X-,\RALKY LHTDROXTLAMISES
January 1965
101
TABLE I SrCHzCH(CH3)NX M.p.,
X
Coniud.
1 2 3 4 .i
Formula
OC.
-Carbon, 7Calcd. Found
-Hydrogen. 5'Calcd Found
-Nitrogen. %Calcd. Found
OH OH OH OH OH
(CsHi3NO)~.CzH204 (CioH15NOpjZ.CzHz04 (CliHiT?J03)2.CzHaOa (CgHi&lNO jz'C2H404 (CioHijKO)z.CzHzOa (CloH&O j2.CzHz04
174-175" 134-135 135-136 192-193 186-187 183-184
58.4 56.2 52,O 62.8 63.4
58.6 56.1 52.0 63.1 63.3
T .1 7.0 # .6 i 7.6 6.7
7.1 7.0 5.4 7.5 6.8
6.2 5 5 6.1 6.7 6.7
6.1 5 5 6.0 6.5 6.7
OH
CirHiJYz0.CzH~04~
180-18 1
57.6
57.8
5.5
5 .7
9.6
'3.8
(CioHi,NO),.C2H,O4 (CiiHiiN02)z.C2H,Oa (C12HdV03)2.C~H204 (CioHi4ClN0)2.C2H204 (CiiHi7KO)2.CzHzOa
129-130 129-130 116-117 128-129 134-135
62.9 60.0 57.9 54.0 64.3
63.0 60.0 57.6 54.3 64.2
7.6 7.5 7.4 6.1 8.0
7.7 7.3 7.6 6.2 7.8
6.7 S.8 5.2 5.7 6.2
6.S 5.7
,
,
6 C T X H O H
H
8 9 10 11 12 13 14 15 16 a Lit.4 175-176'. reported 164-165".
5.3 5.6 6.0
C
c
e
CgHiZClK.HC1 163-16sd CioHijN' HCle 158-159 Acid oxalate. Aldrich Chemical Co., hlilwaukee, \Vis. H. H. D. RIoed, J. van Dijk, and H. Niewind, Ree. trav. chim., 74,919
. Hass
[.
Am. C'hem. Soc., 68, 1009 (1946)]
955).
phenyl-2-methoxyaminopropane (8) and has pointed out the amphetamine-like activity of this compound. We concur with this observation, but our data show this substance to be roughly six times as toxic as the reported figure. Our data on the monamine oxidase inhibitory action of 8, using tyramine as a substrate, are generally in agreement with illajor's observation that this substance shows little or no inhibition of niorianiine oxidase using 5-hydroxytryptamine as a substrate. The N-aralkylhydroxylaniines and the corresponding O-niethyl ethers were synthesized by the following sequence of reactions. 4 r was either phenyl or sub-
were injected intraperitoneally with aqueous solutions of the hydrochloride salts of the test compounds6 a t a minimum of 4 dose levels spaced in geometric progression between completely killing and living doses. The LDjo was estimated by the method of Weil.' Spontaneous Motor Activity (SMA) .-Of the various techniques available for the measurement of Sl\lA,Y it was decided to use the photocell-cage technique on groups of 3 mice/trial to determine the dose necessary to produce a doubling of the motor activity (EDzoo), based upon the number of interruptions of the light beam compared with saline as the control for standard time periods after i.p. injection. Hexobarbital Sleep Time.-Adult, male mice in ArCHZCOCH3 +A S H & ( CH3)=NOR + groups of 15 were injected intraperitoneally with 10 ArCH2CH(CH3)NHOR mg./kg. of the test compound, and after 15 min. hexostituted phenyl, 172,3,-l-tetrahydronaphthyl,or 3barbital sodium was injected intraperitoneally a t a indolyl. R was H for the hydroxylamines and CH, dose of 100 mg./kg. The time between loss and regain for the 0-methyl ethers. The oximes mere reduced to of the righting reflex was taken as the duration of hydroxylamines by catalytic hydrogenation over a sleeping times, which were compared n-ith control platinum catalyst in the presence of 1 equiv. of HCI, sleeping times with hexobarbital alone. The statissimilar to the procedure of Vavon and C r a j e i n ~ v i c . ~ tical significance of the results was tested by means of The corresponding 0-methyl ethers were obtained the Student t-test. by catalytic reduction of the 0-methyl oximes by the Relative Pressor Effect.