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ethy1)propionanilide-d-tartrate,m.p. 194-197', was 30.7 g. Three recrystallizations from ethanol resulted in a 71% yield of pure product, m.p. 204.5-205.5" and [a]: f23.7 (2% in water). Anal. Calcd. for C Z ~ H ~ Z NC,~ O59.4; ~ : H, 7.6; N, 6.6. Found: C, 59.2; H, 7.8; N, 6.6. This product was converted to the hydrochloride by the procedure described above for the 1 isomer. The over-all yield of d-N-( 1-methyl-2-piperidinoethy1)propionanilidehydrochloride, m.p. 202-203' and [a]: $18.9 (2% in water) was 8.1 g. (35%).
[CONTRIBUTION FROM
485
BASIC ANILIDES CONTAINING THE PHENALKYL MOIETY
THE
Anal. Calcd. for C1,HZ7CIN~0: C, 65.7; H, 8.8; C1, 11.4; N, 9.0. Found: C, 65.6; H, 8.8; C1, 11.2; N, 9.4.
Acknowledgment. We are indebted to Mr. L. Brancone and associates for the microanalyses, to Dr. J. H. Clark and co-workers for the preparation of some of the intermediates, and to Dr. A. C. Osterberg and associates for the pharmacological data. PEARL RIVER,N. Y.
ORGANIC CHEMICAL RESEARCH SECTION, LEDERLELABORATORIES DIVISION,AMERICANCYANAMID CO.]
Synthetic Analgesics. 111. Basic Anilides and Carbanilates Containing the Phenalkyl Moiety' WILLIAM B. WRIGHT, JR.,HERBERT J. BRABANDER,
AND
ROBERT A. HARDY, JR.
Received M a y 6, 1960 A series of N-( tert-aminoalky1)anilides and -carbanilate5 containing the phenalkyl moiety has been prepared. Some of these compounds show analgesic potency in the codeine to morphine range. N - [2-(Methylphenethylamino)propyl] propionanilide sulfate, diampromid, has been chosen for clinical trial in man.
N-( 1-Methyl-2-piperidinoethy1)propionanilide hydrochloride (I)?phenampromid, which may be considered a nitrogen analog of isomethadone, was reported in the previous papers of this series2 to have analgesic activity similar to meperidine. Other investigatorss have shown that replacement of the N-methyl group by a phenalkyl group in analgesics such as meperidine, racemorphan, and a-prodine often results in increased activity. We, therefore, were interested in determining whether increased potency could be obtained by introducing CO-CZHs
TABLE I ANALGESICACTIVITY
CHQCH3
H m-CH3 p-CHs p-c1 P-F H m-CH3 p-N& H H
CN-C I H~CH-N~ HCI
-
I CHJ I
R
b
CO-Rz ,N-CnHzn-A+yR1
=alkyl, -
Meperidine Morphine -
alkyl
I1 (1) (a) Presented in part a t the 135th Meeting of the American Chemical Society, Boston, Mass., April, 1959; (b) W. B. Wright, Jr., R. A. Hardy, Jr., and H. J. Brabander, U. S. Patent 2,944,081, July, 1960. ( 2 ) W. B. Wright, Jr., H. J. Brabander, and R. A. Hardy, Jr., J. Am. Chem. Sac., 81, 1518 (1959); J. Org. Chem., 26,476 (1961). (3) (a) T. D. Perrine and N. B. Eddy, J. Org. Chem. 21, 125 (1956); (b) E. L. May, J. Org. Chem. 21, 899 (1956); (c) J. Weijlard, P. D. Orahovats, A. P. Sullivan, G. Purdue, F. D. Heath, and K. Pfister, J. Am. Chem. Sbc., 78, 2342 (1956); ( d ) B. Elpern, L. N. Gardner, and L. Grumbach, J . Am. Chem. Soc., 79, 1951 (1957); (e) B. Elpetn, W. "etterau, P. Carabateas, and L. Grumbach, 133rd Meeting of the American Chemical Society, April, 1858, Abstracts of Papers, p. IlM., Aba. No. 18.
1 1 1 1 1 2 2 2 2 3
H H H H H H H H m-CH30 H H
8 2 3 6 6 4 14 16 15 17 4 11 3
AD60 = The subcutaneous dose which elevates the rat tail radiant heat response time by 100% in 50% of the animals. N- [2-( Cinnamylmethylamino)propyl] propionanilide.
phenalkyl groups in our series of N-(tert-aminoalky1)anilides and -carbonilates. Such compounds are represented by formula 11. One general procedure used for these compounds is that described in our previous papere2 This consisted of acylation of the appropriate alkylenediamines with an acid chloride or anhydride (Tables IV, V, VI). Conventional alkylation of an aniline with a tert-aminoalkyl halide gave the straight chain diamines' (Tables I11 and V). Lith-
486
WRIGHT, BRABANDER, AND HARDY
?@??
