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496 J.M ed . Ch em. 1981,24,496-499literature methoda A? B?JOC,ll Dt 2 F," G,16 ,le 1,17 ? M,lsN,19 0,20?l an d QF 2 Th e pertinent data are summarized inTables I-VI.Me thod K. P r e p a r a t i o n o f 3-Phenyl-5,7-dihydro-S,5,7,7-tetramethylfuro[3,4c]pyridazine Hydrochloride (&). Usinga condenser equipped with a Dean-Stark trap, a m ixture of 4-hydroxy-4-(phenylethynyl)-2,5-dihydro-2,2,5,5-tetramethyl-fu ran -3( W -on e (2.58 g, 10 mmol), hydrazine (0.32 g, 10 mmol),and pTsOH .H20 (0.19 g, 1 01) was heated in refluxing toluen e(50mL) for 18h. After cooling and neutralization with N aHC 03,the solution was evaporated in vacuo and th e resulting residuedissolved in EhO.Recrystallization of the solid resulting fromHCl gas addition to the Et0 olution from CH2C12-hexanegave1.60 g (55%) of pyridazine 8c as a yellow solid, mp 151-152 OC.Method L. P r e p a r a t i o n o f 2-Phenyl-5,7-dihydro-5,5,7,7-tetramethylfm[3,4b]pyrazine 1-Oxide Hydrochloride (Sa).A solution of 1-am inoaceto pheno ne hydro chloride (1.71 g, 10mmol) in toluene (50 mL) was neutralized with concentratedNH 40H. To the mixture was added 2,2,5,5-tetramethylfuran-3,4d ione monooxime (1.71 g, 10 mmol), and th e resulting mix turewas heated a t reflex for 18 h using a D ean-Stark tra p to removeazeotropedwater. Evaporation of the solvent and chromatog raphyof the residue over silica gel gave a brown oil. Dissolution inEt0and HCl gas addition provided 0.37 g (12%) of pyrazine 8d, mp

Acknowledgment. The services provided by thePhysical Chemistry Section of Preclinical Research aregreatfully acknowledged. Th e authors also thank Dr. S.Barcza for m any helpful discussions.

121-125 OC.

Overt Behavior in Normal, FreeRanging Cats. Three catsadministered compound 5b were tested for gross behavioralchanges. After the anima ls were dosed, they were simply handle dand observed for the ensuing 4-6 h an d overt changes in behaviorwere noted.E f fec t s on Gross S p i n a l R e f l e x es in Cats . The effects ofcompound 5b were studied on mono synaptic (patellar) and po-lysyna ptic (flexor) spinal reflexes in inta&chloralw anesthetizedcats. The monosynaptic reflex was elicited by tapping th e patellartendon with a so lenoid-controlled ammer, and the ensuing kneejerk was recorded. Th e flexor reflex was recorded as contractionsof th e tibialis anticu s muscle elicited by electrical stimulation ofthe popliteal nerve.Ca rd iovascu l a r E f fec t s in &bus Monkeys. Blood pressurewas recorded from two Cebus apella monkeys via polyethylenecatheters inserted into a carotid artery of each subject. Followingsurgical implantation of the catheters, the su bjects were placedin restraining chairs and allowed to accommodate for 2.5-3.0 hbefore drug administration. In addition to blood pressure, an EE Gwas monitored in one subject and an EKG was recorded in thesecond.Chemistry. Melting poinh were obtained on a Thomas-Hoovercapillary melting point ap paratus and are uncorrected. Silica gel(0.063-0.2 mm ) was used in preparing column chromatograms,and analytical thin-layer chromatography was conducted onprecoated 40 X 80mm plastic sheets of silicagel G with luorescentindicator. In all workup proced ures, th e drying process involvedswirling over Mg S04 and filtering prior to evaporation. Startingmaterials 1-4 were prepared according to literature method^.^^^Compou nds of type 5, 6, and 8-1 1 were prepared according to

New Analgesic Drugs Derived from Phencyclidine'Yossef Itzhak , Asher Kalir,* Ben Avi Weissman, an d Sasson CohenDepartment of Physiology and Pharmacology, Tel-Aviu U niversity, Sackler School of Medicine, and Zsrael Ins ti tute forBiological Research, Ne ss- Ziona, Israel. Received August 14, 1980

