5-34. I1 35-41.R
2,R=H 3,R=CH
= €1 =
>re
Journal of $ledicinal Chemistry, 1970, Vol. 13, S o . -3 557
NOTES
TABLE I 1-.4LKEXYL-
A N D 1-4LKENoYL-3-ARYLsCLFONYLUREhS
Yield. Compd
R
1
CH3 CHI CH3O CH3O
7
3 4 1
6 7 S
9 10 I1 1':
13 14 13 Tolbutamide
R'
c1 c1
CH3 CH3 CH3 CH3O CHiO CHiO C1 Cl
c1
%
93 79 81 69 7s 7s 43 22 37 36 29 2s 40 36 37
MP,
oc
Formulaa
137-138 94-93. .5 118-119.5 9s-99 121-122 114-1 15 173-17.5 120-122 108-109 167-1 68 131-132 123-124 161-163 166-167 lt76-l.57
Relative potency
0 , X.5 0.00 0.19 0.14 0.30 0.09 0.17 0.16 0.27 0.26 0.00 0.29 0.16 0.13 0.00 1.00
All compounds were analyred for C, H, S and the analytical results were within =t0.45 of the theoretical valiies. MeCN and filtered. Evaporation of the solvent wider reduced pressure and distillation of the residue at 58-60" (14 mm) gave 10.8 g (37.57,) of 4-methy1-2-pentenonitrile sufficiently piire for further work. The nit,rile (10.8 g, 0.113 mol) in Et20 (100 ml) was dropped for 1 hr into a stirred suspension of L.4H 18.6 g, 0.226 mol) in Et20 (600 ml). After 30 min stirring, the reaction mixture was cooled and then cautiously decomposed with 30% KaOH (100 ml). The organic layer was separated, washed with HzO, and dried (KaOH). The solvent was evaporated and the residue was distilled at 48-ZO" (30 mm) to give 4-methyl-3-pentenylamine6 as a colorless liquid (4.96 g, 44%). -4nal. (CsH13N)C, H, N. I-Alkenyl-3-arylsulfonylureas.-A solution of alkenylamine (0.05 mol) and ethyl 5-arylsulfonylcarbamate (0.036 mol) in anhydrous PhMe (120 ml) n-as refluxed for 5 hr. The hot solut,ion was filtered and cooled to separation of a crystalline solid, which was filtered, washed with EtpO, and dried. When concentrated, the mother liquor gave additional but less pure product. 3-Methyl-2-butenamide was prepared according to PitrP.6 The following amides were similarly obtained: 4-methyl-3pentenamide, 96%, mp 78-81"; Anal. (C6HllXO) C, H, K; 5-methyl-4-hexenamide, 78%, nip 83-85; Anal. ( C ~ H U N O ) C, H, 5 . l-Alkenoyl-3-arylsulfonylureas.--A solution of alkenylamide (0.05 mol) and ethyl N-arylsnlfonylcarbamate (0.035 mol) in anhydrous PhMe (120 ml) was refliixed for 48 hr. During this time, the solvent, was gradually distilled off and replaced with fresh solvent to remove the EtOH formed. The hot solation was Experimental Sectiona filtered, evaporated to dryness, and the residue taken up in 5yo 3-Methyl-2-butenylamine.-l-Bromo-4-meth~l-2-b~itene KaOH (50 ml) and Et20 (250 ml). A solid separated which was dissolved in H2O. A4fterfiltering with charcoal, the solution was (111.75 g, 0.75 mol) in Et,O (375 ml) was dropped for 3 hr into HC1 and the precipit,ate which formed was a solution of KaNH2 [from Xa (17.3 g, 0.75 g-atom) and liquid h E t 2 0 , and dried at room temperature iiiider NH3 (900 ml)]. The mixture was refliixed for 2 hr with stirring, reduced pressure. NH3 was alloTved to evaporate, and the residue was cautiously taken up with 30% XaOH and EtzO. The organic layer was separated and dried (NaOH). The qolvent was evaporated and the residue was distilled at 110-112° (lit.4 110.5') t o give a Acknowledgments.-The authors thank Dr. R. colorless liquid (26 g, 40%). 4-Methyl-3-pentenylamine.-l-Bromo-4-methyl-2-butene Perego for the microanalyses, N r . E. Zugna for pre(44.7 g, 0.3 mol) and 977, CuCN (27.7 g, 0.3 mol) were rapidly paring the compounds, and A h . E. Pavesi for the hypoheated to 60" with stirring. After the exothermic reaction had glycemic tests. started, the mixture was cautiously cooled, the temperature was kept a t 50-60" for 30 min, and the suspension was taken up in
by condensing N-arylsulfonylcarbamates with amines or amides in boiling P h l l e . The drugs were tested orally in normal fasting rats. The results are listed in Table I in terms of relative potency, which was calculated as previously described2 and expressed in relation to the hypoglycemic activity of tolbutamide, which has been assigned the potency of 1.o. An examination of the relative hypoglycemic potencies revealed that, among all the tested substances, only 1 was found to display an activity of some interest. This compound was then tested also orally in fasting rabbits as well as in normally fed rats and rabbits; the values for relative potency were 0.63, 0.85, and 0.41, respectively. From these findings, the conclusion may be drawn that 1 [1-(3-methyl-2-butenyl)-3-ptolylsulfonylurea] possesses hypoglycemic properties, which, however, are inferior to those of tolbutamide. Apart from this, the introduction of a branched alkenyl group in the 1 position of arylsulfonylureas does not seem to lead t o interesting hypoglycemic agents.
(3) Boiling points are uncorrected. Melting points are corrected and were taken on a Brichi capillary melting point apparatus. (4) D. Semenoiv, Chin Hua Shin, and G. Young, J . A n e r . Chem. Soc., 80, 5472 (1958).
(5) This compound was previously described in a mixture n i t h &methyl4-pentenylamine by A. C. Cope and K. D. Burrows, J . OTQ. Chem., 31, 3099 (1966). (6) D. Pitre, Farmaco Ed. Sci., 4, 657 (1949).
