mmoles) was rediiced with LiAIH4 (0.3 g, 8.0 mmoles) in 30 ml of tetrahydrofiiran ( T H F ) tiy refliixing for 24 hr. The yellow oil (qiiau tit at ive yield) was c o i iverted lo the hydrochloride salt (6 N HCI), mp 242" (from ethyl alcohol). Anal. Calcd for CZ4H27NO2.HC1:C, 72.6; H, 7.12; X, 3.52. Found: C, 72.5; H, 7.03; S, 3.86. 3-Ethylamino-1,1,3-triphenyl-l-propanol (17).-3-Acetamido1 ,l,~-triphenyl-l-propanol (16, 20.0 g, 0.06 moIe) was refluxed with IJiA1114 (0.18 mole) in THF for 24 hr. The product was isolated by ether ext,raction and recrystallized from cyclohexane to yield 13.9 g (74%,), mp 102". Witting, rt aZ.,g gave mp 104105' for material obtained from the reaction of phenyllithiiim and 3-ethylimino-l-hydroxy-1,l-diphenylpropane. 3-(N-Ethylacetamido)-l,1,3-triphenyl-l-propanol (lS).-Compound 17 (11.7 g, 0.037 mole) was heated for 2 hr at 50" with acetic anhydride (0.066 mole) and acetic acid (0.033 mole). The prodiict crystallized from the hot mixtiire and was isolated tallized from ethanol to yield 11.4 g (83'3), mp 19.5'. hu aiialytical sample, nip 197-~19So,was ohtaiitetl liy l'iirthrr t.t~c~i'yst:illixaI ions from e1h:inol. Anal. CMcd for CsaTi,,h'Oy: C, 80.4; TI, 7.29; N, 3.75. Icoiilld: C, 80.3; IT, 7.31; N, 3.73. 3-(N,N-Diethylamino)-l,1,3-triphenyl-l -propanol (19).-Compound 18 (9.1 g, 0.025 mole) was refluxed overnight with LiAlHa in TIIF. The free base was isolated as a yellow oil in 93yc yield. The hydrochloride salt was prepared with hot 6 N HC1 and purified by recrystallization from dilute ethanol; mp 249' dec. d n a l . Calcd for C?SH~~KO.HCI: C, 75.8; H , 7.64; N,3.54. Foiind: C, 7 , 5 . 5 ; II,7.87; X, 3.68. Methyldiethyl-( 3-hydroxy-l,3,3-triphenylpropyl)ammonium Chloride (20).-13ase 19 ( 3 . 0 g, 8.4 mmoles), 3 ml (80 mmoles) of inel hyl iodide, ;urd I O ml of etli~nolwere heated for 4 hr at 100' iii :L steel lionib. The sollition was concentrated, and the giim anr tritiirated with isopropyl alcohol to give a solid. One recrystallization from isopropyl alcohol yielded the yellow iodide salt, 1.15 g, mp 185-187" dec. It was stirred for 3 hr with Dowex 2 (chloride) resin in 100 ml of methanol. The mixture was then filtered and concentrated, and the chloride salt was recrystallized from isopropyl alcohol-water. The analytical sample had m p 244-245.' .inal. Calcd for C~~H,2CIN0.0.5HzO:C, 74.5; H, 7.76; h',3.34. Foiind: C, i 4 . 8 ; H, 7.79; S, 3.28. (9) G .
IT.T\ itting, 11. J. Schmidt, and TI. Renner, Chrm. Rer.,
95, 2 3 i i
( 1 NE).
3-Amin0-1,l -dimethyl-3-phenyl-l -propanol (21 ).-Ethyl 3amino-3-phenylpr~pionate~(3.8 g, 0.02 mole) was refliised with rnelhy~~nagries~ii~~i I)riini~de(S in ether, 27 nil, 0.0s mole) in ether overnight. The reaction was worked lip and the resuIting oil was stirred with 4 ml of 2.5 S NaOH for 1 hr and left a t 25' in order to hydrolyze a small amount of starting ester. The alkaline mixture was extracted with ether, which was dried and concentrated to give 1.5 g (42%) of an oil which cystxliized. This material showed no ester carbonyl in the infrared. hn analytical sample, mp 7 3 " , WVRSprepared hy reri hiityl chloride. Anal. Calcd for CllHliSO: C, 73.i; I€, 9.56; N, 7.81. Foiind: C, 73.6; H, 9.66; N, 7.84. Biological.-For testing purposes, all amiriopropanols were dissolved either in 0.1 S HCl or suspended (6, 16, and 18) by homogenizing with 0.1 S HCl and 2 drops of Tween 80. These solutions or suspensions were administered to male, albino mice (18-2,5 g) either intraveiroiisly via the tail vein (general Iiehavioi~:il hI€Clj:,c,)or intraperitoneally ( t i ~ r i i i i ~dr ~ t e i ~ f ~ i i i ~ ) . sween, 1,l The aiiinials were pericitlically testetl a i d ut)nei~vrd i i i !Ire lieh:tvioral screen a t 3 , 15, 30, aiid 60 min followirig iiijevtion. T b v o animals per dose level (0.1 log intervals) wei'e iisecl f i l l . I,I):,o determinations. I n the initial tremor-detector experiments carried oiit at 10 min postinjection and a t a dosage of 25 mg/kg ip (espt 1) ten animals were used per compound and ten each for control (tremorine) and b h k (0.1 S HCl). I n espt 2 and 3 at 5, 15, and 45 min postinjection and at dosages of 25 and 15 mg/kg ip, five animals per compound for each of the time periods were used; four test componnda, tremorine, and a blank were evaliiated earh day for 5 days. The tremoi,ine valiies at each time period arc means of 50 mice. In espt 4, 15 mice per timeperiiitl i i i a iq$tneii of three mice per day for 5 days were iised. The tiwnoriire :tiiiI blank controls wei'e evaliiaied iii ten mice per time peiiod. In all experiments, a difierent~groiip of animals was used f o i , each time period to avoid acclimatization and no aiiimal was iiqed more than once, I n espt 1-4, drug concentrations were adjiisted for ail injection of 0.5 ml/animal. I n the antagonism stitdies, 0.2 ml of driig solution was administered.
