Патент USA US3041341код для вставки
3,941,331 ice United States Patented June 26, 1962 2 1 from 5 to 9 nuclear atoms, according to the process ' disclosed by Marshall 'et al., J. Org. Chem. 23, 9,27, 1958, the said N-amino compound having the formula 3,041,331 N-ALKANOYLBENZENESULFDNYL-N'-(CYCLIC . AMINO) UREA DERIVATIVE John B. Wright, _Kalamazoo Township, Kalamazoo County, Micln, assignor to The Upjohn Company, ’ /\ H2N~¢N . . Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Sept. 12,1960, Ser. No. 55,151 5 Claims. (Cl. 260—239) Z, wherein —N . Z V has the value noted above. _ The starting alkanoyl‘benzenesulfonylurethanes can be The present invention relates to novel N-(alkanoyl 10 prepared by reacting anv alkanoylibenzenesulfonamide having the formula: ‘benzenesulfonyD-N’-(cyclicamino)ureas and more spe ci?cally relates to novel N-(alkanoylbenzenesulfonyl) (Ii N'-(cyclicamino)urea free bases and pharmacologically R-C _ acceptable acid addition salts thereof, and to oral anti diabetic compositions containing said novel compounds by the formula: - v ' '- F ' 15 as active ingredients. ' The novel N - (alkanoylbenzenesulfonyl) - N’ - (cyclic amino) ureas of the present invention can be represented ‘ wherein R has the value noted above, with ethyl chloro carbonate in the presence of an alkali-metal carbonate, using the process disclosed by Marshall et al., supra. ' 20 The alkanoylbenzenesul-fonamides can be prepared by the process disclosed by Bur-tonet al., J. Chem.. Soc. 1949,. 178. Alternatively, the alkanoylbenzenesulfon amides can be prepared by reacting an aminoalkanophe 25 none having the formula: . ' wherein R represents alkyl of 1 to 4Vcarbon atoms, in "clusive, i.e., methyl, ethyl, propyl, isopropyl, butyl, iso butyl, and the like. 30 wherein R has the value noted above, with nitrous acid (produced in situ, e.g., by means of an alkali metal ni represents a saturated heterocyclic amino radical having from 5 to 9 ring atoms, inclusive, wherein Z represents trite, such as sodium nitrite, and an acid such as hy a- saturated bivalent radical, e.g., polymethylene, oxa 35 drochloric acid); adding to the diazotized mixture a polymethylene, thiapolymethylene, and azapolymethyl 30% solution of sulfur dioxide in ‘acetic acid to which ene. The term “saturated heterocyclic amino radical” has been added an aqueous solution of a cupric salt ash is employed herein includes unsubstituted saturated heterocyclic amino radicals, as well'as thepmono- and such as cupric chloride, to produce the corresponding alkanoylbenzenesulfonyl chloride; and then reacting the v.polyalkyl-substituted saturated heterocyclic amino, radi 40 alkanoylbenzenesulfonyl chloride with ammonia to ob cals wherein alkyl is of 1 to 4 carbon atoms, inclusive. tain the desired alkanoylbenzenesulfonamide. ' y Representative saturated heterocyclic amino radicals ‘with The starting N-amino saturated heterocyclic‘ amino in the scope of the present invention include, e.g., piper compounds can be prepared utilizing the process of Zim mer et al., J. Amer. Chem. Soc.,77, 790, 1955, which idino, morpholino, thiamorpholino, piperazino, py-rrol idino, hexamethyleneirnino, heptamethyleneimino, octa . involves nitrosating a saturated heterocyclic amino com pound having the formula methyleneimino, homomorpholino, Z-methylhexamethyl eneimino, 2,2-dibutylhexamethyleneimino, 3,6-dimethyl hexamethyleneimino, Z-ethylmorp‘holino, Z-ethyl-S-meth ylmorpholino, 3,3-dimethylmorpholino, 3-methylthiamor pholino, 2,3,5 ,6 - tetramethylthiamorpholino, 2,3,6 - tri 50 methylthiarnorpholino, 4 - butylpiperazino, 4 - isopropyl- ' has the value noted above, with nitrous. acid (produced piperazino, 2,2,4,5,5~pentamethylpiperazino, 2,5-diiso butylpiperazino, 2,4,5-trimethylpiperazino, Z-methylpiper in situ as disclosed above) and reducing the resulting N-nitroso saturated heterocyclic amino compound with idino, 