Journal of Medicinal Chernistry, 1U7'0, "01. I J , ,Yo. 5
NOTES
colorless oil: bp 92-94' (0.01 mm); n% 1.549. Anal. (COHiaOr) G, H . Amino Alcohols I and 11.-The appropriate epoxideI7 (0.075 mole) arid amine (0.1 mole) were dissolved in 70 ml of i-I'rOH a i d heated in a sealed vessel at 80" for 4 hr. The solvent was removed under reduced pressure and the oily residue was distilled. 12esults are summarized in Tables I and 11.
Acknowledgment.-The authors are indebted to Dr. 1'. Vaudescal for chemical cooperation, to Miss A. 11. Conrard for biochemical analyses, and to A h . P. Yassort for spectroscopic arid analyt,icalservices. (17) l-(p-Cyclopropylphenoxy)-2.3-epoxypropane was prepared in a similar manner as for the ortho deri\.ative and was used n.ithout distillation.
2,3,6-Trimethoxynitrostyreneand Its p-Phenethylamine 131. I'TY ?*I.\TSCHlllurin, .I. .Ilcd. Chew., 8, 3.53 (IOti5). (4) .I. Sliulyin, ibid., 9, 445 ( 1 Y t i O ) . (51 I ) . \V. Xatliieson, S u c l . .I.luyn. Rasoiiunce O r y . Cham.. 187 (1967). (61 I,-(ja Iiydroxy-4,;ia- epoxy- A 7 - X - meth?.lisoniorphiriari (11, traris-codeine). Chemistry.-Our earlier report dewibetl :t >-stel) 5)xthesis of fiaris-codeiiic (11) from isoneopitic. i i i I).Sc( overall yield. It appe:ired ]:iter, ho\vever, th:Lt ( - ):i-methox-~iP,Sa-d~tos>,loxj.-4,~aq " y - N - methyliwiriorphiriuii (I),R when he:ited wit)h I.ield (Sl;%). Oppenauer oxidation of ( - )-X-methuxy-Aa-hydrox\.4,.icu-epoxv-N-methylis(~mor~)hiti:~ti(111, fims-dihytlrocodeine) gave t h r &oxo derivative which proved to be ident,ical with :in :iuthentic sample of trar/stlihydrocodeinorw (IV).j Thi,q result provides :in additional proof of the structui-t. of' trarls-codeine. Pharmacology.--Receiitly, Belitley atid c o \ \ o r l w r ~ ~~.iitIiwizedG,14-e11docthenotetr:ih~drotheb:ii1iederiv:itivr~s, the C,--C, linkage of which might be coti4tirrtd tis :i p:trt, of' the C-ring of the B;C tiarrs-morphilie structure.6 Iri view of the very potent :tnalgetic activity of those dc>riv:itivesthe!. suggested that €3 (' /,-airs-morphiiic)woiild h:ivti :I higher potcinc>- t1i:iri thc, i i n t i i i d c i s drriv:ttivc~.!' Table I yreseiits :iti:ilgctic :tctivitit>s"l : i i i ( I >icutci toxicitiesi1 of im?/s-morphine derivatives iis well :ih thc comp:ir:itive data for morphine and codeitit>. ~ / ~ ~ ~ / / ~ s - ~ \ l(1) o ~w ~ a~ s) lt'ourid i i i i ~ to br aril!. 0.1 :is :ictivt' :is ti:itiii~:tI nnorphirir~. I n gc~ric~~xl. tl,nr,.s-rnoil)hin(, (Its-
:ilso
I
Journal of Medicinal Chemistry, 1970, T'ol. 13, -Yo. 6 975
?;OlI.S
analyses are indicated only by symbols of the elements, analytiof t'he theocal result's for those elements were within ~k0.47~ retical values.
+
( )-3-Methoxy-6~-hydroxy-4,5a-epoxy-A7-N-methylisomorphinan (trans-Codeine) (II).-A mixture of I (2.8 g), AcOK (i g), H t 0 ( 2 ml), and DMF (40ml) was refluxed for 23 hr and Biological Data and Correlations. Analeptic Acevaporated in z'acuo. The residue was dissolved in HzO, basified with S H 4 0 H , extracted with CHCl,, dried, and evaporated. tivity.-With fen- exceptions, the compounds listed in Conversion of the residue into the picrate in Et,OH gave 11. this report n ere hcreened for analeptic activity by both: picrate (1.26g, 53.2%), mp 244-245' dec (from ?\le&O-EtOH). (1) the antagonihm of pentobarbital in cats and ( 2 ) the This was identical with an authentic sample. antagonism of chloral hydrate in mice. 3-Methoxy-6-oxo-4,5a-epoxy-N-methylisomorphinan (transDihydrocodeinone) (IV) Picrate.-A mixture of I11 (from 0.35 g Pentobarbital Antagonism.-Cats of either sex, preof the hydrochloride), Al(O-&Bu), (0.35 g), benzophenone (1.7 g), viouhly equipped with chronically indv elling iv canaiid CCHs (5 ml) was refluxed for 20 hr under Nz. The mixture nulas, were individually placed into an observation \vas acidified with dil H2S04.the HIO layer was separated, basified cubicle (60 X 60 x 60 cm) arid allowed to move with 10;' PiaOH, estracted with CHCl,, dried, and evaporated. about freely a t the end of a leash. A dose of 12 mg/kg The residue was chromatographed 011 Alto3 and eluted with CsHs-Et20 ( 9 : l ) . The eluate was converted into the picrate of aq pentobarbital sodium was infused at the rate of and recrystallized from EtOH->\Ie&O to give IV.picrate (0.06 approximately 2 mg kg per min cza tubing contained in g, llc;), mp 220-230" dec, ir, 1723 cm-'. A n a l . (CtrH*&;aOio) the leash. One-half hour after the start of this infusion C', H, S . The free base was crystallized from EtlO, mp 98-99', the animals were in a stage of light anesthesia charidentical with an authentic specimen. (mp, nmr, and tlc).
