July, 1962
ANTIDIABETIC N4-+4RYLSULFONYLSEMICARBAZIDES
815
In a previously reported series,’ 4-amino-6-anilinopyrimidine (L-25043) was assigned a potency of 100% and used as a reference compound. In this report K-(4-amino-6-pyrimidy1)acetamidewas used as the reference compound; i t was tuice as potent as L-25043, so all relative potency figures in this report can be referred to the previous report i f multiplied b j 2. Effect of N-(4-Amino-6-pyrimidinyl)acetamide on Blood Pressure, Respiration and the Electrocardiogram.-The hlood prc’ssure, rrspiration and electrocnrdiogram were studied in two dogs anesthetized n ith sodium phenobarbital. Following 5 mg./kg. given by tube into the duodenum, there was no eignificant change in mean arterial pressure in one dog during :I 1 hr. observation period In the second dog this dose was followed b) a gradual fall in blood pressure (48”; ) reaching a maximum in 40 min. The respiration and electrocardiogram were not altered. I n this dog a second dcse of 10 mg /kg. was administered 4 hr. after the original dose. This was followed by an increase in mean arterial pressure of 14% in 40 min. Respiration and the electrocardiogram mere not altered. In spite of a fall in pressure after 5 mg./kg. in one dog, it appears this compound has very little effect on blood pressure, respiration and the electrocardiogram. Since the blood pressure in this same dog showed a slight increase in mean artery pressure, it indicates that depressor action following 5 mg./kg. was due to anesthesia.
Acknowledgments.-The toxicity and pathology results were obtained by Drs. R. C . Anderson, P. S.Harris and F. G. Henderson of this laboratory. The microanalyses were done by William Brown, Howard Hunter, George Maciak and Miss Gloria Beckman.
Antidiabetic Agents.
N 4-Arylsulfonylsernicarbazides JOHN B. WRIGHTASD IIOREHT E. WILLETTE Research Laboratories of The Cpjohn Company, Kalanaazoo, Michzyan Received X a r c h 5 , 1962
A series of N4-arylsulfonylsemicarbazides (I, Table I ) was prepared by reaction of arylsulfonylurethanes with suitably substituted hydrazines (11). The requisite hydrazines were prepared by reduction of nitrosamines (111) lyith lithium aluminum hydride. A number of the compounds prepared showed appreciable antidiabetic activity.
During the course of continuing work in these laboratories on antidiabetic compounds, we were interested in investigating arylsulfonylsemicarbazides of the general type I. Our initial experiments in this area produced compounds showing several times the blood sugar
816
G e : \/
x
JOHNB. WRIGHTAND ROBERTE. WILLETTE
Vol. 5
ANTIDIABETIC N4-.4RYLSULFONYLSEMICARBAZIDES
July, 1962
m
3
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B. WRIC:IITA X D ROBERT I?. WII.LETTE
JOHX
R X O S O 2 N H C O S H N/
\ri
1
R = alkyl or --N /R
‘R
x - C H ~(‘1,,
5-01. 5
== cyclic amino
CH,O
lowering activity of tolbutamide wheii nicasured iii intact or adreiialectomized rats. Accordingly, a detailed study n-as made of the struc.t,iir~-ac.tirityrelationship in compouiidh of this general class. The compounds prepared and the preliminary results of the testing of these compounds in rats are listed in Table I. Biological Testing and Results.-The compounds listed in Table I \yere tested in intact male Spragiie Don-ley rats follolying overnight fast. At the time of treatment with the tebt cwmpouiid the rats were injected stihcutaiieously with 100 mg. of glucose. The blood sugar lou ering ability n-as compared n-ith that for tolbutamide. Potency eatimates 11-eremade by determining. from the dose response curves, doses of compounds which produce comparable blood sugar lowering.I l’rom the prelimiiiury artil ity data presented in ‘l’able I several teiitativc’ c*oiic.liisioiiscall 1)c clrau n with rchgard to the relationship hetv ccii -triwttirt, a i d :wti\-ity ill tliih \(,rich. I b t , it appears that cyclic aniiiio ckrimtivc\s (i.e., SI%? = pyc.loalkylamiiie) iii general a p p w r to 1 c t l w most x t i \ (’ (lviivati n \ \ , c.apcciully thosc coiitaiiiiiig pyrrolidiilo, piprricliiio or h~~~unir~th:.Icncimiiio rings or homologs of Sccwid. it apprars that inct hyl yubstitutioii 011 the Synitropc.11 c1irniii:itcs ucti\-it>- Third, n-hcrc thr tcrtiary umiiie fuiictioii SIt?of thc molwiilr posbcsses :my npprc~ciublesteric hindrance relative to thc urc:! iiitrogeii. the wtiiyity is le Cliiiicd mid bio1ogic:d stitdics on oiie of these c.ompo~mds(Table I , SIX2= -S(CH?)G. R’= H) i\ere reported receiitly.’,3 L.
