NOTES
May 1968 algetically active beneylmethylamino congener 1 [R = N(CHs)CH2C6H5], pK.' = 7.16 in 50% ethanol. Experimental SectionI2
60 1
values of the basic anilides were memired in ,5070 EtOIT-€120 by Albert and Sergeants' method.14 (14) A. Slbert and E. P. Sergeant, "Ionization Constants of .4cids and Bases," hIetliuen, London, 1962.
1-Methylphenethylamino-2-chloropropane.-Redistilled SOCl2 (125 ml) in CHCl, (125 ml) was added to l-methylphenethylConfigurational Influences in amino-2-propano113 (99 g) in CHC1, (200 ml); the mixture was heated under reflux for 5 hr and then evaporated. The residue AIethadol and Normethadol Analgetics solidified after trituration with ether and was recrystallized from EtOH-Et,O t o give the chloroamine hydrochloride (103 g), mp A . F. C ~ S Y \R'D 11.11.-4 H i s s i x 121-123". Anal. (CIPHi&lZS) C, H, K. The derived base has br, 148' (20 mm). Anal. (CI~HI&IN) Facultg of Phnrnraq, L'niversit y of d lhertrr, Edmonton, il Iherta C, H, ?;, equiv wt. It formed a picrate, mp 111-113" from EtOH. Anal. (CMHXReceived January 19, 1968 ClN40,) C, H. 2- and 3-Methyl-3-methylphenethylamino-1,l-diphenylpropyl The greater analgetic potency of a-( -)-methado1 Cyanides (3a and 2a).-l-l\lethylphenethylamino-2-chloropropane (44.3 g) was added to a mixture of diphenylacetonitrile compared with its dextro enantiomorph has long been (42.5 g), C6H6 (120 ml), and NaNHz (10.3 g) which had previously an awkward anomaly in the study of configurational been stirred at 3040" for 30 min. The product was heated under relationships among diphenylpropylamine analgetics, reflux for 12 hr, then decomposed with H 2 0 and extracted with due to the fact that the more active a-methadol is aqueous HC1. The base (70 g), recovered as iiwal, was a mixderived from the weak analgetic dextro methadone tiire of the cyanides 2a and 3a present in the ratio of 1.0:1.5, respectively (from integrals of the two N-methyl and secrather than the potent levo form.'a2 Evidence of the methyl pmr signals). Petroleum ether (hp 60-80') was added configuration of the secondary alcoholic center (C-3) to the mixture and the solid which separated was recrystallized of the methadols, lacking when attention was first from CeHG-petroleum ether to give the 3-methyl cyanide 2a drawn to this irregular it^,^ is now a ~ a i l a b l eand ~ ? ~it (28 g), mp 97-99'. Anal. (CXH,~S,)C, H I S , equiv a t . The residiies in the mother liquors gave a distillate, bp 198appears from these data (Table I) that the C-3 rather 200" (0.1 mm), which solidified on storage and war iecrystallized than the C-6 Configuration is of prime importance from EtOH-P\IelCO to give the 2-methyl cyanide 3a (30 g), mp respecting the activities of these alcohols. Thus the 72-74", Anal. (C2eHz8N2)C, H, S, equiv wt. two most active methadols [ a and j3-(-)I both have 4,4-Diphenyl-6-methylphenethylamino-3-heptanone.-The the 3s configuration while the C-3 center of the most cyanide 2a (9.25 g) in toluene (60 ml) was treated with EtlIgBr, prepared from EtBr (8.4 g) and M g (1.8 g), in the 11-iial manner active isomethadol [/%(+)I6 belongs to the same to give the amino ketimine 2b (8.5 g), bp 202-205" f0.0ri mm), It was felt that support for this consteric series.' vmax 1710 (w) and 1632 cm-1 (m). It was heated with lOC, tention could be obtained by a study of methadol HCl (50 ml) on a steam bath for 30 min and the recovered base enantiomers lacking asymmetry a t C-6 since it follows, was distilled to give the amino ketone 2c f i . 