Sulfamylsemicarbazide Hypoglycemic Agents. IV - Journal of

Sulfamylsemicarbazide Hypoglycemic Agents. IV. J. M. McManus, C. F. Gerber. J. Med. Chem. , 1966, 9 (2), pp 256–257. DOI: 10.1021/jm00320a031...
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257 TABLE I PIPERIDIN ESULFBMYLSEMICARBAZIDES

R2c6s02NHCo~H~xcHI-, R, RI Rz 1 H H 2 H H 3 H CH3 4 H CH3 5 CHS CH3 6 CHI CH3 7 CH3 C2Hs 8 CzHS CzHj 0 -(CH2),10 -(CHz)411 -(CH*)j12 CH3O H Chlorpropamide E = ether, A = acetone. No.

(I

X

3

6 3

6 a 6 6 6 5 6 6 6 b

Crystn solventa

Mp, " C

E I2

131.5-133 1 5 7 . 5 dec 162-162.5 148 dec 153.5 dec 146 dec 135.5 dec 139.5 dec 154.5-155 155 dec: 152 dec 132-133

A E E E E E E-A E

E E

Formula

---Citlcd, C H

CnH22N403S 45.4 C1zHzaNa03S 47.4 Cl2HZ4K4O3S 47.4 C13H26N403S 49.0 CI~H~~S~O 49.0 ~S ClaH28Sn03S 50.6 52.0 CijH3oN403S 53.3 C16H32X403S 52.3 CijH28N403S 53.6 C16H30N4038 CliH3ZX\T403S 5 4 . 8 C ~ ~ H Z ~ N ~ 46.7 O~S

-'5 P

7.6 8.0 8.0 8.2 8.2 8.j 8.7 9.0 8.2 8.4 8.7 7.8

$6-

;

--Found. C

H

N

19.3 18.4 18.4 17.6 17.6 16.9 16.2 15.5 16.3 l5,6 15.0 16.8

45.5 47.6 47.9 49.1 49.0 50.3 52.3 53.0 52.7 53.7 55.0 46.8

7.5 7.9 8.0 8.0 8.0 8.4 8.6 8.7 8.3 8.5 8.i 7.8

19.5 18.1 18.6 17.0 17.5 16.8 15.8 15.2 16.6 15.3 15.1 16.5

Hypoglycemic activityb

14.8 f7 . 0 11.1 i 1 . 9 26.1 + 2 . 6 33.9 i 1 . 5 39.1 f 2 . 8 34.9 f 3 . 3 42.0 zk 3 . 3 34.4 f 2 . 8 35.6 f 2 . 4 30.8 f 8 . 7 25.0 i 3 . 7 24.si:2.1 35 i 3 . 3

LIaxirnuni per ceiit fall in blood sugar and standard error a t lot, mg/kg.

TABLE I1 AIORPHOLIXE-, THIOXORPHOLIXE-, AND PIPER.~ZIZIESULF~YTLYE~~IC.~RB.~ZIDES

a

NO.

Y

1 2 3

0 0 S

X

Xp, O C

5 153-153.5 6 154dec. 5 150.5-1!52 4 CHICOY 6 172 dec. 6 138 dec. 5 (CH3)zCHCON A = acetone, N = acetonitrile, B = benzene.

Crystn solventa

----Calcd, C H

Formula

---

Found, yo-----

%-N

C

41.1 6 . 9 19.2 41.1 43.1 7 . 2 1 8 . 3 43.1 h CioHzoNaO3Sz 38.9 6 . 5 18.2 38.9 S Ci3HzbN50nS 44.9 7 . 3 20.2 44.9 18.7 47.5 B C1jH29Nj04S 48.0 7 . 8 Not recrystallized. See footnote b of Table I.

