Journal of Medicinal Chemistry, 2971, Vol. 14, AVO.9 895
NOTES methoxyethylamine and ethyl acrylate using a 3-step procedure described by Balyard and McElvain2 for the synthesis of Ialkyl-Ppiperidones. The intermediate N,N-bis@-carboxethoxyethy1)-p-methoxyethylamine boiled a t 111' (0.05 mm). The last 2 steps, the cyclization and decarboxylation, were done consecutively without isolation of the intermediate 3-carbethoxy-l(Z-methoxyethyl)-4-piperidone. The final product, a colorless liquid, boiled a t 72-73' (0.5 mm). Anal. ( C ~ H I ~ NC, O H, ~ ) N. CY- [l-( l-Alkyl-4-piperidylamino)alkyl] benzyl Alcohols (3-11). -KaBH4 (0.125 mole) was added in small portions over 2 hr to a stirred mixt of dl-a-( l-aminoalkyl)-4-hydroxybenzyl alcohol. HCl (0.025 mole), KOH (0.025 mole), and 1-alkyl-4-piperidone (0.177 mole) in 100 ml of MeOH. The reaction mixt was maintained a t about '5 by means of a n ice bath during the addn. After the addn the mixt was stirred for 1 hr at 20" and then acidified to pH 4 with 4 S HC1 in EtOH. The mixt was filtered to remove pptd inorg salts and then evapd to an oil. The residual oil was triturated with boiling i-PrOH. The resulting white cryst prod was filtered off and recrystd (see Table I). a- [ 1-(4-Piperidylamino)alkyl] benzyl Alcohols ( 12 and 13).A soln of CY- [( 1-benzyl-4-piperidylamino)methyl]benzyl alcohol. 2HC1 (4 or 6 ) (0.085 mole) in 125 ml of aq 807, EtOH was hydrogenated for 6 hr a t 3 atm using 5 g of 10% Pd/C as catalyst. The catalyst was removed by filtration, and the filtrate was evapd. The residue was recrystd (Table I ) . Pharmacology Assay Method.-The test substances were assayed in anesthetized dogs on the vascular bed supplied by the carotid artery. I n this prepn a constant flow (peristaltic) blood pump was interposed between the proximal and distal segment3 of the right carotid artery. Prior to drug treatment blood flow rate was set to result in a mean perfusion pressure approximately equal to systemic arterial blood pressure. Perfusion pressure was measured distal to the pump. Drug injections were made into the blood stream distal to the pump. Vasodilation was indicated by a decrease in perfusion pressure. Potency comparisons with papaverine were determined from plots of log molar dose us. decrease in perfusion pressure. I n this assay isoxsuprine was approximately 10 times more active than papaverine. The results reported in Table I are based upon the arbitrary assignment of papaverine potency a t 100. (2) N. (1929).
W.Bolyard and 9 . M. McElvain, J . Amer. Chem.
Soe.. 51, 922
Absolute Configuration of the Optical Isomers of Salbutamol D . H.IRTLEY*A N D D. bIIDDLEMISS
Chemistry Department, Allen and Hanburys Ltd., Ware, Hertfordshire, England Received March 2, 1971
The synthesis and biological properties of t'he psympathomimetic amine, salbutamol (4) , have been described.' This compound is more selective for pz receptors than previously known drugs and therefore it was of interest to test each enantiomer to ascertain if the activity resided mainly in t'he ( R ) - (- ) configuration as is the case with other drugs which act' a t adrenoreceptom2 Attempted resolutions of salbutamol, or any phenolic precursor, were unsu~cessful.~However, when the phenolic group of the intermediate ester 1 was protected as the benzyl ether 2 then resolution was efficiently achieved with eit'her (+)- or (-)-di-p-toluoyltartaric acid. In each case only one isomer formed a crystalline (1) D. T. Collin, D. Hartley. D. Jack, L. H. C . Lunts, J. C. Press, A. C. Ritchie, and P. Toon, J . Med. Chem., 13, 674 (1970). (2) R . B. Barlom, "Introduction t o Chemical Pharmacology," Methuen and Co., London, 1964, pp 282-343. (3) Similar difficulties in resolving phenolic amines have been described see A. Brossi, J . O'Brien, and S. Teitel, Helu. Chim. Acta. 52, 678 (1969).