3-methylpiperidino, V4-met-hylpiperidino, 2-butyl lithium ‘aluminum ‘hydride. Other (reducing agents, e,g., ’ piperidino, 2 - propylpiperidino, 4 - isopropylpiperidino, 55 .a mixture of zinc and acetic acid, can also be employed 3,4-diethylpiperidino, 2-sec—butylpyrrolidino, 2,2-dimethyl pyrrolidino, Z-ethylpyrrolidino, 2,4-dimethylpyrrolidino, Z-isopropylpyrrolidino, hexahydIo-3-isopropylpyrimidino,‘ and the like. , ~ to reduce the N-nitroso compound. Since nitrosation of piperazine, unsubstituted in'the 1 and 4 positions, can occur on both nitrogen atoms, it is generally desirable to utilize l-benzylpiperazine as a starting compound and The novel compounds of the present invention are 60 to ‘debenzylate the resulting N- (alkanoylbenzenesul- , fonyl)-N’-(4Jbenzylpiperazino)urea with hydrogen, in the presence of a palladium catalyst according to the sugar content in mammals, especially humans, to a safe process disclosed in U.S. .Patent 2,415,786. The reduc- ' level and at dosages of the order disclosed below. In ti-on of the N-nitroso compound with lithium aluminum addition, the novel compounds are useful in animal feeds and animal feed supplements as set forth in U.S. Patent 65 hydride is highly exothermic in many instances. Accord ingly, it is good practice to bring the reactants together 2,941,884. The novel compounds are also useful as orally active antidiabetic agents useful for lowering blood wetting, emulsifying, and waterproo?ng agents in the gradually, such as by gradual addition of a solution of paper and leather industry. N - (alkanoylbenzenesulfonyl)-N'-(cyclicamino) the N-nitroso compound in an inert solvent to the reaction mixture containing the lithium aluminum hydride. ' ureas of the present invention can be prepared by re acting an alkanoylbenzenesulfonylurethane with an N 70 present invention can be prepared from the N-(alkanoyl The amino saturated heterocyclic amino compound having Pharmacologically acceptable acid addition salts of the benzenesulfonyl) -N’-'(cyclicamino)urea rfree bases by 3,041,331 conventional methods. For example, the free base can be dissolved in an aqueous solution of the appropriate acid and the salt can ‘be isolated by evaporation of the solution. rAlternatively, the'free base dissolved in an there was obtained 1-nitrosohexamethyleneimine as a yellow oil boiling at 136-138” C./34 mm. (E) l-aminohexamethyleneimiue: To a mixture of 15.18 g. ‘of lithium aluminum hydride and 400 ml. of an hydrous other was added'about 10% of a solution of 51.27 g. of 1-nitrosohexamethyleneimine in 100 of anhydrous ether. The mixture was re?uxed until the re action'started. The remainder of the solution was added organic solvent such as methanol, ethanol, ethyl acetate, ether, and the like, can be treated with the appropriate acid and according to the'natuire of the solvent employed the desired salt will separate spontaneously or can be precipitated by the addition of a solvent in which the at such a rate as to maintain gentle re?ux. Re?uxing was salt is insoluble. Suitable ‘acids include hydrochloric,‘ 10 continued for 2 hours more, followed by the successive sulfuric, hydrobromic, phosphoric, tartaric, acetic, citric, addition of 16 ml. of water, 12 ml. of 20% aqueous so succinic, maleic, benzoic, salicylic, and the like. dium hydroxide’solution, and 756 ml. of water. The in The following examples are illustrative of the products of the present invention, ‘but are not to 'be construed as limiting. 7 Example 1.