5 g), bp 188-10Oo (0.0.5 mm), vmsx 1710 cm-' (s). Anal. (C,i"aXO) C, H, N. from this view, that the Smember of such a pair should It gave a hydrochloride dihydrate, m p 108-110", from Me,CObe the more potent analgetic. EtzO, vmax 3350 ern-1 (H20). iinal. (C28H,&lN0.2HzO) C, H, K. 4,4-Diphenyl-5-methyl-6-methylphenethylamino-3-hexanone. The required compounds l b , termed here normethadols in accord with the designation "normethadone" -The cyanide 3a (9.25 g), treated with EtMgBr as described above, gave the amino ketimine 3b (9.5 g), vmax 1720 (w) and applied to the same analog of methadone8 were ob1631-1 (m), which was hydrolyzed by a 10-hr reflux period with tained by reducing the norketone with LAH. Fracconcentrated HC1 (60 ml). The recovered base was distilled to tional crystallization of the (+)-tartrates gave the pure give the amino ketone 3c (8.5 g), bp 192-194" (1 mm), vmax (+) -normethado1 enantiomer while hydrochlorides of 1710 cm-' (s). Anal. (C28H38NO) C, H, K. (f)- and (+)-normethad$ acetates were formed a-Dibenzylamino-N-phenylpropionamide(6).-A mixture of a-bromo-N-phenylpropionamide(22.8 g), dibenzylamine (19.7 g), directly from the alcohols and acetyl chloride. Ev(41 g), and MezCO was heated under reflux for 48 hr, idence for the configuration of (+)-normethado1 was then filtered, and the filtrate was evaporated. The residue was obtained by comparison of its ord spectrum with that recrystallized from 70% EtOH to give the amino amide 6 (25.5 g), of CY-( +)-methado1 (6R :3R). The latter compound has mp 80-82". Anal. (C~H24N20)C, H, N, equiv wt. N- [2-(Dibenzylamino)propyl] propionanilide (7).-The amino two asymmetric centers but it may reasonably be amide 6 (34.4 g) was reduced with LAH (7.6g) by the procedure assumed that the center closer to the phenyl chroof Wright, et a1.,2 to give the diamine 7 (25 g), bp 190-193" mophore (Le., C-3) will largely determine the sign and (0.1 mm). Anal. (C,4Hz6S2)C, H, N, equiv wt. fine structure of the Cotton effect. Hence ord charI t formed a monohydrochloride monohydrate, m p 90-92', acteristics should reflect C-3 stereochemistry in both from EtOH-EtZO, vmax 3500 cm-1 (HzO). A n d . (C23H27ClN2HzO) Ir;, equiv wt. compounds. It is to be noted that the two Cotton The diamine 7 (3.5 g) with propionic anhydride (7 ml) gave effects (Figure 1) not only have the same sign (positive) the basic anilide IC(3 g), bp 210-212" (0.1 mm). Anal. ( C 2 d h hut also correspond closely in both peak positions and NeO) C , H, N, equiv wt. It formed a hydrochloride, mp 1iO-17l0, from EtOH-EtzO. (1) N. B. Eddy, E. L. M a y , a n d E . Mosettig. J. O r g . Chem., 17, 321 (1952). Anal. (Cz&C1KzO) C, H, N, equiv wt. (2) As part of this study, e(+)and a - ( i ) - m e t h a d o l n e r e submitted Alkylation of propionanilide (3 g ) with 2-chloro-1-dibenzylt o Dr. P. Janssen (Janssen Pharmaoeutica) for hot-plate assay since it \%as aminopropane'3 (5.8g) by a reported methods also gave the basic felt desirable t o confirm t h e original results. T h e new data (EDao 30 mg/kg anilide IC (3 g), hydrochloride mp and mmp 170-lil". for e+)and 22 mg/kg for a-(*)-methadol in mice, subcutaneous route) confirm t h a t a-(-)-methado1 is t h e more potent enantiomorph. Thanks Pmr spectra were recorded on Varian A-60 and Perkin-Elmer are due t o Dr Janssen for these results. R-10 instruments in CDC& with T h l S as standard. The pK,'
(12) Where analyses are indicated only b y symbols of t h e elements, analytical results obtained for those elements were within &0.4%, of t h e theoretical values. (13) hf. M .A. Hassan in footnotr d, Table I.
(3) A. H. Beckett a n d A. F. Casy, J . P h a r m . Pharmacol., 6, 986 (1954). (4) P. S. Portoghese and D . A. Williams, J . P h a r m . Scz., 56, 990 (1966). (5) A. F. Casy a n d M. hZ. A. Hassan, Tetrahedron, 23, 4075 (1967). (6) E. L. M a y and N. B. E d d y , J . Oru. Chem., 17, 1210 (1952). (7) P. S. Portoghese a n d D. A. Williams, Tetrahedron Letters, 6299 (1966). (8) Narcotic Drugq Under International Control, Miiltilingual List, United Ziationi, 1963.
::[ -4
-5'
I
240
I
250
I
260
A,
I
270
I
280
I
290
I
300
mp
'I
u-f -4
-4-
4 250 263 27% 294 313 333 357 1,mp
Figutt. I.--Optiriil rotatory di.per.iori ciiive- of ( A ) ( +)riormethadol tm.e i n EtOH ( c 10 mg/100 ml) and ( B ) a - ( + ) methatiol hydtochloride 111 1120 ( c 200 mg 100 nil).
molccul:u. rotatioiittl value. (Table 11). ( )11 thehc. grounds (+) -normethado1 is assigned the R configitr a t'1011.
