Synthesis and central nervous system depressant activity of new

Synthesis and central nervous system depressant activity of new piperazine and related derivatives. III. R. B. Petigara, Chimanlal Deliwala, S. S. Man...
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September 1969

CSS-DEPRESSANT PIPERAZINES

p- (p-Chloro-a-pheny1benzylamino)ethylchloride hydrochloride was obtained in 71% yield by the action of SOC1, on b-(p-chloroa-phenylbenzy1amino)ethyl alcohol in CHCl, following the usual techniques; it w&s crystallized from EtOH, mp 23C-232O.l4b Anal. (C1&1&13N) C, H, E.

~-[N-(Methyl)-N-(p-chloro-a-phenylbenzyl)amino]ethyl Alcohol.-A mixture of p-(p-chloro-a-pheny1benzylamino)ethyl alcohol (2ti.15 g, 0.1 mole), HCOOH (10 ml, 98%), and HCHO 141 ml, 37-41%) was refluxed for 6 hr. Most of the HCHO aiid HCOOH were removed by distillation under diminished pressure. The residue was made alkaline with cold 5 N KaOH and extracted with EtaO. The combined Et20 extracts were dried (NaaSO4) and concentrated and t,he residue was distilled in vacuo. The fraction distilling a t 184-190' (6 mm) was collected, yielded 18 g (65%). Anal. (C16H~&lPr'o)N. P-[N-(Methyl)-N-~p-chloro-a-phenylbenzyl)amino]ethyl chloride hydrochloride was obtained as an oil by the actioti of SOCln 0 1 1 the corresponding alcohol and was used directly for further . condensation. p-(1,2-Diphenylethylamino)ethyl chloride hydrochloride wits prepared in 91 Toyield by the action of SOClz on the ctorresponding alcohol16 as usual and crystallized (EtOH), mp 212-218" dec. L4Wl. (CieHigC1nN) X. p-[N-(Methyl)-N-(1,Z-diphenethyl)amino]ethylchloride hydrochloride was prepared from 0-( 1,2-diphenylethylamino)ethyl alcohol hydrochloride, following the method described by Kerwin, et al.16 N~-[~-(p-Chloro-a-phenylbenzyloxy )ethyl]-N4-(2-pyridy1)piperazine Maleate (37).-To a mixture of 5-(2-pyridy1)piperazine (1.63 g, 0.01 mole) and EtJ (2.0 g, 0.02 mole) in EtOH (20 ml), was added a solution of P-(p-chloro-a-phenylbenzy1oxy)ethyl chloride" (3.09 g, 0.11 mole) in EtOH (10 ml) and the reaction mixt,ure was refluxed for 25 hr. The solvent was distilled off, (15) L. H . Goodson, C . J . W.Wiegand, and J. S. Splitter, J . Am. Ckem. Soc.. 68, 2174 (1946).

(16) J. F. Kerwin, T. F. Herdegen, R . Y. Heisler, and G . E. Ullyot, i b i d . , 72, 3983 (1950). (17) N. Kato, et d . , Japanese Patent 5028 (Sept 4 , 1951); Chem. S h s l r . , 47, Y362h (1953).

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and the residue was treated with cold 40y0 NaOH till alkaline and extracted with EtnO. The combined EtzO extracts were dried (NaaS04)and concentrated. The resulting oil was t'aken up in 20 ml of EtOH and added to a solution of maleic acid i n EtOH. The solid thus obtained was crystallized. N- (p-Chloro-~-phenylbenzyl)-N'-(2,6-xylidino)ethylenediamine (97) was prepared by the condensation of 0-(p-chloro-apheiiylbenzy1amino)ethyl chloride [obtained by the basificatioii of 9.5 g, 0.03 mole, of 8-(p-chloro-a-phenylbenzy1amino)ethyl chloride hydrochloride] with 2,6-xylidine (3.63 g, 0.03 mole) following the method described for 37. The resulting oil was distilled in vacuo and t'he fraction distilling a t bp 230-242' (7 mm) was collected. The free base was converted to its maleate d t . N-(p-Chloro-a-phenylbenzy1)ethylenediamine(83).--h soliitioii of p-chloro-a-phenylbenzyl chloride (23.7 g, 0.1 mole) in pyridine (25 ml) was added dropwiae with stirring to an icecooled solution of ethylenediamine (24 g, 0.4 mole) in pyridine (50 ml). The reaction mistri1.e was stirred a t room temperature for 16 hr atid then heated o n a steam bath for 1 hr. Pyridine was distilled off at diminished pressiire, cold H 2 0 was added to the residue, and the reaidiie was extracted with Et%(). The combined Et& extracts were dried (SalS04) and coiicentritted. The residual oil was distilled in vacuo and the port,ion distillirig between 176 and 182' ( 2 mm) was collected. The other compounds reported in Tables 1-111 were obtained by the condensation of appropriate halides with various Nmonosubstituted piperazines or appropriate amines, following the method described for 37. 111 case of amines having low boiling points, excess of xmiiies was taken, eliminating the use of triel hylamine. The resulting products were crystallized wheii solid or converted into the appi,opriate salts or distilled under vacuum when an oil.

