967 TABLE I DL-EPHEDRIN E PHOSPHATES
L-, D-! AND
5%
u0-91n 90-91"
--
7'3-8O'L
84 76 90
67 I J
178-1 i9" li8-1igh e 24 2-2 1:J 241-24.3 2.50-2.52
Formula
--n,
7~-
7
~
j
%--
---p, (I--IC Calcd Found 12.64 12.85 12.64 12.51 12.64 12.i8 11.01 10.96 11.01 11.20
Calcd 48.90 C I O H I X C I N O ~ P 48.90 48.90 42.64 CioHliClSO4P 42.64
Found 49.10 48.72 49.07 42.88 42.52
...
...
...
...
...
...
...
49.02 C I O H I ~ N O ~ P 49.02 49.02
49.10 48.88 48.91
6.68 6.58 6.58
6.80 6.44 6.73
6.i6 5.76 5.76
5.84 5.68 5.61
12.66 12.66 12.66
12.51 12.46 12.59
...
... 84 86 i9/
(z---
--c,
Yield Np, QC
Calcd 5.34 5.34 5.34 6.09 6.09
Found 5.50 5,57
5.26 6.22 6.01
Calcd 5.70 5.70 5.70 4.98 4.98
Found 5.i4
5.58 5.56 5.16 5.11
--a, Calcd 14.13 14.43 14.43 12.59 12.59
...
5%-Found 14.43 14 56 14.58 12.68 12.73
...
Cr~--t:tllized from petroleiim ether (bp 60-68"). Crystallized from an ethanol-ether mixture. I n benzene. I n water. ITvRro+c.opir. f The reported yield has been referred to the qiiantity of IIc. Q Barium salt, mp 192-193'; cyclohexylammonium , J t , nip 2 : ~ ' ;sodium salt, mp 254'. h Ultraviolet spectrum: A",:"," 207 mp (log e 3.91), 257 m l (log E 2 . 3 3 ) . e
ToxrcIw
OF
TABLEI1 EPHEDRISE AND DE~ZIVATIVES
7---LUs~
(mouse), mg kg--IP
c UllllJll PO sc Ia.IIC1 400 1000 Ia.IIC1" 970 790 IT-a 1065 2000 IVa" 1142 1707 I b .I-ICl 785 425 IVb 1800 865 I C . IICl 700 900 1150 Is'c 2000 1)etermiiiecl on isolated animals.
260 333 2000 2386 250 815 260 790
__ Iv
120 118 400 1338 175 815 135 840
"prol,aiuol-coii(.eiitrated NH40H-water ( 2 0 : 1 : 2 ) , mid B, c.hloroform-methanol-glacial acetic acid ( 1: 1: 0.1); the time was 2 hr. To detect bephedriiie, the chromatogram was sprayed
with 0.4% ninhydrin in 1-butanol; ephedrine appeared as a mauve >pot. To detect L-ephedrine phosphate, the chromatogram was fir.st sprayed with Neatanz (Nerck, Darmstndt) and then n-ith :t phosphate reagent [TO% HC104-1 S HC1-ammonium molybdate (5: 10: l ) diluted to 100 ml with water]. After heating to 70" and exposure to H,S, ephedrine phosphate appeared as a blue spot. For L-ephedrine aud L-ephedrine phosphate, respectively, the Rf values in solvent A were 0.65 and 0.00 and ill solvent B were 0.53 and 0.27. Pharmacologic evaliiation showed that t,he phosphates 11-a-c have a consistently lower toxicity than the corresponding ephedrines (Ia-c).8 The result,s are listed in Table 11. Tests of the activity of these compounds on the cardiovascular system (cat) did not, reveal any significant difference between the various compounds. However, in comparison with Ia, IVa has shown a significantly lower (eightfold) hypertensive activity. The antibroiichospastic activity is not improved by phosphorylation. (8) L. Coscia, G . De S a t a l e , and P. Causa, Communication a i the 13th Meeting of Societh Italiana di Farmacologia, Palermo, Italy, April 1965.
