Journal of Medicinal and Pharmaceutical Chemistry VOL. 3, S o . 3 (1961)
Note
Monoquaternary Muscle Paralyzing Agents-11.'
Synthesis of N-(w-Phthalimidoalky1)-N-alkylmorpholinium Iodides" HUGH B. DONAHOE,ROBERTJ. S E I W A L D , t SISTER MARY MARGUERITE CHRISTINE NEUMANN, B.V.M.,t and KAZWOK . K I M U R A , t Departments of Chemistry and Pharmacology, St. Louis University, St. Louis, 4, Missouri Monoquaternary N-(w-phthalimidoalky1)-X-alkylpiperidinium iodides have been shown to possess activity paralyzing striated muscle.1 I n a continuation of this study, a series of compounds has been prepared in which morpholine has been substituted for piperidine. Table I. S-( w-Phthalimidoalky1)-morpholines and hydrochlorides 0-C ,H,(CO) ,N-(CH 2)fi-NCdH 8 0 m.p., "C
n
1 2 3 4 5 6
109-110b'*e 130-131 oil 66'5-67 oil 40h4 a
Formula
C13H14N20s Cl,Hl,~,O,C Cl,Hl,N,O, C l a HzoN,O,d CI ,H z N z 0 3 C I ,H p4Nz0,
HCl m.p."C
198-199*' 247-249 243*3 232-234 2 16-21 8 191-1 92
All yields calculated on the basis of hydrochlorides.
Yield,"
yo 58 58 62 79 80 77
Analyses, yo Chlorine r--------
Calcd.
Found
12.5 12.0 11.4 10.9 10.5 10.0
12.6 12.1 11.4 11.0 10.5 10.1
* Moore and Rapalas report: (1) 98-103'
(as hydrate); (2) 196-196°; (3) 247-218'; (4) 40'. c Calcd.: C, 64.59; H , 6.19. Found: C, 6 4 . 7 1 ; H,6.15. dCalcd.: C, 6 6 . 6 8 ; H , 6.99. Bound: C, 66.92; H , 7.05. eHellmannand Loeschmann* report: m.p. 118".
* This work was supported by a Frederick Gardner Cottrell Grant from Research Corporation and was taken from portions of the Ph.D. dissertations of R. J. Seiwald (1954) and Sr. M.M.C. Neumann, B.V.M. (1954). Present addresses: RJS, Department of Chemistry, University of San Francisco, San Francisco, Calif. ; Sr. NMCN, Clarke College, Dubuque, Iowa; KKK, Clinical Research Division, Medical Research Directorate, Chemical Research and Development Laboratories, Army Chemical Center, )Id, 611
H. B. DONRHOE ET AL.
612
With the exception of the monomethylene free base, which was prepared via the Mannich reaction,2$ the N-(w-phthalimidoalkyl)-morpholines (Table I) were obtained by reacting N-(wbromoalkyl)-phthalimides with excess morpholine in benzene to yield the tertiary free bases which were isolated as the hydrochloride salts. The AT-(u-phthalimidoalky1)-morpholines,as free bases, were reacted with methyl iodide, ethyl iodide or benzyl iodide to prepare the monoquaternary N-(w-phthalimidoalky1)-N-alkylmorpholiniuin iodides (Table 11). Because of reduced activity in the Table 11. N-(wPhthalimidoalky1)-A'-alkylmorpholinium iodides
0
-
m'p''
n
"C
Yield,
%
Analyses, Iodine
Formula.
a
DIPD =Minimuin paralyzing dose (lymph-sac injection). C No paralyzing action up to 400 mg/kg.
Frog MPD"
7 -
Methiodides, R = CH3 1 192-194 45 c 12% ,IN2 0 , 2 282-283 40 C l,Hl,IN,O, 3 291 58 C IP z i I N2 0 , 4 260 (d.) 92 C17H2&N203 76 '1SH 26INZo3 5 193-194 84 C19H2,1N203 6 152 Ethiodides, R = C,H, 2 235-237 39 Ci,HziINzOa 3 230 26 C17H231N203 1 ' SH 2 d N Z o 3 4 260 (d.) 86 5 184 88 C19H271N203 C20HBQ1N203 6 154-156 74 Benzyliodides, R = C,H,CH, 4 260 (d.) 71 23H2,1N203 5 201 (d.) 53 C,,H29IN*O, 6 189-191 61 C2.5H311N203 d-Tubocurarine Chloride (DTC)
C, 4 3 . 3 4 ; H, 4.88. C, 4 5 . 0 3 ; H, 6.94.
