R. B. MOFFETTAND B. I). - ~ P E R G R B N
344s
evaporation of the ether. By procedures previously described, viz., co-chromatography with added methyl gallate and gallic acid, the identity of (a) and ( b ) as methyl gallate and gallic acid, respectively, was established. Hydrolysis with Aqueous Sodium Bisulfite.-A solution of tannin B (1.0 g.) and sodium bisulfite (2.0 9.) in mater (20 cc.) was heated under reflux for 6 hr.. cooled and filtered from a yellow crystalline sodium salt (0.34 g.). The filtrate was extracted with ether, acidified and re-extracted with ether. Two-dimensional paper chromatograms showed the presence of pyrogallol and methyl gallate in the first cther extract and gallic acid in the second ether extract. The crystalline sodium salt, suspended in warm water and
[COVTRIBUTION FROM
THE
1'01.
'7s
treated with hydrochloric acid, gave ellagic acid, m.p. >3B0°, , , ,A 366, 256 m p in ethanol. Tannin A.-Paper chromatograms showed the presence of the same phenolic constituents in both tannin -4and B, although in different relative amounts. Tannin X gave a positive Molisch carbohydrate test and appeared to contain free carbohydrate.
Acknowledgment.-The author wishes to thank L. AI, Tl'hite for performing the elementary analyses. PASADENA, C.4LIF
RESEARCH LABORATORIES O F T H E UPJOHN COMPANY]
Antispasmodics.
VIII. Scopolamine Derivatives
BE. ROBERT BRUCEhfOFFETT A N D BROOKE n.i l S P E R G R E N RECEIVEDFEBRUARY 2, 1956 A variety of derivatives of scopolamine have been prepared and tested for their antispasmodic and gastric antisecretory activities. These include several quaternary salts (analogs of Pamine Broniide'32) and a number of 0-acyl esters of scopolamine and their salts. Aposcopolamine, desoxyscopolamine, 6-hydroxptropine tropate and a n ester of scopoline together with their methobromides were also made and tested. Of the above, 0-acetylscopolamine methobromide appears t o be the most active anticholinergic, but several other 0-acyl scopolamines show interesting properties. Most of these compounds are new but a few that have been previously reported are here more completely characterized.
The excellent properties of Pamine Bromide' as a visceral antispasmodic and gastric antisecretory agent3 have prompted us to prepare a number of other derivatives of scopolamine. Besides the methyl bromide several other quaternary salts (I) were prepared. Some of these have been previously reported4Jbut for the most part without analytical data.
ago.z.7 Recently an Australian patent specifications described this hydrobromide, giving considerably different properties from the older literature CH2-CH-CH
K '-C-0-CHz I1 0
xHOCHz
I
Pamine Bromide' was also prepared from radioactive (Cl4) methyl bromide. This was used by Dr. William L. hfiller6 in studies of the metabolic disposition and excretion of Pamine in dogs.
0-Acetylscopolamine and its hydrobromide (11, R' = CHz, RX = HBr) were reported many years (1) T h e Upjohn Company brand of Scopolamine Methyl Bromide (I, R = CHa, X = Br). (2) 0. Hesse, J . prokt. Chem., Iii] 64, 353 (1901). (3) F. E. Visscher, P. H. Seay, A. P. Tazelaar, Jr., W.Veldkamp a n d M. J. VanderBrook, J. Pharmacol. E r p . Therap., 110, 188 (1954); J. B. Kirsner and W. L. Palmer, J . A m . .Wed. Assoc., 161, 798 (1953): J. B. Kirsner, E. Levin, and W. L. Palmer, Gasl7ocntcrology. 26, 852 (1964). (4) E. Schmidt, Arch. Pharm., 232, 409 (1894). ( 5 ) H. Wick, Arch. rxper. Path. Pharmacol., 213, 485 (1951). (6) IT.L. Miller. J.J. Krake a i d M J. Vnuderl3n,ok, to be pliblisliwi C!lrc\i &we.
CHa-N \CH*-CH-CH
I I
\
O,1
*RX
I1
but without analytical data. We have repeated the preparation and our results confirm the Australian work except that our melting point was nine degrees higher. The methyl bromide quaternary salt (11, R' = CH4, RX = CHaBr) was also prepared and found to have excellent anticholinergic properties (Table 1). Its clinical investigation is under way. Besides the acetate, a number of other 0-
esters of scopolamine salts (11) were prepared. These esters were made by the action of a large excess of the acid anhydride or the acid chloride and pyridine on scopolamine hydrobromide. I n the case of the phenylurethan, scopolamine base was treated with phenyl isocyanate. The epoxide ring of scopolamine hydrobromide has been hydrogenated by Fodor and K o v a ~ sbut ,~ they hydrolyzed the product to dl-trans-&hydroxy(7) E Schmidt, Arch Phavm , 2S0, 207 (1802). IR) Riistralian Spec 12181 i l O i 2 ) (iij C. Fodur And 0 K u ~ i i ~ Js . Lheni S u i , 2341 (1953)
ANTISPASMODICS : SCOPOLAMINE DERIVATIVES
July 20, 1956
3440
TABLE I PHARMACOLOGICAL ACTIVITIES CHz-CH-CH CHC-0-CH
CH8-A
R-0-CHz
1 /" \
I
.R'X
Toxicity
L Dw"
1 2 3 4
5 6 7 8 9 10 11 12 13 14 15 16 17 18
R'X
R
NO.
H H H H H H H H CHiCO CHsCO CHsCO (CH3)&CO (CH3)aCCO (CHsCH2)zCHCO (CHzCHz)*CHCO (CHa)zCHCH(CH2CH3)CO (CHa)zCHCH( CHsCHa)CO CHz)4yHCHzCH*CO
r(
CH8Br1s* CH3CH2Br4
CH~=CHCH~CP CH3(CH2)Jd HOCHzCHzB9 C$15CH2Cld Br( CH2)6Bre +O.HB# HBr8 CHaBr -00 HC1 CHtBr HBr CHaBr HBr CHaBr CHaBr
(At.1.) b
Antispasmodic activity (At.I.)b
150 200 83 200 233 233 5.3 >loo0 533 167 650 767 77
6.0 3.0 1.0 0.2 2.0 0.5 0.2 2.0 2.0 6.0