Hot-plate EDjuvalue\ for racemic and dextrorot:itor> ~iormethadcils :irid their :mt:itc wters iri mice : t u x recorded iii T:iblr I. Thanl;~ are duel to 111..E. I,. lIa>-, S:ttioiial Institutes of Hwlth, for :mxngiiig these tests. Thcl greater E13,,, v:-lliie of I&( +)-normeth:idol compared with the r:icemic hytlrochloritlc m d tartrate dcmonstratc~r that thib iiomcr ih ICW potent th:iri the corresponding S-( - ) matitiomer. Hence the niorc active antipode. of a-methadol, @-meth:idol, : i i i d uormethadol 4iow ccinfig~ir:itioii:rl identity vith rezpect to thcir alcoholic^ :isymiiwtric ccriterh, result3 ivhich support the view that the ("-3 geometry governs activity in these a d g e t i c s . The relative activitieb of (+)- arid (-)-a-mcthadol : i r ~reversed when the alcohols :iw :icetylated (Table I ) cr-(+)-acet!lmcth:Ldol derived from (- )-mcthadonc. twing the inor(> potent cstcr. This r e m a r l d i e i l l v(ir.ion of .terr.o~rl(~ctivit?m:t\ he iIitcrprc$cd i i i tcrms of the C-(i center reasserting its doiniristirig rolc,. .Ilternatively, ho\\-ever, it may be considered as clur to esters rcquirliig :LII R configurated C-3 center tor optimd uctivitJ-. Iron1 thP present results the Inttchr seenis the mor(' probable because the simc. HtermJcliemical r e v e r d i ase of the riormethadoli alld acetatt. (.it(> active R-normeth:tdol yielding the morc nctive :in dal form of the aretutc, (Table I). Of further significance, the niorc' artivv :intipode\ of 3-iboniethadol tmtl a-~~cet~~lisoriietIi:i~~~il have S atid K ('-3 coiifiguratioris, respectivelj..fji Jlethadonc am1 diampromid (which also display stereoselertivr iiivcrsion) have been shown t o differ
radically in their preferred conformations and it has been suggested that this fact may have a bearing upon their more active enantiomers (of formally alike asymmetry) differing in configuratio~i.~Conformational differences between methadols and their acetates are also likely to be of importance in this context and a study of this nature is presently in hand. Experimental Sectionlo a-(A)-?vIethadol, mp 100-102" (lit.11 mp 100-lolo), was obtained from (.t)-methadone and LAH; CY-(+ )-methado1 hydrochloride, mp 187-188", [aIz0n$33.5' (c 0.2, HzO) [lit.lz mp 169-171", [aIz5D4-34" ( c 0.26, HZO)], was obtained from (- )-methadone and Ka-PrOH1 (LAH gave racemic material). 6-Dimethylamino-4,4-diphenylhexan-3-ol (Normethado]).Normethadone (26.7 g) was reduced with LAH (1.7 g) in the usual way1 to give the amino alcohol (21 g), mp 1OO-10lo, from EtOII. I t formed a hydrochloride, mp 140-142", from MepCoEtzO. Anal. (C20HBC1NO)C, H, N. Methiodide, mp 183-185", from EtOH-EtzO. ilnal. (Cz1H30INO) C, H, N. Bitartrate [iising (&)-tartaric acid], mp 146-148', from EtOH. Anal. (Cz4H33NO7) C, H, N. Xormethadol (14.85 g) and (+)-tartaric acid (7.5 g) were dissolved in hot 96% EtOH (30 ml) and the solution was stored at room temperature. The solid which separated was crystallized twice from the same solvent t o give (+)-normethado1 (+)tartrate (7.8 g), mp 144-146", [ a ] " D $20" ( c 2, HzO). Anal. (Cz4H33xO7) C, H, N. 3-Acetoxy-6-dimethylamino-4,4-diphenylhexaneHydrochloride.-A mixture of ( +)-normethado1 (3.5 g), EtOAc (80 ml), and AcCl (3 ml) was heated under reflux for 2 hr and then cooled. The solid which separated was recrystallized from EtOHEtzO to give (f)-normethadyl acetate hydrochloride, mp 104-106", as a monohydrate (vmax 3350 cm-l). Anal. (C22H30ClNOz'HzO) C, H, N. Acetylation of (+ )-normethado1 gave the (+)-acetoxy ester hydrochloride, mp 163-165', from EtOH-EtzO, [ a ]2 6 ~$22.5' (c 2, H20). Anal. ( C ~ Z H ~ O C ~C,X H. O~) (9) -4.F. Casy a n d 11. hl. A. Hassan, J . P h a r m . Pharmacol., 19, 114 (1967). (10) Where analyses are indicated only b y symbols of the elements, analytical results obtained for those elements were within 10.4Yo of the theoretical values. (11) E. L. M a y a n d E. Mosettig, J . Org. Chem., 13,459 (1948). (12) A. Pohland, F. J. 3larshal1, and T. P. Craney, J. A m . Chem. Soc., 71, 460 (1949).
