphenyl, (2) Phenyl, (3) Lower alkylphenyl, (4) Lower alkoxyphenyl, (5) Chlorophenyl, (6) Bromophenyl, and (7) Trifiuoromethylphenyl.

The solvents, temperatures and procedures employed in this preparative method are as described in the aforementioned reaction.

Still another preferred procedure for the synthesis of the compounds of this invention involves the reaction of an N,N-disubstituted aminosulfonyl carbamate with an 41. appropriate N,N-disubstituted hydrazine. This reaction can be represented by the (following equation:

R RgNSO NHCONHNR R wherein R R R R and M are defined as described in the first procedure; and R is phenyl or p-nitrophenyl.

This reaction is preferably conducted in the presence of an inert polar, organic solvent. It is desirable that said solvent be present in sufficient quantities to dissolve each of the reactants which are present in substantially equimolar quantities. In general, tthis reaction is conducted from about 20 C. to about C. for a period of about one-half to thirty hours. The desired product may be recovered by evaporation of the solvent and dissolving the residue in an aqueous solution of a mineral acid, such as hydrochloric, phosphoric or sulfuric acid. This solution is extracted with an inert, polar, water immiscible organic solvent, such as ether. After separating the immiscible solvents, the aqueous portion is adjusted to a pH that is between 6 and 7 with an aqueous alkaline solution, e.g., a 10% sodium hydroxide solution, and the precipitated product is separated by filtration or decantation.

The starting materials necessary for the processes of this invention are compounds which are either commercially available or are well known in the prior art. For instance, the N,-N-disubstituted aminosul fonamides can either be commercially obtained or else they can be readily prepared by means of ammonolysis of the corresponding sulfamyl chlorides. A compound of the latter type can, in turn, be synthesized either directly from the corresponding N,N-disubstituted amine by treating this compound with sulfuryl chloride. The N,N-disubstituted aminosulfonamide so obtained is easily converted to the corresponding salts employed in this reaction by any number of standard and conveninet procedures. For example, the N, N-disubstituted taminosulfonamide 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 and then evaporating the resulting mixture to dryness. 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 carbazate or the semicarbazide; in these cases, the N,N-disubstituted aminosulfonamide salt is first formed in situ and then reacts with one of the aforementioned starting materials.

Another starting material required for one of the processes of this invention, aryl-N,N-disubstituted carbazate, can either be commercially obtained or it can be readily prepared from common organic reagents by employing standard procedures well known in the art. For example, the aryl-N,N-disubstituted carbazate may be synthesized by the reaction of a hydrazino compound with a chlorocanbon-ate. This reaction can be represented by the following equation:

wherein R, R and R are defined as aforementioned. In connection with the synthesis of the above aryl-N,N-disubstituted car-bazate, the chlorocarbonates may be prepared by reacting the appropriate alcohol with an equimolar amount of phosgene.

Insofar as the sulfa-mylsemicarb-azides of this invention are amphoteric compounds, they are capable of forming a wide variety of salts with acids and bases. The acids or bases which are employed are those which form nontoxic salts containing pharmaceutically acceptable anions or cations. For instance, acidic salts which may be employed are the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate and phosphate or acid phosphate. The basic salts which may be used include the alkali metal, alkaline-earth metal, and the water soluble amine addition salts. Preferred members of the basic salts include the sodium, potassium, magnesium, calcium and ethanolammonium salts.

In connection with the use of the previously described sulfamylsemicarbazides or one of their pharaceutically acceptable salts as oral hypoglycemic agents, they may be administered alone or, preferably in combination with a pharaceutically acceptable carrier, and as such can be given in single or multiple doses. More particularly, the orally effective, hypoglycemic compounds of this invention may be administered in suitable dosage forms prov-iding a dosage unit of the active ingredient in an amount that is adjusted to the particular needs of the individual. When large doses of these hypoglycemic agents are to. be used, it is preferable to administer two or more doses at various time intervals, as selected by the attending physician.