2IGR
o? 3 3
VOL.
26
ium aluminum hydride reduction of the appropriate propionamide gave the desired branched chain diamines (Table 111) of unequivocal structure.2 A second general procedure was also used, which allowed for the preparation of many end products containing a variety of phenalkyl groups from a common intermediate. Compound I11 was reductively debenzylated to IV in nearly quantitative yield and converted to V by reductive alkylation or by reaction with an aralkyl halide.
CH3'
I
CH, 111
I
3
-
3 3 3 3
Pharmacological results indicated that introduction of the phenalkyl group in the basic moiety of the N-(tett-aminoalky1)anilide series significantly increased analgesic activity in many cases. These compounds were tested by a sequential modification6 of the mouse hot plate method of Woolfe and Macdonald6 and Eddy et al.? and the rat tail radiant heat procedure of D'Amour and Smith.* N-[Z-(Methylphenethylamino)propyl]propionanilide sulfate, diampromid, was found to approximate the potency of meperidine in mice and morphine in ratss9 Extensive pharmacological evaluation led to the selection of this compound for trial in mati. Clinical results indicate that diampromid is a narcotic-type analgesic. Structure-activity relationships in this series (4) (a) F. Leonard and U. V. Solmssen, J . Am. C h m . SOC., 70, 2064 (1948); (b) S. G. Fridman, Zhur. Obshchei Khim., 23,278(1953);(c) M. A. Stahmann and A. C. Cope, J. Am. Chem. SOC.,6 8 , 2494 (1946); (d) M. W. Goldberg and S. Teitel, U. S. Patent 2,746,992,May 22, 1956. (5) A. C. Osterberg, J. D. Haynes, and C. E. h u h , J . Pharmacol. Expll. Therap., 122,59A (1958). (6) G.Woolfe and A. D. Macdonald, J. Pharmacol. Expll. Therap., 80,300 (1944). (7) N.B. Eddy, C. F. Touchberry, and J. E. Lieberman, J. Pharmacol. Expll. Therap., 98, 121 (1950). (8)F.E. D'Amour and D. L. Smith, J. Pharmacol. Exptl. Therap., 72,74(1941). (9) A. C. Osterberg and C. E. Raiih, The Pharmacologist, 1 (No.2), 78 (1959): Abstracts of Papers, Fall Meeting, Am. Soc. Pharmacol. Exptl. Therap., Aug.Sept., 1959,Coral Gables. Fla.
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BASIC ANILIDES CONTAINING THE PHENALKYL MOIETY
Y * ? 222 2 5 :: ???
N
e:
b
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WRIGHT, BRABANDER, AND HARDY
d
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BASIC ANILIDES CONTAINING THE PHENALKYL MOIETY
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WRIQHT, BRABANDER, AND HARDY
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100 ml. of ethanol, 5 ml. of water, 5 ml. of concd. hydrochloric acid, and 1 g. of palladium-on-carbon catalyst was reduced in the Parr hydrogenator until 4.7 lb. of hydrogen was absorbed. The catalyst was filtered and the solvent was evaporated. The residue was made alkaline with dilute sodium hydroxide and extracted with ether. The ether layer was concentrated and distilled. N- [Zp-Aminophenethylmethylamino)propyl)propionanilide was collected a t 190200' (0.1 mm.). 4-Phenylbutyryl chloride. A eolution of 16.4 g. (0.1 mole) of 4phenylbutyric acid in 100 ml. of cold chloroform was slowly EXPERIMENTAL added to a cooled solution of 30 ml. of thionyl chloride in The salts, Zbromopropionamidea (Table 11), Zamino- 100 ml. of chloroform. The reaction mixture was refluxed propionamidea (Table 11), a l k y l e n e d i i e s (Tablea I11 for 90 min. and distilled. The yield of 4phenylbutyryl chloand V), carbanilatee (Tablea IV and V), and some of the ride, b.p. EUI-85" (0.2 mm.), was 8.6 g. (47%). This comanilidea (Tables IV-VI) were prepared by the methods pound was not analyzed. N'-MethyGN1-phenyl-l,f&propanediamine. A mixture of described in the previous paper of thia series.' New pro12.7 g. (0.05 mole) of N*-benzyl-NLmethyl-N1-phenyl-l,% cedures are described below. N-[&(Methylumino)propiorurnili&. A mixture of 31 g. propanediamine, 50 ml. of I N hydrochloric acid, 50 ml. of (0.1 mole) of N-[2-( benzylmethy1amino)propyllpropionani- ethanol, and 1 g. of 10% palladium-on-carbon catalyst was lide, 25 ml. of 4N hydrochloric acid, 175 ml. of ethanol, shaken in a Parr hydrogenator under about 