890
Journal of Mcdicinal Chemistry, 2971, T'ol. 14,S o . 9
NOTES
atives I V were prepared by the interaction of 4-@chloroethy1)-1-piperazinecarboxylicacid Et ester. HCI? and appropriate secondary amines in the presence of anhyd K&Oa in abs EtOH. Compounds 1 and 2 have also been prepared by treating piperidinoethyl cliloPH.\IIH.\SH CH.\~TDRA Il.$S, *' B. B.P~iTR.\! 8. B.CH.IUDHCHI, ride. HC19 arid morpholinoethyl chloride. HCIJ9 respq U. P. B.4sv, with 1-piperazinecarboxylic acid E t ester by the same procedure. Department of Applied Chemislry, I ; n i c c ~ s i l Colleges ~j of Science and Technology, Calczctla, India Biological Testing. Antifilarial Activity.-Cornpounds 1-5, 7, and 9 that passed the short-term oral B.S . KoL.\Y,.\SD S . 11. X\ITR.\ toxicity were screened on 1,. cui-iriii infected albino rats generally at a dose level of 200 nigikg once daily Deparlvccnt of Physiologg, L'niwrsz't?/ Colleges of Scr'ence for 3 consecutive days, and the tail blood (4 mm3) u-as and Technology, Calczdla-3, India examined up t o day 13. N,iCr-Diethyl-4-metliyl-lReceived Seplcniber 8 , 1970 piperazinecarboxamide-treated and untreated albino rats were kept as control. Only 1 shorved definite N,N-Diethyl-4-substituted-l-piperxxinecarboxamides niicrofilaricidal activity even at 100 mg/kg. (I) and 1-piperazinecarboxalic acid Et ester derivAntihypertensive Effects.- All the compounds exative. (11) exhibit pronounced antifilarial activcept 3 a s listed in Table I Tvere tested for hypotensive or it\ Further, tlie ethylenediamine derivative I11 hypertensive effect on pentob.\rbital-anestlietized cats I i a s also been found t o be active :cgainst litomosoidal of either sex a t dose levels of 0.3 mgAg, 5 mg/kg, and infections: I n view of these observations n e wished to 25 mg/ lig iv. The criterion of activity W E taken to be a build up :L structural pattern of the type IV wherein 1fall in blood pressure by 20 mm for :It least 1:i min. piperazinecnrbox>lie acid E t ester itielf will form a part The hypo- or liyperteiisive effect is recorded in Table I. of the ethylenediamine chain. Of the 7 compounds tested for antifilarid :Lctivitj., only one (1) was found to possess definite niicrofilaricidal Me n activity at 100 and 200 mgi kg. I R'N uNR Me,NCH,CH,NCONEt, Encouraging antihypertensive activity was observed I, R'= CONEt> with a small number of compoundi.. :\laximum activI11 11. R COlEt ity vas observed in 4,jvhicli embodies a 1,2$3>4-tetr:iIiydroisoquinoline moiety at one elid of the ethylenediamine chain. 111 a number of other tetrxliydroisoquinoline derivatives. antiliyperterisive activity has been observed.'" 3.4-Dihydro-2(H)-isoquinolirie carIV boxamidine has been found clinically to be L: potent' Since sonie piperazine derivatives6 and also some antihypertensive agent. The parent compound. 4ethylenediamine derivatives7 have been reported as po(~-chloroeth;\~l)-l-piperazinec:~rboxylic acid Et est er tential antihypertensive agents. the antihypertensive HC1 also produced an hypotenrive effect. effect of compounds IV, in which both terminal S atoms of the ethylenediamine chain form part of heterocyclic moieties (with tlie exception of 9) have been studied. Experimental Section'' Chemistry.-The substituted ethylenediamine derivSynthesis of Some 1-Piperazinecarboxalic Acid Ethyl Ester Derivatives as Possible Antifilarial and Antihypertensive Agents'
(1) (a) Taken in part from the Ph.D. thesis submitted b y Prabhasli Cliandra Das, November 1968, t o t h e Calcutta University: (b) presented in
part a t t h e Annual Sessions of the Indian Scienre Congress: P. C . Das, B.B . P a t r a , and C . P . Basu, Pror. Indian Sca. Congr., 67, 131 (1970). (2) T o whom correspondence should be addressed a t t h e Department of Pharmacology, University College of Medicine, Calcutta University, Calcutta-20, India. (3) (a) 6 . Kushner, L. hI. Iirancone, R . I . H e x i t t , W.L. hlcEwen, Y.Subl)aroir, H. W. Stewart, R . J . Turner, and J. J. Denton, J . Org. Chem., 13, 144 ( 1 9 4 8 ) ; ( b ) R . I . H e v i t t , S. Iiushner, H . TV, Stewart, E. White, TI-. S. K a l lace, and Y. Subharow, J . Lab. Clan. .\fed., 32, 1314 (1947). (4) (a) El. I . Hewitt, E. White, IT-.S. Wallace, H . \T-. S t e w a n , S. Iiushner, and Y. Subbaron!, ibid., 32, 1304 (1947): (b) H . TI-. Stewart, R. J. Turner, .J. J . Denton, S. Iiusliner, L. h l . Brancone, \T-. I,. RIcEwen, R . I . Hewitt, and T.Subbarox, J . O r g . Chem., lS, 134 (1948). ( 5 ) P. Seirell and F. Hawking, Brit.J . Phurmncoi., 6 , 239 (1950). ( 6 ) (a) S. M . O h , U. S. Patent 2,858,313 (Oct 28, 1958); (b) Park Davis and Company, British Patent 803,403 (Oct 22, 1958); (c) R . M . Jacoh, R . J . Harclois, and G. L. Reanier, British Patent 802,244 (Oct 1, 1958): (d) L. F. 13ach. ,Jr., H . J . Barbander, and S. Kushner, U. S. Patent 2,909,523 (Oct 2 0 , IOSS), 2,837,522 (June 3 , 1958): (e) Park Davis and Company, British Patent 850,662 (Oct 5 , 1960); (I) B. Rudner, U. S. Patent 2,967,865 (Jan 10, 1961); (g) 8. H a s a o , R . iX Scliut. and G . W.Strycker, J . .Wed. Chem., 6 , 133 (1963) ; (11) J. R . Doissier and R . Rntouis, French Patent 1,318,449 (Feb 15, 1963); hI1784 ( M a y 20, 1 9 6 3 ) ; hI1749 (April 22, 1963); 1320235 (March 8, 1963): ( i ) R . Ratouis, J. R . Boissier, and C . Dumont, J . M e d . Chem., 8 , 271 ( 1 9 6 5 ) ; i j ) €1.Howell, C. B. Pollard, L. B. Iiier. and H . 13. Sislcr, i b i d . , 6 , 604 (1963) : i k ) R . S . Prasad and J . Tietje, i h d . , 12, 551 (1969). ( 7 ) (a) h. P. Sirain and S. I
