Hypoglycemic Activity in Relation to Chemical Structure of Potential Oral Antidiabetic Substances. 11. - h a l o g s of 1- Sulfonyl-3-alkylureas’ BERSTH O K F L L T Uepurltiicnl of Physzology, Karolz7ishu Inslilulel, SLoch-holiii, SuedLn ANI) &\lk;EJ O X S ~ O S
Dc puiliiitnt of Orguiizc C‘twnzstiy, Kuncil. 7 t XiizaXu Hogsholuii, StocXholiic, Research Luboratoraes, d B .I611 a, Sodertalje, Sweilcri
uuIl
Received June 22, 1961
.I number of (*ompoundsstructurally related to csrbutamide arid tolbutamide tiavc been prepared and tested for antidiabetic properties. None of them exerted any appreciable activity in rabbits after oral administration. In Part I of this series1 we reported the synthesis and hypoglycemic activity of a number of 1-sulfoiiyl-3-alkylureas, RS02NHCOn”R’, Le., compounds closely related to the drug l-p-aminobenzenesulfonyl3-n-butylurea (I), p-H&C6H,S02SHC0NH(CH,)&H3. I n these compounds the alterations were restricted to the “end groups.” R and R’, of the molecule. R e now wish to report on compounds in which modifications have been made mainly in the iiiterjaceiit part of the molecule. The compounds, Tables I-IY, either in form of aqueous solutions of their sodium salts or as suspensions in water containing 0.1% Tween 80 and 1% low viscosity CMC, were tested for hypoglycemic effect in rabbits by the method described.’ Kone of the substances exerted any remarkable effect although three, 1-p-toluenesulfonylacetyl-3n-butylurea (11), l-~-(p-tolueaesulfoiiamido)-ethyl-3-n-butylure~ (111) and 1-p-tolueiiesulfonyl-8-isovalerylurca (117) were slightly active. p-CH,C6H4S02CH,CONHCONII(CH?)3CI-1,
IT
p-CH,C6€I,S02NHCH?CI-I2sHCo?JH(CHz)3C1f3
111
p-CH3CsHdkX )?NHCOSHCO(CH2)zCH( CHB)2
I I‘
(1) Part I J M e d I’harm. C h e m , 6, 231 (1962).
242
L"NTKU1ABETIC
ANALOGS OF
1-SULPONYL-3-ALKYLUREAS
243
.If w v (wipouiids, t'specially 1-~-pj'ritioyl-:S-n-})uty1 u r w . l-p-[limethyluminot~eiiseiiesi~lfonyl-3-n-t,utylt hiourea and the sulfoiiyl derivative$ of biguanidine, hhoived hyperglycemic activity. Similar obw-vations with pyridoylbutylurcx hs\-e been reported rwciitly. The cff'ect of the biguaiiidine derivnti\-eb is rather surprising, as the parent alkylbiguaiiidinei: are 11-ell kiio~vii to exert pomrful hypoglycemic activity.3 It has been suggested1 that in the hypoglycemic sulfonylurea det*i\rativcs, RS02?;HCOSHR'. the function of the group6 R and I t ' might be t o provide the compouridr with favorable physical proper1 ies n.herra,h thc interjaceiit part of the molecule might exert niorc' bpecific chemical fuiictions The results discussed in the present uggestioii and illustratc that the structural reyuiwmciits of thib part :ire indeed very rigoiuuG :ii even thc suhstitutioii of the oxygen atom of the urea moiety by wlfur, nhirh can hardly apprccisbly alter the physical properties of the compound, completely destroys the activity.
