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154 J . M e d . C h e m 1980, 3, 154-162

Phenylalkylamines with Potential Psychotherapeutic Utility. 2. Nuclear

Substituted 2-Amino-1-phenylbutanes

Rober t T. Standridge,* Henry G. Howell, Hugh A. Tilson, John H. Chamberlain, He nry M. H olava, Jonas A. Gylys,Richard A. Partyk a,

Research Divis ion, Bris tol Laborator ies , D ivis ion of B r i s to l -M yers C om pan y , Syracuse , N eu i York 13201

and Alexander T. Shulgin

1483 Shu lg in R oad , La f aye t t e , C a l i fo rn ia 94549 . R ece iued Jan uar y 8 , 1979

A series of 2-amino-1-(4-substituted-2,5-dimethoxyphenyl)butanesT able V) was prepar ed as analogues of ( R ) - 2 -amino-l-(2,5-dimethoxy-4-methylphenyl)hutanela). l-(2,5-Dimethoxyphenyl)-2-(N-phthalimido)butane7) wa sutilized as a synthetic intermediate common to many of th e target compounds. Animal dat a are presented indicatingth at m ost of these analogues have low hallucinogenic potential. Selected compounds were compared w ith la inan avoidance-response acquisition model which differentiates between la and the human hal lucinogens DO M (2a)a n d DOET (2b ) . Structure-activity relationships of these analogues are discussed.

In the course of a program directed at p otential non-hallucinogenic performance-enhancing agents, we hadp repa red (R)-2-amino-1-(2,5-dimethoxy-4-methyl-pheny1)butane ( la, dimoxamine,' BL-3912A).2 This

Z H 3 0I

I

3 Y 3 0 C H 3 0

l a ( R s omer) l b (S i s omer)

c.+cI

IC ; i 3 0

2a ( D O M ) , X = C H ,b ( D O E T ) , X = C Z H ,c ( D O B ) , X = Br

compound, a homologue of the well-known hallucinogenDOM (2a),3presented an activity profile in animalsstrikingly different from that of 2a. In addition to ex-hibiting low hallucinogenic potential in the rabbit hy-perthermia test, la enhanced avoidance acquisition in therat 2 and has been shown to block the serotonergic actionof 2a in vitro.*

In th e hallucinogenic phenylisopropylamines, particu -larly pote nt compounds are obtained when a nuclear 2,5-dimethoxy substitution is combined with an appropriate4 ~ u b s t i t u t e n t ; ~ , ~OM, DOET, and DOB (2a, 2b, and 2c,

respectively) are notable example^.^,^ Fur thermore .qualitative as well as quantitative differences in humanactivity with 4-substituent variation have been report-ed,3,5,78

USAN for (R)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)bu-tane hydrochloride; J . Am . M ed. Assoc. , 238 , 1407 (1977).Fo r paper 1 n this series, see R. T. Standrid ge, H. G. Howell,J. A. Gvlvs, R. A. Partvka. and A. T. Shulain. J . Med . Chem..19, 1400-(1976).A. T. Shulein and D. C. Dver. J . Med . Chem. . 18. 1201 11975).

Iand references cited therein.'Donald C. Dyer, Res. Commun. Chem. Puthol . Phurmacol., 14,449 (1976).A . T. Shulgin in "Psychotomimetic Drugs", D. H. Efron, Ed.,Raven Press, New York, 1970, pp 34-35.F. A. B. Aldous, B. C. Barrass, K. Brewster, D. A . Buxton, D.M. Green, R. M. Pinder, P. Rich, M . Skeels, and K . J. T u t t ,J . M ed. Chem., 17, 1100 (1974).A. T. Shulgin, T. Sargent, and C. Naranjo, Pharmacology. 5 ,

103 (1971).

Therefore, as a first approach to investigating struc-ture-activity relationships in our phenyl-sec -butylam ineseries, we elected to reta in th e 2,5-dim ethoxy substitutionpatt ern a nd to investigate the effect of replacing the n u-clear 4-methyl moiety in l . Th is would provide a seriesof compounds parallel to the psychotomimetic phenyliso-propylamines represented by s truc ture 2 from which in-teresting com parisons between the effect of a given sub-stituent upon hallucinogenic activity and performance-enhancing properties could be derived.

Chemistry. Emphasis throu ghout th is work was placedupon obtaining R isomers, since la is the more activeisomer in avoidance acquisition.2 Th e desired opticallyactive compounds could be readily p repare d from th e re-quisite aldehydes via the stereoselective synthesis de-s cr ibed p r e v io u~ ly . ~ ,~n the phenylisopropylamine series2 , it has been showng th at the absolute configuration ofthe product amine was the same as that of the a-me-thylbenzylamine isomer employed. Configurational as-signments in the case of 2a isomers were made by Cas-tagnoli et al. on th e basis of CD curves.1o I t was alsonotedgJOha t diastereomeric amides of the R an d S isomers

were eluted on GLC in a predictable order. For instance,in the case of amides derived from (-)-a-m ethox y-a-(tri-fluoromethy1)phenylacetic acid [(-)-MTPA], amides of Risomers were eluted before amides of th e correspondingS isomers.

It has previously been shown by us2 th at these rela-tionships also applied to 1 isomers. Fu rthe r, the config-uration of la was confirmed by comparison of its ORDcurve with that of (SI-amphetamine. Unequivocal syn-thesis of phenyl-sec-butylamines of desired configurationcould thus confidently be undertaken.

Alternatively, LiA1H4 reduction of th e in term ediatenitroolefins 3 provided racemic amines 6. In one case (6d,Table V), resolution was accomplished utilizing (+)- and( )-?'-nitrot artranili c acids."

Th e compounds actually prepared by these methods andthe appropriate intermediates are listed in Tables 1-111 andv.

Preparation of 1-[2,5-dimethoxy-4-(2-propyl)phenyl]-2-nitro-1-butene (3c)required a somewhat modified proce-dur e which is detailed in the Experimental Section. After

(8 ) S.H. Snyder, H. Weingartner, and L. A. Faillace, Arch. G e n .Psychiatry , 24 , 50 (1971).

(9 ) D. E. Nichols, C. F. Barfknecht, D. B. Rusterholz,F. Bening-ton, and R. D. Morin, J . Med . Chem., 16, 480 (1973).

(10) S. . Matin, P. S. allery, J. S. weig, A. O'Brien R. Rapoport,and N. Castagnoli, ,Jr., J . M ed. Chem., 17, 877 (1974).

(11) T. A . Montzka, T. L. Pindell, and J. D. Matiskella, J . Org.( ' he m . , 33 . 3993 (1968).

0022-2623/80/l823-0l54$01.00~0 1980 American Chemical Society

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Nuclear Substituted 2-Amino- 1 phenylbutanes

T able 1. 1-(4-Substituted-2,5-dimethoxyphenyl)-2-nitro-l-butenesa-d

Journal of Medicinal Chemistry, 1980, Vol. 23 , N o . 2 155

CH3 O

n o . X m p , " C % yie ld recrys tn solv form ula anal .