Acknowledgment.--We wish to thank Mr. :\I. T. Jaokar for elemental microanalyses and Mr. S. Iiouo f lm%iI:il hypiionis ai 15 ing.kg. I'rodiic~etl IO05 blockiug of C h l l i i i ruls a t 30 nig:kg. Effec*tssirnilrlr to thtae seen in cats were also oliservecl in dogs and monkeys. The comporuid possesses a high order of muscle relaxation activity. * Showed mild hypot,ensive activity a t 2.5 mg/kg, and a t 10 niglkg marked hypotensive and mild adrenergic bIocking activity. Produced 60% potentiation of barbital hypnosis at, one-tenth of the LDSo. hlild to marked sedation and loss of muscle tone were observed between 20 and 100 mg/kg. ' Produced 100% potentiation of barbital hypnosis a t 60 mg/kg. a,a,a-Trifluoro-m-t.olyl. u mal, maleate. H

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CNS-DEPRESSANT PIPERAZINES

September 1069

hydrocinnamides were reduced to the corresponding amines (22,24, and 27) , marked adrenergic blocking activity was observed; 24 had also marked hypotensive activity. The propiophenone derivatives 30, 51, 55, 59, and 61 have marked hypotensive and adrenergic blocking activity. When the o-F of 30 mas shifted to the para position (31), the adrenergic blocking activity was diminished t o a great extent, whereas the hypotensive property was retained. Compound 31 has been selected for more extensive pharmacological evaluation; 20 and 22 are undergoing detailed cardiovascular studies.

Experimental Section Pharmacological Methods.-The studies of CNS activity were performed by administering intraperitoneally the suspension of the test compounds made with 0.57, carboxymethoxycellulose (CAIC). The vehicle itself was tested in a control group with negative results. For the studies of hypotensive and adrenergic blocking activity, healthy mongrel dogs (10-15 kg) were anesthetized with sodium pentobarbital (35 mg/kg iv). The blood pressure was recorded by a Hg manometer. The test compound was administered intravenously in different dosages. The effects of test compounds on blood pressure and epinephrineinduced pressor response were studied. Chemistry.6 Intermediates.-The requisite 3,4,5-trimethoxybenzaldehyde,7 3,4,5-trimethoxycinnamic acid,& 3,4,5-irimethoxyhydrocinnamic acid: 3,4,5-trimethoxybenzoyl ~ h l o r i d eethyl ,~ 3,4,5-trimethoxybenzoylacetate,~a 3,4,5-trimethoxyacetophenone, lo ~~bromo-3,4,5-trimethoxyacetophenone,~1 3,4-dimethoxyacetophenone (Fries migration12 of guaicol acetate followed by p-bromopropiophemethylation13), 4-metho~yacetophenone,1~ none,16 and 2-benzylaminopyridine16 were prepared by known methods. +3loro-3,4,5-trimethoxybutyrophenone was obtained as described previously.2 N -(Monosubstituted)piperazines.-The following N-monosubstituted piperazines were prepared according to known methods: N-benzy1-,I7a N-m-(methylben~yl)-,~~b N-(p-t-butylN-phenyl-, 17d N-m-, benzyl)-,l?b N-(p-chloro-cu-phenylbenzyl)-,17~ -0-,and -p-chlorophenyl-,17e N-o-fluorophenyl-,17f N-m- and -pfli~orophenyl-,~~g N-o- and -p-metho~yphenyl-,~~h N-m-, -0-, and -p-tolyl-,'7e N-(2-pyridyl)-,171 N-(2-pyrimidyl)-,171 and 2-(thiazolyl)-. N-(a,a,a-Tiifluoro-m-toly1)piperazinewhich could not be ob-

