clarke 1973 3beta-phenyltropane-2-carboxylic esters and analogs

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r a t ed , com bined wi th th e f i l t r a t e from the second crys t a l l i za t ion ,and recrystal l ized f rom EtOAc giving 0.22 g nf yellow crystals, m p237-239". 'This was fou nd by i r , nrnr . and uv spec tra to have thes t ructure 15 . The pr incipal spect r a l bands ar e : i r172.5. 16M I C - .O j a n d 1620, 1590. 1580 c m - ( C -( E t O H ) 22 0 nip i f 32.050), 265 (19,250). y374 (5150);

h 3.22 and 3.24 ( 2 s. 6. NCH3) . 6.42 I S . 1 . , ? -=CHI . and between6.75 an d 7.65 ( m ' s . 7. a r o m H's) .

Column fract ions 10--17were evaporated giving 0.2 g of near lywhite sol id. This was recrystal l ized f rom i-PrOH yielding 0.18 g of

white needles. m p 226--228.5" . I r . nmr. an d ana lysis showed this

to have the s t ructure 16. The pr incipal spect r a l hands ar e : i r( N u j o l m u l l ) 1740. ( C - 0 ) a n d 1610. 1590. 1570 cm( C = ~ N , / C- - C i : n n i r iCI)C13) 6 1 . 8 ( d . X. 5-CH3j . 3.39 is, 3,N('H3'!. 4.14 l q . I . <i - C H ) .and between '7.05 an d 7.65 ( m ' s . 7.

arom H ' s )

I , 3 ( 2 H , .j H ) - d io n e 2 -M e t h o x y e t h an o l S o l v a t e (17). This was pre-pared f rom 5.39 g (0.02 m ol) of 24 essent ial ly as descr ibed for 13using diethylene glycol-dimethyl ether as a solvent for the f i rsts t ep . T h e i n t e r m ed i a t e l - carbethoxy- : i - [~ -o-chlorophenyl ) -3H-1 .4-benzodiazepin-: ' -ylJurea tai led to crystal l ize hut t lc (SiO2. 5 7 ~hleOH in CHCIS) showed most ly one spot . I t was used in t he sec-ond s t ep wi thout pur i f i ca t ion . Crude I i crystal l ized f rom the xy-lene solut ion dur ing ref lux. I t was col lected and recrystal l izedf i rst f r o m MeO H and the n f rom 2-nie thoxyethano l an d dr ied a tt(X)" ( 0 . 0 2 nim ) for 6 r giving 2.9,5 of solid. m p 225-232". T hi swas found by nmr to conta in one molecule of 2-methoxyethanol .

T h e pr incipal spect r a l hands ar e : ir ~ S u j o lm u l l ) 3250. 3060("/OH). I705 tC'---OI. and 1615. 1596. 1570 c m . - ' IC==N;( ' C i : n n i r I D M S O - ~ ~ I:3.% (s . :1. OCH.1). between 3.0 an d 3.8(in's, -I, O( 'H2CH20Hj . ab cen t e r ed a t -1.3 a n d 4.r' ( 2 , .I = -1 1

H z. 5 - C H z i . an d b e tw een 6 . 8 an d 7.8 ( m ' s . 8, arom H's).1 ( i -Chloro-3-phenyl -BH- 1, ~-benzodiazepin-2-yl)-2-imidazol-

i d i n o n e (18) . T o a solut ion of 7.5 g (0.02 m o l ) of 8 in 100 m l ofT H F u n d e r NP was added por t ionwise with st i r r ing 3.0 g (0 .07m o l ) of 56% NaH in minera l n i l . Af t er s t i r r i ng a t r oom t empera-ture for 18 hr I he mixture was concent r a t ed in ~ ' a c ' u o ,mixed withwater a n d pentane . and neut r a l i zed wi th AcOH. The sol id wascol l ec t ed . washed (H zO and pe nta ne) . and dr i ed g iv ing 6.66 g ofcrystal l ine sol id, m p 217-227" dec. Recrystal l izat ion f rom i-PrOHyielded 4 .45 g (65 .5%) of white crystals. mp 245-2473" , T h e p r i n -c ipal spect r a l bands ar e : i r iSujol mul l ) 3220. 3120 ("I 1710iC - - ( ) I .an d 1605. 1,580 cn] - l l,C = ~ N-=C!: nmr ( ( 'DC13I 6 3.46I t . 2 . ('Hz)..05 i t . 2. C H z , . : i - ( l H ~ oo broad to locate. 6.23

n 7.1 an d 7.7 m 's . 8. rom H's j :

yl) -3H-1 l - benzodiazepin-2-y1 -

;-(o-Chlorophenyl)-a-triazinoll,2-a]1,4]b en zo d i azep i n e -

2- imidazol id inone ( 19 ) . Th is was prepared a s described for 18!rum 3. 1 g (0.01 m o l ) of 10 . The crude product was d i ssolved inRtOAc. t reated with decolor izing charcoal . f i l tered, concentrated.; ~ n d i luted with Et20 giving 1.16 g (3170) of white crystals. mp

The pr incipal spect r a l hand s ar e : ir (Nujol mul l ) 3270.!, 1725 C ~ - 1 . an d 1603. 1580 c m - 1 (C-=N!C-C); n m r

(CDCl:$! 6 3 . l . i i t . 2. ( ' H ~ I . .0 7 ( t . 2 , C H 2 ) . 1.8 ( b r o ad 8 . 2 . 3-

( 'H21 . K A (tiroad s. 1 N H J . a n d he twe e n 7 .0 an d 7. i i ~ n i ' i . . aromH's)

1 - ( i-C'hloro-.j-phen?.l-:~H-, 1-benzodiazepin-2-yl)-:I-methyli-

midazol id in-2-one (20) . T o a solut ion of 2.7 g (0.008 mol) of 18 in50 ml of D M F , u n d e r Nz , was slowly add ed with st i r r in g 0.602 ml(2.0 g. 0.008 mol) of TIO Et. After st i r r ing for 15 min 0.62 m l (0.01

mol ) of Me1 was add ed dropwise . Af ter s t i r r i ng a t r oom t emp era-ture fo r 18 hr t h e mixture was f i l t er ed a nd th e so l id TI1 was ex-t r ac t ed w i t h D M F . T h e D M F so lu t io n w as co n cen t r a ted in i:acuoand di lu t ed w i th water . Th e r esul t i ng sol id was col l ec ted , washed(HZO ). an d dr ied giving 2.58 g of cream-colored sol id showingonly one spot on r lc (SiO2, 5% MeOH in CHC13 or 60% EtOAc incyclohexane) . Recrys t a ll i zat ion f rom i -PrO H yie lded 2.32 g (82%)

of l ight yel low crystals , m p 212-215" (af te r scinter ing at 1 9 5 .5 ~

199" ). Th e pr incipal spec t r a l bands ar e : i r (Kujo l mul l ] 1721lC=-=Oia n d 1605. 1 59 6. 1 58 0 cm - l (C-K-jC-Ci; nmr (CDC1:I) ri

broad to locate, and between 7.22 an d 7.7 ( m ' s . a r om H ' s J .l-(i-Chloro-j-phenS1-3H-lI-benzodiazepin-2-y1)-3-2-(di-

methylamino)ethyl]-2-imidazolidinone21 ). 'To a solu tion of I.;

g (0.005 m o l ) 'of 18 in 25 m l ot DMF. u n d e r ?;2 . was added wi thst i r r ing 0.362 ml (0.005 mol) of T l O E t . A so l id s ep a r a t ed an d 1 . 3m l (0.65 g. 0.006 mol) of 4.6 M 2- (dimethylarnino)e thyl chloridein xylene was add ed . After st ir r ing at room tem pera ture for 18 hrt l c (S iOz, 20% Me OH in PhH ) indica t ed the r eact ion was notcomplet e so 1.3 ml more of the 2-(dimethylamino)ethyl chlor idesolut ion was added and st i r r ing was cont inued for 4 d ay s . T h emixture was f i l t e r ed , concent r a t ed , d i lu t ed wi th HzO. an d e x -t r ac t ed wi th CHC1.1 . Th e ext r ac t s were w ashed (Hz O + N aC l so-

l u t ion) and dr i ed iKa&04) . Evaporat ion of t he so lu t ion gavel ight brown gum which was crystal l ized f rom cyclohexane-pen-

tane and recrystal l ized f rom cyclohexane yielding 1.07 g (52%) off luffy whi te needles. mp 129-130.5" . The pr incipal spectral baare: i r lNujol mul l i 1710 i C - 0 ) a n d 1600. 1580 cm-1 i C ~ ~