3aa H 44-4632 MeOH-H,O

12H l 5

c , H , N3b" E t 64.5-66.5 42 Me OH C 14H 19NO c, H , N3c i-Pr 60.5-62.5 48 p e n t a n e c SH21NO4 C, H , N3 d b C H , S 103-105 70 EtOH-H,O C13H14N04S c , H , N

Prepared by t he proce dure deta i led in ref 2. * Prepared by the " improved" p rocedure fo r 3 ( X = CH, ) . SeeE xpe r imen ta l Sec t ion .

Table 11. 1-(4-Substituted-2,5-dimethoxyphenyl)-2-butanonesa- c

C H30I

C H 3 0

no." X m p o r b p ( m m ) , " C % yield recrystn solv form ula anal.

4a H 121-124 (0.6) 62 12 163 c , H4b E t 37-39 83 Skel ly B 14H100 3 c , H4c i-Pr 117-120 (0.05) 79 C15H2203 c , H

" Com pounds were p repa red by th e p rocedure de tai l ed in re f 2.

T able 111. 1-(4-Substituted-2,5-dimethoxyphenyl)-2-(amethylbenzylamino)butanes 5a-c

% rec rys tn op t [ 0 1 1 f ~ ~ , *

no.a X mp , "C yield solv isomer deg form ula anal .

5a H 228.5-230 50 MeCN R,R +51.3 C,,H,,NO, .HCl c, H , N

5 a H 227.5-229.5 45 MeCN 8,s -50.5 C,H,,NO,~HCl c,H,

5 b E t 2 16-218.5 67 MeNO, R,R +88.4 C,, H , ,NO ;HCl c , H, N

5b E t 215.5-218.5 12 MeNO, s,s -81.3 C,,H, ,NO;HCl c , H , N

5c i-Pr 230-233 44 Et,O R,R +96.5 C,,H,,NO, HCl c,H,

(25)

(23.5)

( 24)

(23)

(20)

" Com pounds were p repa red by t he p rocedure de ta i led in re f 2 . c 1.0, Y5% E t O H .

this work was completed, a more attractive method of

preparation of nitroolefins of this type was noted.12Sui tab le modifications gave excellent results with 1-(2,5-dimethoxy-4-methylphenyl)-2-nitro-l-butene3,X = CH,).

Th e stereoselective sequence,2 hough effective and op-tically efficient, became tedious when applied to a lengthyseries of com pounds. An attractive alternative was the useof 2-amino-l-(2,5-dimethoxyphenyl)butane6a), suitablyprotected, as a common intermediate. Th is procedureconsiderably shor tened th e individual sequences and of-fered an additional advantage in tha t by starting with 6a

of known configuration, product amines of the same con-figuration could be prepared without the necessity of

separa te asymmetric synthesis or resolution. Th is ap-

proach is outlined in Scheme I.A number of DOM relatives had been prepared byCoutts and Malicky through an N-acetyl precursor.13However, removal of th e protecting group required strin -gent basic conditions. Ho14 had employed an N-p hthaloylprotecting group in the synthesis of some DOM metabo-lites; Sargent and co-workersZ1have recently reportedapplication of this m ethod to the preparation of a seriesof radiolabeled 4-iodo-2,5-dimethoxyphenylalkylamines.This protecting group was also found by us to be quitesatisfactory. Following app ropr iate synthetic manipula-

(13) R. T. Coutts and J. M. Malicky, Can. J. Chem. , 51 , 1402

(14) B. T. Ho and L. W. Tansey, J. M e d . Chem., 14 , 156 (1971).(12) J. S. Zweig and N. Castagnoli, J r . , J . Med. Chem. , 20 , 414 (1973).

(1977).

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156 J o u r n a l of Medicinal Chemistry, 1980, Vol. 23 , No. 2 Standr idge et a l .

c, R = n-Pr

t R C O C l , T I C I ~

Table IV . 1-( -Substituted-2,5-dimethoxyphenyl)-2-(-ph tha l imido)bu tanes

L

N 2 H 4

7

J”03

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Nuclear Subst i tuted 2-Amino-1 -phenylbutanes Journal of Medicinal Ch emistry , 1980, Vol. 23, No. 2 157

%-q%I

X

s# 2h

X

0c

0

0 5 - L L Lz z u m m m ,

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158 J o u r n a l of M e d i c i n al C h e m i s t r y , 1980, Vol. 23 , No. 2

tions, hydrazinolysis to the final products was accom-plished unde r mild conditions. Optical purity checksutilizing (-)-M TP A am ides2 confirmed t ha t no racemiza-tion occurred during the preparative sequences.

Thus , l-(2,5-dimethoxyphenyl)-2-(N-phthaloyl)butane(7) eacted smoothly with acid chlorides to give th e 4-acylderivatives 8. Use of TiC1, as catalyst gave none of thepartial 0-demethylation noted by Shulgin and Dye r] withAICIB n related acylations. Catalytic reductio n, followedby hydrazinolysis, yielded th e desired 4-alkyl compounds

9.Similarly, 7 could be formylated with dichloromethyl

methyl ether, giving the aldehyde 10. Stan dard Vilsmeierformylation, as employed by Ho14 upon 1-(2,5-d ime th-oxyphenyl)-2-(N-phthaloyl)propane, as not successful.The aldehyde 10 underwent the Baeyer--Villiger rear-rangement, yielding the phenol 11 . This afforded thealkoxy derivatives 13, as well as the parent aminophenol12. Th e aldehyde 10 can also be employed in the synthesisof the corresponding hydroxymethyl and carboxylic acidderivatives, which are pote ntial metabolites of l.14 Thiswill be reported in a future publication.

Nitration of 7 provided 14 , which was catalytically re-duced to 15. These yielded the nitroamine 16 and thediamine 17 upon removal of th e protecting group. Dia-zotization of 15 also could be used as a ro ute t o halogenderivatives. Only the 4-iodo compound 18c was preparedin this manner; the 4-chloro and 4-bromo materials 18aand 18b were more easily obtained by direct halogenationof 6a in HOAc.

Attempts to util ize 8a in the synthesis of 6c provedfruitless. Reaction of 8a with CH3MgI15 r with CH3Li16gave predominantly recovered starting material, as didatte mp ted Wittig reaction." Th e isopropyl compound 6c

was therefore prepared by our previous meth od2 from therequisite benzaldehyde.

Pharmacology and Discussion. In the first paper inthis series? la was shown to improve avoidance acquisitionin the rat. Recently, Tilson et al.18 have demonstrated th at

la facilitated avoidance behavior in rats without any ob-vious signs of stimu lation, th us differentiating la from(R)-DOM [(R)-2a]and (S)-amphetam ine. In the presentwork, analogues of 1 (Table V) were screened in a catbehavior modellg and selected com pounds were then com-pared with la in avoidance acquisition.ls

The initial screening involved gross behavioral obser-vation for "DOM -like" effects in cats. Th is tes t is amodific ation of th at described by Wallach et al.19 an dconsists of 1 2 behavior categories, each of which may re-ceive a maxim um numerical score of 2. Th e effects pro-duced by 1 isomers were compared with those caused by(R)-DO M, (R)-DO ET, and (R)-DOB. In this cat tes t ,(R)-D OM was distinctively different from amp hetam ineas reported by Wallachlg and observed in our laboratory.