Several esters of 1-(-phenylcyclohexyl)-4-piperidinol(3), -(-phenylcyclohexyl)-4-phenyl-4-piperidinol10) an dits propionate ( 1 ) , nd 1-( -phenylcyclohexyl)-4-phenylpiperidine 13) were prep ared and characterized. Th e newcompounds, which are derived from phencyclidine, exerted analgesic activity in mice. The most po tent is 10,whichis twice as active as morphine. Th e antinociceptive activity of 10, 11, and 13could be well correlated with theirpotency in t he mouse vas deferens bioassay, and both were completely reversed by naloxone.Phencyclidine [1-(1-phenylcyclohexyl)piperidine, CP],now a major dr ug of abuse,2 held intially the promise ofa safe general anesthetic. Indeed , th e drug is unique inits lack of depre ssant effect on the hea rt andIts use, precluded in man on account of the a cute psychoticsyndrome it precipitates, is still practiced with success inveterinary medicine.4~~ C P has also been accre dited with

th e exertion of analgesia,6v7bu t no precise data are available

Scheme I

PhMpBr66 NaCN 5 -I 2H

Taken from the Ph.D. dissertation of Y.I., 1980.R. C. Petemen and R. C. Stillman, "Phencyclidine: A Review",National Institute of Drug Abuse: Was hington, D.C., May,3 9 10978.(a) F. E. Greifenstien, M. Devault, J. Yoshitake, and J. E.Gajewski, Anesth . Analg. (Clevela nd),37,283 (1958); (b) M.Johnstone, Y. Evans, and S. Baigel, Br . J , Anesth., 31, 43 3(1959).E. F. Domino,D. A. McCarthy, and G. A. Deneau, Fed. Proc.,Fed. Am. SOC. x p . Biol., 28, 1500 (1969).G. Chen and J. Can, Anaesth. Soc., 20, 180 (1973).E. C. Maybe, and H. J. Baker, J . Am. Ve t .Med. Assoc., 147,1068 (1965).A. M. Harthoorn, Nature (London),198, 1116 (1963).

On this particular aspect* We assumed that a propermanipulation of the PCP structure might change thebalance between ita antinociceptive an d psychotomimeticproperties in favor of the former. This s not unreasonable,in view of t he successful prec edence offered by ketamine?(8) R. A. Myres, J . Am. Vet . Med. Assoc., 162, 835 (1973).

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New A nalgesic Drugs Derived from PhencyclidineTable 1. 4-Subst i tuted 14 1-Phenylcyclohexyl)piperidines

Journa l of Medicinal Chemistry, 1981, Vol. 24, No . 5 497

1 (PCP), R = R , = Ha3, R = H; R , = OHno. R Rl mp , C formula solventb % anal.

recrystn yield,4 H 3,4-(CH,0),C6H3C0, 154-155 c 6H33N0 A 62 c,H, N5 H C6HSCOZ 146-148 C24H29NOz A 85 c, H, N6 H 114-1 15 C23H28N20Z A 60 c, H, N7 H 4-NH2C,H,C0, 167-168 C24HSN202 D 60 c, H, N8 H CH3COz 195-196 CI,HZ,NO,* B 72 c, H, NHCl-H.010 OH C6H,11 CZH5COZ C6H,

1 3 H C 6 H S103-105 CZ3HZ9N6 E 75 c, H, N214-215 C,H33NO,. B 60 c , H, N131-132 C23H29N C 57 c, H, NHCl.0.5Hz0

a Reference 13. A = ethyl acetate; B = ace tone ; C = ethyl acetate-ethan ol ; D = benzene; E = petroleum ether-hexane.Table 11. Analgesic Activity: Bioassay Results,b Relative Poten cy in Activity Cage,c and Ac ute Toxicity