C - - - C ) : m r ( C D C 1 3 ) 6 2.22 1s. 6. N ( C H 3 ) 2 ] , 2.45 ( t . 2 . C H 2 ) . 3.42( 1 . 2. CH2),3.5 i t. 2 , CHz!. 3.95 i t , 2 . CHz) , 3-CH2 t o o broad tolocat e . and between 7 .1 a n d 7. 7 i m ' s . a r n n i H ' s ) : m ass sp ec t r u m

Acknowledgments. The authors wish to thank the fol-

lowing people who contributed t o this work: our Physical

and Analytical Chemistry Unit for analytical and spectral

data; Messrs. Bharat V . Kamdar, Alfred Koning, and

Walter Friis fo r technical assistance.

2.9 (5 , :3, N C H S ) . 3 . 3 8 ( t . 2. C H z) . 3.95 (t . 2. C H z ) . : I - C H z too

M , + 409 (1 CI! .

References

( 1 ) R . B. loffet t and A . D . R u d z i k . J . M e d . C h e m . . 1.5, 1079

( 2 ) K . M e g u ro , Y. u w a d a , Y. N ag aw a , an d T . M asu d a , Nether-lands Pa ten t 6,913.042 (1970);C.S. Pa ten t 3,652,754 (1972) .

( 3 ) J. B. Hester . Jr . , D . J. D u c h a m p , a n d C . G. Chidest er , T e t r a -h e d r o n Let t . . 1609 (1971) ; J . B. Hest er , Jr., A. D. R u d z i k , an d€3. Y . K a m d a r . J . M e d . C h e m . . 14,1078 (1971) .

( 4 ) ( a ) I ,. H . S t e r n b ach , E . R eed e r, 0 . Kel l er . a nd W . M et les i cs ,.I. Org. C h e n . , 26, 4488 (1961); (b ) S. C. Bel l , C . Gochman,a n d S. . Childress. J . M e d . Pharm. Chem., 5 , 63 (1962); ( c )R . I. Fryer s , J . V . Ear l ey . G . F. Field, W. Zal ly. and L. H .S t e r n b a c h , J . Org. C h e m . ,34,1143 (1969) .

(5) . A. Archer and L. H . S t e r n b ach . i b i d . , 29,231 (1964).(6) R . W . L a m o n . J . Heterocyc l . C h e m . . 6.261 (1969).

( 1972) .

Compounds Affecting the Central Nervous System. 4.3P-Phenyltropane-2-carboxylicEsters and Analogs

Robert L. Clarke,* So l J . Daum, Anthony J . Gambino, Mario D . Aceto, Jack Pearl, Morton Levi tt, Wayne R. Cumiskey,

and Eugenio F. Bogado

S t ~ r l i n g -Winthrop Research In s t i tu te , Rensselaer , Neu i York 12144. Recei ved M a y 4, 1973

Mudif icat ion of the st ructure of cocaine ( I ) by a t t a chm ent of t he aroma t i c r i ng d i rec t ly t o t he 3 posi t ion of the t ro-pane r ing has resul ted in a f ive- to sixtyfold increase in several biological paraineters accompanied by a tenfold dropin local anesthet ic a ct ivi ty an d a fourfold lowering of int rave nous toxici ty.

Cocaine (1 ) has a variety of pharmacological actions,

primary among them being strong CNS stimulation and

local anesthetic action. These effects are accompanied by

high toxicity and dep endence liability. It was of consider-

able interest to see if modification of this molecule could

result in a useful stimula nt or antidepressant.



3p-Phenyltropane-2-carboxyiic sters Journal f Medicinal Chemist?, 1973. Vol. 16 , No. 11 1261

0

1

2% R = C OOC H, ; R ' = Hb. R = H ; R ' = C O O C H 3

The present paper describes modification 2a and ana-

logs. Formally, the phenyl group of cocaine has been a t-

tached directly to the tropane ring. The most active of

these compounds are powerful stimulants which inhibit

norepinephrine uptake in both heart and brain, reverse

and prevent reserpine-induced eyelid ptosis, and produce

only mild local anesthesia. The enantiomers of these com-

pounds are devoid of stimulative activity.

Compound 2a was prepared along with 2b (1:3 ratio) by

the reaction of phenylmagnesium bromide with (-)-anhy-

droecgonine methyl ester (3 ) at -20". The 2-benzoyl de-

rivatives 4a an d 4b were formed in small quantity through

reaction with a second molecule of Grignard reagent; the

2a configuration predominated. At room temperature, 4a

an d 4b were the principal products.1 When 1 equiv of

CuzBrz was used, only highly insoluble complexes re-

sulted. A 5 mol 'YOof cuprous salt produced troublesome

complexes. Phenyllithium could not be substituted for the

Grignard reagent owing to 1-2 addition with carbinol for-

mati0n.l Most of the esters reported were prepared before

opt imu m conditions were defined, and the low yields also

reflect t he early struggles with isomer separation.

3 44 2/3 isomer

b, 2 a isomer

Normally the 2-axial and 2-equatorial esters 2a and 2b

were separated by column or plate chromatography. When

it developed that the axial form 2a was the epimer of in-

terest, the equatorial epimer was removed from the reac-

tion mixture by selective quaternizationt with ethyl io-

dide at room temperature.

Configurational assignments for 2a and 2b were madeon the basis of nmr and ir data.3, 4 The more polar (silica

tlc ) of the epimers showed an nmr coupling consta nt for

the C-2 and C-3 hydrogens which indicated t ha t they were

in a trans-diaxial relationship. Therefore, it was the 3@-

phenyl-2a-carboxylate 2b. The nmr spectrum of the less

polar of th e epimers showed the C-2 an d C- 3 hydrogens to

have a cis relationship. The functional groups at these po-

sitions then had to be ,8,p (as in 2a) or a,a. This final dis-

tinction was made by reducing the epimer with LiAlH4.

The resulting alcohol 5 of necessity had the 2p configura-

t Based on an observation of selective tropane quaternization by Weisz,e t a1.* Methyl iodide can be used where an isopropyl ester is present a tc-2.

tion since its ir spectrum showed intramolecular hydrogen

bonding. The less polar epimer is then properly represent-

ed by structure 2a. As a confirmatory experiment, 2b was

reduced to 6 which showed only the expected intermolecu-

lar hydrogen bonding; it disappeared at high dilution. Th e

acetates of 5 an d 6 were also prepared, primarily for bio-

logical evaluation .

\H -0,'

CHJicH3N\Q \\- CH,OH

5 6

Nmr spectroscopy furnishes a convenient means for

configurational assignment to these esters which are

epimeric at C-2. The ester moiety in the axial (2p) posi-

tion has a shielding effect on the NCH3, producing a shift

of 0.12-0.20 p pm upfield from tha t of the C-2 equato rial

ester.$ There is a minor and unpredictable difference

(A0.03 or less) in the COOCH3 positions of these epimers.