Th e results obtained for 1 and analogues are listed inTable V. T he R isomers of the reference phenyliso-propylamines (Table V, footnote i ) 2 show high activityin this model at relatively low doses (1 mg/kg or less).Potencies of the S isomers in this reference series wereobserved to be consistently lower than those of the cor-

S t a n d r i d g e e t a l .

(15) W. J. Houlihan, J . Org. Chem. , 27 . 3860 (1962).(16) W. J. Hickinbottom, A. A . Hyatt, and M. H. Sparke, J . C h p m .

Soc., 2533 (1954).(17) G . Wittig and M. Schlosser, Chem. Ber . , 94. 1373 (1961).(18) H. A. Tilson, J. H. Chamberlain, and J. A . Gylys, Psycho-

pharmacology (Berl in) ,51 , 169 (1977).(19) M. B. Wallach, E. Friedman, and S. Gershon, J . Pharmncol .

E x p . Ther . , 182, 14 5 (1972).

+ZW0

cc

n.30 0

ww4u l

E :00

E 100

z $Y

t

T

0 1 10 20 40 80 180.2 5 0.5 1 2

DOSE (mg/ g)

F i g u r e 1. The effects of l a ( ip and PO) , l b ( ip) , and ( S ) -amphetamine ( ip) on the acquisition of shu ttle box respondingby naive, retired breeder rats. Data are average percentages (*SE)of contro l for 8-14 rats per group. Con trol avoidances per 12 0trials for la (ip) and (S)-am phetam ine were 49.0 i .4 (mean *SE ;N = 36), while the control values for la (PO) and lb (ip) were40.9 f 6.5 (N 16) and 46.3 f .5 ( N = 24), respectively. IT1shuttles in 120 trials were 59.5 f 7.7, 47.2 i .2 , and 40.0 i 11.3fo r l a ( ip) and (&amphetamine ( ip) , l a (PO) , and l b (ip), re-spectively. Asterisks denote statistical difference from vehiclecontrol ( p < 0.05).

responding R isomers. In contrast to the 2 series, 1 andanalogues exhibited very low activity even a t th e relatively

high screening dose (10 mg/kg) employed. Although mostof the target com pounds show some indication of activity,none of them approached (R)-DOM or other referenceagents. Furthermore, differences between R and S isomerswere not marked, perhaps because of the low intrinsicpotencies observed with 1 analogues. Thu s, th e wholeseries could be considered to have relatively low halluci-nogenic potential on the basis of this cat model. In clinicaltrials (Bristol Laboratories files), la failed to produce anyhallucinations at relatively high doses.

For information on potentially useful activity, a ratavoidance acquisition model was used.'* Com pound la

produced significant increases in avoidance response a t 5,10, and 20 mg/kg ip (Figure 1); the minimal effective dose(MED, Table VI) was 5 mg/k g. Significant changes in IT1

(int ertr ial interval) responses following 1-20 mg/ kg of lawere not observed. The highest dose of la (30mg/kg ip)tende d t o supp ress avoidance response a nd significantlydecreased the number of responses during th e ITI. Orallyadministered la was considerably less potent (MED, 80mg/kg) than when given ip. The S isomer, lb , failed toproduce any significant activity (M ED >40 mg/kg ip).

Comparative data (Figure 1) on (S I-amphetam ine re-vealed that it tende d to enhance avoidance responses at0.25-2 mg/kg ip, but only the effect at 1mg/kg was s ta-tistically significant. (S)-Am phetam ine differed from laand lb in that amphetamine markedly s timulated IT1activity at 0.5-2 mg/kg . For a more detailed comparisonbetween la , (S)-amphetamine, and (E)-D OM ,consult ref18. In general, (R)-DO M (0.5-5mg/kg ip) exhibited a

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Nuc lea r Subs t i tu ted 2 - Amino-1 -pheny lbu tanes

T ab le VI .Avoidance Acquis i t ion Tes t

Rela t ive Potency of l a A n a lo g ue s i n t h e R a t

IC H 3 0

ME DY po tency IT 1

c o m p d X mg/kg ip re1 to l a ac t .

( R -6b E t 2 2. 5 t

(R ) -9a n -Pr 1 5 t b

( R j - 1 8 b B r 2 2.5 ?

l a Me 5 1 N E C( R ) - 6 d S M e 5 1 f

(R) -18a C1 20 0.25 N E

(R ) -6c i -Pr > 20 <0.25 NE

a A minimal dose pro ducing a s ignif icant ( p < 0.05 VS.

Statistically significant increase. N o statistically

( R ) -9 b ~ - B u > 2 0 < 0 . 2 5 N E

vehic le con tro l) increase in avoidance responding.

s ignif icant effec t

biphasic response on avoidance acquisition, facilitating at0.5 mg/kg ip and disrupting a t 1or 5 mg/kg ip. (E)-D OE T[(R)-2b] failed to produ ce any positive effect over a widedose range (0.25-5 mg/ kg ip); in fact, there was an inhi-bitory effect at 1 and 5 mg/kg. Th e corresponding Sisomers of DOM and D OE T were considerably weaker orinactive in affecting avoidance acquisition at doses up t o10 mg/kg ip .

Selected 4-substituted analogues of la were tested inavoidance acquisition, and th e results are summarized inTab le VI. Th e following selection criteria, based mainlyon findings in th e 2 series,6 were used: (a) high biologicalpotency of R forms as compared with th e correspondingS isomer; (b) high biological activity of 4-halo analoguesan d selected 4-alkyl substitu ents. Selection of R isomers

was also suppo rted by higher activity of la vs. l b in theavoidance acquisition tes t (Figure 1). Substitution of anethyl [(R)-6b] or n-propyl [(R)-9a] for the methyl groupof la resulted in comp ounds tha t facili tate avoidance at2-5 a nd 1-10 m g/k g ip, respectively. Facilitation ofavoidance, however, was often acc ompanied by significantincreases in IT1activity, particularly with the ethyl ana-logue (R)-6b. Other alkyl compounds tested included thosehaving a 4-n-butyl or 4-isopropyl [(R)-9band (R)-6c,re -spectively] substitu tion. Ne ither of these compoundsdem onstrated significant activity at doses up to 20 mg/ kgip. 4-Bromo substitution [(R)-18b] esulted in a compoundthat facilitated avoidance at 2 and 5 mg/kg. (R)-18b ap-peared more s timulating than la, as indicated by theconcomitant increases in IT1 activity. Th e chloro analogue,

(R)-18a, appeared less active than the bromo compoundof this series, as indicated by t he relatively high M ED of20 mg/kg. Substitu ting a 4-(methylthio) group [(R)-6d]also produced a behaviorally active substance, which hada M ED of 5 mg/k g ip. Significant increases in avoidances,as well as IT 1 responses, were observed a t 20 mg/kg.