ED,,, mg /kg sed re1 po tenc ycom pd hot- plate test writhing test IC,, pM e in act. cage C LD,, mg/kg scd1345678101113morphine

fg 7.5 (4.7-12.0)15.0 (8.8-25.6)45.0h40.040.0h1.3 (0.9-2.0)12.1 (8.6-16.9)56.0 (43.4-72.2)2.5 (1.6-3.7)

2.8 (2.2-3.4)11.2 (7.5-16.6)5.2 (3.1-8.4)24.5 (14.4-41.6)16.5 (11.1-24.5)9.3 (5.4-15.8)14.5 (8.0-26.1)0.27 (0.18-0.40)5.8 (3.7-8.9 )0.42 (0.22-0.78)42.0 (30.4-57.9)

iiiii0.082 f 0.0080.78 f 0.0427. 5 r 0.400.50 f 0.058

i

2

5.02.30.51.11. 30.72.01. 21. 11. 01. 1

37.5 (28.2-49.8)74.0 (57.1-96.2)nt>300k>300n tnt82.3 (70.3-96.2)>300k>3OOk531

Tested subcutaneously as water-soluble hydr ochlo ride salts. Effect of the com pounds on the mouse vas deferens ac-cording to ref 17 . C Values refer to th e potency of the com poun ds to produce hyperact ivi ty in mice. Untreated mice weretaken as he cont ro l group (potenc y = 1) .refer to the free base; nt = not tes ted. e Concentrat ion which produces 50% nhibition of tw itches plus or minus SEM.f N o t active up to 9 mg!kg sc; higher do ses pro duc ed ataxia. g Not act ive up t o 25 mg/kg sc; higher doses produced ataxia.caused potent iat ion of twitches (which was concentration de pende nt) . I N o change in twitch es was observed up to 100 pM .

Numbers in parentheses are 95%confidence l imits by probi t analys is;z4dataApproximate ED,,. * Concentrat ions up t o 1.0 pM caused no change in twitches; higher concentra tions (up to 10 0 pM)No acute toxici ty up to 300 mg/kg sc. Reference 25.

which has retained the a nesthetic profile of the parentstru ctu re but lost much of its psychotomimetic activity.Some of t he structural modifications we sought borrowedelements f rom the well -known analges ic p r ~ d i n e . ~ herelationship between P C P and its new congeners is shownin Table I.While this work was n progress, disclosure was madel0v1lof a group of analgesics derived from t he struc turally re-lated (1-phenylcyclohexy1)dimethylamine.Chemistry. Th e synthesis of th e new compounds wascarried out according to Scheme I. 1-(1-Phenylcyclo-hexyl)-4-piperidinol (3)12was obtained by us in 45% yield,

Scheme I1 n

12

U13

(9 ) P. G. Stecher, Ed., The Merck Ind ex, 8 th ed., Merck & Co.,Rahway, N.J., 1968, p 40.(10) D. Lednicer and P. F. VonVoigtlander, J.Med. Chem., 22,1157 (1979).(11) D. Lednicer, P. F. V onVoigtlander, and D. E. Emmert,J.Med.Chem., 23, 424 (1980).(12) D. C. K. Lin, A. F. Fentiman, and R. L. Foltz, Biomed.MQSSSpectrom., 2, 206 (1975).(13) A. Kalir, H. Edery, Z. Pelah, D. Balderman, and G. Porath, J.Med. Chem., 12, 473 (1969).

but silylation of its precursor 2 prior to reaction withPhM gBr increased its yield to 77%. Th e piperidinol3 wasfurther esterified to compounds 4-6 and 8 (Table I) withth e corresponding acyl chlorides. Th e 4-aminobenzoate7 was prepared by transesterification.l-(l-Phenylcyclohexyl)-4-piperidone9) was obtainedfrom t he alcohol 3 by the Oppenauer oxidation. A ttemptsto oxidize 3 with chromic trioxide in various media (AcOH ,