Optical rotatory da ta are of questionable usefulness for

configurational assignments to pairs of these C-2 epimeric

compounds. Thus, cocaine (axial 2-COOCH3) has a molar

rotation value which is 17,570' more negative than that of

pseudococaine (equatorial 2-COOCH3). In the parallel

case of ecgonine us . pseudoecgonine, the difference is

minus 12,580". The difference for 2a an d 2b is only minus

2670". The 2-axial benzoyl compound 4a is 31,110" more

positive tha n equatorial compound 4b.

There is indication that the equatorial configuration is

the more stable at C-2. In experiments followed by tlc,

NaOCH3 in CHsOH converted 2a into 2b, but accompa-

nying decomposition destroyed the latter. Under the same

conditions 2b never produced any 2a spot. On one sample

of 2a, hea ting for 30 min a t 150" caused 10% conversion to

2b; 30 min at 200" caused 50% conversion (followed by

tlc). Subsequent samples were stable for 2 hr at 200" andbegan to decompose in a complex manner at 250".

Attempts to influence the ratio of 2a to 2b in their ini-

tial formation were focused on the proton source for the

hydrolysis of the Grignard adduct 7. In order to increase

the amount of the axial isomer 2a, it appeared necessary

to increase the amount of protonation at C-2 from the

,MgBr

CH37\-f C\ OCH3

7

n

COOCH,tClCH,CH,OCN\, I

8

under or more hindered side of the molecule. The usual

hydrolytic procedure of adding ice, followed by 2 N HCl,

was varied by adding acetic acid in ether at both 0 an d

-50", HC1 gas, phenol in ether, BF3aEt20, NH4C1, meth-

INC H3 p e a k p o si ti o ns (p p m ) : 28, 2.22, 15 , 2.31, an d 18, 2.25 (28-C OOC H3 ) ; Zb, .42, 16,2.43, a n d 19,2.39 2u - C OOC Hd .



Ic-

U I



3 ~ - P h e n ~ l t r o p a n e - 2 - c a r b u x ?i c Esters Journal o fk f ed ic ina l Chen i s t r? . 197.7, Voi 16 , N O . 1 1263

anol, and trimethylamine. Dilute HC1 was then added in

each case. These variations had no effect on the ratio of

isomers formed.

The abs olute configuration of cocaine is' known.5 Since

tropane ester 2a was prepared from (-)-anhydroecgonine

methyl ester derived from cocaine, it has the lR,ZS,3S,5S

configuration. All other compounds reported here are re-

lated to this configuration with the exception of enan-

tiomers 24-26 and piperidines 9 an d 10.

Table I summarizes the tropanes which were prepared

in the course of defining the relationship between stru c-

ture and CNS activity. The sole 8-nortropane, compound

23, was prepared by treatment of 2a with ClCH2CH20-

COC16 to form 8 which was then cleaved to the H N <

compound 23 by treatment with chromous perchlorate.'

Compounds 27 and 28 were prepared by simple acid hy-

drolysis of 13 an d 2a, respectively. Compounds 24-26 are

enantiomeric with 2a, 13, an d 14, respectively. They were

prepared from methyl (*)-3-oxo-la~,5a~-tropane-2a-car-

boxylate which was resolved according to the method of

Findlays with slight modification. The bitartrate salt of

the unnatural ( - ) isomer was reduced (Pt, HOAc) to give

methyl (+)-3a- ydroxy-la~,5~-tropane-2a-carboxylate

which was dehydrated with POC13 to form (+)-a nhydro-

ecgonine methyl ester. This enantiomer of natural ( - ) -anhydroecgonine methyl ester (3 ) was then converted to

24-26 by the sta ndard procedure.

It was of particular interest to determine if high rigidity

in the molecule was a requirement for CNS activity. The

unbridged (nonrigid) analog of 2a is the cis ester 9a. It

and the trans isomer 10a have been reported by Plati, e t

d . , 9 without configurational assignment. Reduction

(LiAlH4) of 9a an d 10a has afforded alcohols 9b an d lob,§

only one of which (9b, cis) showed intramolecular H

bonding at high dilution. It was, therefore, possible to as-

sign the cis and trans configurations respectively to the pan d a compounds of Plati and coworkers. The correspond-

ing acetate esters 9c an d 1Oc were made for biological

evaluation.

L\ L\9aR =COOCN, 10%R = COOCH?

b. R = CH2OH b. R =i CH?OH

c .R = CH,OAc c :R = CHzOAc

Biological Studies. Table I1 summarizes the overt be-

havioral effects produced by these Sp-aryltropane-2-

carboxylates. The values reported are the lowest oral

doses which produced an increase in locomotor activity.

The most active compounds of the series are 13 an d 23

which are some 64 times as active as cocaine. With a 4mg/kg dose of 13, stimulation was still evident at the end

of 5 hr. Compound 25, he enantiomer of 13, is a mild de-

pressant. Comparison of 2a with 2b an d 13 with 14 shows

that the 2-COOR group must have an axial configuration

in order to be stimulative. Substitution of a 4-fluorine on

the aromatic ring enhances activity (13 us. 2a), whereas

insertion of a 4-methoxy group reduces it (15 us . 2a).

Reduction of the axial ester function on carbon 2 to a

hydroxymethyl group (compound 5) and ac etylation of th e

resulting alcohol (compound 11) did not lower the stimu-

SPlati . e t a l ,9 solated a l-methyl-4-phenylpiperidine-3-methanolf m p107-109" by reduction of 5-carbethoxy-4-phenyl-2-pyridone i th copperchromi te ca ta lys t . I t probably i s the t rans i somer 10b (our mp 111-113O a sopposed to mp 99-100" of t h e cis isomer).

Table 11. Effect of 3p-Aryltropanecarboxylate sterson Locomotor Activity in Mice

Min M instimulative stimulative

dose, mg/kg dose, mg/kgCompd of base PO Compd of base PO

Cocaine2aa2b b5 "6b9aa9CblOcb1 1 6

644

>2564

>256>256

256<256

4

126131415b16a17a21b22b2325

>2561

>25664

>256>256

441

64

5 The free base was administered. b The salt of the com-Slight depres-ound shown in Table I was administered.

sant.

lative activity appreciably (compare with 2a). However,

removal of rigidity through removal of the ethylene bridge

(compound 9a) destroyed activity. Compound 9c, th e

nonrigid analog of compound 11 , was only very weakly ac-

tive. For all active compounds, the peak effect occurred at

about 1 hr following medication. Further observations onstimulation are recorded in the ptosis study described

below.

Like cocaine,lO the presently reported stimulants pre-

vent as well as reverse reserpine-induced eyelid ptosis.ll

The most active compound, 13, is more than five times as

active as cocaine in the preventive test and 20 times as

active in the reversal test. Table I11 summarizes the re-

sults. Again the enantiomer of 13 is inactive.

The local anesthet ic action of these compounds was

evaluated in parallel with cocaine using an intradermal

anesthetic test in guinea pigs.l2 Compound 13 showed

only about 15% of the local anes theti c activity produced

by cocaine (after making allowance for the different salts

involved). The act ivity of equatorial esters 2b an d 14 an d

the enantiomer 25 was not greatly different from that ofcompound 13. Table IV summarizes these results.