These hypoglycemic compounds may be administered in a wide variety of oral formulations, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of capsules, tablets,.lozenges, troches, hard candies, suspensions, solutions and elixers. The carriers employed include solid dil-uents, aqueous vehicles, various non-toxic organic solvents, and the like. Moreover, these oral pharmaceutical compositions may be sweetened and flavored by means of various agents of the type commonly employed for such a purpose. In general, the sulfamylse-micarbazides of this invention are present in 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 sufiicient to provide the desired dosage.

For purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalciurn phosphate may be employed along with various disintegrants such as alginic 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 tableting 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 beused in this particular type of phermaceutical, 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 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 suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various 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 the scope of the appended claims.

Example I To a solution of 4.80 -g. (0.02 mole) of vphenyl-lphenyl-l-methyl carbazate' in 40ml. of dimethylformamide there was added, with stirring 4.0 g. (0.02 mole) of the monosodium salt of 4-methyl-l-sulfamyl piperidine. The monosodium salt of 4-methyl-l-su1famyl piperidine ml. of water.

6. slowly dissolved and, upon complete dissolution, the stirring was continued at room temperature for approximately 16 hours. Thereafter, the solution was slowly poured into 250 m1. of water and the resulting solution was acidified to litmus with a 6 N aqueous solution of hydrochloric acid. Upon acidification, precipitation occurred and separation waseffected' by filtration. The crystalline material was washed with 200 ml. of cold water and subsequently air dried. In this manner, there was obtained 4-(4-methyl-l-piperidinosul fonyl) 1 methyl 1 phenyl semicarba'zide, which after two recrystallizations from ethanol'melted at 177-178 C.

Analysis-Calcd. for C H N O S: C, 51.51; H, 6.80; N, 17.17. Found: C, 51.47; H, 6.65; N, 16.91.

, Example II To a solution of 4.8. g. (0.02 mole) of phenyl-l-phenyll-rnethyl carbazate in 40 ml. of dimethylacetamide there was'added 4.0 g. (0.02 mole) of the sodium salt of hexamethylene'aminosulfonamide and the resulting solution was-agitated at room temperature for approximately 16 hours. Finally, the solution was slowly poured into 250 The resulting mixture was acidified with 6 N aqueous solution of" hydrochloric acid until the precipita-te which developedupon acidification was complete. The precipitate was separated by filtration and air-dried. This material was subsequently extracted with ether and the undissolived material was removed by filtration. The ether was removed by evaporation and the resulting crystalline material was 4-(l hexamethyleneaminosulfonyl)- l-methyl-l-phenylsemicarbazide, which upon recrystallization from ethanol melted at 162163 C.

Analysis.Calcd. for C H O N S: C, 51.51; H, 6.80; N, 17.17. Found:.C,51.32; H, 6.65; N, 17.03.

Example III To 25 ml. of ether, there were added 2.86 g. (0.01 mole) of. phenyl-l piperidine sulfonyl carbamate and 2.0 g. (0.02 mole) of l-a-rnino piperidine. This mixture was heated at. reflux temperatures for 6 hours. Thereafter, the ether was removed by employing a stream of nitrogen and the residue dissolved in a 6N hydrochloric acid solution. The solution was extracted with ether, separated, and the aqueous layer adjusted to a pH of 6.5 with a 10% aqueous sodium hydroxide solution. The precipitate H which formed was filtered and air-dried. Recrystallization from 25 ml. of ether gave 400 mg. of 4-(1-p-iperidinosulfonyl)-1,1 pentamethy1ene semicarbazide which had a melting point of 131.5-132 C. 1

A'nfllysis-Calzd. for C H O N S: C, 45.4; H, 7.6; N, 19.3. Found: C, 45.5; H, 7.5; N, 19.5.