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498 J ourna l of Medic inal Chemistry , 1981, Vol. 24 , No. 5H2S04,or pyridine) failed. Th e piperidone 9 and phe-nyllithium gave 1-(l-phenylcyclohexyl)-4-phenyl-4-piperidinol (lo),which with propionic anhydride gave thepropionate 11. In addition, the deoxy analogue 13wasprepared from 4-phenylpiperidine and cyclohexanonecyanohydrin (Scheme 11).Pharmacology. Th e mouse hot-plate14and th e writh-ing tests15 (using 0.6% acetic a cid ip) were used to assessth e analgesic activity of th e compounds. In the hot-platetest, P CP did not produce any significant change in latencyup to 9 mg/kg sc, while higher doses produced markedataxia. In the writhing test a steep dose-response rela-tionship with an ED50 f 2.8 mg/kg sc was observed.Among the 4-mon osubstituted d erivatives of PC P, only 4,5, nd 13 produced analgesia in both tests, while 6-8 ex-hibited analgesia only in the writhing test (Table 11).The 4,4-disubstituted derivatives of PCP, 10 and 11,exerted analgesic activity in both tests. 10 was found tobe th e most p oten t in this series (almost twice as potentasmorphine; Table 11). T he ana lgesic activities of 10, 11,and 13 were completely antagonized by 2 mg/kg naloxonesc (in the hot-plate test).In o rder to assess th e opiate-like activity of t he newcompounds, the mouse vas deferens preparation wa s used.Opioids were shown to inhibit the contractions inducedby electrical-field stimulation of th e vas deferens of miceby inhibiting noradrenaline release.16-'*Only compounds 10, 11, and 13 showed a concentra-tion-de pend ent inhibition of contractions; all other com-pounds showed concentration-dependent increases intwitch height (Table 11). Th e maximal inhibition producedby 10, which was six times as po tent asmorphine, 11an d13 could be reversed by 20-50 nM naloxone; th e sameconcentration range was needed to antagonize th e effectof morphine in this bioassay.We have also foundlg th at the pA2 values of naloxonein antagonizing th e inhibitory effect of th e various com-poun ds were as follows: normorph ine, 8.60; 10,8.76; 11,8.74; 13,8.71. However, th e regression lines did no t havea uniform slope and, therefore, one cannot state withcertainty t ha t a single competitive mechanism is involvedin th e antagonism with naloxone, even though the pA2values are very close.Fo r compounds 10, 11, 13,and morphine, a good cor-relation was obtaine d between t he relative analgesic po-tency (hot-plate test) and th e relative potency of th e in-hibitory effect in the mouse vas deferens ( r = 0.95). Whenmorphine was omitted from the claculation of the re-gression line, correlation was even better ( r = 0.99).It has been suggested th at th e psychotic effect of PC Pis associated with induction of hyperactivity in mice andrats.20-22 n this respect, as estimated from t he results of(14) (a ) G. Woolf and A. D. MacDonald,J.Pharmacol. Exp . Ther.,80,300 (1944); (b ) J. I. Szekely, Z. Dunai-Kovacs,E. Miglecz,A. Z. Ronai, and S. Bajusz, ibid., 207, 878 (1978).(15) R. I. Taber, P. D. Greenhouse, I. K. Rendell, and S. Irwin, J.Pharmacol. E x p . Ther., 169, 29 (1969).(16) G. Henderson, J. Hughes, and H. W. Kosterlitz, Br . J. Phar-macol., 46, 764 (1972).(17) J. Hughes, H. W. Kosterlitz, and F. M. Leslie, Br. J . Phar-macol., 53, 371 (1975).(18) J. A. H. Lord, A. A. Waterfield, J. Hughes, and H. W. Kos-terlitz, Nature (London) , 67, 495 (1977).(19) Y. Itzhak, B. A. Weissman, S. Cohen, and A. Kalir, "New De-rivatives of PC P asAnalgesics", Abstracts of th e 46th M eetingof the Israel Pharmacological Society, Jerusalem, Mar 25,1980.(20) C. Chen, C. R. Ensor, D. Russel, and B. Bohner,J. Pharmacol.EXP. her., 127, 241 (1959).(21) R. D. Sturgeon, R. G. Fessler, and H. Y. Meltzer, Eur. J.Pharmacol., 59 , 169 (1979).