As had previously been n oted in th e phenylisopropyl-amin e series6 (2), here appears to be a structural optimumregarding the 4-substituent in the phenyl-sec-butylamineseries ( la and analogues) with respect to the activity inth e avoidance acquisition test. Th e order of potency ob-served was n-propyl > ethyl > methyl = methylthio, w hilen-butyl and isopropyl were not active up t o 20 mg/kg(Tab le VI). Th e potency order for alkyl substitu ents wasin good agreement with that noted in the 2 series using the

J o u r n a l of Medicinal Chemis try, 1980, Vol. 23, No. 2 159

rabbit hyperthermia test.6 However, the halo substituentsin the b utan e series are seemingly less pot ent relative toalkyl substituents, which is not in accord with the findingsin the propane series. In addition, Aldous et alS6ound onlya slight potency difference between bromo and chloroanalogues of the propane series, while the bromo com-pound is more potent than the chloro analogue in thebutane series .

Since the da ta of Aldous et a la6 gree well with w hat isknown of th e hallucinogenic pote ncies of 2-amino-1-(2,5-

dimethoxy-4-substituted-phenyl)propanes,3~6~20t wouldappear tha t hallucinogenic potential of a given 2a analogueis not necessarily predictive of relative activity of thecorresponding 1analogue in the avoidance acquisition te st.It does appe ar tha t th ere is a correlation between activityseen in the cat DOM test and the rabbit hyperthermia te stas repo rted by Aldous e t a1.6

In summary, a number of analogues of 1 have beenprepared, many through a common, optically active in-termediate. Th e majority of these compounds on the basisof a cat behavior model should be of low hallucinogenicpotential. Avoidance acquisition studies of selected com-pounds in comparison with la have shown five of theseanalogues [(R)-6 b, (R)-6d , (R)-9a , (R)-18a, an d (R)-18b]to produce statistically significant enhancement; three ofthese [(R)-6b, (R)-6d, and (R)-18b] were more p otent tha nla. However, these active analogues [with the exceptionof @ )-M a, the com pound of lowest potency] producedsignificant increases in IT1 responses. This is an indicationof general CNS stimulation and thus possible stimulatoryside effects. It is noteworthy th at la did not produce suchincrease at a ny of the dose levels tested .

It has been found th at th e potential performance-en-hancing (avoidance test) activiy of la may be increasedby proper selection of a nuclear 4-substitu ent; the morepotent compounds retain relatively low hallucinogenicliability (c at test ). Also, the effect of a given nuclear 4-substituent upon hallucinogenic potency in the phenyl-isopropylamine series does not necessarily correspond to

the effect of tha t substituent upon avoidance enhan ceme ntin our phenyl-sec-butylamine series.

E x p e r i m e n t a l S e c t io n

Ch em istry . Melting points were determined in open capillarieson a Mel-Temp apparatus and ar e uncorrected. Elementalanalyses were performed by the Microanalytical Department ofBristol Laboratories. Where indicated by symbols of the elements,the analytical results obtained were within &0.4% of the calculatedvalues. Optical rotations were measured with a Perkin-Elm erModel 1 41 polarimeter using 1% olutions in 95% E t O H . GCanalyses were performed on a F & M Model 810 gas chromato-graph equipped w ith a flame-ionization detector. All productsgave IR and NMR spectra consistent with their expected stru c-tures. Th e optical purity of all optical isomers listed in TableV was checked by the method previously detailed.2 All such

isomers showed optical purities of >98% by this technique.2,5-Dimethoxy-4-(2-propyl)benzaldehyde.6 a) To a stirredsolution, unde r Nz, of 0.33mol of MeMgI in 100mL of dry EtzOwas added dropwise a solution of 54 g (0.30mol) of 2,5-dimeth-oxyacetophenone in 150 m L of dry EtzO at such a ra te as tomaintain gentle reflux. After the addition was complete, themixture was stirred an d refluxed on the steam ba th for 1.5 h. Thereaction mixture was cooled and po ured o nto 300 mL of 10%

H 2 S 0 4 n d 300 g of crushed ice. Th e layers were separated an dthe aqueous layer was extracted thoroughly with EtzO. Thecombined extracts were washed with HzO,NaHCO, solution, and

(20) R. W. Brimblecombe and R. M. Puide r, “HallucinogenicAgents”, Wright-Scientechnica, Bristol, Englan d, 1975, p 68.

(21) U. Braun, A. T. Shulgin, G. Braun, and T. Sargent 111,J . M e d .Chem., 20, 1543 (1977).

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160 J o u r n a l of M edic ina l C hemi s t r y , 1980, Val.

sa tura ted brine and then dried (Na2S0, ) . Evaporation of thesolvent gave ca. 62 g of a yellow oil.

Th is oil was dissolved in 500 mL of toluene; a catalytic am oun tof p-toluenesulfonic acid was adde d and the solution was stirredand ref luxed under a Dean-Stark H 2 0 separator for 8 h . T hedark solution remaining in th e flask was evaporated under redu cedpressure an d the oil thus obta ined was dissolved in 100 mL of100% EtOH. Cata lys t (10% Pd on carbon. 3 g) was added a ndthe mixture was hydrogenated a t an initial pressure of 3 atm .After 1 h, the calculated amount of Hz had been absorbed an dno further pressure drop occurred. Th e catalyst was filtered and

the solvent evaporated. Th e residual oil was vacuum distilledto give 47.1 g (87%) of 2,5-dimethoxyisopropylbenzene s acolorless oil, bp 96-104 "C (4 mm) .

(b) A mi xtu re of 101 mL (1.10 mol) of POC1, a nd 117 mL (0.95mol) of N-methylformanilide was stirred at ambient temperaturefo r 1.5h. 2,5-Dimethoxyisopropylbenzene 47.0 g, 0.26 mol) wasthen added port ionwise, and the dark mixture was s ti rred andheated on the s team bath for 3 . 5 h. Th e mixture was cooled to50 "C and the dark syrup was cautiously poured into 1 L ofcrushed ice and H20. The reaction flask was rinsed with two100-mL port ions of H 2 0 and 100 mL of 100% EtOH , and therinses were added to th e quench mixture. Upon stirring well andscratching, a solid began to separate. Th e mixture was storeda t 0 "C (1.5 h) and t he solid was then filtered. Th e filter cakewas dissolved in ca. 350 mL of hot E tO H; the solution was filteredand the filtrate was diluted with 2 0 mL of H 20 . Upon standing

a t room tem perature for 16 h, and then chilling for 30 min a t 0"C, the produ ct sep arated as large tan needles, mp 69.5-73 "C .A second crop was obtained from th e mother liquor. The to talyield of the title compound was 46.9 g (85 %), i t .6 mp 70 "C.

l-[2,5-Dimethoxy-4-(2-propyl)phenyl]-2-nitro-l-butene

(3c) . A mix ture of 6.36 g (30.6 mm ol) of 2,5-d imeth oxy- 4-(2-propyl)benzaldehyde, 0.64 g (2.7 mmol) of n-butylamine, 3.14 g(35.2 mmol) of 1-nitro propan e, and 10 mL of dr y toluene wasrefluxed for 16 h without rem oval of HzO. T he reaction mix turewas cooled and w ashed successively with H zO, 5% HC1 solution,HzO , and sa tura ted brine and then dried (Na,SO,) .