—N-(4-Acetylbenzenesulfonyl) -N' Hexamez‘hyleniminourea organic precipitate was removed by ?ltration and washed with ether. The ?ltrate and ether washes were dried 15 and the ether was removed by evaporation. Upon dis tillation of the residue there was obtained 25.46 g. (56%) of l-aminohexamethyleneimine as a colorless liquid boil ing at 94-_96°- C./55 (A) 4~acetylbenzenesulfonyl chloride: To 13.52 g. (0.1 20 In the same manner as shown in Parts D and E, the following N~amino saturated heterocyclic amines were mole) of p-aminoacetophenone (Beilstein’s Handbuch der prepared 'by_ substituting the corresponding secondary Organischen Chemie, 4th edition, vol. 14, p. 46) was heterocyclic amine having the formula added 100 ml. .of acetic acid and 34 ml. of concentrated x hydrochloric acid. The resulting suspension was'cooled to about 0° C. and to this was added dropwise ‘a solution 25 or 7.59 g. of sodium nitrite in 12 ml. of water. The shown above, for hexamethyleneimine: l-aminopiperi ' slightly turbid yellow solution was stirred for 1/2 hourat about 0‘_’ C. and then 80 ml. ofa 30% sulfur dioxide so lution in acetic acid, to which had been'added a solution dine, 1-amino-4-methylpiperazine, l-‘amino-lé-dimethyl hexamethyleneimine, 1 - amino42,2-dibutylhexamethylene— imine, 1damino-4-methylhexamethyleneimine, l-amino containing 4 g. of cupric chloride dihydrate dissolved in 30 heptamethyleneimine, _1 - aminooctamethyleneimine, 4 7 ml. of water, was ‘added. The mixture was allowed to warm to about 25° C., poured into .ice water, ?ltered, and the ?lter cake was'washed with Water. The ‘resulting 4-acety-lbenzenesulfonyl chloride melted at 87—89° C. (B)._4-acetylbenzenesulfonamide: ' The 4-acetylben -zenesu1fonyl chloride of Part A was added to ‘70 ml. of ,aminomorpholine, 4-amino-2-ethylmorpholine, 4-amino 3,5 - dimethylmorpholine, 4 - *aminohomomorpholine, 4*aminothiamorpholine, 4-amino-2,3,5-trimethylthiamor pholine, 4-amino-2,6-dimethylthiamorpholine, l-aminoe2 35 butylpipeiidine, rl-ramino - 5 - ethyl-Z-methylpipe?dine, 1 - amino - 4 - isopropylpi-peridine, concentrated ammonium hydroxide solution, whereupon l~aminopyrrolidine, 1 - amino-Z-butyl-5-methylpyrrolidine, 1—amino-2,5-diiso an exothermic reaction occurred. After standing for 'propylpyrrolidine, 1-amino-4-butylpiperazine, Lamina-4 about .12 hours the mixture was ?ltered, washed with isopropylpiperazine, and 1-amino-2,4,5-trimethylpipera water, and the recovered solid was recrystallized from 40 zine. ' ethanol. The product, 4 - acetylbenzenesulfonamide,_ weighed 10.92 g. and melted at 176-178° C. - @(C) 4-Jacetylbenzenesulfonylurethane: To . a stirred mixture of 199 g. (0.1 mole) of 4~acetylbenzenesulfonam ide, 36.0 g. of ?nely ground anhydrous potassium car bonate, and 120 ml. of acetone was added 14.26 'g. (0.132 mole) of ethyl chlorocarbonate. The reaction mixture (F) N - (4dacetylbenzenesulfonyl)-N'-hexamethylene iminourea ?r'ee base: A mixture of 11.4 g. of l-aminohex ~arnetzhyleneimine and 25.5 g. of 4-acetylbenzenesulfonyl~ urethane was heated at 130° C. (oil bath temperature) 45 for 2 hours. Theresulting ethanol and unreacted amine were removed at 1100 mm. pressure for 1 hour and at 20 for Zhours while keeping the oil bath at 130° ,C. was stirred at re?ux'temp'erature for 2.5 hours, cooled, ‘The residue was cooled and recrystallized from methyl and 20 m1. of acetone was added. The resulting solid ‘ethyl ketone, giving N-(4-acetylbenzenesulfonyl)-N'-hex was recovered by ?ltration, pressed dry, and stirred with 50 'amethyleneiminourea free base. ' 500 of water for liminutes. The mixture was ?l (G) N - (4aacetylbenzenesulfonyl) -N'-hexamethylene tered, and the clear ?ltrate was acidi?ed with 30 ml. of iminourea hydrochloridezr N-(4-acetylbenzenesulfonyl) concentrated hydrochloric acid, with cooling. The re 'N'-hex=amethyleneiminourea free base was dissolved in sulting precipitate was recovered by ?ltration, Washed ‘ether and gaseous hydrogen chloride was added thereto to with water, and air dried. There was thus obtained 16.49 55 produce N-(4-acetylbenzenesulfonyl)-N’-hexamethylene _. g.) (61%): of 4Aacetylbenzenesulfonylurethane which iminourea hydrochloride. melted at 128-130“ C. An analytical sample prepared Example 2.——N-(4-Pr0pi0nylbenzenesulfonyl)-N'- v by recrystallization from benzene melted at 128.5 130.5° C. > Analysis.