pliariiiacophoric conforiiiatioii-. 111 c~oiiil):irii~g1lit, niode of binding of various narcotic :iii:ilge>ic o t i c ’ inusi consider not only the geometric dkpo\iiion of 1)li:ir11ii~cophoric 1noietit.s but also take i i i t o :iwourit t h t , K J ~ P played by other groups which are riot cieriiicd e for activity. If quite a differctil patteiii of co t ions to drug -receptor binding :ire ni:idc hy wriou- miifigural ioually i-rlnt(4 :tiialgSc~sic.t i i o l w i i l r - , I h ( J ( s o 1 I[alii-
-ioii-
r:ri iloi
( h a i r 11 t rani t h(>threc-point
intrrnctiori conc*cpt f o voiihgurat ioiial select irvily of i rwl)tor- i i i : i \ iiwr-wi,ily I I P \-:ihd
ioiializr
Acknowledgment. ?’he author gratefully acknowledges thc wpport of this project by Public Health Serviw (;rant TI3 05192, from the Satiorial T r i q t itiitr (rf Stw r~)h’gic.*i 1 I )iw
Stereoc.heniical Factors Related LO the PoLenc) of hticholinergic Psychotominietic Drugs
A groiip of glycolate esters of heterocyclic arniiio alcohols have h e n examined froni the point of view of stereuchemistry in an effort t o correlate pharmacological action with molecular configuration. The examination rras confined to the properties of the heterocyclic amino gronp and was conducted with respect to the psychotomimetic properties of the drugs. An important factor for psychotonlimetic potency was the availability of the electron pair on nitrogen, which, presumably, must combine with an electrophilic center of the biological receptor site. Conformational factors were important insofar as they contributed t o 1,3-diaxial interference by axial hydrogel1 atoms. Intramolecular int,eractions involving the noitbonded electron pair on nitrogen %’erebelieved to diminish potency.
C’oiisiderable interest has been focussed on the structurt.-nctivity relationships of wbstituted glycolate (’Stem of heterocyclic amino alcohols which possess ni:irl.ced psychotogenic ( i . e . , psychotomimetic) propcrtir4.l ? I’revious studies were devoted largely to the piperidyl arid pyrrolidyl esters, with eriiphasis on variation in the acid moiety of the eqters. Since it was known that variations in the type of heterocyclic amino alcohol resulted in striking differences in psychotomiinetic effectiveness, an opportuiiit y was at hand to examine the possible role of the amine moiety iu the pliarniacological action of this series of drugs. R R
CH i 1V
CHI I11
CHI I1
I
decreaiing potenry
R
R
R
v
VI
VI1
decreasing potency
*
Pharmacology.- The drug. iiicluded in I his -tidy ~vcreevaluated for their aiiticholinergic poieiicy arid for their effevt 0 1 1 thow parameter, of behavior which are belie\-ed io tie related t o the psyrhotomimetic. action of the agrnt:, in humani. X ni1caIiirmiciit of hyperactivity in rntc has been found to be :isiinple :iiiti effective iiieans of evaluating the over-a11 action of t h r drugs upoii the central nervous sys1eni.l ? .Z inore direct iiieaxiireiiieiii of the drugs’ disturbaiicc of highrr central nervou function can bc made by iiie:iiis of the -win1 maze and “peek” tests.3 *-\description of these arid their reliability 111 predicting the psychotonuiiietic action of t h e glycolate esters i r i liumaris ha5 been dehcribed in detail elwvhere. l , ? Briefly Ihtx i\pim tilaze consist5 of A niazr which caoritains water i r i which a mouse i:, (mipelled to swim i n order to escape' ilro\viiing; t h e iiiore cmtrally nctivc drugs produce :I grwt cr riuiiiber of errors in perforniaric*e. The “perk” i e i t \\ as developed by Iiosnian4 :IS a iiiearis of quarit ipecu1i:tr head-bobhirig :ti load-swiyiiig inovcaassociatrd with t h r c e ~ ly active glycvlatt. nce of this test 111 and although thr 4gri determining the behavioral nberrat ions of the drugs i:, not loo well understood, i i ha5 proved to 1 ) extremely ~ cffecative in predic+itg p~ychotorninic.tii. potency iii huiiiarls. The ability of the drugs to block the acetylc.1ioliiie-induc.ed cmitraction of the isolated rabbit ileum was takcit its :i measure of anticholinergic pu1 Pll(’J-
R=c.g., benzilate .