Evap oration of the solution und er reduced pressure gave 6.12g of a dar k red oil, which slowly crystallized. Recry stallizationfrom pe ntane gave 4.14 g (4870 yield) of th e title compou nd asyellow crystals , mp 60.5-62.5 "C. Anal. (C15H 21N0 4) , H, N.

l-(2,5-Dimethoxy-4-methylphenyl)-2-nitro-I-butene2Im -

proved Procedure ) . 2,5-Dimethoxy-4-methylbenzaldehyde10.0g, 55.5 mmo l) was mixed with 2.14 g (27.7 mmol) of NH,OAc and100 mL of 1 -nitroprop ane, and the so1uti011 (upon heating) wasrefluxed fo r 20 h.

Th e H 2 0 ormed in the reaction and excess nitropropane wereevapo rated under reduced pressure an d the reddish-orange solidobtaine d (12.9 g) was washed thoroughly with H 2 0 and air-dried.

The crude product was recrystallized from 300 mL of MeOHto give 9.65 g of th e title compoun d as orange crystals, mp 119-121"C. A small second crop was obtained. Th e total yield was 10.16g (72% ) .

R e s o l u t i o n of (f)-2-Amino-l-[2,5-dimethoxy-4-(methyl-t h i o ) p h e n y l ] b u t a n e ( 6 d ) I s o m e r s . ( a ) R I s omer . A mixtureof am ine 6d (31.3 g, 123 mmol) and 16.6 g (61.3 mmol) of ( + I -2'-nitrotartranilic acid" was dissolved in 90 mL of hot MeOH.The solution was allowed to stand undisturbed at room tem-perature for 17 h and th en was cooled at 4 "C for 4 h. Th ecrystalline salt was filtered and washed with E t2 0. T he m otherliquor an d washings were saved for recovery of th e S isomer. Theproduc t was dried under vacuum to give 28.55 g (88.670 yield)of yellow crystals, mp 159-164 "C.

Recrystallization from 130mIA f MeOH , filtration, and washingwith 100 mL of cold M eOH afforded 14.85 g (46.1% yield), mp164-170 "C. A second recrystallization from 90mL of MeOH gave8.3 g (25.770 yield) of yellow crystalline salt, mp 171--173 C. Thi ssalt was slurried in 200 mL of saturated NaHC0, solution andthe free base was extracte d with EtOAc. Th e combined extractswere washed with 5% NaHCO,< olution and then with brine, dried(Na2S O4), nd evaporated to give the free amine as a crystallinesolid: yield 3.58 g; mp 60-63 "C ; [ ( Y ] ~ ~ : ~ ~ ~164.2" ( c 1 .0 , 9 5 7 ~E t O H ) .

Th e amin e was dissolved in 100% EtO H and the salt formedwith HC1 (g). Ether was added an d the solid was filtered, washed

S tandr idge e t al .

with E bO , an d dried unde r high vacuum : yield 3.7 g; m p 247-251"C . Two recrystallizations from 100% EtOH provided ' A g(11% ) of pure (R)-Gd.HCl: mp 254-256 "C ; [a]243657r.d* (c 1.0,

95% EtO H) . Anal. (C13 H21N02 S.HCl) , H, N, C1. A sampleof HC1 salt converted to free base ha d m p 64-65 "C and [ c ~ ]

(b ) SI so m er . The mother liquor from isolation of the R isomerwas evaporated to dryness and th e residue converted to the freebase as described in part a. Th e residue (16.8 g, 61.8 mmol) a nd11.7 g (43.3 mmo l) of (-)-2'-nitrotartran ilic acid" were dissolvedin 95 mL of hot 95% EtOH . Th e solution was cooled, seeded with

salt previously obtained on a test-tub e scale, and allowed to standundisturbed at room temperature for 5 h. The solid was filtered,washed with cold 95% EtO H, and dried un der high vacuum togive 20.3 g (89 %) of salt, mp 164-168 "C.

Recrystallization from 125 mL of 95% Et OH as described inpa rt a afforded 15.7 g (69 %) of salt, m p 168-172 "C. A secondrecrystallization from 100mL of 95% Et OH gave 12.4 g (55% )of the pure (-)-2'-nitrotartranilic acid salt of (S )-6d , mp 171-174"C .

Th e salt was dissolved in 150 mL of hot H 2 0 and convertedto t he free base with excess KzC03. Cooling gave the free am ineas a colorless crystalline mass. Filtration an d washing with coldH 20 , followed by drying unde r high vacuum, afforded 6.1 g, m p5 G 6 4 "C. The free amine was dissolved in 100% EtO H an d thesalt was formed with HC l (g). Addition of E h O gave 6.41 g (36% )of HCl salt, mp 247-253 "C. Recrystallization from 100% E tO H

and washing with cold EtOH an d then with Et 2 0 afforded 5.3g (2 9% ) of pu re (S)-Gd.HCl: m p 254-256 "C; [a]2436579.9" (c1.0,95% EtO H). Anal. (C13H21N02S-HC1), H , N, C1. A sam pleof HC1 salt converted to free amine had m p 6 4 4 7 "C and [a]24365

+214.8" (c 1.0, 95% E tOH) .( R ) - -(2,5-Dimethoxypheny1)-2-(- p h t h a 1 i m i d o ) b u t a n e

[ R ) - 7 ] . P r o c e d u r e A. A solution of 8 g (80.0 mm ol) of drytriethylamine and the oily free base ob tained from 19.6 g (80.0mmol) of (R)-Ga-HCl n 250 mL of tolue ne was stirred with 1 2.3g (80.0 mmol) of phthalic an hydrid e; a slight exotherm occurredand solution was attained. Upon refluxing this solution for 16h under a Dean-Stark t rap, the theoretica l quant i ty of H 2 0separated. Th e solution was cooled and washed with 10 % HC l,H 2 0 ,10% NaOH, H 20 , nd saturated brine and dried (Na2 S04).Th e solvent was evaporated and the residue was stripped a t 75"C (0.05 mm ) to give 27.1 g (100% yield) of a thick oil, [ a ] 25D

-183.2' (c 1.0, 95% EtO H), which showed a single shar p peakon GC. Anal. (CzoH zlN04 ) , H, N.(R)-l-(2,5-Dimethoxy-4-propionylphenyl)-2-(- p h t h a l -

i m i d o ) b u t a n e [ ( R ) - 8 b ] . P r o c e d u r e B. To a stirred solutionof 10.2 g (30 mmol) of (R)-7 in 250 mL of dry CH2C12, t -20 "C,was add ed dropwise 6.15 mL (56 mmol) of TiCl,. Prop ionylchloride (2.15 mL, 35 mmol) was then added dropwise an d th edark solution was stirred at -20 "C for 30 min. Stirring wascontinued at ambien t temperatur e for 77 h.

