SOTES
March 1970 their experimental procedure differs from ours in the use of I b as a hydrate for the Grignard reaction, and in their use of distillation and chromatography in the purification of 11, whereas we achieved final purification of I I b through the direct formation of the oxalate salt. Experimental Sections
303
taneous motor activity and blood pressure. They were found to exert a depressant action on the spoiltaneous activity of mice a t a dosage level of 4 mg kg arid effect a prolonged reduction in blood preqture of normotensive rats at this dosage. I t \\as noted that the most active analogs studied were the p-chloroand the p-methoxy-N-(/3-cyarioethy1)-9'-cyclohes;vlbenzamides. This paper reports a conveiiieiit *ynthesis wild pharmacological evaluation for a serieq of amides of ortho-, nzeta-, and para-monosubqtituted benzoic acids
l-Benzyl-3,4-dimethylpyridiniumChloride (Ib).-A solution of 42.2 g of C6H6CH2C1and 35.7 g of 3,4-lutidine in 100 ml of Me&O was allowed to stand overnight a t room temperature. The product, obtained in 81-89% yield in two crops, melted at (1-9). 196-197.5'. And. (CirH16ClK) C, H, N. l-Benzyl-2-(p-methoxybenzyl)-3,4-dimethy~-l,2,5,6-tetrahydropyridine (IIb).-The Grignard reagent from 36.3 g of p-methoxybenzyl chloride (using 3 1. of Et20/mole to reduce coupling) was added to 32.8 g of I b in EtrO. The mixtureq-as stirred and refluxed for 1.5 hr and poured into a solutionof 14 g of SH4Cl in H20. Crude bianisyl was removed by filtration, t,he Et20 layer separated and washed with H20, and t.he dihydropyridine isolat.ed as a crude residue (57.5 g) by removal of the Et2O. This was reduced in EtOH with 3.9 g of NaBHI in H20. The reaction mixture was stirred overnight at, room temperature and t,he EtOH then removed in vacuo. The aqueous phase was extracted with Et20 and the latter extracted in several portions with a total of 17.5 g 1,2,3, R = p-, m-, o-OCH, of 85% Hap04 in 400 ml of H2O. Addition of excess 367, aqueous NaOH to the acid extract,>. ext,raction of the resultant oil into 4,5,6, R = p - , m-,0-C1 EtzO, drying, filtrat,ion, and concentration afforded 32.5 g of 7, 8, 9, R = p - , m-,o-CH, crude base. This was added to 9.1 g of oxalic acid in 100 ml of Me2CO to precipitat,e 31.2 g of IIb.oxalate, mp 163-158'. dnal. Effects on the Central Nervous System of Mice. (CnH2iNO.GH204) C, H, S . Gross Observation.-At a dose of 5 mg kg, adminis3-BenzyI-l,2,3,4,5,6-hexahydro-cis-6,11 -dimethyl-2,6-methtered intraperitoneally (i.p.), 1-9 caused sedation ano-3-benzazocin-8-01 .HBr tIIIb).--4 mixture of 53.8 g of crude without sleep in mice. -4persistent state of tranquility IIb.oxalate, 145 ml of HOAc, and 285 ml of 62VG HBr was redeveloped within 10 min following administration and fluxed for 22 hr, concentrated in uacuo, and diluted with 800 ml of i-PrOH. The slurry was stirred. concentrated to about 250 ml, lasts for several hours. The animals' overall response cooled, and filtered. The prodiict was t,aken up in EtOH and pattern was similar to that observed with chlorpromwprecipit,ated with about an eqrial volume of E t 2 0 to give 23.7 g zine with 1, 3, 4, 5, 7, and 9, demonstrating greater of I I I b as the hydrobromide, mp 259-262'. A n a l . (C21H2jdepressant activity. The test compounds potentiate S O . H B r ) C, H, Br. The i-PrOH mother liquor. contain some of the trans: isomer, the sedative action of reserpine. mp 275-276" corrected. A n d . rCalHajNO.HBr) C, H, PI;. 