—¢Calcd. for CHI-113N055: C, 48.70; H, 4.83; N, 5.16; S, 11.82. ‘Found: C, 48.56; H, 5.02; N, 5.11; S, . Piperidinourea ' 11.91. (D) »1-nitrosohexamethyleneimine: A solution of 89.5 g. of hexamethyleneimine, 75 ml. of concentrated hydro chloric acid, and 26 ml. of water was heated‘ to 70° C. on a steam bath. The solution was made acidic by add ing 5 ml. of 2 N hydrochloric acid. While maintaining >60 " ' ' _ (A) 4-propionylbenzenesulfonylurethane: In the same 'manner as shown in Example 1, Farts A, B, and C, 4-pro >pionylbenzenesulfonylurethane was prepared by using p—aminopropiophenone. (Beilstein’s Handbuch der Organ ischen Chemie, 4th edition, vol. 14, p. .59) ' instead of p-aminoacetophenone. _ ' (B) N-(4-propionylbenzenesulfonyl) - N’ - piperidino urea free base: In the same manner 'as shown in Example the reaction mixture at 70-75" C., a solution of 67 g. of 1, Part F, N-(4-propionylbenzenesulfonyl)JN'-piperidino sodium nitrite in 95 of water was added with stirring urea free base was prepared by using 4-pr0pi0nylbenzene over a period of 1 hour. The mixture was then stirred 70 sulfonyluret-hane and l-arninopiperidine instead of 4-acet ‘at 70° C. for 2 hours, and then cooled. Theupper oily Vylbenzenesulfonylurethane and 1~aminohexamethylene layer was separated and the ‘aqueous layer was then ex tracted with ether. The combined ether extract and oil (C) N - (4-propionylbenzenesulfonyl)-N'-pipetidino was dried over anhydrous magnesium sulfate and con ‘urea citrate: In the same manner 'as shown in Example centrated to dryness. Upon distillation of the residue 75 vl, Part G, N-(4-propionylbenzenesulfonyl)-N'—piperidino imine'. " . 3,041,331 ' 6 5 urea citrate was prepared by using N-(4-propionylben methyleneiminourea free base'was prepared by using 1 zenesulfonyl)-N’-piperidinourea free base and citric acid aminooctamethyleneirnine instead of l-aminohexamethyl instead of 'N-(4-acetylbenzenesulfonyl)-N’-hexamethyl eneimine. eneiminourea free base ‘and hydrogen chloride. ‘ (B) N - (4 - acetylbenzenesulfonyl) - N’ - octarnethyl eneiminourea hydrochloride: In the same manner as Example 3.---N -- (4 - butylrylbenzenesulfonyl) _ N’ - (4 shown in Example 1, Part G, N-(4-acety1benzenesul fonyl)-N’-octamethyleneiminourea hydrochloride was M ethylpiperazino) area prepared by using N-(4-acetylbenzenesulfony1)-N’-octa (A) 4-butyrylbendenesulfonylurethane: In the same manner as shown in Example 1, Parts A, B, and C, 4-bu tyrylbenzenesulfonylurethane was prepared by using p methyleneiminourea free base instead‘of N-(4-acety1ben Zenesulfonyl)-N’-hexamethyleneiminourea free base. amino-butyrophenone (Beilstein’s Handbuch der Organ ischen Chemie, 4th edition, vol. 14, p. 65) instead of p Example 7.—-N - (4‘- Propionylbenzenesulfonyl) - N’ (B) N - (4 - butyrylbenzenesulfonyl) - N’ - (4 - methyl (A) N - (4 - propionyl-benzenesulfonyl) - N’ - mor Morpholino‘urea aminoacetophenone. piperazino)urea free base: In the same manner as shown 15 pholinourea free base: In the same manner as shown in in Example 1, Part F, N-(4-butyrylbenzenesulfonyl)-N’ Example 1, Part F, N-(4-propionylbenzenesulfonyl)-N’ (4-methylpiperazino)urea free base was prepared by using morpholiuourea free base was prepared by using 4-pro 4-butyry1benzenesulfonylurethane and 1~amino-4-methy1 pionylbenzenesulfonylurethane and 4-aminomorpholine piperazine instead of 4-acetylbenzenesulfonylurethane and instead of 4-acetylbenzenesulfonylurethane and l-amin-o l-aminohexamethyleneimine. hexamethyleneirnine. ' (B) N - (4 _- propionylbenzenesulfonyl) - N’ - mor (C) N - (4 - butyrylbenzenesulfonyl) - N’ - (4 -methyl piperazino)urea sulfate: In the same manner as shown pholinourea maleate: In the same manner as shown in in Example 1, Part G, N-(4-butyrylbenzenesulfonyl)-N’ (4-methylpiperazino)urea sulfate was prepared by using xample 1, Part G, N-(4-propionylbenzenesulfonyl)-N' morpholinourea maleate was prepared by using N-(4-pro 25 pionlybenzenesulfonyl)-N’-morpholinourea free base and N - (4 - butyrylbenzenesulfonyl) - N’ - (4 - methylpiper maleic acid instead of N-(4-acetylbenzenesulfonyl)-N' hexamethyleneiminourea free base and hydrogen chloride. azino)urea free base and sulfuric acid instead of N-(4 acetylbenzenesulfonyl) - N’ - hexamethyleneiminourea, free base and hydrogen chloride. Example 8.