Acknowledgment.-The authors want to thank h l r . Val Putnnm, Jlr. Floyd Goodspeed, arid Jlr. Alex Sarros for t.he tremor-det'ector bioassays and Dr. Samuel Ferguson and his st'aff for thc nmiisc hchaviornl data and toxicities.
Aryloxyalkylaminoguanidines. Their Synthesis and Biological Properties' J . AUGSTEIN,S. 11. GREEN,A. 11, YIOKRO,~ T. I. WRIGLEY, Research Division, Pjizer Ltd., Sandwich,Kent, England
A. R. KATRITZRY, B N D G. J . T. TIDDY T h e Srhool o j ChPmiral Sriences, University of East Anglin, -4-orwich, lVorfnlk, Enqland Received August 5 , 1966 Revisrrl Jlanusciipt Received Drcembtv 25, 196B Proton magnetic resonance has been iised to show that the productr of guanylation of aryloxyethylhydraziiieq are (aryloxyethy1amino)giianidines. Several such aminoguanidines containing chlorine and methyl substitiieiits in the aromatic ring have been showli 1 o possebs adrenergic nc1iron blocking properties ant1 to inhihit dopamine 6'-oxidase in vitTo.
There is a striking similarity about certain features of the structure-activity patterns displayed by several series of compounds n-hich affect the functioning of the adrenergic system. Thus, in a series of biologically (1) Presented in part before the Division of hfedicinal Chemistry, 9th National Medicinal Chemistry Symposium of the .4merican Chemical Society, Rfinneapohs, lMmn, June 21-24, 1964. A preliminary report of some of this work has been priblished by J . lugstein and S RI Green Vnture, 201, 628 (1964). (2) To alrom enqiiiries should he a i l d r ~ ~ q e d .
L4rY(CT€,),,B I1 NR B = a, NR2;b, +NRs; e, N H C Q N H R ; d, h R 2 N H 2 a r ( CHz),B
I
active bases of general formula I where extension of the chain by one methylene group leads to 10% of activity, chain extension by introduction of a group y7 (see II), where y can represent 0, s, ~ T H , or CH=CH, freqiicntly nllows retention of nrtivity.
Illustration of this i, found in the classical sympat homi met ic effect i ( ) f phew t h ylanii I I e deri va t ive:, , \\ Iiich arc virtually h w i t III ~ S - ~ ~ h e i i y l ~ ~ r i ~ ~ ~ y l a ~ i i i ~ ~ ~ ~ derivatives, yet found again in compounds of typr II:r (n = 2 ) . 3 Similarly, the well-lino\vn exercise4 of introducoing alkyl or aralkyl substituents into the amiw group of Ia to produce CY antagoriizts is effective i i i prodticing :tdrenolytic derivut ivc- of ~~he~ietliylamiiie.' :m(1 of thc analog:, II:r, \vhercas tlic i~(~rr~IsI)~)ii(liii~ (lwivatiws of .3-phenylpropyl:iiiiiiir' h:~\-c only fwl)Io :I tlrciiolyt ic* propertiei.7 13~lle:iuhas siiggestcd that the 4milarity of ndrenergic+ I)locl. 13ovet and F. 13ovet-Sitti, "Xtrricture e t .lctivit6 Pharmacodynamique des M6dicament dii SystBme KervPit\ \'Pp&atif," Verlag S.Karger, I i a s r l , 1948, pp 74, 106. 170, 177, l i 8 . 1 3 ) E , .I. .lriena, .A. AI. Simonis. ani1 .I. A I , r a n Rossum in "hlolecular t'liarmacology," Vol. I , E. ,J. .IriPne, Ed, Academic Press, London, 1964, p 215. ( 5 ) E. .J. Ariens in Ciha Foundation Symposium, .Adrenergic Mechanisms, .J. arid .\, C'hurcliill 1,td.. London, 1960, p p 2.53, 261. ugstein. \V. c'. Austin. R. .J. l i o s c o t t , S. 11. Green, a n d c'. I f . \\ o r t h i n g , J . Me