Cocaine is known to inhibit the uptake of tritiated nor-

epinephrine (NE- 3H) by heart , brain, and other adrenerg-

ically innervated tissues. For determination of this type of

inhibition in heart tissue by some of the presently re-

ported compounds, these compounds were injected subcu-

taneously into mice. After 15 min, 1 pCi of NE-3H was in-

jected into the tail vein. After 2 hr the animals were sacri-

ficed, their hearts were incinerated, and the amount of

NE-3H therein was compared with that found in con-

trols.= Figure 1 shows the inhibitory effects of compounds

2a an d 15 and how they compare with cocaine and

desmethylimipramine (DMI). Compound 2a and DMI are

about equiactive and some 15 times more active than co-

caine.The role which various substances play in influencing

the normal action of norepinephrine in rat brain can be

studied by introducing tritiated norepinephrine (NE-3H)

directly into the lateral ventricle of the brain.l3 This pro-

cedure circumvents the blood-brain barrier to norepineph-

rine and allows the tritiated material to equilibrate with

endogenous stores. Thus, when a compound like cocaine

inhibits the absorption of norepinephrine by the neuron,

administration of the compound prior to the administra-

tion of the tritiated norepinephrine results in significantly

lower levels of radioactivity in the brain tissue as com-

pared to unmedic ated controls.

: . Le v i t t a n d W . R. Cumiskey, unpubl i shed me thod



Table 111. Effect of 3p-AryltropanecarboxylateEster s on Reserpine-Induced Ptosis in Mice

Prevention test Reversal testDose,Compd mg’kgip MPSa PVh MPS‘ PV” Overt behavior I2a 0.1

0.5

1

10

30

50

G.T.e

2b

5

6

11

12

13

30

50

H?O‘1

10

30

50

G . T . c

30

50

H20’0.1

0.5

110

30

50

H2OI

30

50

HzOf0.1

0.5

1

10

30

HZO’

23 110

30

50

25 30

50

27 30

50

H20Cocaine 1

10

30

50

HLO‘

H?O

H ? O J

2.6

2.1

1.4

0.75

3.1, .1

3.4

2.6

3 . 1

3.4

2.6

2.3

1 .6

3.3,3.3

3.1

2 . 9

3.4

2.6

2.2

3.4

3.4

3.4

3.4

2.5

2.1

1.4

3.4, .1

3O1.8

0.9

0.9

3.3, .1

3.1

3 O

3.4

3.5

3.1

3.3

3.5

3.4

2.9

2.4

3.6

NS0 .0380.000

0.000

NSNS

NSNS0.054

0.018

NSNS

0.064

0.030

NSNS

0.064

0.006

0.000

NS0.0060.000

0.000

NSNS

N SNS

NSNSNS0 .010

3 O

2.9

2.4

1.8

1.3

1.1

3.5, .4,3.3

2.6

2.5

3.4

3.3

1.8

1.8

1.8

3.3, .4

3 O

2.8

3.4

3.4

2.6

2.11.1

1.3

1.6

3.4, .5,

3.3

2.8

2.8

3.5

3.1

2.4

2.4

1.1

1.8

3.6, .3,

3.5

2.4

1.5

1.3

1 o3.3, .4

2.8

3 O

3.5

3.1

3.1

3.4

2.42.1

1.5

0.5

3.4

NSaNS0.038

0.002

0.000

0.000

NS

0.038

NS0,002

0.002

0.002

NSNS

NS0.064

0.0060.000

0.002

0.000

0.038

0.064

NS0.010

0.004

0.000

0.002

0.050

0.002

0.000

0.000

N SNS

NSNS

NS0 .0100.002

0.000

0.5 nd 1mglk g controls questionable stim,0.5 r; 10, 30, an d 50 mg/kg controlsstim, running, jumping, biting, squeak-ing, hyperexcitable a t 0.5 an d 3 hr; mildstim at 6 r; reversal 10, 0, nd 50mg ’

kg stim, running, biting, squeaking, vaso-

dilation, some salivation a t 0.5hr

30 an d 50mgi kg controls mild s tim , somebiting, squeaking; reversal, 30 an d 50

mg, kg, moving abou t a t 0.5hr10, 0, nd 50 mg ’kg stim, running, jump-

ing, biting, squeaking, tea ring, salivation,hyperexcitable a t 0..5 hr: moderate stima t 3 hr: reversal, 10, 30, nd 50 mg kg.stim, running, biting, squeaking a t 0.5 r;prevention, dead at 30 and deada t 50 mg ’kg before reserpine

10,30,nd 50mg kg controls stim, running,jumping, biting, squeaking, hyperexcit-

able at 0.5 an d 3 hr; mild stim at 5 hr ;0.5 an d 1 mg/kg control questionablemild stim at 0.5 hr

0.5 an d 1 mgtkg controls stim, running,jumping; 10 ,30, nd 50mg/kg stim, run-ning, jumping, biting, squeaking, somesalvation, still stimulated at 3 nd 5 hr ;reversal, 10, 0, nd 50mg/kg stim, run-ning, jumping, vasodilation, mild stimu-lation at 3 hr; prevention, 30 an d 50mgtkg, vasodilation

Stim, running, jumping, biting, squeakinga t 10, 0, an d 50 mg’kg; still stimulateda t 3 nd 5 r

No changes obsd at 30 an d SO mg kg

50 an d 100mg, kg controls excitement, con-vulsions; reversal, 50 an d 100 mg’kg,convulsions, complete recovery from reser-pine; at 100 mg kg 1 dead at 0.5 hr

‘I Mean ptosis score. * Probability values (PV) were calculated on “two-tailed” probabilities. Values of 0.05 are con-

sidered significant. ? Effect of compound alone unless otherwise specified as “reversal” or “prev entio n” tes t. i NS denotes“not significant.” 1 5 um t ragac anth mucilage controls. 1 H20 control.

Table V shows the results of such a study wherein grad-

ed doses of compound 13 were administered subcuta-

neously. Cocaine was run in parallel for comparison, but

higher doses of the latter were not practical owing to tox-

icity. 13 appears to be about 22 times more active than

cocaine and apparently crosses the blood-brain barriereasily. Whereas 13 an d DM I are about equiactive in the

mouse heart, 13 is about 20 times more active than D M I in

rat brain. This comparison is based on a report by Schild-

kraut. ~t a / , I 4 that 25 mgjkg of D M I caused a 30 f 3%drop in NE-3H concentration in rat brain.

Toxicity studies on compounds 2a an d 13 in mice gave

24-hr LD50 values of63 (48-53) and 7 1 ( 64 - i 8 ) mgjkg iv. re-

spectively, compared with 18 (17-19) mg/kg for cocaine.

Both of these 3-aryltropane s showed abou t the same oral

toxicity as th at of cocaine, the values being in the 200-400

mg/kg range. Fu rther indications of toxicity are containe d

in the notes on overt behavior in Tabl e 111.

Conclusions

Attachment of the benzene ring of cocaine directly to

carbon 3 of the tropane moiety produced strongly en-

hanced stimulant activity. Using structure 2a as a point

of reference, replacement of the N-methyl group by a hy-

drogen atom (23) or subs titut ion of a fluorine for hydrogen

in the para position of the benzene ring (13) enhanced



3 P - P h e n y l t r o p a n e - 2 - c a r ~ o ~ y l ~ csters

I 1 I I I I

0. 0.5 1.0 5.0 10.0 50.0mg/kg ( l og s c a l e )

Figure 1. Inhibition of NE-3H uptake in mouse heart.