Th e dark solution was vigorously shaken w ith 250 mL of ice-H2 0; the layers were separated and the aqu eous layer was ex-tract ed well with CH2C12. Th e combined extr acts were washedwith H 20 , diluted HC1, H,O, saturated Na HC 03 solution, andsatura ted brine and then dried (Na 2S0 4). Evaporat ion of th esolvent gave a yellow oil which crystallized upon standin g. Thiswas recrystallized from EtOH to give the title compound ascolorless, fibrou s needles: mp 112-113 "C; yield 7.25 g (61 70).Anal. (CZ3Hz5NO 5) , H, N.

(R)-2-Amino-1-[2,5-dimethoxy-4-(-p ropy1)pheny l lbu taneH y d r o c h l o r i d e [ ( R ) - 9 a] . P r o c e d u r e C. To a solu tion of 4 g

(10 mm ol) of (R)-8b in 100mLof glacial HOAc was add ed 20 dropsof 60% aqueo us HC10, solution and 1.5 g of 10% P d on carboncatalyst; the mixture was hydrogenated at 3 atm for 3 h. Th ecatalyst was filtered and washed with CH2C12.The f i l t ra te wasshaken with H 2 0 and the organic layer was separa ted. Th eaqueous layer was extracted with 3 portions of Ego; he combinedorganic solutions were washed well with H20, satu rated Na HC 03solution, and saturated brine and dried (Na,SO,). Evaporationof the solven ts gave 3.79 g of crude (R)-l-(2,5-dimethoxy-4-n-propylphenyl)-2-(N-phthalimido)butanes a green oil, 87% pureby G C.

A solution of th e crude phthalim ido compoun d (3.75 g, 8.5mmol) and 3 mL (94.6 mmol) of 95% hydrazine in 100 mL of

-210.9" ( C 1.0, 95% EtOH).

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Nuc lea r Subs t i tu ted 2- Amino - 1 -pheny lbutanes

100% EtO H was s t i rred and ref luxed for 2 h an d then s tood a tambien t temp era ture for 16 h. Th e solvent was removed underreduced pressu re an d excess N2H4 was chased with 2 portions oftoluene. Th e solid was stirred for 1.5 h with 10% HC1; theresulting slurry was warmed on th e steam bath and filtered. Thefiltrate was made basic with N aOH solution and ex tracted with4 portions of E tO . Th e combined extracts were washed with H 2 0and s atu rate d brine and dried (NazSO,). An excess of HCl (9)in dry EtzO was added; the sa l t s lowly separa ted. Th e mixturewas chilled at 0 "C for 1 h and then f i l tered. Th e sa l t wasrecrystallized from MeCN to give 2.0 g (75% yield) of the title

compound as a colorless solid: m p 174.5-176.5 " c ; [ci]23'5D10.9"(c 1.0, 95% EtO H). Anal. (C15H25N02-HC1) , H, N, C1.l-(2,5-Dimethoxy-4-frmylphenyl)-2-(-ph tha1 imido)bu-

tane (10). Procedure D. a) R Isom er. A stirred solution, underN O , f 9.2 g (27 mmol) of (R) -7 in 75 mL of dry C HzC lz wasmainta ined a t 0 "C while 5 mL (8.63 g, 45 mmol) of TiC14 wasadded dropwise. a,a-Dichloromethyl methyl e ther (3.1 g, 27 mmo l)was then a dded, dropwise, at 0 "C. The reddish-brow n solutionwas stirred a t 0 "C for 30 min; the temperatur e was then raisedto 25 "C over a period of 15 min. Th e solution was then stirredat 35 'C for 15 min an d then refluxed for 15 min. The warmreaction mixture was then p oured into 200 mL of ice-H20. Th emixtur e was shaken vigorously, th e layers were separated, a ndth e aqueous layer was extracte d with 3 portions of CHZCl2.T h ecombined organic solutions were washed with H 2 0and saturatedbrine and dried (Na2S04 ).Removal of the solvent gave 9.6 g of

green oil which crystallized upon seeding. Recrystallization fromMeO H-H2 0 gave 6.36 g (64% yield) of @)-loas colorless crystals:m p 111-113 " c ; [ci]24'8D 258.6" (c 1.0, 95% E tO H) . Anal.

(CziHaN05) C, H , N .The product was initially obtained crystalline by chromatog-

ra ph y of 2.0 g of the cr ude oil on 150 g of ne utra l silica gel. Th ecolumn was eluted with Skellysolve B containing increasingproportio ns of CH2C12 nd finally with pure C H2Cl2. Evapo rationof the combined fractions containing the compound first elutedgave 1.35 g (67%) of an oil which crystallized upon standing.

(b) Race mi c Isom er. This materia l was prepared by theprocedu re described in p art a from 35.7 g (105 mmol) of (*)-7and prop ortionate quantities of other reagents. Th e crude, oilyproduct was chromatographed on 1 kg of Woelm activity I11neutral alumina, eluting with SkellysolveB containing increasingproportions of CHZCl2 5,10 ,15,2 5,and finally 50%). The productbegan to appear in fractions containing 25% CHzC?z. Thefractions were comb ined and solvents evaporated to give 21.61g of an oil. T his was dissolved in 150mL of hot 95% EtOH an dthe solution was incubated a t room temperatu re for 24 h and th ena t -15 "C for 48 h. Large, pale green crystals were obtained: yield15.97 g ( 43% ); m p 92-96 "C. Anal. (C21H21N05) , H, N.

(R)-l-(2,5-Dimethoxy-4-hydroxyphenyl)-2-(- p h t h a l -i m i d o ) b u t a n e [ ( R) -1 1 1. P r o c e d u r e E. To a stirred solutionof 10.0 g (27.2 mmol) of @)-lo in 200 mL of CHC13 was add ed,all a t once, 6.92 g (34.1 mm ol) of 85% m-chloroperoxyb enzoicacid.Th e resulting solution was stirred a t room te mpera ture for 22 h.The solution was concentrated under reduced pressure until asolid began to separate. Th e residual mixture was taken up inEtzO and t he solution was washed with dilute N aH S0 3 solution(2 portions). Th e solvent was evaporated to give 10.4 g of th eformyloxy com pound as an am ber resin.

Th e crud e ester was dissolved in 200 mL of 100% E tOH, and

HC l (9) was bubbled through t he solution for 15 s. Th e flask wasthen sealed and th e solut ion s tood a t room temperature for 18h. Th e solvent was evaporated and traces of HCl were chasedwith 2 portions of 95% E tOH . Th e crude solid was recrystallizedfrom i-P rOH to give 6.77 g (70% overall) of (R)-11 as crystals:

(R)-2-Amino-1-(2,5-dimethoxy-4-ethoxyphenyl)butaneHydr och lo r ide [ (R)-13a] . P roced ure F. To a stirred solutionof 2.0 g (5.63 mm ol) of ( R ) - l l in 50 m L of dry DM F was added0.253 g (6.0 mmol) of 57% N aH in mine ral oil. After gas evolutionha d ceas ed, a solution of 0.97 mL (1.87 g, 12.0 mm ol) of icdoethan ein 10 m L of dry DM F was added dropwise. Th e solution wasstirred a t room tem perature for 30 min, at 45-55 "C for 1.5 h,and t h e n at amb ient temperature for 16 h.