-Effect of the test conimethod of Jones and R1ajor.j The 1-aryl-2-propanones pounds on blood pressure was measured in a heparinized required as starting materials were procured comniercat preparation under pentobarbital anesthesia. Drugs cially or synthesized by published procedures. All of were administered intravenously through a jugular the aralkylhydroxylamines arid the 0-methyl ethers cannula, and the change in the mean systolic pressure were converted to their neutral oxalates for purificawas measured by means of a Buffington universal tion and storage. pulse transducer oriented dorsally on the tail.g Blood dl-l-(-l-Chlorophenyl)-2-aniinoproparie(15) and dl-1pressure effects were compared with the rise obtained (-l-tolyl)-2-aminoproparie (16) were prepared by rewith a standard dose (0.1 mg.) of phenethylamine duction of the corresponding substituted l-aryl-2nitro-1-propenes with lithium aluminum hydride. All (6) It was noted early in this study t h a t solutions of the liydrocliloride salts of these bases underyo gradual decomposition in aqueous solution even amphetamines were converted t o the hydrochloride a t refrigerator temperature. Hence, all compounds were stored as the salts for use. oxalate salts, and solutions of the hydrochlorides were freshly prepared Pharmacological Methods. Toxicity Experiments.from the oxalate8 by treatment with a n equivalent amount of C"aCl2 and reriioTal of the insoluble calciiiin oxalate by filtration, Groups of 5 mice (Swiss white, random-bred, 25-35 g.) (4) G \ a \ o n and ZI Crajeino\ic Bull so6 chzm Belges, [ 4 ] 4 3 , 231 (1928) (5) L Jones and R T Malor, J Am Chem Soc., Sa, 669 (1930)
( 7 ) C. S.\Veil, Biometrics. 8 , 2 4 9 ( 1 9 3 2 ) . ( 8 ) P. I3. Ilews and W.H. l l o r s e , A n u . Reu. Z'hn,maiul.. 1, 1-13 ( 1 9 t i l ) . ( 9 j F. R. Ryrom and C . Wilson, J . Physiol. (London). 93,301 (15138).
1c 2
"0
sA
xA 1
20 50 10
SA 4 A Sh
30
s.1 10 10 I I
* S o t statistically significant.
* I'
(statistical probahility) < 0.l101.
aiid calculated as the pressor effect relative t o the effect of phenethylaniirie = 1. Cat Behavior Tests.-Gross behavior effects O I I iiornial, healthy, adult cats of both sexes injected i.ni. with 25 mg./kg. of the test conipounds were o b s e r i d The behavioral components of aggressive behavior. withdrawal, hiss, growl, pupil dilation, pilomotor effect, and salivation mere used as indices to the overall behavioral patterns of the anirnals as discussed t)), Sortori and de Beer. lo Rectal temperatures wert~ measured with a Thermistor probe." Monamine Oxidase (MAO) -Inhibition of this enzyme was determined by comparing the extent of deaniinatioii of tyramine (5 x l o - " Jt) as a substrate" by a solubilized AIAO preparatiori13 froiii rabbit livw i i i tlie absence arid presence of thc test coinpourids at tj X AI.