Table IV . Local Anesthetic Activitv in Guinea Pies

No. Meanposi- anes- TAC:,, Ac-

Concn,b tive/no. thetic % tivityDrug. % test ed score (g/ml) ratioc

Cocaine

2a

Cocaine

2b

Cocaine

13

Cocaine

14

Cocaine

21

Cocaine

25

0.125

0.06

0.031

0 . 5

0.25

0.125

0.06

0.03

10.5

0.25

0.125

0.06

0.03

10 . 5

0.25

0.125

0.06

0.03

10 . 50.25

0.1250.06

0.03

10 . 5

0.25

0.125

0.1250.06

0.0310.5

0.25

4/4414

4/4

4/4

4 /4

414

4/4

4 4

4/44,f4

4/4

414

3/44 j 4

4/42/'4

4/4

4/4

3/4414

414

414

4/4

4/4

4/4

4/41/ 4

4/44/4

3/44/4

4/42/ 4

41

214

2/ 4

718

32

14

527

117

24

17

19

13

9

35

21

5

27

182

27

14

5

23

15

1

31

25

3

21

19

111

29

14.5

422

113

1.5

0.033

0.25

0.035

0.16

0.03

0.27

0.031

0.30

0.03

0.15

0.034

0.3

0.13

0 . 2

0 .11

0.10

0.2

0.ll

a Th e free base 2a was dissolved in dilute lactic acid fortest. T he remainder of the compounds were tested in theform of salts as listed in Table I. Cocaine was tested as itsHC1 salt. b The concentrations shown are those of saltsused except for that of base 2a. c Activity of cocaine = 1.

stimulant action even further. Other modifications of 2a

tended to diminish this activity. The enantiomer of 13

was not a stimulant. Removal of the ethylene bridge (9a)

also destroyed activity. Moving th e 2-carbomethoxy group

from an axial to an equatorial configuration gave a com-

pound (2b) which was inactive in the locomotor screen

Table V. Effect of Compound 13 and Cocaine on NE-3HConcentrations in Rat Brain

Dose, % reduc-mg/kg nCi/g of tion of

Compd (base) brain 1 S.E. NE-3H

13 2 1 5. 3 1 0 . 5 6 1

13 5 .3 5 .7 1 0 . 3 59

13 1 . 3 9 . 2 ~ k 0 . 7 33Cocaine 28.5 10.3 1 1.2 25

Control 13.7 3 ~ 0 . 5

( >256 mg/kg) but appeared to produce slight stimulation

as judged by th e operator of the ptosis test.

The general activity profile of these 3P-phenyltropane-

2P-carboxylic esters appeared to parallel that of cocaine.

Compound 13, the most broadly studied member of the

series, was about five times more active than cocaine in

preventing reserpine-induced ptosis and some 20 times

more effective in reversing it. Concurrently, the level of

local anesthetic activity dropped to about 15% of that of

cocaine. Finally, the inhibitory action of cocaine on up-

take of norepinephrine in adrenergically ennervated

tissues was observed with 2a and 13 in mouse heart and

rat brain, these 3-phenyltropanes being some 15-20 times

more active tha n cocaine.

Experimental Section**

General Method for 3P-AryltropanecarboxylicEsters. Thebest method for preparing these compounds became apparentnear the end of this work and is given in general terms here. Spe-cific details follow under the appropriate compound heading withadditional data in Table I . To an efficiently stirred solution of 1.0mol of the Grignard reagent in 1.0 1. of Et20 under NZ nd main-tained at -20" (rt3") was added a solution of 0.5 mol of ( - ) -

anhydroecgonine methyl ester in 300 ml of Et2O. Stirring wascontinued at this temperature for 1 hr and then the mixture waspoured onto 500 g of ice. This mixture was acidified with 2 N HC1to dissolve all solid and the Et20 layer was then separated anddiscarded. The HzO layer was made basic with concentratedNH40H and saturated with NaC1. Three extractions with Et20separated the product which was then distilled (0.4 mm). A

minor amount of unchanged anhydroecgonine ester distilled first,followed b y an unseparable mixture of the 2a- and 2$-carboalk-ox y isomers. The 2-benzoyl-3-phenyltropane by-products, exem-plified by 4a and 4b, remained in the still pot.

If isolation of both the 2a and 2P epimers was desired, the mix-ture of these isomers was chromatographed on silica gel (4 0 g /g ofcompound) using i-PrNHz-EtzO-pentane (3:30:67) for elution.The 2/3 epimer was eluted first. If only the biologically interesting2P epimer was wanted, the mixture was heated under reflux for 5hr with 4 vo l of acetone and 1.1equiv of EtI. Removal of acetoneand excess Et1 in uacuo and partition of the residue betweenEt20 and HzO gave the pure @ epimer in the Et20 layer and thequaternary salt of the cy epimer in the HzO.

Chromatography of the still pot residue above on silica gel af-forded the 2P-aroyl-3-aryltropane (such as 4a) as a quickly elutedmaterial and the 2u-aroyl isomer (such as 4b) as a more polarcomponent.

Compounds 2a and 2b were formed in 75% yield, bp 128-134"(0.4 mm). Epimers were separated by chromatography. 2ashowed M + 259; A (oil) 5.72 and 5.82 p ; A (KBr) 5.70 g;

nmr on HC I salt (10% in D M S O - d s i 'J2.3 = 6.5 Hz. 2b showedA (oil) 5.76 g; nmr on HC1 salt (10% in D M S O - d 6 ) 5 2 . 3 =

Compound 4a: E254 n m (EtOH) 11,200; A (KBr) 5.93 g; nmrJ I , ~nd52.3ca. 1.5 and 3 Hz but unassigned (axial benzoyl).

Compound 4b: e246 , (EtOH) 13,800; A (KBr) 5.97 F ; nmrJ2,3 = 11Hz,51.2 = 2 Hz (equatorial 2-benzoyl).3P-Phenyl-1u~,5u~-tropane-2/3-methanol5). A solution of

2.96 g (11.4 mmol) of 2a in 15 ml of Et20 was added dropwise

**Al l me l t ing points a re uncorrec ted . Nmr spec t ra were measured inCDC13 unless otherwise noted using T M S as an in te rna l s tandard . Wherewate r was used, the TMS was exte rna l . Brinckmann Ins t rume nts s i l i ca ge lgrade PFm was used in 1-m m thickness for preparative plate chromatog-raphy. Ana lyt ica l re sul t s for indicated elements are within *0.4% of th etheoretical values.

11-12 Hz, 5 3 , 4 = 5 .5 , 1 2 Hz.



with st i r r ing to 0.47 g ( 12 . 4 mmol) of LiAlH4 in 25 mi of Et2O.The mixture was s t i r r ed a t r oom t emperature for 2 hr , t r ea t edwi th 1 .1 ml of H20 , an d f i l t e r ed . Concent r a t ion of t he f i l t r a t e andrecrystal l izat ion of the residue f rom pentane gave 2.43 g ( 9 2 % ) oineedles, mp 94-96.5" . A l 'ur ther recrystal l izat ion f rom hexanegave 2.10 g of compound 5 of T a b l e I: ir (cc14) road O H bond at3231 cm

T h e ace t a t e e s t e r of 5 (A.c*O--pyridine, 1 hr. 100") was an oilwhose crystal l ine hydrochlor ide sa l t i s comp ound I 1 of T a b l e I .

4P-Pheny1-laH,5,H-tropane-Z~-rnethanol ( 6 ) . This a l coholwas prepared f rom 2b and LiAlH4 in the man ner descr ibed imm e-

dia t e ly above except t ha t t he cake r esul t i ng f rom hydrolys i s hadt ii be extracted thoroughly w ith CHCl3. Th e basic product wasrecrystal l ized to give compound 6 of T ab l e I: ir (Cc14) inglesharp peak a t 3648 cm in 0.001 M so l u t i o n .