—-—N - (4 - Propitmylbenzenesulfonyl) - N’ - (Z-Ethylmorpholino) Urea Free, Base Heptamethyleneiminourea In the same manner as shown in Example 1, Part F, N (4 - propionylbenzenesulfonyl) - N’ - ‘(2 - ethylmorpho (A) 4-isobutyrylbenzenesulfonylurethane: In the same lino)u’rea free base was prepared by using 4-pr0pionyl manner as shown in Example 1, Parts A, B, and C, 4~iso benzenesulfonylurethane and 4-amino-2-ethylrno1'pholine butyrylbenzenesulfonylurethane was prepared by using p aminoisobutyrophenone instead of p-aminoacetophenone. 35 instead of 4-acetylbenzenesulfonylurethane and l-amino Example 4 .——N- (4-Is0butyry lbenzenesulfonyl ) -N' (B) N - (4 -isobutyrylbenzesu1fonyl) - N’ - hepta hexamethyleneimine. methyleneiminourea free base: In the same manner as shown in Example 1, Part F, N-(4-isobutyrylbenzenesul morpholinourea fonyl)-N'-heptamethyleneiminourea ‘free base was pre pared by using 4-isobutyrylbenzenesulfonylurethane and .l-aminoheptamethyleneimine instead of 4-acetylbenzene ' Example 9.-—N '- (Butyrylbenzenesulfoayl) -VN’ - Homo 40 (A) v N - (4 - butyrylbenzenesulfonyl) ->N' ,- homomor pholinourea freebase: In the same (manner as shown in Example 1, Part-F, N-(4-butyrylbenzene'sulfonyl)-N’ sulfonylurethane and 1-aminohexamethyleneimine. as shown in Example 1, Part G, N-(4-isobutyrylbenzene homomorpholinourea free base Was prepared by using 4 butyrylbenzenesulfonylurethane and 4-aminohom0mor pholine instead of 4-acetylbenzenesulfonylurethane and sulfonyl) - N’ - heptamethyleneiminourea hydrochloride 45 1"-aminohexamethyleneirnine. was prepared by using N-(4-isobutyrylbenzenesulfonyl) N’-heptamethyleneiminourea free base instead of N-(4 pholinourea hydrobromide: In the same manner as shown (C) N - (4 - isobutyrylbenzenesulfonyl) - N’ - hepta methyleneiminourea hydrochloride: In the same manner (B) N - (4 - butyrylbenzenesulfonyl) - N’ g- homomor in Example 1, Part G, N-(4-butyrylbenzenesulfonyl)-N’ homomorpholinourea hydrobromide was» prepared by acetylbenzenesulfonyl ) -N'-hexamethyleneiminourea ' free base. ‘Example 5.-—N - (4 - Propz'onylbenzenesulfonyl) - N’ -(3, 50 using N -(4 - butyrylbenzenesulfonyl) - N’ - homomor pholinourea free base and hydrogen bromide, instead of d-Dimethylhexam ethyleneimino) area N - (4 ,- acethylbenzenesulfonyl) - N’ - hexamethylene iminourea free base and hydrogen chloride. (A) N - (4 - propionylbenzenesulfonyl) - N’ - (3,6-di methylhexamethy1eneimino)urea free base: In the same manner as shown in Example 1, Part F, N-(4-propionyl 55 Example 10.—N - (3 - Isobutyrylbenzenesulfonyl) - N’ Thiamorpholinourea ' benzenesul-fonyl) '- N’ - (3,6 - dimethylhexamethylene imino)urea free base-was prepared by using 4-propionyl benzenesulfonylurethane and 1-amino-3,6-dimethylhexa methyleneimine instead of 4-acetylbenzenesulfonylure thane and l-aminohexamethyleneimine. (A) N - (3 - isobutyrylbenzenesulfonyl) - N’ - thia-' morpholinourea free base: In the same manner as shown in Example 1, Part F, N-(3-isobutyrylbenzenesulfonyl) 60 N’-thiamorpholinourea free base was prepared by using 3-isobutyrylbenzenesulfonylurethane . '(B) N - (4 - propionylbenzenesulfonyl) - N’ - (3,6 - di and 4-aminothia methylhexamethyleneimino)urea tartrate: In the same morpholine instead of 4-acetylbenzenesulfonylurethane manner as shown in Example 1, Part G, N-(4-propionyl and 1-aminohexamethyleneimine. , (B) N - (3 - isobutyrylbenzenesulfonyl) - N’ - thia benzenesulfonyl) --N’ - (3,6 - dimethylhexamethylene imino)urea tartrate was prepared by using N-(4-propionyl 65 morpholinourea phosphate: In the same manner as shown , in Example 1, Part G, N-(3-isobutyrylbenzenesulfonyl) N’-thiamorpholinourea phosphate was prepared by using imin0)urea free base and tartaric acid instead of N-(4 N - (3 - isobutyrylbenzenesulfonyl) - N’ ? thiamorpho acetylbenzenesulfonyl)-N'-hexamethyleneiminourea free linourea free base and phosphoric acid instead of N-(4 base and hydrogen chloride. vbenzenesulfonyl) - N’ - (3,6 - dimethylhexamethylene Example 6.