(6) I r spectra were determined in CIICls using a Perkin-Elmer Infracord spectrophotometer. Where analyses are indicated only b y symbols of the elements, analytical results obtained for those elements were within 1 0 . 4 % of the theoretical values. ( 7 ) L. Kalb and 0. Gross, Ber., 59, 727 (1926); Chem. Abstr., 20, 2671 ( lY26). ( 8 ) K. H. Slotta and H. Heller, Be?., 63, 3029 (1930). (9) L. F. Fieser, "Experiments in Organic Chemistry," 2nd ed, D. C. Heath and Co.. Boston, Mass., 1941, p 381. (10) J. Koo. .I. Am. Chem. Soc., 7 0 , 720 (1953). (11) W.J . Horton and G. Thompson, ihid., 76, 1909 (1954). (12) A. Ya. Berlin, S. M. Sherlin, and T. A. Serebrennikova, Z h . Ohshch. K h i m . , 19, i s 9 (1949); Chem. Bbstr., 44, l058f(1950). (13) H. Erdtman and B. Leopold, Acta Chem. Scand., 3, 1358 (1949) ( E n g l ) ; C h e m . Ahstr., 44, 73388 (1950). (14) Y. I. Jlaksimov and 2 Pryakhina, Zh. Obshch. K h i m . , 28, 246 (lY58); C h e m . Abstr., 52, 12816h (1958). (1.5) E. L. Foreman and S. h1. McElvain, J . Am. C h e m . Soc., 62, 1435 (1940). (16) J-. Sprinzak. "Organic Syntheses," Coll. Vol. I V . J o h n Wiley 6; Sons, Inc., New Tork. K.Y., 1963, p 91. (17) !a) R. E . Lutz and N. H. Shearer, J . Org. Chem., 12, 771 (1947); !I,) B.G . Bopgiano, G. B. Jackman, V. Petrow, and 0. Stephenson, British Patent 840,358 (July 6, 1960); Chem. Abstr., 56, 588a (1961); (c) T. Fujii, K. Tomino, and H. Watanabe, J . P h a r m . Soc. Japan, 74, 1049 (1954); (d) C . B. Pollard and L. G. MacDowell, J . Am. Chem. Soc., 56, 2199 (1934); (e) C . 13. Pollard and T . IT. Wicker, ,Jr,, ihid., 76, 1853 ( 1 9 5 4 ) ; ( f ) R. Ratouis, .J. It. Huissier. and C. Dumont, J . ,!fed. C h e m . , 8, 104 (1965); ( e ) P. A. J . Janssen, U. S. Patent 2,979,507 (April 11. 1961): C h e m . Ahstr., 56, 18T85a (1961); ( t i ) C. 13. Pollard and J. B. Christie, J . Org. C h e m . , 23, 1333 (1Y58); ( i ) E;. L. Howard, H. W.Stewart, E. A. Conroy, and J. J. Denton, ihid., 18, 1484 (1953).

