Journal of Medicinal Chemistry, 1970, T'ol. 13, -Yo. 6 975
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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 SH40H, 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. The residue was chromatographed 011 Alto3 and eluted with about freely a t the end of a leash. A dose of 12 mg/kg 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-'. Anal. (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
Joiirnd of Jlcdicind Chemistry, 1.970, Vol. 1.3, A\vo.5 977
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15, arid bemegride had EDSOlb of 10 mg/kg sc or lehs, 1, 3, 7, 10, 11, 12, 14, and 16 had EDjOfs of 11 to 3.5 mg/kg sc, and 4 was inactive. Further testing in the rat of the 4 most active compounds by the tail flick method6 and the AgSOo inflamed joint test7 indicated that none of these compounds possessed significant analgetic properties. The results of analeptic screening show that 8 and 13 compare favorably Ivith bemegride as analeptics, and warrant further evaluation in the CSS area. Experimental Section
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1-Formimidoy1indolines.-A solution of eqiiimolar amounts of indoline and appropriate amide i n I ,2-dichloroethane [250 ml (0.1 m)] \Tab treated dropni5e n i t h an equimolar solation of POC1, in 1,2-dichloroethane [50 ml (0.1 m)] over a period of 0.5-1 hr. The mixture, after being stirred for 15 hr, was poured onto crushed ice, and made qtrongly basic with 20% KaOH with stirring. The organic layer ?I as separated and extracted with dilute HC1. The acid solution mas made basic with 2070 NaOH and extracted again (EtnO). The extract was concentrated to obtain the crude product. The HC1 salt nas prepared in the usual manner and recrystallized from appropriate solvent as shown in Table I.
Acknowledgment.--We wish to thank Nessrs. L. E. Allen, T. J. Eaton, T. C. JIays, Jr., J . F. Purcell, Jr., T. F. Williams, Jr., and R. A. Winnecke for their technical assistance. (6) IT. R. Bass and .\I. J. Vander Brook. J . d m e r P h n r m A b s Scz. Ed., 41, 569 (1952). (7) A. LrtDrPle and H . Tisloir, J . Pharmncol. E r p . Ther.. 98, 19 (1950).
Synthesis of Some Local Anesthetics P. K. SRIVASTAVA AND P. S . SRIVMTAVA Department of Chemistry, University of Roorkee, Roorkee, India E
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Received April 22, 1970
It has been found by many workerslV2 that the ebsential structure requirements for a local anesthetic are a lipolytic end containing an aromatic nucleus, a hydropilic end consisting of a tertiary amino group, and an intermediate alkyl or substituted alkyl chain. Compounds having a dialkylamino alkylamino group connected to an aromatic or heterocyclic nucleus as a lipolytic moiety confer greater activity and less toxicity. Therefore, it was thought worthwhile to synthesize some pyridine-2-aminoacetyl-2-aminobenzothiazoleand N , N-diethylanilino-p-aminoacetyl- 2 - aminobenzothiazole derivatives, by condensation of chloroacetyl chloride with different 2-aminobenzothiazole~ followed by treatment with 2-aminopyridine and p-amino-N,N-die thylaniline, respectively. Experimental Section Different 2-aminobenzothiazoles were prepared according to Hugershoff . g Chloroacetyl-2-aminobenzothiazoles were prepared by known methods.' Pyridine-2-aminoacetyl-2-aminobenzothiazole.-2-Chloroacetylaminobenzothiazole (5g) dissolved in EtOH (30 ml) was added t o 2-aminopyridine (3 g) dissolved in EtOH (20 ml) and the reac( 1 ) F. F. Rlicke and H. C'. Park, J . A m e r . Chenr. Soc., 61, I200 (1939). (2) A. .\I. XIattocks and 0. 9. IIutcliinson, i h i d . , 70, 34i4 (1048). ( 3 ) .i. Hugerslioff. Chem. B m . . 34, 3130 (1901); 36, 3121 (1903). (4) P. N.Bliarya\-a and G . C. Sinrli, J . Irtdtirn Chsm. SOC.,98, i i (1YB1).