Example IV A mixture of 2.27 g. (0.012 mole) of the sodium salt of N-sulfamyl piperidine and 5.8 g. (0.02 mole) of 4,4- diphenyl-l,l-pentamethylene semicanbazide was heated in 40 ml. of dime-thylformamide on a steam bath for 16 hours. The resulting pale yellow solution was added to a mixture of 200 ml. of water and 200 ml. of ether. The

, solid, which developed at the interface of the two immiscible liquids was filtered and suspended in 50 ml. of water. This'suspension was slowly adjusted to a pH of 6.5 to 7 by the gradual addition of a 3 N hydrochloric acid solution. After the solid had been filtered, air-dried and recrystallized from ether, there was obtained 1.75 g. of 4-(1- piperidinesulfony1)-l,l penta-methylene semicarbazide which had a melting point of 131.5 to 132 C.

Comparing this material with the material obtained in Example HI by the use of mixed melting points and infrared spectrums, they were shown to be identical.

Example V The procedure described in Example IV was'repeated using other starting materials and reagents in place of those specifically mentioned. In this manner, the compounds listed below were obtained.

Analyses Sulfamylsemicarbazide Ml. C.) (lalcd. Found C H N C H N 4-(4-r1;1orpi0linesulfonyl)-1,1-pentamethylenesemi- 153-1535 41.1 6.9 19.2 41.1 6.7 19.3-

03.! 321 e. 4-(4,4-1;etramethylene-l-piperidinesulfonyl)-1,1-penta- 154.5-155 52.3 8.2 16.3 52.7 8.3 16.6

methylene semicarbazide. 4-(4-methyl-1-piperidinesulfonyl)-1,1-pentamethylene 162-1625 47.4 8.0 18.4 47.9 8.0 18.6

semicarbazlde. 4-(4-thiomorpholinesulfonyl)-1,1-pentamethylene 150.5-152 38.9 6.5 18.2 38.9 6.6 18.1

semicarbazide. 4-1()1-pi1eridinesulfonyl)-1,1-hexamethylene semiear- 157.5 dec 47.4 8.0 18.4 47.6 7.9 18.1

221 e. 4-(4,4-tetramethylene-1-piperidinesulfonyl)-1,1-hexa- 155.5 dec 53.6 8.4 15.6 53.7 8.5 15.3

methyl semicarbazide. 4-%;Lmgrpholinesulfonyl)-1,1-hexamethylene semicar- 154 dec 43.1 7.2 18.3 43.1 7.1 18.6

3Z1 8- 4-(4,4-dirnethyl-l-piperidinesulfonyl)-1,1-penta- 153.5 dec 49.0 8.2 17.6 49.0 8.0 17.5

methylene semicarbazide. 4-(4,4-dimethyl-l-piperidinesulfonyl)-1,1-hexamethyl- 146 dec 50.6 8.5 16.9 50.3 8.4 16.8

ene semicarbazide. 4(4,4-diethyl-l-piperidinesulfonyl)-1,1-hexamethyl- 139.5 dee 53.3 9.0 15.5 53.0 8.7 15.2

ene semicarbazi e. 4-(4-ethyl-4-methyl-l-piperidinesulfonyl)-1,1-hexaF 135.5 dec 52.0 8.7 16.2 52.3 8.6 15.8

methylene semicarbazide. 4-(1-acetyl-4-piperazinesulfonyl)-1,l-hexamethylene 172 dec 44.9 7.3 20.2 44.9 7.2 20.1

semicarbazide. 4-(4-methyl-l-piperidinesulfonyl)-1,1-hexamethylene 148 dec 49.0 8.2 17.6 49.1 8.0 17.0

semicarbazide. 4-(4meth0xy-1-piperidinesulfonyl)-1,1-hexamethyl- 132-133 46.7 7.8 16.8 46.8 7.8 16.5

ene semicarbazide. 4-(4,4-pentamethylene-l-piperidinesulfonyl)-1,1-hexa- 152 dec 54.8 8.7 15.0 55.0 8.7 15.1

methylene semicarbazide. 4-(1-isobut;yroyl-4-piperazinesulfonyl)-1,l-hexa- 138 dee 48.0 7.8 18.7 47.5 7.2 18.5

methylene semicarbazide.