3 atm. of hyand 2 g. of 10% palladium-on-carbon catalyst was shaken in drogen pressure until the theoretical amount of hydrogen a Parr hydrogenator under about 3 atm. of hydrogen prea- was absorbed. The catalyst was filtered off and the filtrate sure until the theoretical amount of hydrogen was absorbed. was concentrated. The residue was triturated with ether The catalyst was filtered off and the filtrate was concen- until crystallization occurred and the product was filtered. trated to a sirup and treated with aqueous d u m hy- The yield of N*-methyl-N'-phenyl-l,Zpropanediamine, droxide. The product was extracted into ether and distilled. hydrochloride, m.p. 96-99", was 9.3 g. (93%). RecrystallisaThe yield of N- [2-(methylamino)propyl]propionanilide, tion from ethanol by the addition of ether raised the melting point to 100-102°. b.p. 112-116' (0.2 mm.) and n y 1.521, was 71%. A d . Calcd. for ClaHl,, ClN,: C, 59.8; H, 8.5; C1, 17.7; N, A d . Calcd. for ClaHmNtO: C, 70.9; H, 9.1; N, 12.7. 14.0. Found: C, 59.7; H, 8.9; C1, 17.7; N, 13.9. Found:C,70.5;H,9.3;N, 13.1. The base was obtained by treating the hydrochloride with N- [%(Phaatkylmethylamino)prqpyl]propiononjlides. A mixture of 0.025 mole of the appropriate phenalkyl halide, aqueous alkali, extracting the product with ether, and dismethylamino)propyl]propionanilide, and tilling, b.p. 90-96' (0.1 mm.) and n y 1.547. 0.05 mole of N-[Z( N-(,%Anilin&l -methylethyl)-N-meth yl-4-phen ylbutyramirle. 40 ml. of ethanol was heated on the steam bath overnight, concentrated to remove the solvent, and diluted with 10 ml. A solution of 8.6 g. (0.05 mole) of 4phenylbutyryl chloride of water. The reaction mixture was extracW with ether in ether was added to a cooled solution of 16.4 g. (0.1 mole) and the combined ether extracts were dried over magnesium of NLmethyl-N1-phenyl-l,Zpropanediaminein 100 ml. of ether. The reaction mixture was refluxed for 2 hr. and then sulfate and distilled. cooled overnight. The salt was filtered and washed with N- [&( pAminophaethylmethy&mino)~~yl] prophunilide. A mixture of 23.0 g. (0.1 mole) of p-nitrophenethyl ether. The organic layers were combined and shaken with 50 ml. of 1N sodium hydroxide. The layers were separated bromide, 18.0 g. (0.11 mole) of Ntmethyl-N'-phenyl-l,Z propanediamine, 150 ml. of toluene, and 21.2 g. of sodium and the aqueous layer was extracted with ether. The organic carbonate was heated a t reflux for 48 hr. and then cooled. layers were combined and distilled. N-( 2-Anilinc-1-methylEnough water was added to dissolve the solids and the ethyl)-N-methyl-4-phenylbutyramide, b.p. 195-200' (0.4 toluene layer was separated. The aqueous layer was ex- mm.), was obtained in 60% yield. Anal. Calcd. for C S ~ H ~ ~ NC,~ O 77.4; : H, 8.4; N, 9.0. tracted with ether. The organic layers were combined, dried over magnesium sulfate, and concentrated to a syrup. Found:C,77.1;H,8.6;N,9.4. Propionic anhydride (50 ml.) was added and the reaction Acknowledgment. We are indebted to Mr. L. mixture was heated on the steam bath for 3 hr. and then concentrated to remove the propionic acid and excess pro- Brancone and associates for the microanalyses, to pionic anhydride. A solution of 10 ml. of concd. hydrochloric Dr. J. H. Clark and ao-workers for the preparation acid and 100 ml. of water was added and the mixture was extracted with ether to remove non-basic products. The of some of the intermediates, and to Dr. A. C. aqueous layer was treated with 30 ml. of 5N sodium hy- Osterberg and co-workers for the pharmacological droxide and extracted with ether to remove the crude N- data. [2 (methyl p nitrophenethylamino)propyl]propionanilide PEARL RIVER,N. Y. (9.8 g.). A mixture of the above crude intermediate with
are generally similar to those described in our previous paper.a However, the greatest activity in the phenalkyl series waa found when the alkylene chain between the two nitrogens was analogous to that of methadone. A variety of phenalkyl groups gave active compounds with a considerable range of potency as illustrated in Table I.
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