A

CioHzoXAOaS

c

CiiHzzNaOaS

163-185'). The analytical sample was recrystallized once again; mp 168-170". Anal. Calcd for CaHllN302S: C, 29.1; H, 6.7; N, 25.4. Found: C, 29.4; H, 6.7; N, 24.9. l-Sulfamy1-4-acetylpiperazine.-To a suspension of 16.5 g (0.1 mole) of 1-sulfamylpiperazine in 230 ml of methylene chloride was added slowly 11.2 g (0.11 mole) of acetic anhydride. The resulting mixture was refluxed for 2 hr, and was then cooled and filtered, t o yield 20 g, mp 177-159". The product was further purified by recrystallization from ethanol: mp 179-181". 4naZ. Calcd for C6H13N303S: C, 34.8; H, 6.3; N, 20.3. Found: C, 34.4: H, 6.1; N, 20.3. l-Sulfamyl-4-isobutyroylpiperazine.-By a similar procedure, 12.7 g (0.077 mole) of 1-sulfamylpiperazine and 11.0 g (0.07 mole) of isobutyric anhydride in 100 ml of CHzC12gave 11.7 g of the desired product, mp 179-181'. Anal. Calcd for C ~ H I ~ N ~ OC, ~ S40.8; : H, 7.3; N, 17.9. Found: C, 40.6; H, 7.1; N, 17.9. l,l-Pentamethylene-4,4-diphenylsemicarbazide.-To a solution of 171 g (0.75 mole) of diphenylcarbamoyl chloride in 300 ml of diniethoxyethane was added 153 g (1.51 moles) of l-aminopiperidine. The addition was made dropw-iqe, with cooling, over a period of 2-3 hr. The mixture of product and hydrazine hydrochloride was filtered and suspended in 1500 nil of water. Filtration of the aqueous suspension, followed by drying of the filtered solids afforded 186 g of crude product, nip 154-158'. Two recrystallizations from acetone gave 142 g of pure product, mp 167.5-169". Concentration of the aqueous filtrate gave 97.8 g of recovered 1-aminopiperidine as the hydrochloride salt. Anal. Cdcd for ClsH21N30: C, 73.2; TI, 7.2; N, 14.2. Found: C, 73.0; H, 7.2; N, 14.1. l,l-Hexamethylene-4,4-diphenylsemicarbazide.-Inan analogous manner 91 g (0.39 mole) of diphenylcarbamoyl chloride and 90 g (0.78 mole) of 1-aIninohoniopiperidine in 150 mi of dime-

H

6.7 7.1 6.6 7.2 7.2

N

19.3 18.6 18.1 20.1 18.5

Hypoglycemic activity*

14.8 z t 2 . 9 22.5 f 2 . 6 6.5 k 1.7 23.8 f 3 . 5 11.7 f 3 . 7

thoxyethane gave 80.6 g of the desired product, nip 107.5-108.5", and 55 g of recovered 1-aminohomopiperidine as the hydrochloride salt. Bnal. Calcd for C1gH23N30: C, 73.8; H, 7.5; N, 13.6. Found: C, 73.8; H, 7.4; N, 13.8. 1-Aminopiperidine.-1-Nitrosopiperidine (44 g, 0.386 mole) was reduced with zinc dust and acetic acids to give 36.5 g of the pure product, bp 41-44" (12 mm), lit.9 bp 146" (728 mm). Anal. Calcd for CbH12N-2: C, 60.1; H, 12.1; X, 28.0. Found: C, 59.7; H, 11.8; N, 27.9. 1-Arninohomopiperidine.-By a similar procedure 180 g (1.4 moles) of 1-nitrosohomopiperidine gave 86.8 g of the desired hydrazine, bp 86-86.5" (25 mm). Anal. Calcd for CaHlaNz: C, 63.1; H, 12.4; N, 24.5. Found: C, 62.9; H, 12.0; N, 24.9. 1-Nitrosohomopiperidine.-To 79.5 g (0.8 mole) of hexamethylenimine was added, with cooling, 80 ml of 12 N HC1. The viscous liquid was warmed to 70°, and 69 g (1.0 mole) of NaNOz in 160 ml of water was added. During the addition, which required 1 hr, the product separated as an oil on the surface. After an additional 2 hr of stirring a t 70", the product was extracted with ether. The ether layer was dried, and the ether was removed i n vacuo leaving an oil. Distillation of the residual oil gave 72.7 g of the desired product, bp 83-86' (2.0 mm). Anal. Calcd for CGH12N20: C, 56.2; H, 9.4; S , 21.9. Found: C, 56.4; H, 9.6; N, 21.8.

Acknowledgments.-The authors are indebted to Alessrs. Harold Ramus, Andrew Popson, and Frederic Smith for their technical assistance. (8) A. H. Blatt,"Organic Synthesis," Coll. Vol. 11, 1st ed, John Wiley and Sons, Inc.. New York, N . Y., 1955, p 212. (9) L. K n o r r , Ann., 221, 299 (1883).