New Compounds Piperazinesulfamylurea Hypoglycemic Agents. V. J. AI. l\Ic>\l.z~us Medical Research Laboratories, Chas. Pjizeize, Cy: Co., Inc., Groton, Connecticut
Received J u n e 9 , 1966 Previoiis publications from these laboratories1 have demonbtrated the hypoglycemic activity associated with a series of sulfamylurea arid sulfamylsemicarbazides. This communication deals with the synthesis of a series of sulfamylureas in which the siilfamyl portion of the structure is derived from an acylated piperazine derivative.
n
RN
NS0,NHCONR'
W The preparation of the filial prodiivti (Table I ) was mobt coilveiiiently (wried oiit by a previously described method.' Acyla1ion of 1-stilfamylpiperazine with the appropriate acylatiiig agent provided a synthetic roiite t,o the requisite intermediates. Using reported screening methodology1 compounds 2 and 5 showed hypoglycemic activity, but of a degree less than the standard, chlorpropamide. Experimental Section2
1 -( 1 -Acetyl-4-piperazinesulfonyl)-3-cyclohexylurea.-A mixture of 3.4 g (0.015 mole) of 4-ac.etyl-l-sulfttmylpiperaai11e sodium and 4.99 g (0.017 mole) of X,N-diphenyl-?;'lohexylurea' was heated overnight on a steam bath. The cooled reaction mixture was diluted with 125 ml of water arid
extracted with t,hree 100-ml portions of ether. The aqueous layer was separated and acidified with 6 S HCl. The precipitated solid was filtered and dried in 21acuoover PzOs. The sulfamylureas were prepared by a similar procedure in yields of 50-657,. The sulfamylureas and their physical properties are listed in Table I. l-Sulfamyl-4-chloroacetylpiperazine.-To a suspension of 12.2 g (0.075 mole) of 1-~ulfamylpiperazine~b in 90 ml of methylene chloride was added 18.6 g (0.11 mole) of chloroacetic anhydride in 60 ml of the same solvent,. The mixture was allowed to stir for 1 hr and was then filtered, 15.4 g, mp 156-160". Recrystallization from methanol gave the pure product, 10.8 g, mp 172173". Anal. Calcd for CsHl,C1?;303S: C, 29.8; H, 5.0; N, 17.4. Found: C,29.8; H, 5.1; N, 17.4. l-Sulfamyl-4-methoxyacetylpiperazine.-~fetho~yacetylchloride (5.9 g, 0.055 mole) was added gradually t o a stirred solution of 8.25 g (0.05 mole) of 1-sulfamylpiperaziiie and 5.5 g (0.055 mole) of triethylamine in 75 ml of dimethylformamide (IIIIF). The resulting solution was allowed t o heat on a steam bath followed by cooling and the addition of ether. The resulting precipitate was filtered aiid washed with ethanol, 7.8 g, mp 146-151'. Recrystallization from ethaiiul gsve 6.7 g, mp 158-160". Anal. Calcd for C?H,,N304S: C, 35.4; H, 6.4; N, 17.7. Found: C, 35.1; H,6.0; N, 17.6. (1) J. M. MeManus, J. W. hIcFarland, C. F. Gerber, 11' 51. McLamore, and G. D. Laubach, J . .Wed. Chem. 8, 766 (1965); (a) J. W. hIcFarland. C. I. Gerber, a n d W. AI. XcLamore, abzd , 8 , 781 ( 1 9 6 i ) , (b) J . 11. 3IclhIanus and C. F. Gerber, zbzd.. 9,256 (1Y66). (2) Melting points mere determined on a Tllomas-€Ioo\ er capillary melting point apparatus a n d are correcied. T h e analyses uere carried o u t b y the Pliyslcal Measurements Laboratory of Chas. Pfizer & Co., Inc.
I:' 0 0
3 4 5 6 7 8 9 11 12 13 14 13
11
Some I)erivati\ es of Cyclododecatle'
21, I: 22, I: 23, I:
= = =
()It ('I SC'jk
H 24