Example VI water. The resulting aqueous solution is made alkaline 'th aqueous sodium hydroxide washed by means The procedure employed in Example IV was again re- W peated with still other starting materials and reagents to f gg r t 5 1 ig polrtloils i i l ig gffi sd prepare other sulfamyl semicarbazides. The compounds e a e 0 Is i S OW y p0 e 1 Obtained in this manner are H Ste d below aqueous solution containing an excess of hydrochlor c acid. The crystalline material which precipitated is re- 4-[4-(n-propyl)-1-piperidinosulfonyl] 1,1 [bis(ethylcovered by filtration and is 4(n-piperidinosulfonyl)-1- ene) oxa] semicarb azide methyl-l-phenyl semlcarbazide. 4-[4,4-dirnethyl-l-piperidinosulfonyl] 1,1 [bis(ethy1- 40 ene)thia]semicarbazide Example VIII 4-(l-pyrrolidinosulfonyl) 1,1 [bis(ethylene)oxa]semi- The non-toxic acid addition salts of amphoteric sulcarbazide famylsem-icarbazides are prepared by dissolving the acid 4-(3-tetrahydro-l-pyridinosulfonyl)-1,1 pentamethylene of the corresponding hydrochloride, nitrate, sulface and semicarbazide phosphate salt and the respective sulfamylsemicarbazide 4-[4-ethyl-4-methoxyl 1 piperidrnosulfonyl] 1,1 penseparately in ethanol. The two solutions are then mixed, tamethylene semicarbazide followed by the addition of acetone to the reaction mix- 4-[4-e-thoxy-l-piperidinosulfonyl] 1,1 hexamethylene ture in order to effect precipitation of the desired acid semicarbazide addition salt. I 4-[2-methyl-4-thiamorpholinosulfonyl]-1,1 pentamethyl- In this manner, equnnolar amounts of 4 -(4-methyl-1- ene semicarbazide piperidinosul-fonyl)-1-methyl-1 (p bromophenyDsemr- 4 (N,N dimethylaminosulfonyl)-1,1-[1-bis(ethylene)- carbazide and hydrochloric acid react to form the coroxa]semicarbazide responding acid addition salt. 4 (N methyl N propyleneaminosulfonyl)-1-ethyl-1- Example IX I (isopropyl) semicarbazide 5 4-(4-morpholinosulfonyl)-1-methyl 1 cyclohexyl semi- A sulfamyl semicarbazide is dissolved in an equimolar carbazide amount of a 1% aqueous sodium hydroxide solution at 4-(N-cyc1opentyl N methylaminosulfonyl) 1 ethoxya temperature of approximately 27 C. The resulting eihyL (isobutynsemicarbazide solution is then adjusted to a pH of 9.0 by the addition of 4-(N-dimethylaminosulfonyl)-1,1-diethyl semicarbazide small amounts O15 either the sulfarnylsemicarbazide or 4 (N methy1 N e,thy1aminosulfonyl) 1 1 15% aqueous sodium hydroxide solution as the case may propynsemicarbazide be. This solution is cooled and allowed to stand until 1 Semi crystallization of the desired salt occurs, e.g. the sodium 4 gig z g 1 (P chloropheny salt of 4-(N-phenyl-N-ethylamlnosulfonyl)-1,1-dimethyl semicarbazide 1s obtaied 1f the latter compound is the 3'nonane sulfonyl] dlpropyl particular sulfamylsemicarbazide employed as the starting semicarbazide material Example VII In like manner, the use of lithium hydroxide or potas- A suspension consisting of 2.43 g. (0.013 mole) of the sium hydroxide in place of the sodium hydroxide emmonosodium salt of N-piperidino sulfonamide and 5.12 g. ployed above alfords the corresponding lithium or potas- (0.016 mole) of 4,4-diphenyl-l-methyl-l-phenyl scmisium salt. carbazide in 30 ml. of anhydrous dimethylacetamlde 1s Example X heated at 135 C., on an oil bath for approximately 16 v I 7 hours. At the end of this period, the reaction mixture is When a sulfarnylsemlcarbazlde prepared as described cooled to room temperature and diluted with ,125 ml. of in Examples I-VI is dissolved in an equimolar, amount of 'calcium salt of the particular"sulfamylsemicarbazide employed crystallizes from solution. In this way, the calcium salt of 4-(4-morpholinosulfonyl)-1,1-hexamethylene semicarbazide is obtained when the latter sulfamylsemicarbazide is the particular compound employed as the starting material. 1