7-Oxabicyclo[2.2.l]heptane-2,3-dicarboximides w i t h Anticonvulsant Activity EARLR. BOCKSTAHLER, LAWRENCE C. WEAVER,ASD DONALD L. WRIGHT Human Health Research and Development Laboratories, The Dow Chemical Company, Zionsville, Indiana Q60?7 Received October 9, 1967
During an exploratory study of various derivatives of 7-oxabicyclo [2.2.l]heptane, we encountered marked anticonvulsant activity in the N-phenethyl-2,3-dicarboximide (I, R = phenethyl), a compound which may
@E.-:
0 0
be regarded as an elaborately substituted succinimide. Since its acute toxicity was relatively low, we undertook a study of the manner in which activity might be altered by variation of the R group.
Grogan and Rice' have described a number of imides of this sort. Some pharmacological testing was done, but revealed little significant activity. Beyond their work, only scattered examples of derivatives of this oxygen-bridged ring appear in the literature; it has been little used in the synthesis of potential drugs. We prepared a series of imides (Table I) by heating primary amines with ezo,cis-7-oxabicyclo [2.2.1Iheptane-2,3-dicarboxylic acid or its anhydride, essentially according to published procedures. The products were considered to be exo, in conformity with the starting material. This assignment was confirmed by nmr examination in a number of instances; in no case was splitting of the signal for the protons at positions 2 and 3 of the cyclohexane ring by the protons at 1 and 4 observed ( J < 0.5 cps). Unexpectedly, two products, 46 and 47, mere obtained from 6-chloro-o-toluidine. Upon nmr examination, these were identified as rotationally isomeric forms of the expected imide, each containing 3-4y0 of the other rotamer. The signal for the protons at positions 2 and 3 was normally a single sharp line near 6 3.0. In the spectrum of 46, it appeared as a pair of lines, a major one a t 3.07 accompanied by a very small one a t 3.02. For 47, a similar but reversed pair appeared, the major line being at 3.05, the minor one at 3.09. Confirmatory evidence of restricted rotation about the N-phenyl bond and consequent rotational isomerism among the phenylimides in general was afforded by the appearance of pairs of lines for the H-2,3 signal for those having only one ortho substituent, and for the protons of o-methyl groups, equal in size for the 2,6-xylylimide, unequal for o-tolylimides. Also, a small shift was seen between the two aromatic protons of the 2,4,6-trihalophenylimides1and in some cases two groups of lines could be seen for the protons at positions 1 and 4. I n pharmacological testing of the imides (Table 11), considerable anticonvulsant activity was observed. Some of them showed potency in animal tests comparable to that of drugs currently used in therapy. Activity was essentially limited to compounds in which R was aryl or aralkyl with a one or two-carbon link between aryl group and imide N. Alkyl and heterocyclic imides had only feeble activity, if any. Of the simple aralkyl derivatives, phenethyl (4) and benzyl (3bj were moderately active against both electroshock and pentylenetetrazole convulsions. pMethylphenethyl (8) showed good activity in the electroshock test, but insertion of an a-methyl group (6, 7) almost completely destroyed activity. Substitution on the phenyl ring tended to reduce potency. The phenylimide (3a) was only feebly active. However, its monochloro derivatives were more active, and introduction of a second C1 or of an o-CH3 substituent led to the most potent compounds of the series. The 2,3-dichlorophenylimide (25) showed the greatest overall activity. It was rivalled in potency against electroshock seizures by the 2,4- and 3,5-dichlorophenyl-, 3-chloro-o-tolyl-, and 2-chloro-5-trifluoromethylphenylimides (26, 30, 48, 52) and against pentylenetetrazole seizures by the 2,5-dichlorophenyl- and 4-chloro-o-tolyl(1) (a) C . H. Grogan and L. M. Rice, J. M e d . Chem., 6, 802 (1963); (b) L. M. Rice, C. H. Grogan, and E. E. Reid, J. Am. Chem. Soc., 75, 4911
(1953); (c) ibid., I?, 616 (1955).