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tained according to a patent method,'* was prepared in 35% yield by heating a stoichiometric amount of hydrochlorides of diethanolamine and m-trifluoromethylaniline with simultaneous removal of HzO following the method of Pollard and NacDowell described for the preparation of N-pheny1piperazine;l7d b p 120' (1 mm). Anal. (CllH1,F3N,) N. The free base (5.0 g) was taken up in 15 ml of EtOH and added to 15 ml of i-Pr-HC1 (22%). This on dilution with E h O gave a white solid, which on recrystallization from EtOH afforded the monohydrochloride, mp 232-233' dec. Anal. (C11H13F3Nz.HCl) C, H, N. N1- [( 3,4,5-Trimethoxybenzoyl)acetyl]-N44o-toly1)piperazine (lo).-A mixture of 11.28 g (0.04 mole) of ethyl 2,4,5-trimethoxybenzoyl acetate and 7.04 g (0.04 mole) of N-(o-toly1)piperazine was heated in an oil bath a t 120' for 2 hr and a t 150" for 3 hr. I t was then cooled and treated with HzO. The solid thus obtained was filtered and crystallized (EtOH). Other members of the series (I, A = COCH2CO) were obtained in a similar manner by taking the appropriate N-monosubstituted piperazines or other amines. The ir spectra of the representative compounds were as expected. N 1- [@-Hydroxy-@-( 3,4,5-trimethoxyphenyl)propionyl]-N4.(otoly1)piperazine (ll).-To a solution of 2.06 g (0.005 mole) of 10 in 120 ml of EtOH (or MeOH), freshly prepared Raney Ni W-7 (2.0 g) was added and the mixture was shaken for 10 hr under H2 a t 0.42 kg/cm2. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The resulting semisolid mass on crystallization (hexane) gave the desired product. The other @-ketoamides were reduced in a similar manner. Their spectra of a representative compound were as expected. N1-(3,4,5-Trimethoxycinnamoyl)-N4-( 2-pyridy1)piperazine (20). -To a solution of 5.0 g (0.021 mole) of 3,4,5-trimethoxycinnamic acid in 50 ml of o-xylene, was added a solution of 3.26 g (0.02 mole) of h'-(2-pyridyl)piperazine in 25 ml of o-xylene. The mixture was refluxed for 10 hr with azeotropic removal of H2O uqing a Dean-Stark water separator. The solvent was removed under diminished pressure (10 mm). The residue solidified when treated with EtzO (or hexane). This on recrystallization (EtOH-EhO) gave the desired compound. N1-(3,4,5-Trimethoxyhydrocinnamoyl)-N4-(o-chlorophenyl)piperazine (21) was obtained from 5.05 g (0.021 mole) of 3,4,5trimethoxyhydrocinnamic acid and 3.93 g (0.02 mole) of N-(ochloropheny1)piperazine by following a procedure similar to the one above. I t was crystallized twice (EtOH). Other compounds of both these series n-ere obtained as above. The absorption peaks of ir spectra of a representative hydrocinnamide were as expected. N1- [ y-(3,4,5-Trimethoxyphenyl)propyl]-N4-(o-chloropheny1)piperazine Hydrochloride (22).-To 250 ml of Na-dried E t 2 0 , 2.0 g of LAH was added and refluxed for 30 min. To this a solution of 1.5 g of 21 in 30 ml of T H F was added dropwise and refluxed for 24 hr. Excess of LAH and metallic complex were decomposed by the slow addition of 5 ml of HzO while stirring. The precipitates were filtered off and washed with EtZO. The filtrate was dried (NazS04) and the solvent was removed. The oily residue was taken up in 20 ml of AIezCO and added to 7 ml of 2-Pr-HCl ( 2 2 5 7 ) diluted with 200 ml of dry Et2O. The white solid was filtered and recrystallized (EtOH-Et20). The other amides (I, A = CHzCH2CO) were also reduced similarly to the corresponding amines and the resulting oily bases were converted to the appropriate salts. The ir spectra of a representative compound (as free base) were as expected. N- [( 1-Methyl-2-phenyl)ethyl]-3,4,54rimethoxybenzamide(37). -To a solution of 2.7 g (0.02 mole) of d-amphetamine and 4.0 g (0 04 mole) of Et3N in 20 ml of anhydrous CHC13, a solution of 4.61 g (0.02 mole) of 3,4,5-trimethoxybenzoyl chloride in 20 ml of anhydrous CHC13 was added slowly. The reaction mixture was refluxed for 5 hr. I t was then cooled, washed (HzO), and dried (KaASO4) and CHCL was removed in VQCUO. The rehidue solidified when treated with hexane. The solid was then recrystallized twice from boiling hexane. ~-(Morpholino)-3,4,5-trimethoxyacetophenone Hydrobromide (46).-To a solution of 8.67 g (0.03 mole) of ~-bromo-3,4,3trimethoxyacetophenone in 40 ml of 2-PrOH, was added dropwise a solution of 2.61 g (0.03 mole) of morpholine in 20 ml of i-PrOH. The reaction mixture was refluxed for 3 hr and left overnight after coilcentrating it t o half of its volume. The solid was filtered and (18) 4 . S. F. Ash, 1.hl. Creighton, and IT.R . Wragg ( t o May b- Baker Ltd.), B r i t k h P a t e n t 948,767 (Feb 5 , 1964); Chem. Abstr., 60, 12029a (1964).