' In'like manner, the strontium and barium salts of each of the sulfamylsemicarbazide of this invention are obtained by merely substituting'the appropriate alkalineearth metal chloride, i.e., ether strontium chloride 'or barium chloride may be used in place'of the calcium chloride. :7 C

.HExa p l t V Equimolar amounts of -a.sulfamylsemicarbazide and monoethanolamin'e' are dissolved in a"sufiicier 1t amount {of-water at-58"C. toaffor'd a 20% solution of the free *sulfamylsemicarbazid compound. Uporrevxaporation of the'aqueous -solvent underreduced pressure at 40 C.,

there is obtained a residue which is the monoethanolammonium salt of the desired compound.

In like manner, each of thesulfamylsemicarbazide of this invention individuallifo'rr'ri salts. with diethanolamine,

;triethanolamine, ethylene diamine, diethylamine, triethylamine and pyridine by contacting one of the aforesaid sulfamylsemicarbazide with the appropriate lower alkanolamine or lower alkylarnine, as the case maybe, in accordance with this reaction procedure.

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

yrrolidinosulfonyD-l,1-[bis'(ethylene)oxa]semi 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 XIII A dry solid pharmaceutical composition is prepared by combining the following materials in the proportions by weight specified below:

4-(1 pyrrolidinosulfonyD-l,l-[bis(ethylene)oxa]semicarbazide 50 Calcium carbonate 20 Polyethylene glycol (average molecular weight,

The solid mixture so prepared is thoroughly blended and then packed into gelatin capsules. A suflicient quantity of the blend is incapsulated to furnish 250 mg. of active ingredient in each capsule.

Example XIV A dilute aqueous-levulose solution of the calcium salt of 4- l-pyrrolidinosulfonyl l lbis (ethylene) oxa] semicarbazide may be prepared by dissolving said salt in a 50% aqueous levulose solution in such amount that each ml. of solution contains 75 mg. of the sulfamylsemicarbazide calculated on the basis of its free sulfamylsemicarbazide form. The so obtained solution can then be sweetened and/ or flavored as desired to order to mask the taste of the essential active ingredient. This solution is rendered more viscous by the addition of the appropriate amount of methyl cellulose.

10 What is claimed is: 1. A compound selected from the group consisting of sulfamylsemicarbazides having the formula and the pharmaceutically acceptable salts thereof wherein R and R when considered separately are selected from the group consisting of (1) hydrogen provided that when one of said R and R substituents is hydrogen, the other is a member selected from the group consisting of lower alkyl, lower alkenyl, trifluoromethyl-lower alkyl, trifiuoromethyl-lower alkenyl, lower alkoxy-lower alkyl and lower alkoxy-lower alkenyl; (2) lower alkyl; (3) lower alkenyl; (4) trifluorome-thyl-lower alkyl; (5) trifluoromethyl-loweralkenyl; (6) lower alkoxy-lower alkyl; -(7) lower alkoxy-lower akenyl; (8) cycloalkyl having from 4 to 8 carbon atoms;

(9) bicycloalkyl having from 7 to 9 carbon atoms; R and R when takenv together with the nitrogen atom to which they are attached form a nitrogen heterocyclic ring selected from the group consisting of 1) pyrrolidino,