%
b
d
Calcd.
Found
32.6 31.5 30.4 29.5 28.6 27.7
32. ?b 31.4d 29.8 29.6 28.7 27.8
30.4 29.5 28.6 27.7 26.9
30.5 29.4 28.5 27.4 26.8
25.1 24.4 23.8
25.4 24.4 24.0
mg/kg
C
r c
80 60 60 0
200 150 60 60 100
40 40 2
Calcd.: C, 4 3 . 3 1 ; H, 4.41. Bound: Calcd.: C, 4 4 . 7 8 ; H, 5 . 7 6 . Found:
IVIOKOQCATERNARY MUSCLE PARALYZIKG AGENTS-11.
613
lower members of the series, compounds with methylene chains above six carbon atoms in length were not prepared.
Pharmacology All quaternary ammonium salts were tested for activity in paralyzing striated muscle in frogs (Rana pipiens) by lymph sac injection following a previously described pr0cedure.l The monoquaternary morpholinium compounds of this type were either devoid of paralyzing activity in the frog or were two to three times less active than the corresponding piperidinium methiodides and ethiodides. Only the five- and six-carbon chain benzyliodides were more active than the N-benzylpiperidinium iodides containing the same w-phthaliniidoalkyl groups. I n this series, N-(5-phthalimidopentyl)-N-benzylmorpholinium iodide and N - (6-phthalimidohexyl)-n'-benzylmorpholiniumiodide were most active. This activity, however, was only half that of the most active N-(w-phthalimidoalky1)-N-alkylpiperidiniumiodide.
Experimental*
N-(w-Bromoalkyl)-phthalimides. The 3-( w-bromoalkyl)-phthalimides were prepared from potassium phthalimide and w-dibromoalkanes by a previously described meth0d.l N-(w-Phthalimidoalky1)-morpholines.The tertiary morpholine bases were prepared in one of two ways. Method A . N-Phthalimidomethyl morpholine. The monomethylene derivative was prepared by a Mannich reaction following the procedure of Hellmann and Loe~chmann.~ Method B. Morpholine ( 7 0 g, 0.08 mole) and the appropriate AT-(w-bromoalkyl)-phthalimide( 0 02 mole) in benzene (60 ml) were heated on the steam bath for 1 h. Benzene and excess of morpholine were removed under reduced pressure and the residue was dissolved in ether. The solution was filtered to remove morpholine hydrobromide, decolorized with charcoal and dried. * Carbon and hydrogen analyses are by Du-Good Chemical Laboratory, St. Louis, Missouri, and Clark Microanalytical Laboratory, Urbana, Ill. Ionic halogen was determined potentiometrically in this laboratory. All melting points are corrected. 40
614
H. B. DONAHOE ET AL.
The dried solution was saturated with hydrogen chloride gas and t,he salt was filtered, washed with ether, and dried. The base was liberated from an aqueous solution of the hydrochloride with sodium carbonate solution. If solid, the free base was recrystallized from alcohol or petroleum ether. If an oil, it was taken up in ether, dried, and used directly in the quaternization step. N-(w-Phthalimidoalky1)-N-alkylnaorpholinium iodides. The X(w-phthalimidoalky1)-morpholine (0 * 005 mole) and the appropriate alkyl iodide (0.05 mole) in dry ether (100 ml) were mixed and allowed to stand overnight at room temperature. The precipitated quaternary salt was removed by filtration and the filtrate set aside until no more product was formed. The quaternary salts were recrystallized from either absolute ethanol or 2-propanol.
(Received 14 .November, 1960) References For Paper I see: Donahoe, H. B., Seiwald, R. J., Neumann, SI*. M.M.C. and Kimura, K. K. J . org. Chern., 22, 68 (1957) Moore, M. B.and Rapala, R. T. J . Arner. chern. SOC., 68, 1657 (1946) Hellmann, H. and Loeschmann, I. Chern. Ber., 87, 1687 (1954)