The HCI sa l t of 6 i s descr ibed in Table I. T h e ace t a t e e s te r of' 6

(&&pyridine. 2. 5 hr . 100") was an oil whose crystal l ine naph-thal ene-1 ,5-di sul fonate a l t is compound 12 of' T a b l e I.

C o m p o u n d s 1.7 and 14. CuZC12 (7 mol 70) was used in thisprepara t ion . The r eact ion was run a t - 10". On a smal l sca l e t heywere separa t ed by th i ck- l ayer p l a t e chromatography ( s i l i ca gel ) .O n a large scale, epimer 13 was separa t ed f rom 11 by select ivequaterni za t ion of t he l a t t er wi th Et I .

C o m p o u n d s 15 a n d 16 . T h e u n sa t u r a t ed e s t e r was ad d ed a t 0'hut the react ion was al lowed to warm to 25' dur ing th e s t ir r ingper iod . Epimer s were d i s t i l l ed together and then separa t ed onsi l ica preparat ive plates. The st i l l pot residue crystal l ized andyielded compound 17. A r epeat run a t -20" wi th quenching a tt h a t t em p e r a t u r e g av e a 43.5% yield of the dist i l led mixture ot'esters 15 a n d If ; , bp 16&179" (0.8-1.5 m i .

C o m p o u n d s 18 a n d 19 . T h e s t an d a r d p r o ced u re g ave 38% re -covery o f s t ar t i ng mater i a l and 34 % of' t h e 18--19 mixture . bpl;iO-170" (0.5 m m ) . N m r i n d i ca t ed a 3: 1 rat io of 2tu:23 es t er s . Re-flux of t h i s mixture wi th 2 equiv of benzyl chlor ide in CHsCS fo r27 hr left most of the 26 ep i m er 18 u n c h an g e d ( 4 . 5 7 ~ ) .t was pur i -f ied f ina lly by p l a t e chromatography (n mr compat ib l e . NCH3.>2. p p m ; e273 111,1 1980, nII , 1810) nd th e oi ly base was used inthe prepara t ion of 20 wi thout fur ther charact er i za t ion .

The benzyl quaternary of th e 2c1 epimer was debenzyla t ed( P d I C c a ta l ys t plus I equiv of HCI in 95% E t O H w i th H2 u n d e r3 5 kg /cm 2) to g ive th e crys t a l li ne 2 r r epimer . Prepara t ive p l a t echromatography gave the analy t i ca l sample . compound 19 ofT ab l e I: n m r N C H 3 2 .3 9 p p m : c 2070. l Z X 0 1900.

C o m p o u n d 20. A solut ion of g (1 1methoxy es t er 18 in 25 ml(11 48% HRr was refluxed fo r 1 and chi l led. and the crystal l ine: l i f - im -hydroxyphe nyl ) - l~ \H .5 t rH- t ropa ne -23-c a rboxyl ic cid hydro-

hromide was col lected ( 3 . 6 2 g. 667~) ) .t was mixed with 80 ml ofMeOH and gaseous HC1 was bubbled in to sa t u r a t io n . T h e r e -sul t ing solut ion was ref luxed gent ly fo r 6 hr with a slow st ream of

H Cl pass ing through. The solvent was r emoved. concent r a t ed",OH was added. and the bas i c es t er product was ext r ac t edwith ethe r . Conversion of the oi ly has e t o it s HCI sal t gave compound 20 of T a b l e I .

I so p r o p y l e s t e r s 21 a n d 22 were prepared f rom the isopropylester ot' - ) - anhydroecgonine which i s descr ihed immedia t e lybelow.

( - ) - A n h y d r o ecg o n i n e I so p r o p y l E s t e r . A mixture of <'io p of

natura l ecgonine hydrochloride an d 100 ml of POC13 was refluxedfo r 1 hr and the excess POC13 was removed by warming in c a c u o .

The r es idue was t r ea t ed wi th 350 ml of i - P r O H an d l et s t an d f o r6.5 r . Removal of the solvent . basi f icat ion with 35% S a O H , a ndfourfr)ld ext r ac t ion wi th Et20 pave 45.8 g of oil . Distillation gave4% ( 9 0 % ) of product . bp 87-96" (0.8 m m ) . A center cu t furni shed

the analv t i ca l samole: I ( t l z 5 r ) -3:I.l" (1% in CHC13); n Z 5 ~.4860:( E t O H r W ! 7 : ir and ninr spec't ra uinipat ihle wi th struc-

t ur e . A n a / . ( C I Z H I ~ Z O Z ). H , S .

M et h y l 8-(2-Chloroethoxycarbonyl)-:3~-pheny~-la~,5~~~-nor-

t r o p an e - 2 d - ca r b o x y l a t e (8) . .1mixture of 5.40 g 12.08 m m o l ) otthe '-axial ester 2a a n d 4 . 3 mi (5.9 g. 4.16 mm ol) of 2-chloroethylchlorof'ormate was hea ted a t 100" for 1.25 hr . G as evolut ion ceasedaf t er 10 min. The excess chloroformate was removed b y warming~n L'acuo and the residual oi l in Et20 was percolated through 200g of' silica ge l . T h e 4 .8 g (65%) of oil in the first 400 ml of eluat eshowed a s ingle spot by t l c an d i t s spect r a ( i r and n mr ) werecomplet e ly compat ib l e wi th the s t ructure fo r t h e ex p ec t ed p r o d -i i ~ t . h i s mater i a l was used wi thout fur ther t r ea tmen t .

,Methyl :13-Phenyl-ltr~,5a~-nortropane-2a-carbox~late2 3 ) .

A11 solu tions and th e ap par a tus were f lushed with argon. Ast i r red solut ion l i t 10 ml of ( C H Z N H ~ ) ~n 800 nil of D M F wast r ea t ed wi th 100 mi (84m eq u i v i of 0.83 N Cr( ('104)2.6 The t em -perature rose tn 42". It was brought back to 25' a n d 4.80 g (1.36

not d i lu t ed out i n 0 .001 Msolut ion .

mmol ) of t he chloroethylure thane 8 in 20 ml of 1)MI; was ad d edThi s mixture was s t i r r ed fo r 2 hr , al lowed t o s t and overnight , andthen poured in to ice-water . ( ? jH4)2C 03 i10 g ) w as ad d ed an d t h eweakly basic mixture was extracted three lime5 a i i h ('HC'L3E t O H ( 2 : l ) . The ext r ac t s were t r ea t ed u i th an ex (and conce nt r a t ed to a past>- esidue by warm ing in L'

The pas ty r es idue wab t r ea t ed wi th excehs v o i d : .V SaOH L i d

t he prod uct was ext r ac t ed wi th EtzO. T he o i l c fht a inet ! f r o m i l i cext r ac t s was chromatographed on eight 20 x 4 0 c111 p r e p

i th d ev el op m en t h > i - P r S H 2 ~tz!)0.5g) f rom the pr incipal p r o t i u : . t k i ~ i

, compound 23 o t 'Table I .: ~ . j - ( p - F l u o r o p h e n ~ l ) - ~ ~ , t i , ~ ~ ~ H - t r o p a n ~ - ~ , j - ~ ~ ~tc id

( 2 7 ) .A solut ion of 1.23 g I :.,4 m m o l i of es t er 13 i n 6t i m i o t 2 V

H('i w as heated under ref lux tor 24 h r ant i concentratcci 1,o givi ii

crystal l ine residue. 'Two recrystal l izat ions f r om acr tont> nmishr~ !0 . 8 3 g o f c o m p o u n d 27ofTahlel.

