I,o\c;-Ac~~i(; THASQCILIZEHS
July, 1963
347
Esters of 4- { 3-[2-(Trifluoromethyl)phenothiazin-10-yl]propyl~-1-piperazineethanol as Long-Acting Tranquilizing Agents. Synthesis of 4- { 3-[2-(Trifluoromethyl)phenothiazin-10-yllpropyl ] -1-piperazineethanol-ethyl-C'*and its Ester with Heptanoic Acid. I11
T h e Syiiibb Instztiite Jor JIedzcal Research, .Yew Hrunswlck, AY.J
h nuniber of esters of 4- { :~-[2-(trifluort~nnethyl)-phenothiazin-l0-g1]prop~l) -1-piperazineethanol have been prepared with triet,hylacetir, heptanoir, deranoir, undecglenir, stearir, S-rarbomethoxgortanoic, azelair, and 2,6dimethyl-p-anisic arids. Several of these, administered in sesame oil solution, have shown long duration of tranqiiilizing artivitg. The heptanoate, for example, in a single dose of S to 32 mg./kg., has shown a duration of activity ranging froin 1% t o 15 days in the trained rat; the same compound has been tried in man and a single dose of 25 nig. has shown rlinical efiectiveness for 2 weeks.
Aii objective of our program 011 ceiitral nervous system depressants' has been the synthesis of a loiigacting tranquilizing agent. Earlier comparisons of the dihydrochlorides of 4- { 3- [2-(trifluorometliyl)pheiiothiaziii-10-yllpropy1)-1-piperazineethanol( I ) and its ester with acetic acid (11), had demonstrated no significant pharniacological differences or duration of activity betiwen the two conipouiids, due to the rapid A
I R = HO I1 R CII:COi I11 R = CaH ,CO? I V R = CHISOI
V R=Cl
ciizymatic hydrolysis of 11.' X nuniber of esters of I with higher molecular weight' carboxylic acids have now been preparrd, aiid the pharmacological evaluation of these has show1 that several possess loiig duratioii of tranquilizing activity. 1;or example, the ester with heptanoic acid ( I I I ) , dissolved in seasame oil and injected subcutaneously iiito rats, iii a single dose of 8-33 mg. ' k g . , has shon.n a duration of activity ranging from 12 to 1.7 days3; the same compound has been tried in man and a single dose of 23 mg. has shon-ii cliiiical effectiiwiess for 2 ~ v e e k s . ~ The general procedure for the syiithesis of t'liese compounds invol\.rd the reaction of I with the acyl chloride, in chloroform, under reflux. I n this fashion, csters were prepared x i t h triethylacetic. heptaiioic, decanoic, uiidecylenic, stearic, 8-carhoniethoxyoctanoic, and azelaic acids. While the ester with 2,(i-dimethyl-panisic acid could not he prepared hy this method, it was synthesized by the reaction of potassium 2,6(1) 1'oi t h p preceding Iiaijeis i n this series, see ( 2 ) 1 1 . I,. T e l e , F. Sowinski. a n d .J. I!prnstrip. .I. .lm. Chem. Soc.. 79, 137.5 (19,>7) ( I ) ; ( b ) €1. L. Tale a n d 1;. Sowinski, i h i d . , 82, 2038 (1060) (11); see also, I'. S o n i n s k i anri 13. L. \-ale. .I. .lied. .d'hnrm. L'hem.. 5, A4 (1962). ( 2 ) C . I. Stiiitli a n d .J. C . I3iirke. T o l i d A p p l . I ' h n r m a t o i . , 2 , .j.53 (1960); .T. 1'. Hi.11. C:. L . Hassert, J r . , 13. Riihin. .J. J. I'lal::, .J. C'. I3rirke. a n d 13. S . aqueolls potassium carbonate and ether until two phases formed. The ether layer was eeparat,ed, dried, and treat,ed with a saturated solution of maleic acid in acetone to give t,he maleic acid derivative. The purified maleate was decomposed in the usual manner with aqueous sodium bicarbonate solution t.o give the hase. 4- (3-(2-Trifluoromethyl)phenothiazin-lO-yl] propyl 1 -1-piperazineFthanol, 2,6-Dimethyl-p-anisate Ester.