.-
Results The results of the above pharmacological nieasurcnients are summarized in Tahle 11. Relative Pressor Action.-Pressor data are presented re1ati.i-e to phenethylarnine as a unitary standard. With the exception of 1,14, and 15, all of the compounds tabulated exhibited less pressor activity than t h r > standard. A11 of the compounds examined gave a, prompt increase in blood pressure which returned to the control base-line systolic pressure within about 10 min. after drug administratioii. Spontaneous Motor Activity.-% out of the sixteeii compounds examined did not show a significant change in activity ( S A ) in this experimental design. Most of the compounds which caused significant changes in motor activity were equal or less potent than 2-amino1-phenylpropane (13) ; 1-(4-chlorophenyl)-2-substituted propanes (4, 11, and 15) were notable exceptions, in that this subgroup showed a higher SkIA than any of the corresponding unsubstituted compounds. ~ , l O jS. Sortonand E. J . de I3eer, A n n . A'. 1'. A c n d . S c i . , 66, 2kU (l\).->til. ( 1 1) Yellow Springs Instrument Co. Telethermonieter. (12) IC. 13, Logsdon, Ann. .\;. 1'. Acod. Sci., 81, 801 (19601. ( 1 3 ) 0 . c'. Cotzias, I. Serlin, and J . J. Greenough. S c i e i i c ? , 120, I N ( I !i 34 J
.
So sigtlificant inhihitiuii.
li
1'
that those compourids producing it positive rage rrqx,iise correlate wc.11 \vith a general icwbnrbital sleepiiig time which could be a ( ~ t w i t ral (witstory actioii. Notttbli, o t liis I I c ~ i t litrti 1-(:1,4-diiiiethoxyphenyl)iiitiopi opaii I) (3) mil 1- (3-iiidolyl)-2-hyiropaiic. (71 ; 3 has iio sigriificarit iiifluc~iicc~ tal slcrpirig time a i d does not induce rag('like bcliavior i i i t h cat, ~ wliweas 7 is t h c olily riiciiibcr of this g r o ~ i p\\ Iiicali both potciitiatcs slecpiiig tiiiic arid produces i.ngr. 111 strong rag(' producing conipoulids were fouiid t i t w u a c :L niodcizte t o large iwreasc i r i body tcniperatui v. C'oinpourid 1 !'13 iiig.,'kg.) evokes a clualitatively lower levo1 of ragc iwponse than does 2-amino-1 pheiiylpropane, litit tliv effects are longer lasting. .\~iiiiiaIs i eceivirig t hi> c.ompourid exhibit an umisunl C I I c d a r I i c d iiiotioii accoriyaiiirtl by profust. salivritioii l'rc t reat 1 1 it' of tlic ariiiiials with c.hlorpi~oiiiszir~~~ a 1)loclradc of the mge reactioii ( L O I l l & kg.) Ciill c
( 6
January 1965
N-ARALKYLHYDROXYLAMINES
without inhibiting the head motion14; atropine sulfate administration failed t o block salivation. Monamine Oxidase Inhibition (in vitro).-The results of these inhibition studies are tabulated in the last column of Table 11. 1-(3-Indoly1)-2-hydroxylaminopropane (7) caused no significant inhibition of monamine oxidase while 1-(3-indolyl)-2-aminopropane is a potent inhibitor of this enayme.l5 Compound 1 is moderately active and is an hydroxyamino analog of the well-known M A 0 inhibitor 2-hydrazino-1-phenylpropane. The most strongly inhibiting substance within the group examined is p-1,2,3,4-tetrahydronaphthylhydroxylaniine (6) which diff ers pharmacologically from 1,2,3,4-tet rahydro-P-napht h ylamine in that the latter compound is not a M A 0 inhibitor, is strongly pyretogenic, and induces rage in the cat.'6 Methyl-2propynylbenzylaniine, clearly established as a RIA0 inhibitor, effected a pronounced inhibition of the enzyme system a t a concentration of 5 X M . In repeated experiments under controlled conditions, a typical level of inhibition was 81-82y0. Structure-Activity Relationships.