Experimental Section5 4-Hydroxyphenylpyruvic Acid Hydrazone Hydrazine Salt.-- A solution of 5.0 g (0.027 mole) of 4-h~droxyphetiylprri1vi(.acid, 5.1 g (0.1 1 mole) of 99% hydrazine hydrate, aiid 700 nil uf iiiethaiiol wa8 stirred at 60" for 1.5 hr. Coiireiitraiiirii of the reactiiiii mixture to about 70 nil under reduced preh-iire resulted i i i thtx ta1liz:ition of 5.2 g (84%) of prodiic:t, mri I86---1~7'dw. -187" (lev, n.ct'e otii:i,iiid frorri i r i c ~ i l i : i i r o l :
:tcteri:,tic. of a n a,miiie salt of a c.art)osylic, acid? li.1 i c ' 6.42 p (c:irhosylate). .Incll. Calcd flJr c g ~ I i 4 ~ 4 0 a :c, 17.7b; 11, 6.21: s,24,;;. F o i i n d : C, 47.70; 11, 6.38; S , 24.48. 11~-2-Hydrazino-3-(4-hydroxyphenyl)propionic Acid.---A solut i o i i of 4.0 g (0.018 mole) of the above hydrazoiie and 50 nil of wat>erwas htirred at, rooni temperature for 2 daj-z with 120 g of 2.3(;; SaIIg. The aqueous solution was separated froin the made zicridic to congo red tvith HC1. The product, ized as white needles, T ~ c,ollec1ed, Y washed with :i of water, aiid air dried. n:t!er (Sriciinr) gave 1.2 g (41';) of wlii cleca; infrared, broad ab 011 band with :I aeries of peak:, f r o m ;;.O to 4.3, :md carbo, ahsnrptioii at 6.32 p ; iiltrnviole! (W',?; inet,lianol), 20 , and 27!l 1 x 1 ~i enlRX 17,NO, 26,100, :MU); chromatography, JVhatniitn No. 1, decending, 1-proImiiol-water (70: 30); detection, iiiiihydriii, ~howcd siiig1e-spi)t /ti 0.77. .Inal. Calcd for C 9 1 1 j 2 S 2 0 3 : 33.09; 11. 6.17: S , 14.2h: 0, 24.28. Found: C, 55.16; TI, '1; s,1.3.96; 0 , 24.6:.;. 'The inhibitory activity of nr.-2-h propionic. acid o n aromat,ic amino a c t o I>e rnrich lower than that, of D L - ~ 1 )propionic acid (tiydrazino nri:tlog of niet,hyldopn) lioth o a n d i 7 ~v i t ~ o . \\-hen compared n-itli DL-2-hydrnzino-4phenylpropionic acid (hydrazinc :ma.log of phenylalanine) t lic compound .qhowed eyiiivalent activity in i,iz,oitiid greater activity in v i f r ~ . ~ ( 5 ) l l e l t i n p points were taken on a Hoover Lni-lIelt capillary apparatus arid are corrected. Infrared spectra were taken in I i B r disks using a PerkinElmpr Infracord 137. T h e ultraviolet spectrum was determined on a PerkinElmer spectrophotometer lIodel 202. Elemental analyses TT-ere perforniecl by lIicro-Tech Laboratories, Skokie, Ill. (6) I n ch,n studies were carried o u t bs (', Ii. C'reveling, J. \\ . Ualy, : i n i l 14. \\-itkop, J . ,lied. Ciirm., 9, 2 8 1 (1566); i n v i t r o stiiihes were parried out i i y .1. LV. Daly and B. K i t k o p , i n press. \Ye wish t o thank the alio\-t: for making these results available to us.
1
C' 11 O('fl==( H( I-I 2
+
N,CHCOOC-H
-.-
3
4
CONHSH.
>€I.