Itzhak et al .the activity cage test (Table 111,th e new compounds aremuch less active than PCP, but as yet the data are in-sufficient to draw any conclusions abou t their psychoticeffects.We presume t ha t different mechanisms are involved inthe antinociceptive effect of PCP and the new compounds,particularly 10,11 , and 13. Th e facts th at there is a goodcorrelation between the relative potencies found in thehot-plate te st and the m ouse vas deferens bioassay, theseeffects are reversed by naloxone, and th e new com poundsare structurally similar to th e known 4-phenylpiperidinenarcotic analg e~ic s?~mply that the analgesic effect ismediated by th e opiate receptors. This view is supportedby preliminary results of the radioreceptor assay (with[%]morphine) which is being carried out in our laboratory.Experimental Section

Melting points were determined on a Fisher apparatus and wereuncorrected. Infrared sp ectra (in CHC13) were taken on a Per-kin-Elmer spectrophotometer Mo del 137B. Analytical resultswere within h0.3% of the theoretical values.1-( l-Phenylcyclohexyl)-4-piperidinol(3)as prepared bymo&fication of the published procedure.'2 A solution of 28 g (0.35mol) of the 4-hydroxypiperidinocyclohexylcarbonitrile2) in 200mL of pyridine was treate d with 50 mL of hexamethyldisilazaneand 30 mL of trimethylchlorosilane. After stirring for 1h at roomtemp erature, the solvent was removed, and th e residue was takeninto CHC13, filtered, concentrated, and recrystallized from pe-troleum ether to give 30 g of crystals, mp 90 "C. A solutioncontaining 28 g (0.14 mol) of th is nitrile i n 200 mL of benzenewas added to PhM gBr (p repared from 47 g of bromobenzene and8 g of Mg in 250 mL of ether), refluxed for 5 h, left overnight atambien t tempera ture, and then poured into ice-NH4C1. Th eorganic layer was separated a nd washed with water, an d the basewas extracted with 10% HzSO4, liberated with 20% NaOH,reextracted with benzene, dried, and concentrated. Th e residuewhich solidified was recrystallized from he xan e-et han ol(5 1) togive 20 g of 3: m p 116-118 "C (lit.12 mp 117-118 "C).Esters 4-6. Th e corresponding arom atic acid was refluxed for1h w ith a considerable exceea of freshly distilled thio nyl chloride;after concentration, the residue was treated with dry benzene andthe n distilled again. Th e residue was trea ted with piperidinol3 in 50 mL of pyridine, refluxed for 2-3 h, cooled, d iluted with50 mL of ice-water, extracted with CHClS, washed with 5%NaHC03, dried, concentrated, and recrystallized until TLC(alumina, CHC13-ethyl acetate , 4:l) showed absence of impu rities.1-(l-Phenylcyclohexy1)-dpiperidyl cetate (8) as preparedfrom 8 g (0.1 mol) of acetyl chlorid e and 6 g (0.023 mol) of 3 ndry benzene. After refluxing for 2 h, th e solvents were removed,an d the pro duct was converted into its HCl salt an d recrystallizedfrom acetone.4-Aminobenzoate was prepared as follows: 2.6 g (0.01 mol)of 3 was heated with 0.15 g of sod ium (0.065 g-atom) in 30 mLof toluene for 2 h, then a solution of 1.5 g (0.01 mol) of meth yl4-aminobenzoate in 20 mL of toluene was added during 20 min,an d methanol w as removed by slow distillation during 1.5 h untilthe tempe rature reached 110 "C. Th e mixture was cooled andwashed with water, the organic layer was concentrated, and t heresidue was crystallized from benzene.

1-(l-Phenylcyclohexyl)-4-piperidone9). A solution of 26g (0.14mol) of alum inum isopropox ide in 6 0 mL of benzene wasslowly added to 20 g (0.77 mol) of 3 n 60 0 mL of benzene and40 0 mL of acetone. Th e mixture was refluxed for 7 h (moreprolonged reflux did not improve the yield), concentrated, dilutedwith CHZClz, xtracted with 3 N HzSO4, liberated with 20%NaOH, extracted with benzene, dried, and concentrated. Th eoily residue was chromatographed on neutral alumina (Fluka) andeluted with 500 mL of petroleum ether-benzene (4 1) and againwith 500 mL of benzene. After the solvents were removed, theresidue was crystallized from heptan e to give 6 g (25%) of 9: m p

(22) T. F. Murray and A. Horita, Life Sci., 24, 2217 (1979).(23) A. F. Casy, Prog. Drug Res., 22, 149 (1978).