3,1-Phenyl-laH,3~\H-tropane-2d-carboxylic cid (2X). .A st)lu-

tion (i t 1.6 i O . O l A mii l l h i t e> t r r 221 in 75 m i 01 2 ! H('1 s a + e.

f luxed fur 20 hr and concent r a t ed t i r a residual oi l b y warming in

I ' Q C U O . Tr i tur a t ion wi th acetone produced a solid which w as recrystal l ized to give compound 28 o t 'Table 1. N m r ( 5 % in I ) 1 0 )

showed the Ci hydrogen at 3.5 ppni wi th a pat t ern ! J s . ~ 12

H z. J3.4 an d J z . : ~ 6 an d 6 .5 Hz) uppor t ive of t he s t ructure 'is

signed.R eso l u t i o n of M e t h y l (*)-3-Oxo-lcur~,3[iH-tropane-2~~-carbox

y la te . Th e method of Findlay8 was used on his crude keto esterwhich. incidental ly. crystal l ized quickly and conipletely upon :i d

di t ion of 2 equiv of H20. In the or iginal precipi tat ion of hi tar t rntesal t only 1 .2 ni l (i t H2O was used for each gram I I ~eto ester dihjd r a t e an d t h e w a r n ] . h o m og en eo w m i x t u re was t w c i t v d 11 t : i l

charcoal before allowing the salt t t i c,r?-itallize. Slow civilin;: anti

lization trom a n equal weight ut ' H20 t hen gave adeqi t ar t r a t e d ihydra t e [ [ o ] ~ % )+lt i . l ' n i p 10cl IO:<' ( l i t .*

seeding g a v e an eaaii! fil tera ble mass ot n e r d l e s , O n e

L15 .1 ' . r n p S l - % ~ ' i ; nM% v i e id [ i l ' , rep i>ried , ' J ,Following isolation I$ riliighly an equal quant i t \ r,t the eniiri-

t ionier f rom the processed mother l iquors uhing ( .- 1-tarraric acid.the f i l t ra tes were brought t o p H 8 and thc r emaining bas i c i n a t e -rial was extra cte d with (. 'FICl;. Sh ilri -pa th distillation iii' t h i sbasic residue a t 0 , 2 nim using steam heal at fi ir ded wbsta nt i a l r ecover?. of white. crvstal l ine. unresolved keto ester which c o a l d hc

reprocessed.( + ) - M e t h y l ;i~t-Hydroxy-lLttx,3~tH-tropane-2ct-carboxyIate

[ ( + ) - P s e u d o a l l o e c g o n i n e M e t h y l E s t e r ] . A solut ion of 7 . 0 0 g

((i.O18:imol^ o i me t liyl I -- i - ~ ~ . ~ i ~ ( i - l ~ ~ H . ~ ~ ~ H - t r o p ~ n ~ -

( - ) - b i t a r t r a t e d i h y d r a t e i n 100 ni l 01' HzO was diluted \vir ti 20 0ml of HO.1i,.:t 1 . i ~ ( i f P t O ? \va>ar i t ied. a n d the ni ixturt i Ii\tir.o

genated a t room t em p e r a t u r e u n d e r $ .2 kr; c m 2 lor 1 9 h r . T h ecatalyst and solvent were removed and the residual oi l \sas t r ea ted with ( 'HC l3 and a x c ew of cold 35% XaOH. The aqileCJUSla>-er was ext r ac t ed t \ wi th CHClo a n d the cornhinrd CH('1,layers were concent r a t to g i v e an oil. 'I'hih oi l was tiissol\ ed i n

10 0 ni l of F:t2O. the solution was filtered to renit,p u n t \ . a n d t h e >ol\e n : \ \ < I - i1 ~ i [ ) o r u ~ ~ ii ' < i \ v iii

fied ( . l . i )5 g, 62.5% I .

T h i s 1+ -I1.~rutioalloec#c,nine m et h y l eb t e r w

twice frtJni h ex an e ( sm a l l am o u n t of insoli.tblee brcgive massive pr isnis: mp 82.5-84.5": [:,i2'1) +:M.2

ir c u r v e superinipcrsable o n t ha t 01 i t s en ant icimer: ninr peak:. all

peared in expected posi t ions3 b u ~hr coupl ing const ant s . ./2,.j =

3 4 Hz an d J3,* 2: :{ .1. 1 Hz, are !ower in ; .due tha n those x -pur red by Sinnema. r i i n ! . ? S u p p l e . et ai.,' t t r ibure thih to n t l a -

t en ing 01 the piper idine r i n g caused by t h e :3[,-OH gr oup . . A n d

(+ - A n h y d ro e c g o n in e M e t h y l E s t e r ( L n n a t u r a l ) . .I mixtur f .of' 15.7 g (0.079 m o l l of (+ ) - a l lopseudoecgonine methyl eht er 2nd

50 mi of POC13 w ab refluxed fo r 2. 2 h r an d co n cen t r a t ed t o ii re -sidual oi l b l- warming i n i w c u o . 'The oi l was poured o nto i ce andt he mixture made bas i c wi th 35% S a O H . T h e p r o du c t w as e x -t r ac t ed wi th two por t ions 01' Et20 an d four portions of CMC13 an ddist i l led, pract ical ly al l (8 .72 g. 6170) boiling a t 67-74" (0.1 m m i .A center cut showed n% 1.5011; [ C Y ] % +38.3" (1% in CH CI3) . ir

A 1712 ( C 0 ) n d 1 6 3 c m ( C = C , . A n a l . ( C I OH , d i O z i ( '.

H . N .

(C:nH1;S03) C . H. S .

t i \Vhen the ke to es t er was dissolved i l i dn Hz 0 -HOAr m i x t u w l i h i n g

hea t to a id d i ssolut ion, cons ide rable enol ace ta te was formed .: Recrystall ization r equire s a b o u t 12 m l of hexane lg h u t considerahi?.

m o r e hexane IS necessarv to exrrac t al l t h e product from t h e hroun pmv.der.



Sp-Phe ng lt ropane-2-carhoxg 11c Esters J o u r n a l of Medicina l C hernistr ) .. 197.7. Vol. 16. N o . I 1 1267

Compound 24. The s t andard procedure us ing phenylmag-nesium bromide an d (+) - anhydroecg onine methyl es ter (3) andno Cu s al t gave a mixtu re isomeric a t C-2: 42.6 g (72%); bp 129-135" (0.5-0.6 mm); isomer rat io 18:82 2 & 2 a (by vpc, 160" isother-ma l , OV -17) . Ref lux of the m ixture (0.16 mol) wi th 0.20 mol ofbenzyl chlor ide in 100 ml of CH3CN for 5 hr , addi t ion of EtaO,an d f i l t rat ion sepa rated most of the qua tern ary sal t of the 201-es t er . The f i l t r a t e was ext r ac t ed wi th 2 A HC1 and the ext r ac t swere made bas i c wi th concent r a t ed NH40H. Ext r ac t ion wi thEt a0 gave 8 .2 g (14%) of t he 2P-es ter whose 1 ,5-naphthalenedi sul -fonate sal t i s compou nd 24 of Ta ble I .

Compounds 25 and 26. CuzClz (6 mol %) was used in this reac-t i on . The t em peratu re was held a t 0 t o -5" dur ing addi t i on of(+) - anhydroecgonine methyl es t er and su bsequent s t i r r i ng . Theepim ers were sepa rated o n a si l ica gel column (50: l rat io) usingi-PrNHz-Etz O-pentan e (0.5:69.5:30) for elut ion.cis-l-Methyl-4-phenylpiperidine-3-methanol9b) . P l a t i , et

repor t a mixture of cis- a n d t r a n s - m e t h y l ( f ) - l - m e t h y l - 4 -phenylpiper idine-3-carboxylates f rom which they removed mostof what i s shown here to be th e t r ans i somer as t he HB r sa l t . Theenr iched cis isomer (Plat i 's 6 i somer) (10.6 g, 0.046 mol) was re-duced with LiAlH4 in the manner descr ibed for the preparat ion of5 above. The crude product was recrystal l ized twice f rom EtOActo give 6.12 g of ma ssive prism s: m p 99-100"; ir (CC14) broa d O Hband a t 3322 cm- l not d i lu t ed out i n 0.001.h' solut ion. .4nni.(C13H19NO) C, H, neu t equiv .