5
6
Experimental Section Tlie iiiirarecl ~p,cctra werc dei,erniiiled o i i ii Ue(ik~~i:tii1 I:> double-beam hpectrcJphoturneter m-ith S a C l optics. G:w eliriiiiia\veri, carried oiit i i i i n Beckniaii C X 2.1 pi* 1ieriiiotr:i C teniper:Lt tire prograninier, :iiitl Sargeiit recorder 1Iodel St:. Tlie nieltiiig point. were deter~iiirii:ti on a Uni-Melt Thorii:th--TIoover c:apillar)- nielt~ingpoint a p p i t i x t i i y and are corrected. Allyl phenyl ether ( 1 ) was prepared :is described l)y horribliiiit :tiid Luriej in 86.6';; yicld: bp 74-73' (10 mm) [lit.5bp 74-76' ( I mrti)]; n2on 1.5205 ( l i t . 5 7h?or) 1.220~); 11356, 1 2 g ~WL ~ 928, and 692 c m - 1 . 'The vpc shorvetl :I single l)aid. cis-Phenyl propenyl ether (2) was prepared by the isoiwrix: procedure of Priw :iiitl Snyder;Z bp i 2 " (13 iliin): yield 7
ycit:li
2-RIethyl-3-phenoxycyclopropylamine
Ethyl cis~f~uns-2-;Methyl-3-phenoxycyclopropanecarboxylate (4).-To a solut,ioii of 45 g uf pheiiyl propeiiyl ether (2) in 100 iiil of dry xyleiie with 1 g of copper powder aiid 1 g of powtlertd Cu804 stirred and heated a t 110-120°, :t solutioii of 31 g of ethyl tliazoacetate6 in 100 nil of dry syleiie 17-as added at, :L r:itc I iiiaint,aiii a, steady, gt:iiLle evolutioii of iiitrogeli. 'Thcili ( l i t . reaction was refluxed for 2 hr and filtered, and the filtrate K:I* Since ~--pheiioxycyclol)ropylamirielis a pot erit A\ LIO ~ I inhibitor, we prepared 2-i~iethyl-3-phexiox~cyclopro- coiicent,rated z'n, L'CICM and distilled. The liquid, I J S7--102' nini), was collected a ~ i dredistilled t o obtaiii 1111. p r o i l ~ ~:c i 111) pylainine ( 6 ) in order t o study the effect of such :I 1704, structural change on the biological activity. Lllthough 96-95" ( 1 niriil); >-kid 1,; g (7456); 658 Clll-'. \'a1J ccivorerl ~ v i t hL'Oo lid t r f c%ther:~iiii Ftirrcvi :It 0". ( I
I,
ZJ~~~\'~~
(b) c'. Id. Zirkle, C. Kaiser, D. €I Tedeuclil, It. C Tedeschi, and \ Burgri ~ h ~ 6d, 1263 , (1962) ( 2 ) C . C . Price and \\ li sngiler, 1 m C l i r m hoc., 83, 1 7 7 , (19bl) ( 3 ) A. bchneslieim, J. E. Hofirrann, and C. 1. Itohe, Jr., abtd., 83, 3; $ 1
.~
.
(1961).
0
~...
( 5 ) S . Kornbluin ancl 1.P.Lurie, J. Sin. Chtni (6) F. B. La Forge, W . A. Gersdorff, 5 . Green. and 11. 9. dchaclitf~r,./. ~ y Chem., . 17, 381 (1!25Z).
May 1966
44 1
KOTES
A solutio11 of 7.6 g of N a S 0 2 in 20 ml of water was added dropwise and stirred 15 min, and the separated ether layer was dried. The filtered azide solution was added to 350 ml of dry toluene, heated on a steam bath to distil the ether, and the resultant solution was refluxed for 6 hr. The toluene was evaporated in uacuo (nitrogen). The liquid residue was redissolved in dry toluene, added to 30 ml of concentrated HC1, and warmed. After the gas evolution which t,ook place at about 50" was complete, the solution was refluxed for 18 hr, made alkaline with 30% NaOH solution, and pxtracted with ether. The liquid remaining after evaporating the ether was distilled, bp 73-79' (1 mm). I t &-asconverted into its hydrochloride and recrystallized from ethanol-ethyl acetate mixture; mp 161-183", yield 4 g (19%). I n a l . Calcd for CloH,,SO.HC1: C, 60.30; H, 7.03; K, 7 . 0 3 . Found: C, 60.53; H, 7.03; X, 7.04. Biological Results.-In comparison with several active cumpounds, 2-niethyl-3-phenoxycycloprop~-laminedemonstrated no in v i t ~ oactivity and very lit,tle in vivo activity against brain niorioaniine oxidase (rats) (Table I).