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J.M ed. C hem. 1981,24,499-502 49985-86 "C; IR 1720 (C=O) cm-I. Furth er elution of the columnwith CHC13 (300 mL) an d then CH 30H (200 mL) yielded abou t8 g of the starting material 3.I -(l-Phenylcyclohexyl)-4-phenyl-4-piperidinol10). Asolution of 5 g (0.019 mol) of the ke tone 9 in 1 0 mL of ben zenewas added dropwise to phen yfithium (from 6.3 g of bromobenzenean d 0.56 g of lith ium ribbon in 40 mL of ether). After 1h of reflux,the m ixture was poured into ice-water-AcOH, ammo nia wasadde d, and t he basic substanc e was extracted with benzene, dried,an d concen trated. Th e residue was recrystallized yield 5.0 g(77%).

I - (l-Phenylcyclohexyl)-4-phenyl-4-piperidylropiona te(1 1). A solution of 2 g of the pip eridin ollo in 3 mL of pyridinewas refluxed for 5 h with 5 mL of propionic anhydrid e, dilutedwith 50 mL of CHC13, washed with aqu eous NaH C03 , dried,concentrated, and converted to the hydrochloride, which wasrecrystallized from acetone: IR 1750 cm-'.1- (l-Phenylcyclohexyl)-4-phenylpiperidine13). 1-(4-Pheny1piperidino)cyclohexanecarbonitrile 12) was prep ared from24.5 g (0.152 mol) of 4-ph eny lpip erid ine A ldrich) an d 18.7 g (0.15mol) of cyclohexanone cyanohydrin by refluxing azeotropicallyin 60 mL of benzene for 3 h. The residue was recrystallized frommethanol-ethyl acetate (l:l), p 106-107 "C. A solution of 12g (0.044 mol) of 12 in 50 mL of benz ene wa s added dropwise toPhM gBr (from 2.0 g of Mg and 12.5 g of bromobenzene in 20 mLof ether). Th e mixture was decomposed after 2 h of reflux andthen treated as described for 3.Ph arm aco log y. All compounds as hydrochloride salts weredissolved in saline or twice distilled water (for bioassay). MaleICR mice weighing 24-28 g were used for analgesic kats, and miceweighing approximately 30 g were used for bioassay.Hot -P la te Test. Th e method of ref 14 was used. Mice wereput on a hot plate a t 57 f 0.5 "C. Th e reaction time (jumpingor licking the h ind paws) was observed once before and the n a fteradministration of the compound sc.

To = control time; Tt = latency time a t the peak; Tm, = 30 sW r i t h i n g Test. Mice were injected ip with 0.6% acetic acid(0.1 mL /10 g) after ad ministration of the com pound sc, and th enumber of writhing movements were noted in control mice ( W J

and in treated m ice (WJ.

% inhibn of acetic acid induced stretching resDonse =.100 - [ ( + I ]