-
- -. - -
G. Almod arid J. II. 13iel Intern. Km. Seurobiol., 4, 217 (1962). ( 2 ) I,. G. Abood, A. Ostfeld, and J. >I. Riel, A r c h . intern. piiarmacodyn. 120, 186 (19591. (1) I..
I:+)
SI. 1.; liosman, Proc. Suc. Gzptl. Biol. .\fed., 115, 728 (1964). iEid., in press. 1 1 . C. (’hang and J. H. Gaddurn, J . Phg.~iut., 79, 255 (1933).
( 4 ) 11. E. Kosman, f,!)
STEREOCHEMISTRY OF PSYCHOTOMIMETICS
September 1965
Chemistry.-Inasmuch as it would be highly improbable for any of the glycolate esters to exhibit a mode of action on the molecular level different from the others, a rationalization of this mode of action may be attained by a consideration of the physicochemical properties of t’he most potent drug. It is readily apparent upon examination of the st’ructures of the amino alcohols that the most potent of the esters (I) has an amino alcohol group, viz., 3-( *)-quinuclidinol, which is a rigid structure formally related to the “boat” form of cyclohexane. The atoms making up this bridged, bicyclic ring are incapable of changing their relat’ive positions via rotation about the axes of the bonds involved in ring formation. Since the acyl portion of the ester and the nonbonded pair of electrons of the amino group are directed away from each other (because of the rigidity of this structure), the possibilit’y of intramolecular hydrogen bonding, chelation, and similar neighboring-group, electronic interactions becomes remote. It can, therefore, be concluded that involvement of the electronpair on nitrogen in t’hese stated intramolecular interactions does not play a significant role in the mode of action of these drugs. Indeed, the occurrence of such int’ramolecular interactions in the glycolate esters of the other amino alcohols probably detracts from their psychotogenic efficacy. TABLEI BEHAVIORAL AND ANTICHOLINERGIC EFFECTSOF BENZILIC ACIDESTERS OF VARIOUS HETEROCYCLIC AMINOALCOHOLS Activity cagea
Compd.
Swim mazeb
Peek testC
.hticholinergic EDaod RDIe
I I-CH,~ I1 I11 IV
5.2 5.8 5.2 70 16.2 4.2 4.0 4.4 250 12.6 5.1 5.6 5.1 300 15.8 4.4 4.5 2.9 300 11.8 4.0 4.4 4.0 150 12.4 v 4.4 3.7 3.5 350 11.6 10.0 VI 3.5 3.7 2.9 350 VI-benzylP 1.5 2.6 2.7 1 6.8 VI1 1.8 2.9 2.7 100 7.4 Saline 0.6 2.6 2.5 5.7 Activity cage values (rats) are expressed as oscillations/3 X 10-2 min. b Swim maze values (mice) are in terms of errors on the fourth trial: ref. 3. c Peek test values (mice) are in terms of total number of peeks. The dose in all tests was 1 mg./kg. i.p. Anticholinergic potency was expressed in terms of the EDbOus. acetylcholine; Le., the dilution of the drug (parts per million) necessary t o produce a 50% inhibition of acetylcholine-induced spasms. e Behavioral disturbance index (an arithmetical sum of activity cage, swim maze, and peek test values). f Methyl Benzyl group in place of a methyl group substituent on C-2. on nitrogen.
