Journal of Medicinal and Pharmaceutical Chemistry VOL. 4, KO.2 (1981)
N-Alkoxy-N-alkyl(ary1oxy)acetamides and their Hypnotic Activity RANDOLPHT. MAJOR* and KARL W. OHLY, Cobb Chemical Laboratory, University of Virginia, Charlottesville, Virginia The compound N,N-diethyl(4-allyl-2-methoxyphenoxy)acetamide, CH,=CHCH,(CH30)C,H30CH2CON(C,H,),,is a hypnotic of considerable interest, a-g I n view of the similarities between the pharmacological activities of some derivatives of hydroxylamine and those of the corresponding amines2 it was felt worthwhile to prepare N-ethoxy-N-ethyl(4-aIkyl-2-methoxyphenoxy)acetamide, CH,=CHCH2(CH,0)C,H30CH2CON(C2H6)OC,H,, as well as some other N - alkoxy-N - alkyl(aryloxy)acetamides, ArOCH,CON(R)OR. All these new compounds were colourless oils which were rather insoluble in water. Each of the new compounds was synthesized from the corresponding aryloxyacetic acid through its acid chloride, which in turn was prepared by the action of thionyl chloride on the acid. The AT-alkoxy-N-alkyl(ary1oxy)acetamideswere formed by the slow addition of a solution of a molar equivalent of the acid chloride in ether t o a stirred solution of two molar equivalents of the appropriate N-alkoxy-N-alkylamine in ether. The crystalline or oily precipitate was removed by filtration. After hhe ethereal solution had been washed with water, dried and distilled, the amides wese obtained. Purification was achieved by filtrationof a benzene solution of the amide through an alumina column. The impurities were readily absorbed on the alumina. I n this way N-alkoxy-ATalkyl(ary1oxy)acetamides in which the N-alkoxy-N-alkyl groups were hT-methoxy-N-methyl and AT-ethoxy-N-ethyl were made. The aryloxy groups used were phenoxy, 5-methyl-2-isopropyl2-methyl-5-isopropylphenoxy, 4-allyl-2-methoxyphenoxy, phenoxy and 2-methoxy-4-n-propylphenoxy.For purposes of comparison, N , N - diethyl - (2-methoxy - 4 - n - propy1phenoxy)acetamide was prepared by the above general procedure. ,41so,
* Author to whom corrrespondence with respect to this paper should be sent. 317
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R. T. MAJOR AND K. W. OHLY
N,N-diethyl-(4-allyl-2-methoxyphenoxy)acetamide1~ was prepared by published procedures. I n order t o obtain a compound of this general type which would form a water-soluble salt, an effort was made to produce an N-alkoxy-N-alkyl(quino1yl-8-0xy)acetamide.This was unsuccessful, but in the course of this work quinolyl-8-oxyacetamide and quinolyl-8-oxyacethydrazidewere synthesized. These were prepared by the action of ammonia or hydrazine hydrate respectively on the corresponding ester. Ethyl quinolyl-8-oxyacetate was prepared by the action of a mixture of absolute alcohol and concentrated sulphuric acid on the corresponding acidU3Attempts to prepare quinolyl-8-oxyacetyl chloride were unsuccessful ; only black tars were obtained when efforts were made to purify the chloride. Pharmacological activity. Dr S. S. McKinney and associates in the Merck Institute for Therapeutic Research, West Point, Pennsylvania, to whom we are much indebted, have kindly given us the information shown in Table I on the toxicity and hypnotic activity of these new compounds. On the basis of potency and therapeutic index (lethal dose/ hypnotic dose), compounds I, I11 and V in Table I would appear t o have potential interest as intravenous short-acting anaesthetic agents, similar to the known anaesthetic agent, compound XII. la-g The most promising compound on the list is compound I. However, the other two compounds mentioned above, namely I11 and V, have therapeutic indices similar to or greater than those obtained for barbiturates that are used as anaesthetics. It is quite clear that a t least some of the N-alkoxy-N-alkylamides in this series possess hypnotic activity equal to or greater than that of the corresponding N,N-dialkylamides. Experimental