Th e DM F was removed under reduced pressure and t he residuewas partitioned between E&O and H 20 . Th e layers were separated

mp 123-125 "c ; [ c i ] 2 3 ~176.2" (C 1.0, 95% E tOH) .

J o u r n a l of Medicinal Chemis try, 1980, Vol. 23 , No. 2 161

and the aqueous layer was extracted with 2 portions of Et O . Th ecombined organic solutions were washed with 5% NaO H solution(3 port ions) and HzO (3 portions), dried, and evaporated.

Th e oil th us obta ined an d 2.13 mL (2.15 g, 67.2 mmol) of 95%hydrazine were dissolved in 100 mL of 100% E tOH, and thesolution was stirred and refluxed for 5 h and then s t i rred atambient temperature for an addi t ional 14 h. The m ixture wasevapora ted under reduced pre ssure an d residual N2H4 was chasedwith 2 portions of 95% EtOH . Th e residue was tritu rate d with5% HC1; the solid was filtered and the filter cake was washedwith 5% HCl and then w ith H2 0. The f i l t ra te was made basic

with NaOH solution and the oi l was extracted with EtzO. Th ecombined extracts were washed well with H 20 ,d r i ed (MgS0 4) ,and evaporated. The oi ly residue was taken up in dry E h O andthe salt was formed with HC1 (g). Th e product slowly separatedas a yellow powder. Th e mixture was chilled at -15 "C andfiltered. Th e crude salt was recrystallized from acetone to yield0.81 g (59% yield) of th e title comp ound: yellow crystals; mp189-190.5 "C; [f,?Iz3D13.9' (c 1.0,95% EtOH ). Anal. (C14H23-

(R)-l-(2,5-Dimethoxy-4-nitrophenyl)-2-(N-phthalimido)-bu ta ne [(It)-141. To a stirred solution of 16.2 g (47.7 mmol) of(R)-7 n 270 mL of glacial HOAc was added, all a t once, 14.1 mL(20.1 g, 223 mm ol) of concentrated H N 03 n 120 mL of H2 0. Th esolution was stirred a t room tem peratur e for about 4 h, darkenin gduring this time to a reddish-orange color. T he solution was thenpoured into 1L of cold H2 0; he produ ct separated as a yellow

gum which crystallized within 30 min. Th is material was filtered,washed well with H2 0, air-died, and then recrystallized from 95%EtO H to give 16.35 g (9 0% ) of (R)-14 as yellow crystals: mp

C, H, N.( R -1-(4-Amino-2,5-dimethoxyphenyl)-2-(- p h t h a l -

im ido )b uta ne [(R)-15]. A suspension of 12.6 g (32.8 mmol) ofthe nitro com pound (R)-14 and 4.0 g of 10% P d on carbon catalystin 200 mL of 100% EtO H was hydrogenated at an initial pressureof 3 atm. Pressure drop was rapid and heat was evolved. T hehydrogenation was continued for 16 h.

Th e pressure drop was 107% of th e calculated value. Th e solidswere filtered an d the filter cake was washed with C HzClzuntilth e washings were colorless. Th e filtrate was evaporat ed to givean amber solid, which was recrystallized from 50% aqueous EtO Hto provide 10.46 g (90%)of the title com pound as glistening ambercrystals: m p 141-142.5 "C; [a]24D197.6' (c 1.0,CHC13). Anal.(C2oHzzN204) C, H, N.

( R ) - 2 - A m i n o -1-( -amino-2 , 5 -d ime th o x y p h e n y l )b u t a n e[ (R) -17] . P rocedure G . To a stirred, hot solution of 2.0 g (5.65mmol) of (R)-15 in 120 mL of 100% EtO H was added all at once2.0 mL (2.02 g, 63.1 mmol) of 9570 hydr azine. Stirr ing an drefluxing was main tained for 5 h; separation of phthalhydrazidewas observed within 90 min. Th e reaction mixture was thens t i rred a t room temperature overnight (1 4 h).

Th e mixtur e was evaporated a nd residual NzH4 was chased with2 portions of EtOH. Th e residue was then tri tura ted with 5%HC1 solution and th e resulting suspension was filtered. Th e filtercake was washed with 5% H C l( 1 por tion) and H 2 0 2 portions),and t he filtrate an d washings were combined and m ade basic (p H9) with 40% N aOH solution. Th e insoluble material was extractedwith 3 portions of CH2C12. Th e com bined extracts were dried(MgSO,) and evaporated.

Th e residual solid was recrystallized from ca. 200 mL of HzOto give 0.824 g (65% ) of pro duc t as fluffy, am ber needles: m p79-80 "C ; CY]^^.^^ -210.1' (c 1 , 9 5 7 ~ t OH ) . Anal. ( C 1 2 H a 2 0 2 )C, H , N .

(R)-2-Amino-l-(4-bromo-2,5-dimethoxyphenyl)butaneHyd rochlo ride [(R)-18b]. Pro ced ure H. To a s t irred solut ionof (R)-6a [obtained from 20.0 g (81.6 mmol) of the correspondinghydr ochlor ide] in 150 mL of glacial HOAc was adde d dropwise,a t -10 "C, a solution of 13.1 g (82 mmol) of Br2 n 50 mL of glacialHOAc. After the additio n was complete, the solution was stirredat -10 "C fo r 1 h; the reaction mixture solidified. Th e coolingbat h was removed and the reaction mixture stood at room tem-perature for 40 h.

The m ixture was diluted with 150 mL of Et 20 and allowed tostan d for 2 h. Th e white solid was filtered, washed with EtzO,and dried t o give 22.65 g of the hydrobromide salt of th e product.

NOyHC1) C, H, N, C1.

140.5-142.5 "c; C Y ] ~ D224.8" (C 1.1, CHCl3). Anal. ( C a d @ , )

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162 J . Med. Chem 1980,23 , 162-166

Th e hydrobromide was converted to th e free base and the sa l twas formed with HCl (g) in dry Et 20 . Th e crude materia l wasrecrystallized from i- Pr OH to give 18.8g (71 %) of the title com-pound as colorless crystals: mp 2 4e 24 2 "C; [ ( Y ] ~ ~ ~58.0' (c 1.0,95% EtO H) . Anal. (C,2H,8BrN02 .HCl)C, H, N.(R)-2-Amino-1-(2,5-dimethoxy-4-iodophenyl)butaney -

droch lo r ide [ R)-18c]. Concentrated HC l(3.52 mL, 42.3 mmol)was added all at once to a hot, stir red solution of 5.0 g (14.1 mmol)of (R)-15 in 200 mL of 100% EtO H. Th e darkened solution wascooled rapidly to 15 'C. Wate r (120 mL) was added (a gelatinousprecip itate dissolved) and th e solution was cooled to 2-3 "C and

ma intai ned a t this tem pera ture w hile a solution of 1.07 g (15.51mm ol) of N aN 02 in 20 mL of H zO was added dropwise withstirring. After 40 min , a solution of 2.57 g (15.51 mmol) of K Iin 20 mL of H 2 0was added dropwise with stirring to th e reactionmixture; a dar k red-brown semisolid began to separate.

