Stereochemical aspects of antihistamine action. 4 ... - ACS Publications

Nov 4, 1970 - With, el al. Stereochemical Aspects of Antihistamine Action. 4.1. Absolute Configuration of Carbinoxamine Antipodes28. V. Barouh,21> H...
0 downloads 0 Views 386KB Size
1534 Journal o j Medicinal Cheniialry, 2972, Vol. 14, No. I )

JIITc:, el a!.

Stereochemical Aspects of Antihistamine Action. 4.’ Absolute Configuration of Carbinoxamine Antipodes2”

v. . h R O U H , 2 b H.DALL,2b D. I’ATEL,

ANI)

Q. HITE*

labor at or^ oj Medicinal Chemialrp, College of Pharntaceutical Sriencea in the City of New York, Columbia Uniueraity, New York, New York 10083 Received Sepleniber 18, 21)i’O The antihistamiiiically more active (-)-antipode of carbinoxtimiiie ( I ) ha5 1 he S eonfigitration iirid is btereochemically superimposable iipoii the aiitihistcimitiic.allymore avtive (S)-(+)-ailtipodes of the pheiiiramines (11). The salient features of the scheme used to establish 1 he trmfigttratioti of ( - )-I involve its iwiversion into a piire diastereoisomer of the piperidine analog, (+)-IIIb, the new ettdocyclic center of ahyrnmetry of which was maintained intact while the original exocyclic center was destroyed i t 1 the firiul -tep, oxidation of the crtrbinol, (+)-Vb, to the ketone, (&(-)-VI. The relative configuration ( J f the 2 cetiters of uhymmetry in (+)-Vb was assigned on the basis of the J values for the benzylic prototis of (+)-Vb arid authentic racemic erythro and threo compounds (Vb and VIIb). While biologiral data suggest that the cwbitioxumiries I and the pheniramiiies I1 may bind differently to the same receptor, the diq)arity is not hiivh a h to invert the configurational requirements for atit ihistaminic activity.

The 0 atom joining the asymmetric center and the aliphatic amine side chain in analogs of carbinoxamirie I marks the only structural difference between them and the phenirumines 11. However, in studies con-

X

4 I1 ducted using the I V histamine cliallenge, tlie f:icts that the antipodal potency ratios of the CI analogs differ significantly, 37:i3 and 95: 1,‘ respectively, arid that para substituents do not accord the stme increments in potency495 in both series, suggest tli:Lt, I arid I1 may iiot, bind to the recept,or in tlie s:ime ni:inucr.fi Ilivergence in receptor biridiiig arid its reflection in inversion of configurational requirements of receptors tire of considerable contemporary it~tcrest,.~Tliese cotisideratioris :uid the possibility t h t I, like T I , l c coiild bc converted into n benzoylpiperidine (VI) of kiiowri iibs configlo provided the impetus for dctermiriiiig the abs confignu of tlic! carbinoxamiiie (I) :itit ipodes, the first of the untiliistnminic diary1mc:tliyl c.tli:iiiol:imine ethers t o bc so studicd. The sequence of tlie reactions shown in Sclicme I wns dictated by several corisider:Lt,iori.s. Sirice I1 ( I ) (8) I’apcr 1: ,\. Sliafi’eeand G.Ilite, J . I’hnrm. Sed., 66, 1041 (1967): (I)) paper 2: ibid., e$, IO89 (1967): (c) paper 3: J . .%fed. Chem., 14, 200 (1908). (2) (a) Sirp1,orterl in pnrt lip Grant NIl-036‘J:l from the U. S.Piildio Ileultli Service, Ilotliescla, Md.: (1)) iin~lar~rarlciate rencarcli participantn: Recirjimtw, l~iinnforil-I~i~!linr~lnon Aivarcl. 1988, First Prize, Norlliennt Regional

Competition. (3) ,\, P. Ilorrskowaki nnd \V. hi. Govier, f’lrarniwoluuial, 1, GO (IW!h): caloiilai.ed on a rnolur Iuvh. (4) (a) I?. E. ItuLIi, C/ictriolkenip6r, 1, 120 (I!JIil): (11) 1’. 15. Itotli and \V. 81. Govier, .I. I’liiirrniicol, 1Srp. Ylier., 141, 347 l l ! + W . (6) A. h l J C l l 0 and Ic13) identical with that of (P)-Vb. Anal. (CMHS~NOBS) C, H, N. ( R ) - (- )-l-Benzenesulfonyl-2-benzoylpiperidine (VI).-To 0.1 g of (PR,aS)-(+)-T'b i n 20 ml of Et20 was added 1.5 ml of oxid soin prepd from 5 g of Na&rpOi"2H,0, 3.75 ml of coned H2S04 and HzO to make 2.5 ml of soln. After stirring for 3 hr, the Et20 was sepd, washed with H 2 0 and base, dried, clarified, filtd, and evapd to give a residue. This was crystd from heptane to afford 67 mg of (R)-(-)-\'I: mp 103-103.~j0,[ a ]( T ~ k F ) -18 3~ 3" (c 0.8.5); lit.*cmp103", [ a ]( T~ H F ) -20 & 1'.

+

+

Acknowledgment.-The authors wish to thank Dr. Cornelius Cain of McNeil Laboratories for generous samples of racemic carbinoxamine maleate and of (+)-carbinoxamhie tartrate, the dextrorotatory salt of (-)-carbinoxarnine with (+)-tartaric acid. Our thanks also to >[r. Jin-Shung Chang who determined the nmr spectra.

Some Aryloxyalkylamines, N-Arylethylenediamines, and Related Compounds as Anorectic Agents R. S. SHADBOLT, C. J. SHARPE,* G. R. BROWN, Chemastry Department

A. ASHFORD,AND J. W. Ross Pharmacology Department, Twyford Laboratories, London, S.W.10, England Received Sovember 4, 1970 The anorectic and stimulant properties of some 2-phenoxytriethylamines and related compounds have been compared. The effect of phenyl-ring substitution differs from that in the amphetamine series. A p-CN group is particularly effective in producing anorectic activity without stimulant effects.

Most' anorectic drugs have associated undesirable propert'ies such as CXS stimulation, euphoria, a,ddictiveness, and hypert'ension. A considerable number of modifications have been made t o the amphetamine structure with a view to reducing it's stimulant properties while retaining anorexigenic activity. The most successful compound of (1) (a) "Amglietamines and Related Compounds,"

S. Garattini and

E. Costa, E d . , Raven Press, New T o r k , X. Y . , 1969; (I?) D. L . Marsh and U. A . Herring, J . Pharmacal., 100, 298 (1950); ( c ) 0. F . Holland, C. J , Buck, and A . Weiseman, J . .$fed. Chem., 6 , 519 (1963).

this type is t,he N-ethyl-m-trifluoromethyl derivative, fenfluramine.2 Some I-phenoxy-2-propylamine derivatives are also claimed t o have a favorable ratio of anorexigenic to stimulant a ~ t i v i t y . ~We have observed anorexigenic activity in some tertiary phenoxyalkylamines (Table I) and find that substitution in this series has different effect,s on anorexigenic and central stimulant H.Schmitt, Therapie, 19, 831 (1964). (3) Boehringer, Ingelheim, French Patent 1,529,480 (1967); Chem. A b a f r . .

(2) J. C . Le Douarec and 71, 12806 (1969).