-Replacement of amino by hydroxyamino in the amphetamine structure decreases but does not abolish the central nervous stimulation effects of this group of compounds. However, when the hydroxy group is methylated to the corresponding methoxyamino derivative, the stimulating effects are abolished and this group of compounds teiids to produce central nervous system depression, as evidenced by their potentiating effects on hexobarbital sleeping time in mice. Hydroxyaniino compounds in which the aryl group was not phenyl or substituted phenyl exhibited some anomalous effects. The cyclic analog 6 is a depressant and does not induce a rage response in the cat, yet the hyperthermic effect remains. Substitution of 3-indolyl for phenyl potentiates hexobarbital sleeping time, yet induces a hyperthermia and excitation in the cat. As was found with phenethylamines,la introduction of inethoxy, chloro, or methyl into the 4-position of the benzene ring intensifies the excitant and CNS stimulant effects of both substituted amphetamines and aralkylhydroxylaniines. Substitution of more than one methoxy group on the aromatic nucleus, as in 3, abolishes the excitant activity of this class of compounds. 0-Alethylation of the aralkylhydroxylamines profoundly alters the pharmacological activity of these substances. The 0-methyl ethers are significantly less toxic, do not induce excited behavior in the cat, and appear t o be CNS depressants rather than stimulants in their primary action. The delayed response observed with 8 may indicate that the 0-methyl ether is cleaved enzymatically t o the active coinpound 1. Experimental" dZ-l-(4-MethoxyphenyI)-2-hydroxyaminopropane(2).-1-(4Methoxyphenyl)-2-propanone, b.p. 82-85" (0.1 mm.) [lit.'* 102-105" (0.5 mm.)], was obtained in 867c yield by reduction (14) F. Benington, R. D. hlorin, and L. C . Clark, Jr., A'ature, 202, 813 (1964). (15) E. I. Kuznets, V. S. Shashkov, hl. N. Ter-vartanian. N . N. Preo-
brszhenskaia, T. P. Suvrov, T. P. Sycheva, a n d M. N. Shcukina, Dokl. Akad. Nuuk S S S R , 136, 1231 (1961); M. E. Greig, R. 4. Walk, and A . J. Gibbons, J . Phaw"o2. EzptE. Therap., 127, 110 (1959). (16) L. C. Clark, Jr., unpublished results.
103
of 1-(4-methoxypheny1)-2-nitro-l-propenewith iron and hydrochloric acid.19 This ketone was converted to its oxime20 in 97y0yield by reaction with hydroxylamine hydrochloride and sodium carbonate in an aqueous system a t room temperature; m.p. 50-51" (lit.2o58-61"). A solution of 35.8 g. of l-(4-methoxyphenyl)-2-propanone oxime in 230 ml. of 807, ethanol containing 7.3 g. of HC1 was hydrogenated for 3 hr. in a Parr hydrogenation apparatus a t 3.5 kg./cm.2 (50 p.s.i.g.) over 0.5 g. of platinum oxide catalyst The catalyst was removed by filtration, the filtrate was diluted to 1 1. with water and extracted twice with ether to remove any acid-insoluble material. The aqueous layer was made alkaline with solid SaHCOa (to pH 8-9), and the basic oil which separated was extracted with two 300-ml. portions of ether. The ether solution was dried (hIgSO4) and filtered, and the ether was removed by evaporation. The residual crude product solidified; yield, 27.5 g. (76%); m.p. 54-55". T o an ether solution of this base was added a solution of 9.6 g. of oxalic acid dihydrate in a small volume of methanol. The oxalate salt of 2 which separated solidified gradually; it was collected and recrystallized from methanol; yield, 31.2 g. (69%); m.p. 136135". dl-l-(4-MethoxyphenyI)-2-methoxyaminopropane (9).