—N - (4 - Acetylbenzenesulfonyl) - N’ - 0cm‘ methyleneiminourea (A) N - (4 - acetylbenzenesnlfonyl) - N’ - octamethyl 70 acetylbenzenesulfonyl) - N’ - hexamethyleneiminourea and hydrogen chloride. Example 11.—-N-(4-Acetylbenzenesulfonyl)-N'-(2,3,5 Trimethylthiamorpholino) Urea Free Base .eneiminourea free base: In the same manner as shown in , Example 1, Part F, N-(4-acetylbenzenesulfonyl)-N’-octa 75 ,In the same manner as shown in Example 1, Part F, 3,0a1,331 Exaiizp le 1 7.-'—N- (4-Valerylbenzenesulfonyl) -N' Hexamethyleneiminourea (A) 4-valerylbenzenesulfonylurethane: In the same N - (4 -,acetylbenzenesulfonyl) - N’ - (2,3,5 -' trimethyl thiamorpholino)urea free base was prepared by using 4 amino-2,3,S-trirnethylthiamorpholine instead of’ l-arnino rhexarnethyleneimin'e. , , ' . ' y manner as shown in Example 1, Parts A, B, and C, 4 valerylbenzenesulfonylurethane was preparedtby using p arninovalerophenone (Sugirnoto et al., J. Pharm. Soc. Japan 71, 1161, 1951; CA. 46,5011, 1952) instead of Butylpiperidino)Ureu Free Base ,7" In the. same manner as? shown-J in Example 1, Part F, p-arninoacetoplienone. - (4 - propionylbenzenesulfonyl)‘- N’ -' (2 - butylpiper _ (B) N - (4 - valerylbenzenesulfonyl) - N’ - hexa idino)urear free base was prepared by using \4-propionyl benzenesulfonylurethane , and l-arhino-Z-butylpiperidine 10 methyleneirninourea free base: In the same manner as shown in Example 1, Part F, N-(4-valerylbenzenesulfon instead of 4-acetylbenzenesulfonylurethane and l-amino yl)-N’-hexamethyleneiminourea free base was prepared hexarnethyleneirnine. by using 4-valerylbenzenesulfonylurethane instead of 4 acetylbenzenesulfonylurethane. ButyZ-S-Methylpyrrolidiuo) Urea Free Base 15 (C) N - (4 - valerylbenzenesulfonyl) - N’ - hexa In the same manner as, shown in Example 1, Part F, r rnethyleneiminourea hydrochloride: In the same manner as shown in Example 1, Part G, N-(4-valerylbenzenesul methylpyr'rolidinwurea free base was prepared by using fonyl)-N'-hexamethyleneiminourea hydrochloride was 3~propionylbenzenesulfonylurethane and l-amino-Z-butyl prepared by using7 N-(4-valerylbenzenesulfonyl)-N'-hexa S-methylpyrrolidine instead of 4-acetylbenzenesulfonyl 20 rnethyleneiminourea free base instead of N-(4-acetylben urethane and l-aminohexarnethyleneimine. "zenesulfonyD-N’-hexamethyleneirninourea free base. As indicated hereinbefore the compounds of the present Example 14.—N- (Z-Butyrylbenzenesulfonyl) - ‘N - (3 - propionylbenzenesulfonyl) - N’ - (2 - butyl - 5 invention are useful for the treatment of diabetes peroral ly and for this purpose the active compounds are asso N’-Pyrr0lidinourea (A) N - (2 - butyrylbenzenesulfonyl) - N’ - pyrroli 25 dinourea free base: In the same manner as shown in Ex ciated with a’ pharmaceutically acceptable carrier. _ ample '1, Part F, N-(Z-butyrylbenzenesulfonyl)-N’-pyr ‘lrolidinourea free base was prepared by using Z-butyryl methyleneimine. _ r 30 suspensions and solutions (depending on concentration desired), and ?avored oil suspensions and solutions where in edible oils such as corn oil, cottonseed oil, coconut oil, s (B) N - (2 - butyrylbenzenesulfonyl) - N’ - pyrroli ,dinourea salicylate: In the same manner as shown in :peanut oil, sesame oil, or mixtures ‘of these, and the like Example 1, Part G, N-(Z-butyrylbenzenesulfonyl)-N'- V 'pyrrolidinourea' salicylate was prepared by