206
J . Med. Chem. 1980, 23, 206-209
pressure. The solid residue was recrystallized from 1100 mL of ethanol after treatment with activated charcoal. The precipitate formed was collected by filtration, washed twice with ethanol. air-dried, and gave 342.9 g of pale yellow solid. The combined filtrate and washings above were reduced to about one-half volume, cooled to 4 "C, filtered, washed with cold ethanol, air-dried, and gave an additional 71.9 g of pale yellow solid. The combined filtrate and washings of the above solid was combined with an equal volume of diethyl ether and cooled to 4 "C. The solid formed was filtered, washed with 100 mL of 1:l ethanol/ether, air-dried, and gave 84.7 g of a tan solid. The combined weight of 4-(3bromopropy1)pyridine hydrobromide was 499.5 g (82.4%). To the 499.5 g of the preceding product in 500 mL of benzene was added a solution of 8.0 g of sodium hydroxide in 200 mL of cold water at 10-15 "C with stirring. The two-layered liquid was poured into a separatory funnel and an additional 50 mL of 10 N sodium hydroxide was added with thorough mixing. The aqueous layer (pH 13.0-13.5) was separated from the benzene layer and extracted with 200 mL of benzene. The benzene extracts were combined and dried over anhydrous potassium carbonate and anhydrous magnesium sulfate. The benzene solution was cooled to 5 "C and a total of 226 g of dimethylamine gas was added over a 2.5-h period with stirring. Stirring was continued while the solution was allowed to cool to room temperature overnight. A 300-mL portion of 10 N sodium hydroxide was added to the cooled reaction mixture with stirring, the layers separated and the aqueous layer was extracted with two 250-mL portions of benzene. The combined benzene extract was washed with three 100-mL portions of cold water and dried over anhydrous potassium carbonate and anhydrous magnesium sulfate. The aqueous layer was saturated with potassium carbonate, resulting in separation of an organic top layer which was insoluble in benzene. The organic layer was extracted twice with 250 mL of benzene as was the saturated aqueous layer. The combination of benzene extracts was dried over anhydrous potassium carbonate and anhydrous magnesium sulfate, stripped of solvent by water-pump evacuation. and gave
283.2 g of residual oil, which was distilled through a 15 X 2 cm Podbielniak Helipak filled column at a bath temperature ranging from 150 to 180 "C and controlled pressure of 9.0 to 10.0 mm. The 243.1-g (8370) fraction collected at a distillation temperature of 112-114 "C was 4-[3-(dimethylamino)propyl]pyridine. A 16.4-g (0.10 mol) portion of the above product was dissolved in 100 mL of i:l ethyl alcohol/water and 34.2 mL of 5.85 N hydrogen chloride in isopropyl alcohol and reduced with 1 g of platinum oxide over 40 psi of hydrogen. The reduction mixture was filtered through diatomaceous earth, and the filter cake was washed with 50% aqueous ethanol. The combined filtrate and washings was stripped of solvent,by water-pump evacuation. The residue was dried in vacuo over phosphorus pentoxide at 110 "C and gave 4- [3-(dimethylamino)propyl]piperidinedihydrochloride as an off-white solid, mp 233-239 "C Idec). A mixture of 7.75 g (0.0195 mol) of N-[2,3-bis(4-methyl-lpiperazinyl)-6-quinoxalinyl]formimidicacid ethyl ester and 8.5 g (0.050 mol) of the preceding product (free base) above was heated at reflux in an oil bath at about 140 "C for 2.5 h. The condenser was removed and the distillate was allowed to boil off. The reaction mixture was slurried with 150 mL of boiling hexane, cooled at --lo "C, and filtered. The pasty material collected was dissolved in 90 mL of hot acetonitrile. This solution was treated with activated charcoal and filtered. The filtrate was cooled at -~10"C, and the yellow solid formed was collected by filtration, dried in vacuo at '78 "C over phosphorus pentoxide, and gave 3.9 g (38.570) of 6-[ [ [4-[3-(dimethylamino)propyl]piperidino]methylene] amino]-2,3-bis(&methyl-1-piperaziny1)quinoxaline (1I), mp 13,5--139"C.
Acknowledgment. We thank L. Brancone and staff for microanalyses, W. Fuimor and staff for spectral data, Dr. P. J. Kohlbrenner and staff for large-scale preparation of intermediates, and Dr. E. J. Burden and S.Carvajal for the biological testing data.
Synthesis and Antiarrhythmic Properties of Some 5-Benzamido-2-methyl-trans -decahydroisoquinolines Ian W. Mathison* and Robert J. Pennington' School of Pharmacy, Ferris State College, Big Rapids, Michigan 49307. Receiued September 4 , 1979 An efficient synthetic route to produce exclusively 5-amino-2-methyl-trans-decahydroisoquinoline is described. The preparation of ten 5-benzamido-2-methyl-trans-decahydroisoquinolines from this precursor has been accomplished, and each has been screened for both antiarrhythmic potency and toxicity. The selection of structures for synthesis was based on our previous report of the significant antiarrhythmic potency of 5-(3,4,5-trimethoxybenzamido)-2methyl-trans-decahydroisoquinoline(15). Molecular modifications of this single structure were made in order to ascertain structureactivity relationships in this group of compounds. AU the compounds synthesized showed significant antiarrhythmic potency. The lipophilicity of the benzamide moiety appears to play a significant role in developing optimal antiarrhythmic potency. Interestingly and surprisingly, the most potent compound of the present study was 15, a compound described in our original work. Structure-activity relationships of the series are described.