It may be further readily inferred that the “boat” form type of geometry displayed by the bicyclooctane system of 3-( )-quinuclidinol is not in itself necessary for psychotogenic activity. For although the esters of the other amino alcohols are capable of existing in “boat” form conformations, the extent to which this conformation would be present in the piperidyl esters (excluding the effect of intra.molecular, electronic interactions) is exceedingly small.6 The most unique differentiating feature of the bridgehead nitrogen of 3-( )-quinuclidinol is the accessibility
*
*
(6) E. L. Eliel, “Stereochemistry of Carbon Compounds,” McGraw-Hill nook Co., Inc., New York, N. Y., 1962, p. 207. A t 2 5 O the ratio of cyclohexane ”chairs” to cyclohex8ne “boata” i s approximately 1000: 1.
617
of its nonbonded electron pair. Quinuclidine (VIII) has been found to react with methyl iodide over 50 times as rapidly as triethylamine.’ The difference becomes even more pronounced if a larger, more hindered substrate is employed. Kucleophilic substitution of isopropyl iodide with quinuclidine is over 700 times as rapid as substitution with triethylamine.’ The alkyl substituents on the nitrogen atom of quinuclidine are restrained, allowing very little steric interference with the substrate, whereas the alkyl groups of triethylamine, possessing a large degree of rotational freedom, diminish the availability of the electron pair and, consequently, the nucleophilicity of the nitrogen atom. The dependence of psychotogenic activity on the availability8 of the electron pair can be demonstrated by
VI11
IX
x
comparing the activity of the other esters with the nucleophilicity of their amino groups. Although data on the relative rate of nucleophilic substitution are not available for the other cyclic amines under consideration, a meaningful estimate of their nucleophilicities may be obtained through the technique of conformational analysis. The two most stable conformers of l-methylpiperidine are the two “chair” forms in which the methyl group can be either equatorial (IX) or axial (X). Although the nonbonded electron pair on nitrogen usually has a steric requirement similar to a hydrogen atom, its steric requirement appears to be much larger in hydroxylic solvents by virtue of hydrogen bonding.9 Interaction of I X with an electrophilic center would be subjected to unfavorable 1,3-diaxial interference from the two axial hydrogen atoms located on C-3 and C-5 of the piperidine ring. Similar interaction of X would be free of such steric inhibition. This steric interference with the availability of the amino electron pair of I X would decrease its nucleophilicity compared to quinuclidine. However, inasmuch as the inversion of substituents on nitrogen is extremely rapid and since X is undoubtedly a much better nucleophile than IX, interaction with an electrophilic center may proceed almost completely by way of X . This mixture of I X and X which constitutes 1methylpiperidine may, therefore, be expected under similar environmental conditions to exhibit almost the same nucleophilic character as quinuclidine. In conformity with this assumption is the finding that the BDI (behavioral disturbance index) of the glycolate esters of 1-methyl-4-hydroxypiperidine (11) is almost identical with the BDI for the quinuclidyl esters. The observation that the esters of 1-methyl-3-piperidinol (111) are generally less active than those of 1methyl-4-piperidinol (11) can be explained by considering the greater ease with which the 3-isomer can undergo intramolecular, electronic interactions of the (7) H. C. Brown and S. R. Eldred, J. A m . Chem. Soc., 71, 455 (1949). ( 8 ) Sucleophilioity generally connotes coordination of the attacking group with carbon. Since the mechanism of action of psychotogenics is not
implied herein, the more general term, “availability of the electron pair,” in employed. (9) E. L. Eliel, personal communication.