Experimental ' l ' l i ~ cminpouiids used in this inveat,ig:rtioii a11 Lvere prc.parcd I)y well-knowri rw(*Only :t fe.ll-of them appear t o have been described in the lit,erat urc. JIcltirig points anti andyticnl data of the IIPK .rubst,ancrs arc listed in Tables 1-11?. The melting points arc corrected. 1-Acyl- and I-Aroyl-3-n-butylureas.-Tlic. ;rppropri:Ltci acid chloride: (0.2 niolc~)was added i n portions to a mixture of ,n-l)utylures (0.24 mole) :iIid anhydrous pyritlinr 130 nil.). K h e n the initi:il esot hermic reaction had suhsidcd th(, mixture was heatrd at 100-110" for :iboiit 2 hi-., :tnd thcii poured into w:ttclr. The solid that formed \\-as filtered off arid crystallized from ethanol or aqiieoiivthanol. Th? yield of material once rec.rystallized \\-as in the, order of 50 t o 85%. Benzenesul:'onylacetyl and p-toluenesulfonylacetyl chloride i v ( w ol)t,aiiic.d 11) refluxing the acaids (0.4 mole) with thionyl chloride (150 ml.) :tiid rcnioviiig the. excess tliionyl chloride under reduced pressure on t,he witcr Iiath. rid were u s e d in the eubsc:qiicnt, reaction without purifiaition, Benzenesulfonamidoacetyl chloride, similarly prepared, was purified hy ~~ystallization froin hcnzriic~-pi~troleuni et.her, arid formed needles, 1n.p. 86-88". A4na/. Calcd. for C8H8C1X03S:C1, 13.2. Foiind: C1, 14.9. 1-p-Hydroxybenzoyl-3-n-butylurea was obt,ained from its itcrtate e s t w hy heating this (35 9.) in a mixture of sodium hydroxide (20 gJ. et,hanol (150 ml.) and water (50 ml.) for 0.5 hr. on the water Iuith, diluting w i t h water (500 ml.), t ioiie.
(2) Th. Wagner-Jauregg, R-. Taterlia, and 0.Bhch r,,eimi(t~l-k'oiaciL.,10,tj86 ( 1 980) (3) K. H. Blotta a n d R. Tschesohe, Ber., 62, 1398 (1929).
March 1962
hTIDI.4BETIC
r\sa~oosO F ~ - S U L F O N Y L - ~ - . ~ L K ~ L 245 UH~BS
filtering, precipitating by acidification with dilute hydrochloric acid and crystailization from aqueous ethanol. l-Sulfonyl-3-n-butyl-2-thioureas.-The sodium salt of the appropriate sulfonamide (0.2 mole), n-butyl isothiocyanate (0.3 mole) and freshly distilled nitrobenzene (75 ml.) were heated a t 120-140" for about 15 hr. with occasional shaking. The solvent was distilled off with steam, the aqueous solution of the thiourea treated with decolorizing carbon and filtered. Acidification of the filtrate with acetic acid afforded the desired product usually as an oil which soon solidified. It, was purified by crystallization from methanol. The yield of crude material \vas 60 to 80%. l-Sulfonyl-3-n-butylguanidines.-To a stirred mixture of di-(n-butylguanidine) sulfate (0.1 mole), the appropriate sulfonyl chloride (0.2 mole) and acetone (200 ml.), there was added over 1 hr. a solution of sodium hydroxide (25 g.) in water (50 mL)>the temperature being kept a t 20-25". Stirring was continued for a further hr., wat,er (500 ml.) was then added and the solid precipitate filtered off and crystallized from methanol. 1-Sulfonyl-5-n-butyl- and -5,5-dimethylbiguanidines were prepared similarly from the corresponding biguariidine hydrochlorides. 1-n-Butylbiguanidine Hydrochloride.