In a continuing investigation of the antiarrhythmic properties of variously substituted decahydroisoquinolines, a more extensive study was conducted of some of our earlier work related to the 5-substituted decahydroisoquinoline series. The early studies indicated that the more lipophilic trans ring junctured isomers possessed the op(1) The work reported constituted a segment of the thesis sub-
mitted by R. J. Pennington to the University of Tennessee, Center for the Health Sciences, in partial fulfillment of the Master of Science degree requirements in medicinal chemistry. 0022-2623/80/ 1823-0206$01.00/0
timal antiarrhythmic potencies.2a,b Subsequent studies on several examples of 6-3 and %substituted4 decahydroisoquinolines yielded similar conclusions. In addition, the ( 2 ) (a) I. U'. Mathison, R. C. Gueldner, J. W. Lawson, S. J. Fowler, and E. R. Peters, J . M e d . Chem., 11, 997 (1968). (b) I. W.
Mathison, P. H. Morgan, R. It. 'ridwell, and C. R. Handorf, J . Pharm. Sci., 61, 637 (1972). (3) I. W. Mathison and R. R. Tidwell. J . M e d . Chern., 18, 1227 (1975). (4) 1. W. Mathison and P. H. Morgan. J M e d . Chem.. 17, 1136 (1974).
1980 American Chemical Society
5-Benzamido-2-methyl-trans-decahydroisoquinolines
Journal of Medicinal Chemistry, 1980, Vol. 23, No. 2 207 Table I. Physical Data of 5-Benzamido-2-methyl-trans-decahydroisoquinolines
Scheme I
R
1
02
N-CH3
tosylate
2
1 N-OH
3
4 NHCOR
5-1 5
general observation was made that amide substitutions yielded compounds possessing higher LDS0/EDs0ratios. The optimal compounds of the 5-, 6-, and 8-substituted series were benzamide derivatives. These results prompted a more thorough investigation of the 5-substituted class of compounds to include a larger selection of trans-decahydroisoquinolines substituted with various benzamides. An efficient synthesis for 5-amino-2-methyl-trans-decahydroisoquinoline,or a compound which could be readily converted to this amine, was needed. Previous approaches to obtaining the pure diastereoisomers of the several decahydroisoquinolines involved time-consuming fractional recrystallization procedure^.^,^ Since the production of only a trans-decahydroisoquinolinewas sought, utilization was made of the equilibration of 2-methyldecahydroisoquinolin-5-oneto its more stable trans ring junction isomer. A diastereoisomeric mixture of 5-amino-2-methyldecahydroisoquinolines was obtained from the platinum oxide catalyzed hydrogenation of 5-nitroisoquinoline as previously reported.' Deamination of this amine mixture with nitrous acid according to previously reported proceduresk7 yielded the corresponding hydroxy compounds in good yield. Oppenauer oxidation5 of the resulting isomeric mixture of hydroxy compounds provided pure 2-methyltrans-decahydroisoquinolin-5-one(2). Preparation of the oxime (3) from this ketone, followed by LiA1H4reduction, produced the desired trans ring junction isomer of 5amino-2-methyldecahydroisoquinoline(4)in good yield without the tedium of isomeric separation procedures. Confirmation of the complete stereochemistry of 4 (including the expected LiA1H4reduction of the oxime to an equatorial positioned NH, grouping) was obtained by conversion of 4 to its 3,4,5-trimethoxybenzamide(15). The product 15 was identical (mp, mmp, spectral data) with that of the known compound.2a The amine 4 was converted to the appropriate benzamide by standard metho~~~~
~~~
(5) I. W. Mathison and P. H. Morgan, J. Org. Chem., 39, 3210 (1974). (6) I. W. Mathison and R. R. Tidwell, J . Chem. Soc., Perkin Trans. 1, 757 (1976). (7) I. W. Mathison and R. C. Gueldner, J. Org. Chem., 33, 2510 (1968).
no.
recrystn yield, solvent %
R
-
mp, "C
-NHCOC,H, -NHCOC,H," . 4-C1 -NHCOC,H,2.4-C1, -NHcoC,H,3,4431, -NHCOC,H,4-CF, -NHCOC,H,4-N02 -NHCOC,H,4-OCH3 -NHCOC,H," 4-CH3 -NHCOC,H,3-C1 -NHCOC,H,4-F -NHCOC,H,3,4,5-(OCH,)e
5 6
EtOAc EtOAc
80 61
203-204 225-226
1
EtOAc
81
200-212
8
EtOAc
54
204-205
9
EtOAc
77
217-218
10
EtOAc
74
238
11
EtOAc
73
208-209
12
EtOAc
73
218-220
13
EtOAc
89
206-207
14
EtOAc
63
207-209
15
Prepared previously; see ref 2a. Table 11. Antiarrhythmic Potencies and Toxicities of 5-Benzamido-2-methyl-trans-decahydroisoquinolines ED,