The acet a t e es t er of 9b (AcaO-pyr idine, 3 hr , 100") was a n oi l ,t he H Cl sa l t of which formed longp r i sms , mp 191-194" (CH3CN ) .

A d . C i S H z i N 0 2 . H C l ) C . H . C1.~ ~~

trans-l-Methy~4-phenylpiperidine-3-methanoll o b ) . T h e CY

isomer of methyl (f)-l-methyl-4-phenylpiperidine-3-carboxylate

repor ted by Plat i , et al.,9 (5.4 g) was reduced with LiAlH4 in themanner descr ibed for t he prepara t ion of 5 above. Recyrstal l iza-t ion of the product f rom EtOA c gave 3.9 g of pr ism clus ters, mp109- l l l " , which probably is t he same mater i a l as t ha t i somer ofunknown conf igurat ion repor ted by Plat i , et al .,9 with mp 107-109" . Th e present mater i a l showed a s ingle sha rp i r peak a t 3647cm-1 (nonbonded O H) in 0 .005 M solut ion (CC14) . The i r andnmr spect r a were comp at ib l e wi th the expected s t ructure .

T h e ace t a t e e s t er 1Oc of 10b (AczO-pyr idine, 2 hr , 100") was a noi l , the HC1 sal t of which formed needles, mp 213.5-215"

Biological . Th e s tudies on locomotor ac tiv i ty (Tab le 11),ptosisr eversa l an d prevent ion (Table I I I ) , norepinephr ine uptak e inhi -b i ti on in mouse hear t (F igure l ) , and acute t oxic ity were done

using male Swiss-Webster mice (2 0f

2 g) . Th e norepinephr ineuptake inhibi t ion exper iments on brain t issue were done withmale Sprague-Dawley s t r a in r a t s (220 f 20 g) and the local anes-thet i c det erminat ions were made on Har t l ey s t r a in guinea p igs(250-370 8) . When comp ounds were adminis tered as suspensionsin 1% gum trag aca nth, a volum e of 0.1 ml was given per 10 g ofanimal body weight .

For t he locomotor ac t iv i ty det erminat ions the compounds wereadmini s t er ed ora l ly as suspensions in 1% gum t r agacanth . Thelowest doses which produced an increase in locomotor act ivi tywere gauged by visual observat ion of a group of six mice at thevar ious dose levels beginning 30 min af t er medicat ion. The r esult swere conf i rmed with the aid of actophotometers.15

The ptosis prevent ion and reversal tests were done as descr ibedby Aceto and Harr is. l1 In Table I11 where the controls are record-ed a s G . T . (170gum t r agacanth) , t he compounds in f r ee baseform were given as suspensions in that vehicle. Otherwise, thecompounds were admini s t er ed in sa l t f orm in aqueous solu t ion .

( C H 3 C N ) .Anal. (C15HziNOz.HCl ) C, H , C1.

Each value for a mean ptosis score IMPS) represents observat ionof eight mice. Th e doses repor ted are in term s of the sa l ts whenused.

The local anes thet i c ac t iv i ty was measured by the in t r adermalmethod of Bulbr ing and Wajda us ing guinea p igs . The averagethreshold anes thet i c concent ra t ion (TACs) was obta ined f rom thedose-effect curve (semilogar i thmic plot of durat ion in m inutes us .

dosage) as described by Luduena and H oppe.16In the mouse hear t norepinephr ine uptake inhibi t ion exper i -

ments, aqueous solut ions of DMI and cocaine hydrochlor ides wereused, as was an aqueous solu t ion of compound 15.1 ,5-naphth-

alenedisulfonate. Com pound 2a was dissolved in lactic acid. Thedosage plot ted is that of the sal t used except for 2a which was afree base. Each point in Figure 1 r epresent s t he mean f S . E . o b -tained f rom six individual mouse h ear ts.

In the r a t br a in norepinephr ine uptake inhibi t i on s tudies ,aqueous solut ions of compound 13.1,5-naphthalenedisulfonate

and cocaine.HC1 were used. The compounds were administeredsc 45 min before int raventr icular inject ion of 1 pCi of NE-3H in aweakly acidic and buffered solut ion of 0.01-ml volume. The ratswere sacrificed 2 hr af t er t he N E-3H in j ect ion . Each value inT a b l e V represents the mean f rom six individual rat brains.Doses have been recalculated to a f ree amine basis.

Acknowledgment. We are indebted to M r. Harry Ben-

tley for technical assistance in the ptosis assays and t o Dr.

R. K . Kullnig and his staff for the physical measure-

ments.

References

(1) H. E. Zaugg, R. J . Michaels, and R. W. DeNet , J . Org.

( 2 ) I. Weisz, P . Agocs , M. Halmos, and K . Kovacs, Acta Chim.

( 3 ) A . S i n n em a , L . M aa t , A. J. Van der Gugten , and H. C.

(4 ) J. H . S u p p l e , L. IS. r idgen, and J. J. Kaminski , Tet r ahe-

(5 ) E . H a r d eg g e r an d H . O t t , Helu. Chim.A cta , 38,312 (1955).(6 ) J. A. Campbel l , J . Org. Chern., 22, 1259 (195 7); B. J . Calver t

a n d J. D. Hobson, J . Chem. Soc., 2723 (1965).( 7 ) H . L u x an d G . I l lm an n , Chern. Ber. , 91, 2143 (1958) ; J . K .

Kochi , D . M . Singleton, and L. J. Andrews, Tetrahedron, 24,3503 (1968) ; 3. K. Kochi and P. E . M o cad l o, J . Ame r . Chem.

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Chern., 23,847 (1958) .

(Budap est ) , 56 (2 ) , 195 (1968) .

B ey e r m an , Reel. Trac. Chim. Pays-Bas, 87,1027 (1968) .

dron Let i . . 1829 (1969) .

(8 ) S . P . F i n d l ay, J . Org. Chern., 22, 1385 (1957 ).(9 ) J. T . P l a t i , A. K . I n g b e r m an , an d W . W en n e r , ibid., 2, 261

(1957) .(10) J . W . Kissel in "Ant idepressant Drugs," S. G ar a t t i n i an d

M . N . G. Dukes . Ed . , Excerpta Medica Foundat ion , Am-ste rda m, 1967, pp 233-240.

(11) M . D. Aceto and L. S. Har r i s , Toxicol . A p p / . Phar rnacol . , 7 ,329 (1965).

(12) E. Bulbr ing and I . Wajda , J . Pharmacol . Exp. Ther . , 85 , 78(1945) .

(13) G. Mi lhaud and J . Glowinski , C. R. A c a d . Sei . , 255, 203(1962) .

(14 ) J . J . Schi ldkraut , S. M. ch an b e r g , G . K. reese. and I . J .

Kopin. Arner . d . Ps,vchiai.. 124,600 (1967) .

( l j )M . D. Aceto, L. S. Harr is, G. Y. Lesher , J. Pear l , and T. G .Brown. . J r . , J . Phar rnncoi . b xp . Y 'her. , 158,286 (1967) .

(16) F . P . L u d u en a an d J. 0. H o p p e , ibid., 04,40 (1952) .

clarke 1973 3beta-phenyltropane-2-carboxylic esters and analogs

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