-Cupric chloride dihydrate (341 9.) was dissolved in water (500 ml.) and added to dicyanodiamide (168 g.) and n-butylamine (250 g.). The mixture was refluxed for 20 hr., and after cooling the pink copper complex was filtered off, washed with dilute ammonia and Jvater and dissolved in 4 N hydrochloric acid (600 ml.). The solut,ion was saturated with hydrogen sulfide, the copper sulfide filtered OK and washed with dilute hydrochloric acid, and t,he combined filt,rate and washings were evaporated in V U ~ C Z L Oon a \vat,er bath. The resulting syrup was dissolved in ahsolut,e ethanol (250 ml.) and again evaporated, this operation being repeat,ed twice more. The anhydrous sticky mass was dissolved in absolute ethanol (150 ml.) and carefully treat,ed wit,h ether (250 nil. ). The butylbiguanidine hydrochloride separat,ed as faintly yellow leaflets, which were filtered off and drird: yield, 183 g. This product was purified I)y polut.ion in t,he niinimuni amount of et,hanol and reprecipitation with ether, yielding 173 g. of a product melting a t 163-165" (dec.). dnal. Calcd. for C,H1&.JSi: CI, 18.4. Found: C1, 18.2. l-Sulfonyl-4-n-butylsemicarbazides.-These were obtained by t,reatment of the appropriate sulfonyl hydrazide (0.1 mole) with n-butyl isocyanate (0.12 mole) in dioxane (75 ml.) a t 70-90" until a clear solution resulted. The produrt was precipitated by the addition of witer and crystallized from aqueous methanol. l-p-Toluenesulfonyl-3-isovaterylurea.-To a mixture of p-toluenesulfonylurra (42.8 g., 0.2 mole) and isovaleryl rhloride (30 g., 0.25 mole) was added anhydrous pyridine (25 ml.) in small portions with shaking and cooling with t a p water. When the reaction subsided the mixture was heated for 2 hr. on a water bath and then poiired into water. The precipit,ated oil solidifid on scratching, nredlm from methanol. l-p-Sulfamoylphenyl-3-n-butylurea.-n-But~l isocyanate (0.11 mole), sulfanilamide (0.10 mole), and dioxane (100 ml.) were refluxed for 10 hr. The clear solution was diluted carefully with water, and the solid precipitate crystallized from was analogously prepared methanol. l-p-Sulfamoylphenyl-3-n,-butyl-2-thiourea
from n-hutyl isothioc~yan:ttct. 1 -p- (p-Toluenesulfonamidoj -ethyl-3-n butylurea..---I/ - Tolircnesu1fonaniidoet.h>,lamine (0.15 mole) was treated with n-butyl isocyanate (0.18 mole) for 4 hr. on the water bath. The oily product was cooled a,nd tritur:*td with methanol, and the solid obtained crystdized from aqueous methanol. F-n-Valeryl-p-toluenesu1fonamide.-The sodium salt of 11-t olucnesulfonamidc (29 g,) WLS suspmded in anhydrous tlioxnnc- (100 1nl.j. u-Valeryl chloride (21 g.) was added arid the mixture heated on thc 1v:tter kjiitli for 2 lir. nnd poiired into rvator. Thc solid product TV:P filtered off arid crystallized from bcnzene and from mcthmol. l-p-Methoxybenzenesulfonyl-3-n-butyl-O-methylpseudourea.--'Toii stirred solut,ion of X-n-hutyl-0-methylpseudourca (26 g.), and triethylarnirie (30 ml.) in dioxanc (50 mi.) there was added dropwise :t solution of p-methoxybenzeneStirring Tas continued sulfonyl chloride (23 g.) in dioxane (100 ml.) at 5-10'. for 2 hr. aftor completed addit,ion, the mixture was diluted wit'h water (500 ml.) :ind made alkaline with 6 S sodium hydroxide. The preripitatcd product \vas collected and crystallized from ayueow ethanol.
-
Acknowledgment.--The authors arc iiitlehted to Messrs. .Jail Gyllarider arid Lemhit, Mikiver for skillful assistaiicc in t'lie synthetic \\-ark. Mirroarialyses by Dr. Alfred Rerrihardt, I\licroanalyt,ical Laboratory, Muhlheim, Germany. (4) J. S. Roth and
E. F. Degering, J . Am. Chem. Soc., 67, 126 (1945)