EDM an d 95% confidence limits were obtained from probitanalysis, according to Litchfield and Wilcoxon.% At least 40 micewere used for each determination of EDwBioassa y. Effects of the compounds on the mouse vas deferenswere examined according to Hug hes et al." Mice were killed bycervical dislocation. Both vasa deferen tia were d issected out asa single unit. Th e tissue was bathed in an organ bath of 50 mLvolume a t 37 "C in modified Krebs solutio n and gassed with 95%O2 and 5% C02. Contractions were recorded by an isotonictransdu cer. Th e intramu ral nerves were stimulate d (0.2 Hz, 2-msduration, supramaximal voltage) through a pair of platinumelectrodes around the tissue. When twitches were co nstant, 0.14 .3mL of a solution of the co mpoun d tested was injected into th eorgan bath.ICm, the concentration which produced 50% inhibition oftwitches, was determined from p robit an alysis. At least threedose-response curves (four to six concentrations) were obtained.Complete reversal of t he maximal inh ibitory effect (80-90%)wasobtained with 20-50 nM naloxone, for compou nds 10,11,1 3, andmorphine hydrochloride.De te rmina t ion of Locomotion Act ivi ty in Mice. Th e lo-comotor activity was measured in th e anim al Activity Monitor"Varimex" (Columbus, Ohio). Thr ee male ICR mice weighing25-30 g were injected sc with th e compoun d tested (EDm fromth e analgesic assay) and th ree with saline (controls). Ea ch grou pwas transferred to a cage, and counts were recorded at 6-minintervals. Th e counts at the peak effect of each compoun d wasdivided by the value found for ita control group (taken as 1.0).At least nine mice were tested for each compou nd. (Th e testswere car ried ou t bet we en 8:OO an d 12:OO).Acknowledgment. We thank Dr. Y. Sarne and Mrs.0. K e r e n f o r their sugges t ions for th e bioas say .

(24) J. T.Litchfeld and F. Wilcoxon, J.Pharmacal. E x p . Ther.,96,99 (1949).(25) C. D. Barnes and L. G. Eltherin gton, "Drug Dosage in Labo-ratory A nimals", University of California Press, Berkeley, CA,1966.

Oxazepam Esters. 3.' Intrinsic Activity, Selectivity, and Prodrug EffectGBbor M a k s a y , * fiva PBlosi, Zsuzsanna T e g y e y , an d LBszld Otvo sCentral Research Insti tute for Chem istry of the Hungarian Academy of Sciences, H-1025 Budapes t Pf . 17, and ChemicalWorks of Gedeon Richter Lt d . , Budapes t , Pf . 27 , Hung ary. Received February 28, 1980

Antimetrazol a nd muscle-relaxant activities of 11aliphatic esters of oxazepam were studied as a function of timein mice. Th e esters given intravenously retained antim etrazol activity, while musc le-relaxan t activity was gene rallydecreased. Th e administration of a dose equivalent to the antimetrazol EDm resulted in co nstant oxazepam brainlevels for most e sters; therefore, the intrinsic anticonv ulsant activity of th e intact ester is insignificant. Th edimethylphenylpropionyl ester appeared to antagonize the effect of o xazepam, since it elevated the free oxazepamlevel required to achieve the EDM n the antimetrazol assay. Th e administration of doses equivalent to themuscle-relaxantEDm values resulted in no correlation with totalbrain benzodiazepine levels, suggesting th at changesin th e selectivity of action a re th e consequence of different sites of action.

O x a z e p a m (7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-3H-1,4-benzodiazepin-2-one)s a wide ly used c e n t r a l l ya c t i n g d r u g . 2 A l t h o u g h i t ha d been c o n c l u d e d that 3-s u b s t i t u t i o n d i m i n i s h e d t h e a c t i v i t y o f 1 , 4 -b e n z o-d i a z e p i n e ~ , ~evera l 3-substituted derivatives of oxazepam(1) For paper 2 in this series, see G. Maksay, Zs. Tegyey, and LOtviis,J. M e d . Chem., 22, 1443 (1979).(2) E. Van der Kleijn, T. B. Vree, and J. J. M. Guelen, Psycho-pharmacology ( N . Y . ) ,2(Part 2), 997 (1977).

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were synthetized and i n ~ e s t i g a t e d . ' ~ The hemisucc ina tees te r of oxazepam and its e n a n t i o m e r s w e r e e x t e n s iv e l y(3) L. H. Sternbach, L. 0. Rand all, R. Banziger and H. Le hr, in"Drugs Affecting the Central Nervous System", Vol. 2, A.Burger, Ed., Marcel Dekker, New York, 1967,p 237.(4 ) S. C. Bell, R. J. McCaully, C. Gochman, S. J. Childress, andM. I. Gluckman, J. Med. Chem. , 11,457 (1968).(5) A. Nudelman, R. J. McCaully, an d S. C. Bell,J. Pharm. Sci.,63, 1880 (1974).

0 1981 American Chem ical Society