recrystallized (i-PrOH) to give the desired coinpound. The free base was liberated and converted to its h>-drochloride ,*alt, mp 218-220" dec. N- [p-Hydroxy-P-i3,4,5-trimethoxyphenyl)ethyl] morpholine Hydrochloride (47).-To a sollition of 5.64 g (0.013 mole) of 46 in 120 ml of dry i-PrOII, 45 ml of molar A1(2'-PrO)3 sol~itioii i i t i-PrOH was d i e d . The reaction mixtiire wad 1,efluxed for :3 hr iiiid the distillate wii3 tested for the pi'eseiice of acetime j2,4diiiitrciphertylhydrazc,ne test'). Ilefiiis was coiitiiiiied (7 h r ) till i h r a w t o n e test. became negative.. The solvent was removed iiiider dirninis re (100 mm), mid the reaction inistiire was basified R queoiir; XaOH a i d extracted with Etd). w e dried il\i'a2SOa) and ad rejiilting white solid o n Nl- [ p-( 3,4,5-Trimethoxybenzoyl )ethyl]-N d-( p-fluorophenyl )piperazine Hydrochloride ( ~ ~ ) . - - -:T i solutioii II of 3 . 2 5 g (0.Ol.j mole) of S-(p-fiioropheriyl)pipera~iiie hl-drochloride in 60 nil of 15tOH, 2.2 rril ( - 0 . 0 2 2 mole) of aqueous C H 2 0 i:37--41Y;i and :1.7X g 10.018 m d e j of :~,4,.i-trimethoxyacetophe1iotiewere added : i i i d the mixture was reflused for 7 hr. Additional aqueoiis CH,O (2.2 ml) was added aiid reflux continued for 7 hr. The iwctioii mixtiire was conrelitrated to one-fourth of its volume and :illowed to cool overitight, when a white shiny crystallir poruid separated out. This was filtered, dried, arid re as rortvrrted qiiantitatively lizetl. The hydrochlori lized from EtOH. The maleate salt f t w tmhe which was recr IJf this h s e was prepared by the addition of its solution iii EtOII t o [he cdianlated amouiit, of malrii8 ac7itl i n E:tOH follov.-ed hy clilritioii with Et.0. l'tir rest of the ketouic .\Iaiiiiich ~ J L L S ~ +11. .I = C:OCH?('FI,j w e i prepared ~ by following this method. ~,~-Bi~(Pu'~-(ni-fluorophenyI)-~~-piperazinylJ -3,4,5-trimethoxypropiophenone.--To a *oliitiori of 3.25 (0.01.; mole) of l - ( t t l fliioi,ophen?.l)piprrazitiehydrochloride i n 70 nil of EtOH, 2.2 ml [-O.D'22 mole) of aqiieoiin CH,O aiid 3.47 g (0.0165 mole) of :~,~,3-triii~et,hox~ace~iipheiioiie werr added and the mixtiire vias i,efliised foi. 7 hr. Additional aqueoiis CHI0 (2.2 ml) war added arid reflux continried for additional 7 hr. The reaction mixtiire

Synthesis and Pharmacological Activity of iilkylaminoalkyl Esters and Amides of 2-Hydroxy- (or Alkoxy-) 3-methoxybenzoic Acid

A belies of alkylamitioalkyl esters aiid amides of 2-hydroxy- (01' alkosj.- i 3-irtet,lioxybeiiLoicacid were syut,h(ssized and their hydrochloride, methiodide, or oxalate salts were tested for local atiest,hetic activity. Oiily the tliet hylamino and n-butylamino ethyl esters of 2-butoxy-:3-met hoxybenzoic acid arid morpholi~loethyl2-ethoxy-2Inethoxybenzoate exhibited greater local anesthetic artivity than lidocainr. However, these compounds wew highly irritating and generally more toxic.

continuation of our irivestigatiori 011 local m e h - j studies of the well-known local anesthetic iicI ivity of :ilkylaminoalkyl esters arid amides of substituted benzoic acids arid the reported physiological activity of t h v wtcr, amicles, a n d alkoxy derivatives of v:i,Is :I

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riillic :icid"-Ysuggested that 2111 esploixtiori d't 11(, :ICI i\.ity of alkylamixioalkyl esters ;md amides of L'-hytliusj.[or alkoxy-) 3-methoxybenzoic acid might rosult i i i t ti(, discovery of potentially useful local anest,heticagent .s. Chemistry.------The ester derivat,ives synthesized IY(Whe diniethpll~iniI I I I-. diet hylaminu-, piperidiiic I-. :I I I( I iiiorpholinoethyl esters of 2-hydroriy-3-mcthos~~~iizoic acid, 2,3-dimetjhoxybenzoic acid, 2-et,hoxy-:3-mct1-1oxybenzoic acid, 2-propoxy-3-methoxybenzoi~x i d , (ti)

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I,. ('auuiiicn. and E. Pavanati. d t t i So