/CH, Ph 'CMe3
l,R=H 2, R = PhCHz
0
HOCH, /
GHOHCHJ
R,O\
2
C'
1
Me3
3, R, = PhCHI 4,R,=H
salt and the antipode was recovered from the mother liquors in good yield and reasonable optical purity. Seutralization of the purified salts liberated the resolved bases 2 which on reduction with LAH follon-ed by catalytic debenzylation gave the required isomers 4. The (+) and ( - ) forms were both characterized as their acetate salts. The p-adrenoreceptive activities of these isomers were compared with those of the racemic compound on the PI receptors4 of the isolated atria of the guinea pig and on the receptors4 of the intact trachea of the guinea pig (Table I). I n the latter test5 the (-) isomer was apTABLE I BIOLOGICAL ACTIVITY OF
THE
-------Biological Trachea Compound
(P?)
ES.\NTIOMERS O F
S.ILHUT.\hIOL
testa------Left atrium Right atrium (131)
(131)
1,000 Racemate 4.3 1.5, OOOb 10,000b ( - ) Isomer 6.6 15,OOOb 100,000* 423 Inactive (+ ) Isomer a These results represent the ratio of the amount of drug required to produce an equivalent response to a unit of isoprenaline. * Denotes partial agonist activity.
proximately equiactive with the racemate and SO times more potent than the (+) isomer. A similar pattern was shown in the much weaker effects on the force of contraction of the electrically driven left atrium.6 However, both isomers were much less active than the racemate in increasing the rate of contraction of the spontaneously beating right a t r i ~ r n . Although ~ this result has been verified on several occasions, the very low order of activity precludes any useful interpretation of t'he apparent synergism in the racemate.8 Comparison of t'he C D spectra of the salbutamol isomers with that of ( E ) - (-)-octopamineg showed that (-)-salbutamol had the R configuration. Both levorotatory compounds showed a clear negative Cotton effect at 276-280 nm. At lower wavelengths, 220230 nm, the curves t'ended toward a further negative peak although this is somewhat masked by the high aromatic absorption. (4) (a) A . M. Lands, A. Arnold, J. P. McAuliff, F.P. Luduena, and T . G. Brown, Jr., Nature ( L o n d o n ) , 214, 597 (1967); fh) A. M. Lands, F . P . Luduena, and H. J. Buzzo, Lrje Sei., 6, 2241 (1967). (5) For pharmacological method see J. B. Farmer and R . A . Coleman, J . Pharm. Pharmacol., 22, 46 (1970). ( 6 ) For pharmacological method see J . R . Blinks, J . Pharmricol. E z p . Ther., 161, 221 (1966). (7) For pharmacological method see J. W.Biack, W. .4.h l . Duncan, and R . G. Shanks, Brit. J . Pharmacol. Chemolher., 25, 577 (1965). (8) A more detailed pharmacological evaluation of these isomers will he submitted for publication elsewhere by J. B. Farmer and R . J. Marshall. (9) (a) V. Erspamer, Nature (London), 169, 375 (1952); (b) T. Kappe and hf. D. Armstrong, J . M e d . Chem., 7 , 569 (1964).