( 2) tetrahydropyridino,

(3) piperidino,

(4) 4-l0wer alkyl piperidino,

(5) 4-lower-alkoxy piperidino,

(6) C-mono-lower alkyl piperidino,

(7) 4,4-di-lower alkyl piperidino,

(8) 4-lower alkyl-4-lower' alkoxy piperidino,

(9) 4,4-tetramethylene piperidino,

(10) 4,4-pentamethylene piperidino,

( l1) 4,4-tetramethylene oxypiperidino,

(12) 4,4-pentarnethylene oxypiperidino,

(13) homopiperidino,

(14) piperazino,

(l5) N'-lower alkyl-piperazino,

(l6) N-lower acylpiperazino,

(17) morpholino,

(18) thiarnorpho-lino, and

(1B) C-mono-lower alkyl thiamorpholino;

R and R when considered separately are selected from the group consisting of 1) hydrogen provided when one of said R and R substituents is hydrogen, the other is selected from the group consisting of lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, phenyl, lower alkyl phenyl, lower alkoxy phenyl, chlorophenyl, and trifiuoromethylphenyl,

(3) lower alkyl phenyl,

(4) lower alkoxy phenyl,

(5) chlorophenyl,

(6) bromophenyl,

(7 trifiuoromethylphenyl,

(8) lower alkyl,

(9) lower alkenyl,

(10) lower alkoXy-lower alkyl,

(11) lower alkoxy-lower alkenyl,

12) cycloalkyl having from 4 to 7 carbon atoms and R and R when taken together with the nitrogen atom to which they are attached form a ring system of the formula OHZCHZ wherein X is selected from the group consisting of CH CH CH O and S.

2. A compound of claim 1 wherein R and R when taken together with the nitrogen atom to which they are attached form 4,4-di-lowe1' alkylpiperidino and R and R together with the nitrogen atom to which they are attached form the ring system of the formula onion:

omen,

3. A compound of claim 1 wherein R and R when taken together with the nitrogen atom to which they are attachedform 4,4-tetramethy1ene piperidino and R and R together with the nitrogen atom to which they are attached form the ring system of the formula CH CHH 5. A compound of claim 1 wherein R and R when taken together with the nitrogen atom to which they are attached form 4-lower alkyl-4-lower alkoxy piperidino and R and R together with the nitrogen atom to whichthey are attached form the ring system of the formula 1'2 6. 4 (4,4 tetramet-hylene l piperidinesulfonyD- i. 1,1-hexamethylene semicarbazide.

7. 4-(4-morpholinesulfonyl)-1,1-hexamethylene semicarbazide.

4 (4 4 idi hyl .1 p in smtqn' n 1 1- hexamethylene semicarbazide.

9. 4 4,4 diethyl 1- piperidinesulfonyl) 1,1 hexamethylene semicarbazide.

10. 4 4 ethyl 4 methyl 1 --piperidinesulfonyl 1,1-hexamethylene semicarbazide.

11. 4 (1 acetyl 4 piperidinesulfonyl) 1,1 hexamethylene semicarbazide.

12. 4 (4 methyl 1 piperidinesulfonyl) 1,1 hexamethylene semicarbazide.

13. 4 (4-- methoxy 1 piperidinesulfonyl) 1,1- hexamethylene semicarbazide.

References Cited by the Examiner UNITED STATES PATENTS 3,0054022 10/1961 McLamore et a1 260-553 3,013,072 12/1961 McLamore et al. 260-653 3,063,903 11/1962 Wright t 260553 FO EIGN PATENTS 1,087,125 8/1960 Germany.

OTHER REFERENCES Haack: Arzn. Forsch., vol. 8, pages 444 to 448 (1958).

Marshall et al.: J. Org. Chem, vol. 23, pp. 927-929 (1958).

Ruschig et al.:

Arzn. Forsch, vol. 8, pages 448 to 454 (1958).

WALTER A. MODANCE, Primary Examiner. 1

IRVING MARCUS, Examiner.

E. E. BERG JOHN DJRANDOLPH, Assistant Examiners.

Claims

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF SULFAMYLSEMICARBAZIDES HAVING THE FORMULA