1,2,3,4,5,6-Hexahydro-cis-6,11 -dimethyl-2,6-methano-3-benzExperimental Section2 azocin-8-01 (111, R = H).-Reduction of 11.8 g of IIIb.HBr in General Method of Preparation of Amides.-Eq~iimolecular DMF using a 1072 Pd-C catalyst gave, after removal of the amounts of the substituted benzoyl chloride aiid S-(@-hydroxycatalyst and solvent and basification u-ith ?;HIOH, 6.0 g of ethyl ) cyclohexylamine (Abbot t Labora t ories, ?;ort h Chicago, product, mp 234-235°.6 -4nal. (C,,H1&0) C, H, N . Ill.) were dissolved in freshly distilled DlIAC. The acyl halide Alkylation of t,his base with l-bromo-3-methyl-2-butene to solution was then added to a cooled, well-stirred mixture of the give pentazocine has been de..crihed.' A--( @-hydroxyethy1)cyclohexylamine soliltion and Et3K. When the additioii of the acyl halide solution was completed, the crude ( 5 ) Melting points are not corrected for emergent stem errors. wbstituted benzamide was precipitated by the addition of cold (6) E. hl. Fry and E. L. JIa>- [ J . Oru. Chem.. 24, 116 (1959)l report mi, 232-235' corrected. H20 and collected. The crude product \va.. re ( 7 ) S. Archer, K. F. Alhertson. L. S. Harris, Anne E.Pierson, and J. G. EtOH-H20 to give the pure compounds L t e d iii Table I . Bird, J . .Wed. Chem., 7 , 123 (1964). Pharmacologic Methodology. Gross Observations.-To study the in vivo effects, C3H mice weighing betmeii 20 and 25 g were used. ,411 test compounds were dissolved in p~vpylenegl!-col and administered orally and i.p. Dose-response ciirves were cibtained Substituted Benzamides. Analogs of living 8 mice (rats) a t each of four dose level.. aiid the median effective dose (ED:,) was calculated. fi-Hydroxyethylcyclohexylaminewith CNS The effect of the compounds on reserpine-induced setlatiun was Depressant and Hypotensive Activity studied in mice by injecting them i.p. 4 hr follo~~-ing the administration of 2.5 mg/kg of reserpine i.p. and compared with that of the control groups at varying intervals. W I L L I ~D. V ROLL Wistar rats dosed simultaneously with amphetamine ( 0 . 4 5 ) 4 mg/kg i.p. and test compounds 1, 3, 4,7, and 9 did not exhibit Department of Medicznal Chemistry, College of Pharmacy, the characteristic symptoms (tremors, pacing, piloerection) noted T h e Cniversity of Toledo, Toledo, Ohio 4,3606 in control animals receiving only the aforementioned dose of amphetamine. Received September 10, 1969 Spontaneous Activity.-The depressant activity of the te5t compounds was det,ermined in mice with actophotonieters I n a previous publication' n e reported the synthesis (Metro Industries, Inc., Kew Tork, X. I-.).The total body
and pharmacological evaluation of a series of ringsubstituted N-(@-cyanoethy1)-N'-cJ- c lo hex y 1benz amides. The biological activity of these compounds was studied in mice and rats for their effect on spon(1)
W.D. Roll, J Phurm. Sci 157, 1671 (1968).
( 2 ) Melting points were determined using a Xettler FP-I melting and Iioiling point apparatus and are corrected. Analyses ( C . H ) were ohtained x i t h a Coleman C-H analyzer, and where they are indicated only hy symbols of the elements analytical d a t a ohtained for these elements were uithin 10.4% of the theoretical ralues. I r spectra were ohtained v i t h a PerkinElmer spectrophotometer Model 137-B ( I i B r ) .
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