t y j ~depicted t)y S I . Iiitcmctioii of thc wrboiiyl groiip of this ester with the noiihontletl c.lcctioii 1):iii. oil tlitrogciii n ould i i o t I I ( Y ~ it:tt(b :L“1)o:tI” lo1 I I I voiiloi.iiiii in the bcnzoyl dcrivnt ive of Iiorpseudotroliinc (XIII).l o The> glycolnt cbl ers of tropine ( V I ) , 9-niethyl-:2graiiwtaiiol (\-), :ind 1 , ~ ~ 2 , ~ ~ - t ~ ~liyl--r-l)iperidinoi ti.~iiiiet (I\’) slioiv :t Iitrgv d ( ~ r ( woff ~cwliiparable niagnitude in 1)sychotogcwic I)otcncy. The iii:ignitudP nnd dircctiori of‘ this change i i i potcwcy correlate well with decreasing :tvnilability of thc electron pair. Through nil elegant (1
OH
”9-
CsHsCON
@ Y
XI11
:q)plication of 1i.in.r. spectroscopy, Closs deterniincd the equilibrium constants of the iiitrogeii iriversioii process for several tropane bases.” It wa5 found that conformer XV predominates over confornier XIT’ b j a ratio of 20: 1 in atropine and beiizoyltropine. Sevei.theless, it has h e w reported hy E’odorl? that in nertrl,~
XX
XIX
R CH?
Nm cH3’Nm /
OCOCsHs
XIV
OcOcsH~
XV
:dl c:ts~5 troptiie derival ivee yield 011 yuaterriizutioii cwdusively that isomer in which the entering subst iluent is located on the same side of the pipcridine ring as the ethylene bridge. Thus, it would seem that despite the predoniinance of conformer XV, its rate of reaction with an electrophilic centcr is negligible iii comparison to conformer XIV. Presuinably steric hindrance due to 1,3-diaxial interactions is involved, although the presence of a significant concentration of “boat” forin cannot be precluded. The evidently more favorable approach by an electrophilic center to conformer XIV will, however, be offset by steric hindrance frorri the ethylene bridge hydrogens. This hindrance cnii lead to decreased availability of the electron pail o i i nitrogen. (10) G. 1 odor and K. Sador, J. C h e m SOL.,i 2 1 (1953). ( 1 1 ) G. 1,. Closs, J . A m . Chern. SOL.,81, 3 4 X (I%%). (12) ( i . I (idor, ’I’rtiahidron, 1, S i (145i) I. Ch,,rr lrlrri 6. {ill ( I ‘ t . i . i l / rprrrvnlin 1 1 , 120 (1045).
\,L
IIWi,,
XXI
XXII
pair of thc~sc~ coriforiiiers would h~liiglily hiiidrrc~lhy 1,4-diaxinl “ho~~sijrit-flagy)(~le” 1111 erwt ions Thihindraricc (Jviiici+ itself in the ~ifol.ciiieritioi1c.d d i niiiiished pq-chot ogenic potcwcy of ilie 9 - n i ~ f11\-1-:1graiiatanol r?tei i: (T-). The dillllllish~”1 efficacy of tllc’ e b t c r ot 1,2,2,0tetraniethyl-~-pi],cl.idiriol (IT-) duo corrcl:i t v PI I 11 ith decreased :i\-ailability of thc electroii p:ui oii nitrogen. The iiirthyl group, on C-6 should be eqiiatorial in t h e predominant conformers (XXIII aiid XXIY).l4 It i. apparent that there are associated with CH
CNS-AFFECTIXG '&PIPERIDONES
September 1965
the electron pair of conformer X X I I I four 1,3-diaxial noribonded interactions due to the hydrogens on C-3 and C-5 aiid the methyl suhstitueiits i i i thc 2- and (ipositions. Since there are only three such interactions which are due to the methyl groups for XXIV, interaction with an electrophilic center may occur primarily in this somewhat less hindered conforniational form. Finally, the glycolate esters of 1,2,2,6,6-pentaniethyl4-piperidinol (VII), n-hich are virtually devoid of psychotogenic activity, can be seen t o have a highly hindered amino nitrogen. -4n approaching electrophilic center would be subjected to four 1,3-diaxial norihonded interactions in each of the two possible CH,
CIH,
xxv
CH, XXVI
619
conformers (XXV and XXVI). As corroboration for the inaccessibility of the amino group of VII, it should tw noted that 2,~,,(i,G-tetrai~ietliylI,iprridiiie is alkylated in a very lorn yield even after prolonged heating with an excess of ethyl p-toluene~ulfonate.~~ Quaternization can be expected to be even more difficult. Although further refinements could be made regarding the nucleophilicities of these drugs, they would be unn arranted in view of the semiyuantitativr nature of the pharmacological assays. -4s an addendum, however, substituent groups on nitrogen larger than methyl will decrease nucleophilicity and should, therefore, decrease potency, as has been verified. Replacement of the ?;-methyl group by hydrogen will promote rapid destruction of the drug via transfer of the acyl group to nitrogen to form an amide. It must be emphasized that although the drugs were differentiated by their degree of nucleophilicity, it remains to be demonstrated whether an alkylation step is essential for their pharmacological action. (15) H. K. Hall, Jr., J . -4m. Chem. Soc., 79, 5444 (195i).