Aryloxyacetyl chlorides. A 30 per cent excess of thionyl chloride was refluxed with the appropriate aryloxyacetic acid for 30-60 min. After removal of excess thionyl chloride by distillation the oily acid chloride was distilled in vacuo. N -Alkoxy - N - alkyl - (aryloxy)- 4 - acetamides. To a vigorously stirred solution of 0 2 mole of O-N-dialkylhydroxylamine(where
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Prepared by the method of Clauser.s Prepared by the method of Sbigematsu and Kobayashi.'g Prepared by refluxing a solution of 2-methoxy-4-n-propylphenol and sodium chloracetate in water for 10 h. \Then poured into dilute acid an oil precipitated which crystallized as needles, recrystallized from alcohol, m.p. 78". Fujita, Watanabe and Matsuura give m.p. 71-72°.8 d Prepared by the method of Spica.' e Prepared by the method of Jlameli.B i Prepared by the method of Hantzsch.* II Prepared by the method of Rosemund and Zetzsche.lo a
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HYPNOTIC N-ALKOXY-A'-ALKYL(ARYL0XY) ACETAMIDES
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almost colourless or slightly yellow oils, which decomposed rather readily on distillation. They were dissolved in benzene and filtered through an alumina column. Most of the impurities were adsorbed while the N-alkoxy-N-alkylamide passed through the column. Evaporation of the benzene and vacuum distillation of the residue gave analytically pure compounds as shown in Table 111. Ethyl quinolyl-8-oxyacetate. A solution of quinolyl-8-oxyacetic acid3 (30 g) in a mixture of absolute alcohol (300 ml) and concentrated sulphuric acid (33 ml) was refluxed for 5 h, concentrated in vacuo and made alkaline with sodium carbonate. It was then extracted repeatedly with chloroform and dried, and the chloroform was evaporated. Distillation in vacuo gave 22 g of a colourless, viscous oil, b.p. 160"/0.03 mm. I n the infrared it exhibited absorption bands a t 5 7 p and a t 8 * 9 p. Picrate. The ester formed a picrate, m.p. 167" (d.). A n a l . Calcd. for C,,H,,N,O,,: C, 4 9 . 5 7 ; H, 3.50. Found: C, 49.29; H, 3.48. Quinolyl-8-oxyacetamide. Ethyl alcohol was added to a mixture of ethyl quinolyl-8-oxyacetate and an excess of concentrated ammonium hydroxide until solution took place. After the solution had stood overnight, long colourless needles had formed, which were recrystallized twice from alcohol, m.p. 170". The infrared spectrum showed bands a t 6 . 1 5 p and 9.0 p. Anal. Calcd. for C,,H,,N,O,: C, 6 5 . 3 3 ; H, 4 . 9 9 . Found: C, 6 5 . 4 3 ; H, 4.83.
Quinolyl-8-oxyacethydraxide. A solution of ethyl quinolyl-8oxyacetate (6 g) and hydrazine hydrate (1 5 g) in absolute alcohol (50 ml) was refluxed for 2 . 5 h. After the solution had stood a t room temperature overnight colourless needles had precipitated. These were recrystallized from absolute alcohol; m.p. 140"; yield 80 per cent. A n a l . Calcd. for C,1HllN30,: C,60.81; H, 5 . 1 0 . Found: C, 6 0 - 7 7 ; H, 5 . 1 2 . was preSummary. A series of N-alkoxy-N-alkyl(ary1oxy)acetamides pared. Several of these compounds showed some hypnotic activity in the mouse. The most active was N-ethoxy-N-ethyl-(4-alkyl-2-methoxyphen0xy)acetamide. I n order to obtain an analogous compound which
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would form soluble salts in water an effort was made to prepare N-alkoxyN-alkyl(8-quinolyloxy)-acetamide. This was unsuccessful. However, were prepared. quinolyl-8-oxyacetamide and quinolyl-8-oxyacethydrazide
Acknowledgements. The authors are indebted to Merck and Company, Inc. for a grant in support of this research project. Microanalyses were done by Geller Laboratories, Bardonia, New York and by Mrs. Margaret Logan of this Laboratory, to whom we are indebted.
(Received 14 December, 1960)
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