using N-(2 butyrylbenzenesulfonyl)-N’-pyrrolidinourea free base and salicylic acid instead of N-(4-acetylbenzenesulfonyl)-N'~ hexamethyleneiminourea free base and hydrogen chloride. Example 15.,—N-(2-Pr0pi0nylbe‘nzenesulfonyl -N' ' can be employed. , 35' For preparing compositions such as tablets and other compressed formulations the composition can include any compatible and edible tableting material used in pharmaceutical practice such as corn starch, lactose, di-_ basic'calcium phosphate, stearic acid, magnesium stearate, 40 talc, methyl cellulose, and the like. (4-Butylpiperazino) Ure'a Free Base ' ' . Similarly, the compounds of‘ the present invention can be mixed with suitable adjuvants for the preparation of resorbable hard gelatin or soft capsules utilizing conven In the same manner as shown in Example 1, Part F, N - (2 ~ propionylbenzenesulfonyl) - N’ - (4 - butylpiper- i tional pharmaceutical practices. The following illustrative compositions are within the .azino)urea free base was prepared by using 2-propionyl benzenesulfonylurethane and 1-aruino-4-butylpiperazine scope of the present invention: instead of .4-acetylbenzenesulfonylurethane and I-amino hexamethyleneimine. ( 1) ~ HARD GELATIN CAPSULES Example ' 16.—’N- (3-Prop‘i0nylbenzenesulfonyl) -N’ ' Solid forms include capsules, tablets, powders, pills, and the like, and liquid forms include suitably ?avored aqueous benzenesulfonylurethane and l-aminopyrrolidine instead of 4-acetylbenzenesulfonylurethane and l-aminohexa For such oral administration'the active compounds can 1be administered in liquid or solid dosage form. 10,000 two-piece hard gelatin capsules for oral use, each containing 200 milligrams of N-(4-acetylbenzenesul Piperazz'nourea (A) 1sarnino-4-benzylpiperazine: In the same manner .as shown in Examplel, Parts D and E, 1-arnino-4-benzyl piperazine- was ‘prepared by using 4-benzylpiperazine (US. Patent 2,415,785) instead of hexarnethyleneimine. (B)"N - (3 - propionylbenze'nesulfonyl) -,N"- (4 benzylpiperazino)urea free base: In the same manner as 50 , fonyl)¢N’-hexamethyleneiminourea free base are prepared from‘ the following amounts and types of materials: 3 _ V ‘ Gm. N - (4 - acetylbenzenesulfonyl) ,- N’ - hexamethyl eneiminourea free base _______ __' _________ __ 55 shown in Example 1, ‘Part F, 7N-(3-propionylbenzenesul 2000 .Corn starch, _ ‘ 1616 Mineral oil, U.S.P. ________ _; ______________ __ 129.6 fonyl)-N’-(4-benzylpiperazino)urea free base was pre ,Magnesiurn stea/rate, powder _______________ __ pared by using 3-propionylbenzenesulfonylurethane and 1~amino-4-benzylpiperazine instead of 4-acetylbenzrene sulfonylurethane and l-aminohexamethyleneimine. Talc, 'U.S.P. the rest of the ingredients and then capsulated. azinourea free base: In the‘ same manner as shown in N’-piperazinourea free base was prepared by debenzylat 65 ing N - (3 - propionylbenzenesulfonyl) - N’ - (4 - benzyl ’ (2) SOFT ELASTIC CAPSULES » VOné-piece soft elastic capsules for oral use, each con- ’ 'piperazino)urea free base with hydrogen in the presence raining ‘100 milligrams of N-(4-acetylbenzenesulfonyl) ‘ *(D) N - (3’ - propionylbenzenesulfonyl)' - N’ - piper ample 1, Part G, N-(3-propionylbenzenesulfonyl)-N' 162 The ?nely powdered N-(4-acetylben2enesulfonyl)-N' -U.S.~Patent 2,415,786, N-(3-propionylbenzenesulfonyl) iazinourea tar'trate: In the same‘ manner as shown in Ex 1,62 hexamethyleneimino free base is mixed thoroughly with (C) N - (3 - propionylbenzenesulfonyl) - N’ - piper ' ‘ of p‘alladium-on-charcoal catalyst. __' 70 N'-hexamethyleneiminourea free base are prepared in the usual manner by ?rst dispersing the active ingredient in sui?cient corn oil to render the material capsulatable. . piperazinourea' tartrate was prepared by using N-(3-pro 7(3) OIL SUSPENSION pionylbenzenesulfonyl)-N'-piperazinourea free ‘base and tartaric acid instead of N-(4-acetylbenzenesu1fonyl)-N’ An oil suspension for oral use; containing in‘each 5 ‘hexamethyleneirninourea tlree base and hydrogen chloride. 