Acknowledgment.-The authors express their gratitude to Dr. Everette L. l l a y , Sational Institutes of Health, for his aid in deterniinat'ion of the analgetic activity. T h a n h are also due to Ah. 31. 17amazaki, Dr. S. Sugimoto, and Dr. S. Sugasawa, Professor Emeritus of Tokyo University, for their interest and encouragement.
Analeptics.
1-Formimidoylindolines
T i o - H c i WvJ1W;LTI:R G. LOBZCK, JR., Department of Chemacal Research, IND
JOHL W. KISSLL
Dipartmtnt of Pharniacology, Mead Johnson Kescai ch Centw, Evansville, Indiana IZeceiced dlarch 23, 1970
Although the value of analeptics in the treatment of C I S depression is uncertainJ2bemegride has been generally recognized as useful in treating patients with severe barbiturate intoxication. I n the course of investigation of amidines as medicinals, we discovered that certain 1-formimidoylindolines (I) have analeptic effects comparing favorably with bemegride. We wish to report the results of analeptic screening on these compounds. I n I, X represents H, Ac, and KO2 groups; X
OJ I
RJ=CR, (1)
and R1, R2 represent H, alkyl, and alkylamino groups. R1 and R2 may join together to form a cyclic moiety. These compouilds were synthesized by the action of ail amide-POCl3 adduct3 on an appropriate indoline. Their physical constants are tabulated in Table I. (1) T o wliorn inquiries slioulii he addressed. ( 2 ) F . llatm. I'harmcwd. Keu., 12, 447 ( 1 9 6 0 ) . (:1) H . Hrederick and E;. Iirederick. Chem. Ber., 94, 2278 (1961).
acterized by unconsciousness. immobility, relaxed nictitating membranes, and irresponsiveness to handling, but active pinnal, palpebral, and pam-pinch withdrawal reflexes. At this time the test compound in aq solution was infused in a concentration of 10 mg/ml and a t a rate of 0.2 ml/min until (a) consciousness was restored, (b) a total of 25 mg/kg of test compound was administered, or (c) mounting toxicity interfered. Recovery of consciousness was recognized by the presence of alertness to surroundings, including the ability of the eyes to follow the movement of a nearby object, and attempts to change to an upright position. Results are presented in Table I. All compounds were tested in two cats. Chloral Hydrate Antagonism.-Groups of 20 fasted, male, albino mice were administered an oral dose of 20 mg 'kg of the test compound followed immediately by an ip dose of 300 mg, kg of chloral hydrate. If the duration of the erisuirig hypnosis was 50% or lesi of that produced in saline-treated controls additional doses were administered and the dose which would reduce sleeping time by 50% was determined graphically from a dose-response curve. Results appear in Table I. Three compounds (8, 13, and 17) approximated the analeptic potency of bemegride in this test. Discrepancies between the results of these two test> may result from the chemical difference in the hypnotics themselves as well as the species in which they are employed. I n addition, the infusion technique used in cats requires that the test compound be prompt i~ exerting its analeptic effect before its toxic actions ink!,vene. Indeed, convulsant stimulation is a commo i toxic manifestation in this series and in some cast'\ analepsis may actually have been a result of it. Extended testing with the more active compounds demonstrated that motor stimulation is not a necessarj. concomitant of analeptic action. According to an activity cage technique using rats,4 2 and 8 were inactive, 6 and 13 were depressant, and 17 was mildly stimulant. Bemegride is mildly depressant to motor activity, although amphetamine is markedly stimulant. Other Tests. Analgesia.-Thirteen compounds n-el'e screened for analgetic properties in mice b\- mean. of the phenylquinoiie writhing test.: Compounds 6, 9, 13, (4) J it Kiasel, Science, 139, 1224 (196d) ( 5 ) L C . Hendersliot and J Forsaitli, J Pti~irimicol E x p Ther (195Y).
128, 2 d i