Compounds Affecting the Central Nervous System. I. 4-Piperidones and Related Compounds C. R.GAXELLIK ASD
R.G. R. SPICKETT
Smith Kline R. French Laboratories, Ltd., TPeZwyn Garden Pit!/, Hprtfordshirr, England
Received February 23, 1966 l-Arylalkyl-3-alkyl-4-piperidones, the corresponding secondary alcohols and their esters, and 2,2-dimet hyl-6aryl-Ppiperidones (111) were prepared as modifications of 9,10-dimethoxy-3-isobutyl-~-oxo-l,~,3,4,6,7-hexahydro-llbH-benzo[a]quinolizine for pharmacological testing. Other related structure>, IT-VI, were also bynthesized. None of these compounds possessed reserpine-like activity, but structures I11 and IT had a combination of stimulant and depressant effects on the central nervous system.
Reserpine possesses therapeutically useful sedative and antihypertensive properties,' but major modifications of the pentacyclic nucleus of the alkaloid destroys this biological activity.2 Kralt, et suggested that t'he pharmacological properties of reserpine are determined by three chemical groups in the molecule: (I) the P-indolylethylaniine group, ( 2 ) the tert,iary nitrogen atom, and (3) the alcohol group esterified by triniethoxybenzoic acid. Other investigators have shown that' activity does not reside specifically in the trimethoxybenzoyl ester group and that trimethoxybenzoic acid may be replaced by other acids* or even by a1kyl.j Brossi, at aZ.,'j>' during synthetic studies in the emetine field, discovered reserpine-like activity in the benzoquinolizines I (X = =0, or H and OH), thus indicating that the P-indolylethylamine (1) R . E. Woodson, J r . , H. TI-. Yangken, E. Schittler, and J. A. Schneider, "Rauwolfia: Botany, Pharmacognosy, Chemistry and Pharmacology," Little, Brown and Co., Boston, Rlass., 1957. (2) M..1.Karim. Pakistan J . Sci., 12, 119 (1960). (3) T. Kralt, W.J . Asma, H. H. Haeck, and D. H. hloed, Ree. trao. chim.,
VMe I1
I11
I
R3
IV
0
V
Rz
I
RI-N
/
\
CH2CHC02R3
CHZCH~COZR~ VI1
80, 313 (1961). (4) R. A. Lucas, X. E. Kuehne, M . J. Ceglowksi, R. L. Dziemian, and H . B. MacPhillamy, J . Am. Chem. Soc., 81, 1928 (1959). ( 5 ) hl. RI. Robison, R. A. Lucas, H. B. MacPhillamy, TT-. Barrett, and A , J. Plummer, Etperientia, 17, 14 (1961). (6) A. Brossi. H. Lindlar, AI. Walter, and 0. Schnider, Helc. Chim. Acta, 41, 119 (1958). (i) .\. Rronsi. 1,. H. Chopard-rlit-.Jran, nntl 0. Srlinider, ;hid., 41, 1793 (IQ*58).
residue can be replaced by arylethylamine. The noteworthy features common to both structures appear to be an oxygen-containing function, a basic tertiary nitrogen atom which is sterically shielded, and an aromatic ring system. Tetrabenazine@ (I, 13 =