Chemistry.-The
compounds listed in Table I n w e all prepared by
(X = CHs,CI, Br, CH30)
X ~ S O ~ N H C O N H N t R ?C H ~ O H
treatment of arylsulfonyluret,hanes with hydrazines, according to the (1) K e are indebted t o Dr. William E. Dulin, A h . Fredricka Schmidt and eo-workers of these laboratories for the biological results reported here. (2) TT. E. Dulin, H. Oster and F. G. McMahon, Proc. Ezptl. Biol. M e d . , 107, 245 (1961). (3) W. Abelove, Fourth Congress of t h e International Diabetes Association, Geneva, Switzerland, July 10-14 (1961).
ANTIDIABETIC ~4-.4RYI,SUI,FON~I,SEMICARBAZIDES
July, 1962
819
geiieral method of Marshall and Sigal4 for preparing sulfonylureas. The requisite hydrazines (11) mere prepared by lithium aluminum hydride reduction of the corresponding nitrosamines (111) in ether solution. RJVH
+ HONO
LiAlHi +
RsXNO I11
RpNNHp I1
---+
In most cases the hydrazines were characterized by conversion to their hydrochlorides. Those hydrazines and nitrosamines previously not reported in the literature are listed in Tables I1 and 111, respectively. The one trisubstituted hydrazine (V) listed in Table I1 1R' = CH3,
R
r - i =
-N(CH&] was prepared by treatment of the disubstituted
hydrazine, 1-amiuohexamethyleneimine, with formaldehyde solution to give l,l-hexan~ethylene-2-rnethylenehydrazine (IV), and reduction of this with lithium aluminum hydride, according to the general method of Class, et 0 l . j
CNNH' + - CN.=m2 CH~O
IV
~
1
~
1
~
CNNHCH~ 4
,
V
Since all of the final compounds of this series contain a basic nitrogen function one would expect them to possess greater solubility at lower pH's. Experiments carried out in these laboratories6 indicate 1 hat at least one of these compounds, namely, 1, I-hexamethylene-4p-tolylsulfonylsemicarbazide, is in fact much more soluble a t stomach pH's than sulfonylureas such as tolbutamide. This may account, at least in part, for the greater activity of sonie of these compound^.^
Experimental*,9 1-Nitrosohexamethyleneimine. General Procedure for the Preparation of Nitrosamines.-A
solution of 89.5 g. (0.9 mole) of freshly distilled hexamethylene-
(4) F.J. Marshall a n d M. V. Sigal, Jr., J . Org. Chem., 23, 927 (1958). (5) J. B. Class, J. G. Aston and T. S. Oakaood, J . Am. Chem. Soc., '76, 2937 (1953). (6) These experiments were carried o u t b y Dr. Arlington Forist a n d Mr. Leo Humphrey of these laboratories. These authors will report a detailed description of these experiments elsewhere. (7) Before completion of this work one of the compounds t h a t we prepared (I, X = CHI; -NRz = piperidyl) was reported by F. Haack [ A r m e i ~ i t t e l l o r a c h u n g8, , 447 (1958)l. No mention was made of biological activity nor the method of synthesis. (8) All melting points and boiling points are uncorrected for stem exposure. (9) We are indebted to Mr. William A. Struck and co-workers of these laboratories for the microanalytical d a t a reported a n d t o Mr. Marvin F. Grostic and Dr. Robert Rinehart for spectral studies. We are indebted especially t o hlr. Albert Lallinger for a great amount of technical assistance a n d t o Dr. Richard V. Heinaelman for helpful discussions.