-To 5.1 g. 10.025 mole) of 2,6-dimethyl-p-anisic acid in 10 ml. of 05(;~;ethanol was added 1.7 g. (0.026 mole) of 85% potassium hydroxide in 25 ml. of 95';; ethanol. The solution was filt,ered, concentrated t,o 10 i d , , and 50 ml. of anhydrous et,her added. The'precipitated solid \vas filtered, washed with ether, and dried to give 4.1 (67Yo)of the potassium salt, m.p. 279-280'. Anal. Calcd. for CIOHIIOIK:K, 17.91. Found: 17.43. To 21.9 g. (0.05 mole) of I in 250 nil. of dry benzene \vas added 7.1 g. (0.06 mole) of thionyl chloride, the mixture kept overnight, heated for 3 hr. under reflux, rooled, and treated with an excess of ethereal hydrogen chloride. The solid was filtered and recrystallized from absolute ethanol-anhydrous ether to give 18.4 g. of product, m.p. 215-216" de(,.,suitahle for further synthesis: pure 10-[ 3 - [ 4 -(2-chloroethyl)-l-piperazinyl]propyl) -2-(trifluoromethy1)phenothiazine (V) dihydrochloride, ni.p. 224-225" der., \v:a.s obtained hj. :in :idditional recrystallization from absolut,e ethniiol.8 A n a l . Calcd. for C22H2,F3C1S.,S.2HC1: total C1, 20.11 : X, 7.94. Found: C1, 20.27; S , 7.96. To 2.7 g. of the above potassium salt in 25 ml. of T,S-dimethylformamide, under nitrogen, ~ : t sadded the 1- obtained from 5.3 g. (0.01 mole) of the dihydrochloride. The mixture w ~ stirred s and heated for 5 hr. on t,he st,eani bath, cwled, diluted nit,h cold water, 10'; aqueous sodium hydroxide added to p H 10, and the product eztr:trted with ether. The ether extracts were dried, and filtered and t,he filt,rat,ewas concentrat.ed to give 3.5 g. (58'; yield) of the crude ester, as a viscous yello\v oil. To the crude ester, in 50 nil. of anhydrous ether, \vas added 1.5 g. (0.013 mole) of maleic acid in 10 nil. of acetone. The precipitated solid was filtered :ind rerrystallized from ethyl methyl ketone to give 3.6. g. i i S ( , c ) of the maleate, m.p. 160-161". The maleate was added to 60 nil. ( i f cold, saturated aqueous sodium bicarbonate solution and 50 ml. of ether and the whole stirred until no solid remained. The ether layer was separat,ed, dried, and toncentrated to give 1.6 g. of the pure ester as a viscous oil. Attempted Preparation of 1V.-The following summarizes t h e unsuccessful experinient,s carried out: I and niethanesulfonyl chloride in wetone, in the presence of anhydrous potassium rarbonate: renction of I wit,h sodium hydride in xylene to give t,he sodium salt, followed by treatment with niethanesulfonyl rhloride: I and methanesulfonyl chloride in pyridine: and, I and methmesulfonic anhydride-pyridine complex. lO,lO'-Ethylenebis( 1,4-piperazinediyl)bispropylenebis[2-itrifluoromethyl)phenothiazine]. (AI.--A mixture of 3.93 g. r0.01 mole) of T'II,Ib3.64 g. 10.008 mole) of V, 1.5 g. of anhydrous, potassium c a r h n a t e , 100 nig. of copper poivder, and 25 ml. of toluene vas stirred and heated under reflux for 16 hr., filtered, and the filtrate concentrated to dryness in c"xo. The residue rrystallized when treated with acetone and cooled. Recrystallization from ethyl met,hyl ketone gave 0.9 g. (l4r;) of product, m.p. 146-14io, and this m.p. was not depressed by t,he product obtained in 1B) below. -4nal. Calcd. for C1YH46 S , 7.89. Found: C, 12.64: (B).-From the reaction between 3.113 g. (0.01 mole) of 1-11, 1.9 g. (0.012 mole) of VI, 1.4 g. of anhydrous potassium cubonate, 100 mg. of copper bronze, and 25 ml. of toluene, after 16 hr. of heating under reflux, t'here was obtained 350 mg. ( 8 ' ( yield) of product, m.p. 146-147", after recrystallization from ethyl me thy1 ketone. Reaction between N-Methylaniline and VI.-A mixture of 21.4 g. (0.2 niole) of N-methylaniline, 15.8 g. (0.1 mole) of VI, 13.8 (6) E. L. .-inderson, G. 13. Uellinzona, P. N. Craig, G . E. Jaffe, I