75 milliliters 500 milligrams of N-(4-acetylbenzenesu1fonyl) 3,041,331 1 10 N'-hexamethyleneiminourea free base is prepared from the following types and amounts of materials: sweetening agent gm I claim: 1. A compound selected from the group consisting of (1) N-alkanoylbenzenesulfonyl - N’ - (cyclicamino)urea 3.5 free bases having the formula: N - (4 - acetylbenzenesulfonyl) -N'-hexamethy1ene 0 iminourea free base _________________ .._gm__ 1000 Preservative am 20 . Antioxidant Flavoring _ gm 1 ml 25 Aluminum monostearate-corn oil gel to make 10,000 ml. II R-C 0 II Z 10 wherein R is alkyl of 1 to 4 carbon atoms, inclusive, and (4) TABLET 10,000 oral tablets each containing 250 milligrams of A —N Z V N-(4 - pripionylbenzenesulfonyl)-N’-piperidinourea free is- saturated heterocyclic amino selected from the group 0 base are prepared from the following types and amounts 15 consisting of unsubstituted and mono- and polyalkyl sub of materials: stituted piperidino, morpholino, thiamorpholino, piper - azino, pyrrolidino, hexamethyleneimino, heptamethyl eneimino, octamethyleneimino, and homomorpholino, Gm. N - (4 - propionylbenzenesulfonyl)-N'-piperidino urea free base 2500 wherein each alkyl is of 1 to 4 carbon atoms, and (2) Dicalcium phosphate _______________________ __ 3050 Methylcellulose, U.S.P. (15 cps.) ____________ __ Talc, bolted ' Calcium stearate, fine powder ________________ __ pharmacologically acceptable acid addition salts thereof. 65 20 2. A compound having the formula: 450 35 ‘1? R-C The ingredients are mixed in a conventional manner and compressed into tablets, each containing 250 mg. 25 of active ingredient. ‘(5) SYRUP A 2 \./ @somnonnnr wherein R is alkyl of 1 to 4 carbon atoms, inclusive, and A sugar-free syrup for oral use containing in each 5 -—N milliliters 250 milligrams of N-(4-butyrylbenzenesul fonyl)-N'-(4-methylpiperazino)urea sulfate is prepared 30 from the following types and amounts of materials: piperazino)urea sulfate ______________ "gm..Methylparaben U.S.P. _________________ __gm__ Sorbic acid ' gm-.. Sweetening agent 2111 Flavoring ml _ Glycerin Deionized water to make 10,000 ml. ml‘ 3. A compound having the formula: I N - (4 - butyrylbenzenesulfonyl)-N’ - (4 ~ methyl Z is piperidino it 13-0 500 3 35 3 wherein R is an alkyl of 1 to 4 carbon atoms, inclusive, and 18 3 1500 —N Z is pyrrolidlno 4.0 vA dose of 1 teaspoonful (5 ml.) to 1 tablespoonful (15 ml.) will give the patent 250 to 750 mg. of N-(4»butyryl benzenesulfonyl)-N’-(4-methylpiperazino)urea sulfate. The dosage of the novel compounds of the present in 4. A compound having the formula: 0 ll 0 . R—C ' vention for the treatment of diabetes depends on the age, 45 weight, and condition of the patient being treated. Gen erally speaking for adult oral administration the pre ferred unit dosage is 100 to 500 mg. of active compound with a suitable pharmaceutical diluent and/ or lubricant. One or two unit dosages are given one to four times a 50 day. A total daily dose of from 100 to 1500 mg. given singly but preferably in divided doses, embraces the effec II . /\ SOzNHONH-N z V wherein R is alkyl of 1 to 4 carbon atoms, inclusive, and -N Z is morpholino 5. A compound having the formula: tive range for the treatment of diabetes. In addition to the foregoing principal active ingredients, the present compositions can also include, as supple 55 mentary active ingredients, other blood sugar lowering compounds, such as tolbutamide, chlorpropamide and phenformin. Such supplementary active ingredients can be included in these compositions in amounts approxi mately equal to or less than the concentrations employed where such materials are the sole active ingredients. wherein R is alkyl of 1 to 4 carbon atoms, inclusive, and -N Z is hexamethyleneimino Nov references cited.