820
July, 1962
ANTIDIABETIC N*-ARYLSULFOSYLSEMICARBAZIDES
IC)
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c
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iinine'c in 7 5 1111. of concd. HC1 and 36 nil. of water \\-its \varmetl to 70" :tritl 111at1r acidic to test paper by the addition of 2 S HC1. T o the solution was :tdded with stirring a solution of 67 g. (0.97 mole) of sodium nitrite in 03 r i d . of water. Stirring \vas continued for 2 hr. maintaining the teiiipernture at 70". Thc. misturts \ v : t ~ :tllowed to cool and estracted with ether. T h ethc~realextracts w r e drietl ovvr anhydrous niagnesiiim su1f:itc.. t h e c,thcsr rc~movcdby distil1:itiori :iiitl t h e wsi(Iii(~ distilled in vacuo. 1-Aminohexamethyleneimine. General Procedure for the Preparation of Disubstituted Hydrazines.-A solution of 43.4 g. (0.38 mole) of l-nitrosohesamethyleneimine in 100 mi. of anhydrous ether 1 ~ : ~added s to :I reflusing and stirrcd solution of 28.0 g. (0.76 mole) of lithium :iluininum hydride in 730 inl. of a~ihydrotis ether :Ita rate determined 1))- the reflux rat(.. ' I After refluxing for 2 hr. t,hc rcvwtioii mixture w s decomposed by the successive addition of 30.4 nil. of \v:ittlr, 22.8 i d . of ZO?;, SaOH solution :ind 10G ml. of nxtcr. l'hr inorganic precipit:ite TWR removed by filtration and washed n.011 with ethcr. The ethere:rl filtrate \v:ts tlried :mtl thr Irsiclric tiiptillcd over anhydrous iixignesirim sulfato, t,he t,thcir rc~niovc~i.
in vacuo. I,l-Hexamethylene-4-p-tolylsulfonyIsemicarbazide.General Procedure for the Preparation of N4-Arylsulfony1semicarbazides.-A misturtl of 30 g. (0.13 I mole) of p-tolueiiesiilfomethyli~rc~thari~~ :itid 16.4 g. (0.144 molt:) of l-:tminoh(xs:tniethylenciiiiine \vas heated in an oil hath it 1:10" for 2 hr. iri :L flask fit,toti \vith :L condenser placed don-nxwd for distillnt m i . Ihiring this tiin(, thf. riieth:inol fornied \vas nllo~vetlto distil. '\-iLcuiini iicr. 25 inin.) \vas t in:~i~itaining the s:me oil hath tempc,r:ttiirct. 'I'hc. rosiduc. w \v:ts purified bj, recrystallizatioii. l-Methylaminohexarnethyleneimine.-riYi(~ goiic~r:tl p i ~ ) ( ~ ~ii3c.d l u r was ~ ~ tliut of Cl:iss, et aZ.5 To 22.84 g. (0.2 mole) -amiiiohesaiiiethyleii~~iniiiir~ \vat9 :itltlmi with stirring 21.10 g. (0.26 molo) of a 3( tqueous formaldehydc solution, kecpiiig the teinpr:tturc a t 23--:30". 'l'lie rwctioii inistnre \vas st,irrcd for :in ;dtlitional 4.5 inin. The oil W:IS scp:tr:itcti :ind the. : q w o i i s h y e r extracted \vith tsther. T l i e coinhinrd oil and c t h r r c-str:icts i\-rr(' rlricd O V ( T c:ilciiiiii hytlritltb. tliv ctt1ic.r \\:is rr,movcd :iiid thc' residiic tiistilled in m r ) / o froiii c:ilciiuri hydride through :i distilling coliui~i~.Thcw \\-as ol)tuinrd 1(i.