-To a stirred mixture of 33.5 g. of 1-(4-met,hoxyphenyl)-2-propanone, 21.7 g. of methoxyaniine hydrochloride, and 40 ml. of water was added gradually a solution of 13.8 g. of sodium carbonate in 25 ml. of water a t about 10". The mixture was then stirred a t room temperature for 14 hr., and the oily product layer was extracted wit'h ether, dried (MgSO,), and distilled; of a colorless oil. b.p. 79-80" (0.4 mm.); yield, 34.3 g. (8is) Anal. Calcd. for CI~HISXO?: C, 68.4; H, 7.8; N, 7.3. Found: C, 68.6; H, 7.6; N, 7 . 2 . A mixture of 19.3 g. of the 0-methyl ketoxime, 200 ml. of SOTc ethanol, 3.7 g. of HC1, and 0.4 g. of platinum oxide was hydrogenated in a Parr apparatus a t 3.5 kg./cm.2 (50 p.s.i.g.) iintil 1 mole of hydrogen/mole of compound was absorbed (1 hr.). The catalyst was removed by filtration, and the product was recovered and converted to the neutral oxalate as previously described. The oxalate was recrystallized from methanol-ether; m.p. 129-130'; yield, 13.5g. (54%). dl-l-(3,4-Dimethoxyphenyl)-2-hydroxyaminopropane(3).1-(3,4-Dimethoxyphenyl)-2-propanone,b.p. 135-140' (0.5 mm.) [lit.'g 129-133" (0.4 mm.)], was prepared in 78% yield by the procedure described by Shepard, et a1.19 The oximez' of this ketone, obt,ained in 83Yc yield, was an oil, b.p. 140-141" (0.3 mm.). The oxime (31 g.) was reduced by catalytic hydrogenation in exactly the same manner as described previously, and the hydroxyamino compound was converted to the neutral oxalate and recrystallized from methanol-ether; yield, 12.5 g. (33%); m.p. 135-136". d-l-(3,4-Dimethoxyphenyl)-2-methoxylaminopropane (IO).Treatment of 33.5 g. of 1-(3,4-dimethoxyphenyl)-2-propanone with methoxyamine as described previously gave 34.4 g. (91%) of 1-(3,4-dimethoxyphenyl)-2-propanoneoxime 0-methyl ether, b.p. 111-113' (0.3 mm.). Anal. Calcd. for CI~HI,P~O,:C, 64.6; H, 7.6; N , 6.4. Found: C, 64.3; H, 7 . 7 ; N, 6.2. Catalytic hydrogenation of this compound by the procedure described afforded the oxalate of 10 in 41Y0 yield; m.p. 116-117". dl-l-(4-Chlorophenyl)-2-hydroxyaminopropane (4).-1-(4Chlorophenyl)-2-propanone, b.p. 75-79' (0.3 mm.), was prepared by the method of Overberger and Biletch.22 The oxime of this ketone was a colorless, viscous oil, b.p. 111-113" (0.7 mm.), obtained in 92Yc yield. Anal. Calcd. for CgHIoClh-O: C, 58.8; H, 5.5; S , 7.6. Found: C, 58.9; H, 5.4; X, 7.4. Catalytic hydrogenation in the same manner described previously afforded 4 in 78% yield. dl-l-(4-Chlorophenyl)-2-methoxyaminopropane (111.Treatment of 20.5 g. of l-(4-chlorophenyl)-2-propanone with ( 1 7 ) All melting points a e r e taken in a Fisher-Johns melting point apparatus. Calibration of the apparatus against standard compounds showed no need f o r correction. (18) R. L. Huang, J . Chem. Soc., 2539 (1954). (19) E. R. Shepard, J. F. Noth, H. D. Porter, and C. K . Simmsns, J . A m . Chem. Soc., 74,4611 (1952). (20) F. W. Hoover and H. B. Hass, J . Org. Chem., 1 2 , 501 (1947). (21) L. Balbino and 1 '. Padini, Guzz. chim. itul., 36, 291 (1905). (22) C. G. Overberger and H. Biletch, J . A m . Chem. Soc.. 73, 4880 (1951).