benzylaminomethyl)cyclohexane.5 This report describes the synthesis of some miscellaneous related compounds. The biological activities of these and other compounds of this s e r i e ~ ~are - ~ reported separately. l The first group of compounds consists of the unsymiiietrically S,S'-disubstituted cyclohexanebis(niethy1amine) derivatives (IV-VI, Chart I). They were prepared from cyclohexane-t~uns-l,4-bis(i~iethyla1~iine) (I) by reducing the Schiff's base foriiied with 1 equiv of a carbonyl component, to yield the monosubstituted derivatives I1 and 111, and then condensing these with a second carbonyl component to yield, after reduction, the unsymmetrical disubstituted compounds IV-VI. The properties of the final products arid intermediates as their hydrochloride salts are presented in Table I. CHARTI
TABLE Ia Brain
Compd
4( NCjH4)CO;"jHNHCH(CH,)zb C6HbOCHCHh Hz
3IAO i n riti.0 ~ 5 0 %inhib, ~ ,lf
in U I x 10-3
25.0 50.0
x
0.37
\/
CHCH, trans-C6HsOCHCHSHpC
v
1.6
10-7
CHz
~~CL~S-CGH~~OCHCHKHZ'
v
1,s x
10-7
0.35
CH,
~~~~S-C~H~CHCHK'H..~
v
8
x
10-6
0.25
CHI The pharmacological data were obtained under the direction of Dr. L. 0. Randall, Director of the Pharmacological Laboratories. The met'hods are described in detail by L. 0. Randall and R. E. Bagdon, Ann. S.Y . dcacl. Sei., 80, 626 (1959). Iproniazid, Hoffmann-La Roche, Inc. Reference 1 . J. Finkelstein, E. Chiang, F. 31.Srane, and J. Lee, in press. e Tranylcypromine, Smith Kline and French Laboratories, Inc.
CHJNH,
CH,NHR1
0-0 EH,NH* I
-
CHJH~
CH,NHRL
- (i CH,NHRA -
11, R' = 2-ClC6H4CHz 111, R1 = cyclohexyl
IV-VI
IV, ltl = 2-C1CsH&H2; R 2 = cyclohexylmethyl V, R1 = 2-C1CeH4CHz; R2 = cyclohexyl VI, R1 = cyclohexyl; R2 = cyclohexylmethyl
A second group of compounds, represented by the series shown in Chart 11,are analogs of a 1,4-bis(benxylaminomethy1)cyclohexane in which one of the nitrogens is replaced by oxygen, sulfur, the sulfoxide, or the sulfonyl group. They mere prepared from l-hydroxymet hyl-4-c yclohexanemet hylaniine (VII) as indicated in Chart 11. The physical properties and analytical data are given in Table 11.
Similarly, Zirkle and co-workerslb observed that although 2phenylcyclopropylamine has potent RIA0 inhibitory activity, 2methyl-3-phenylcyclopropylamine has relatively little activity.
Acknowledgment.-The authors wish to thank Dr. ,41 Steyerniark and his staff for the microanalyses, N r . S. Traiman for the infrared spectra and interpretations, and llessrs. H. J. Jenny and J. Manius for the gasliquid partition chromatography.
Agents Affecting Lipid Metabolism. XXI. Jfiscellaneous Compounds Related to trans-1,4Bis(2-chlorobenz ylaminomethy1)cyclohexane' LESLIEG. HUMBER A yerst Research Laboratories, Montreal, Canada
Received August 25, 1965
We have recently reported the synthesis2-4 of many symmetrical compounds derived structurally from the potent cholesterol-lowering agent trans-l,4-bis(2-chloro(1) P a r t XX: L. G. Humber, C . I. Chappel, A . V. illarton, RI. Kraml, and J. Dubuo, J . .?fed. Chem., 9, 329 (1966). (2) L. G. Humber, d i d . I , 826 (1964).
VIII, It = H ; Y = OH IX, R = C1; Y = OH X, R = H ; Y = C1 XI, R = Y = C1 XII, R = H ; X = S XIII. R = C1: X = 9 XIV: R = H: X =SO x v j =~ H: x = soz XV1,R = H ; X = 0
I
u
0 XII-XVI
The primary amino group of VI1 was substituted by either the benzyl or 2-chlorobenzyl group, by reducing the Schiff base formed with the appropriate aldehydes, to give VI11 and IX, respectively, which mere con(3) L. G. Humber, G. Myers, L. Ifaukins, C. Schmidt, and 11,Roulerice, Can. J . Chem., 42, 2852 (1964). (4) L. G. Humber, J. .>fed. Chem., 8 , 401 (1965). ( 5 ) C. I. Chappel, J. Dubuc. D . D i o r m k , &I. G i \ n e r , L. G. Humber, 11. Kraml, K. Voith, a n d R. Gaudry, Aature, 201, 497 (1964).