Stirring was continued a t 2-3 "C for 3 h. Th e cooling bath w asthe n removed a nd stirring continued for an additional 2 h; thetemperature of the reaction mixture had risen to 20 "C. Thetempe rature was the n held a t 40-50 "C for 30 min. Th e darkreaction mixture was diluted with an equal volume of H 2 0an dextracted with 3 portions of Et20. Th e combined extracts werewashed successively with 2 port ions of 10% N aHS 03, 5% HCl,5% NaOH , and finally H 2 0 3 portions). Th e Eh O solution wasdried (MgSO,) and evaporated to give 2.91 g of dark red oil.

Th e crude material was chromatographed on 300 g of activityI11 alumin a. Elu tion w as with 25% CH2C1, in Skellysolve B an dprogress was followed by TL C (alum ina, 1:l CH2C12-SkellysolveB, visualization with shortwave UV). Th e material first elutedwas (R)-l-(2,5-dimethoxy-4-iodophenyl)-2-(N-phthalimido)bu~e:yield 1.06 g (1 6% ) of clear, yellowish oil 97% pure by GC.

Witho ut further purification, t he phthalimido compound washydrazinolyzed as described for (R)-13a. The crude hydrochloridesalt of the pro duct w as recrystallized from i-P rOH to give 0.376g (44 %) of colorless needles: mp 255.5-257 "C dec; [a]2436556.8"(c 1.0, 95% Et OH ). Anal. (Cl2HI8INO2.HC1) , N, I; C: calcd,38.18; found, 39.27.

Pha rm aco logy . Ca t Behav io r . T h i s p rocedure repre sen tsa modification of th at described by Wallach et al." Adu lt femalecats were placed in sepa rate cages appro xima tely 12-15 sq f t infloor area. The anim als could see the experimenter a nd each otheracross the room and could have auditory and olfactory con tactamong them selves in adjacent cages.

After animals had become accustomed to this environment (30

min ), test compou nds were administered subcutaneously into the

back of the neck. Following dosing, animals were observed for3 h. Scoring was done at the tim e of peak drug -induc ed effects,usually about 1 h postdosing. Th e effects were scored using anobservational checklist consisting of 1 2 categories, each containing2 items. Each item was worth 1 point , with a m aximum tota lnum erical score of 24. A totalscore of 10 or greater was considered"DOM-like".

Th e categories were: body posture , arched back/st iff tail;extens ion of limbs, legs/legs a nd toes; muscle rigidity, legs/a b-domen, abnormal leg/immobility; motor coordination, ataxia/lossof righting reflex, open mou th/protrud ing tongue, claws out/

a t tempts to bite or claw, teeth baring/hissing or growling; contac twith environment, reduced/absen t; piloerection, tail/back; pu-pillary con striction, mode rate/extrem e; salivation/emesis.

Either two or four animals were used per test. For N = 2, anaverage of the individ ual scores was take n. For N = 4 , meansplus or minus standard error were reported.

Avoidance-Response Acquisition. Male, retired breeder ratsof th e Long-Evans strai n (Blue Spruce Farms , 600-800 g) weregiven 120 massed acquisition trials in a shuttle box (BRS/LVE,Model 146-04) as described elsewhere.'* Briefly, each trial was30 s in du ration and consisted of a 5-9 light (conditioned stimulus,CS) presented on th e side of the s hut tle cage occupied by thesubject. If the ra t did not cross to the other side of the chamberwithin the 5-s CS period (avoidance response), the grid floor underthe animal was electrified with 0.8 mA of scrambled shock(BRS /LVE, Model 1531 shocker). Th e animal was permitted 5s to make a n escape response before termina tion of the light an dshock stimuli. Avoidance responses turned th e CS off, while anescape response terminated both th e CS and the shock. Ei therresponse initiated th e intertrial interval (IT I), which was 20-30s, depending on the response of the subject during the CS or shockperiods. Responses during th e IT1 were taken as a measure ofnonspecific motor activity and were not punished. Drugs weredissolved in a distilled water vehicle and injected ip 5-10 min oradministered by intragastric gavage (PO) 30 min prior to the 1-hbehavioral test. Differences between the means of control anddrug groups were tested for statistical significance by a S tude nt'st-tes t. Th e accepted level of significance was set a t p < 0.05.

Poten cy differences between some of the drugs were determ inedby comparing the minimal effective doses (MED) required toincrease avoidance responding significantly (see Table VI). Th eME D was established by evaluating a set order of doses withinth e 0.25-20 mg/kg ip range (i.e., 5, 2, or 10, 1 or 20, followed by0.5, 30, or 40 mg/kg, i f necessary).

Synthesis and Analgesic Activity of Some 14P-Substituted Analogues of Morphine

Peter O s e i - G y i m a h and S y d n e y A r c h er *

Chemis try Departm ent , Rensselaer Polytechnic Ins t i tute , Troy, New York 12181. Received August 29, 1979

Trea tme nt of 1 4P-nitrocodeinone with sodium borohydride gave the codeine derivative which was reduced w ith zincdu st in acetic anhydride-acetic acid solution to give 14/3-acetamidocodeine 6-acetat e. 14P- Thioc yanato codein onewas obtained from t he reaction of thebai ne with thiocyanogen an d was reduced t o 14P-mercaptocodeine with lithiumalumin um hydride. 14P-Bromo- and 14~-chloroco deinonewere prepared by the reaction of thebaine with N-bromosuccinimide a nd N-chloros uccinim ide, respectively. The se 14P-sub stituted codeine an d codeinones were

0-d em eth ylat ed to the corresponding morphine analogues with boron tribromide. With the exception of 14p-nitromorphinone, which was weak in activity, all the o ther 140-substituted morphine derivatives were approximatelyequal in potency to normorphine in the guinea pig ileum preparation.

The s u b s t i t u t i o n o f h y d r o x y l g r o u p s at the 14p pos i t ionof the m o r p h i n e sk e l e t o n has produced compounds pos-

s e s s i n g s i g n i f i c a n t p h a r m a c o l o g i c a l a c t i v i t i e s . Oxy-m o r p h i n o n e (1, R = CH,) i s a p p r o x i m a t e l y ten t i m e s as

potent as m o r p h i n e s u l f a t e as a na rco t i c ana lges ic ' andn a l o x o n e (1, R = CH2CH=CH2) i s a u s e f u l n a r c o t i c an-t a g o n i s t w h i c h possessesno a g o n i st p r o p e r t i e s i n h u m a n s . 2

(1) N. B. Eddy, J . Chronic Dis., 4 , 59 (1956).(2 ) D. R. Jasinski, W. R. Martin, and C. A. Haertzen, J . Phar-

macol . E x p . T h e r . , 157, 42 0 (1967).

0022-2623/80/ 1823-0162$01.00/0

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O t h e r than such c o m p o u n d s h a v i n g o x y g e n f u n c t i o n a li t ie sat the 146 p o s i t i o n , t h e r e i s a p a u c i t y o f a n a l o g u e s ofm o r p h i n e b e a r in g o t h e r f u n c t i o n a l g r o u p s at t hi s p ~ s i t i o n . ~

1980 American Chemical Society

j . m e d . c h e m

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