896 Joitrnal of Jledicinul Chemisfry, 1971, Vol. 14, S o . 3
Experimental Section
SOTES
Research Institute, Yellow Springs, Ohio, for the sample
of ( R ) - (-)octopamine, and to Professor W. Klyne lleltiiig points were determined oii a AIettier FP 1 apparatu. :uitl the microanalyses on an F and 11 18.5 C, H, and N analyzer. arid Dr. P.11. Scopes of Westfield Coliege. London, for JVhere :mil. are indicated only by the symbols of the element-. CD determinations and valuable discussions. : t i i d . vnlites obtained were within 4 ~ 0 . 4 ~ of; the calcd values. Compd.: gave satisfactory uv, ir, and nmr spectral dxta obtained, rehp, on Perkin-Elmer 3Iodel 137, Cnicam SP 100, arid \.ariati Awc.i:ites AGOX spectrometers;. Optical rotation5 -n-ere meaYured in AIeOH :it, 23'. Circular dichroism curve; were 1ne:LSynthesis and Local Anesthetic Activity hitred in JIeOI1 :it 2.7" with a lioussel Jouan Ilirhrogrnph 185 :itit1 :ire expressed iit mol ellipticity uiiith [el. of N-Diethylaminoacetyl Derivatives Methyl 5 - !2-(Benzyl-fert-butylamin0)-1-hydroxyethyl] -2-benof Naphthylalkylamines compoiiiid \va> prepared by colizyloxybenzoate (2).-This deiisitig rrie\hyl '-he ~ l o x y - ; , - h r o n i o a c e t ~ l b e i i ~ ~with ~ a t e ~t e r f 1~iityll)eiizylamirrei i i CO1Ie nut1 rediiciiig the cntde prodt:ct with X:il3II: i i i 1:tOFI by the g e n e d procedure> already debc,iilied.l The prodiict, mp 96' [from CeHG-petr ether, (bp 60icO"'l, W:IS o i ~ t t li r i 4:3( yield f i u m the bromo ketotic. A n u l . I c.,irl,xol) c, fr, s. Resolution of Methyl 5- [2-(benzyl-tert-butylamin0)-1-hybenzy1oxybenzoate.-The racemic eiter (30 g, d ( - !-di-p-toliio?-lta~t:~ri(~ arid (25.6 g, 0.064 mole)1a Our finding' that some a-n:~phthyl:tll;ylamines pos1 nil! :it 70" were :illowed t o c*ool to room temp t o i-niethyl .T- [2-t)enxyl-t/r~-t)tityl~iiiiitio)-l-ti~di[)xy- sess marlied local anesthet'ic activity has led us to synC t hyl] - ~ - t ) e l i ~ ~ ~ l ~ ~ S t ) (Cl l) ~- d ( ~ J -~ ~~-~t O ( ~~ ~ l O I ' thesize an extensive series of l\T-diethyiaminoacet~-l g ; nip I:j0.9': [.]I) -48' i c 1 . 0 ) . TWJrec derivatives of iiaplith?-lalliylamiIles; of the general gave i i i n t e h l o f c,oi!ytaiit nip and t,otatioii: structures 1-111, in u-hich R w ~ H, s or alkyl, or amino[ m i l ) -47" (C 1.31. Ann!. fC4,If:lSOyj C, 11, K, alkyl; IZl was SHCOCH2SEt2or CH2SHCOCH2SEt2; i i I.:tO.l(. iva,. estd sever;il times with SaHc'O3 S A d was n tertiary amino group; 7i = 2-4. 11,> uiid filtered through :I ~ t i i s l lquanti he e1u:tte was evapd uiitlei reduced pre. :itid h e re4tliie crystd from pew et,her fhp 60-iiO") t u give A-. ( ;-I2 I :is cwlorless needle.: 4..i g ; nip % i n[ c y,; I) t 18.:3' I c / \ I).:i:J1. .i?LtI/. ( ~ & ~ ~ 3 , c, j If, ~ ~ ?;. ~ 4 ) ( It)-(+ ) - a ' - ( Benzyl-ic,~t-butylaminomethyl)-4-benzyloxy-m-a,a'-diol (3).-:1 ~ l i ofi (X)-( + ) - ( 2 ) (2..i g, 0.003 mole) TIIF (2.5 1111) \KIA added with .tiiring t u LAH (O..i g, 0.0123 iti dry TlIF i.i0 mi). T h e niis! wac heated to reflux arid tlieii cooled, :uid the exc>e.dride w:~. tlecompd by cautious :idtlii of I I 2 0 . The TI-IF solti i. filtered through Hyflo, and the -(ilvciit w : i ~removed under r iced preo+ure. The residue wa? I, substituted a t position 1 I11 tii-.olvetl iii IICt,O, dried iAIg8Or), and evapd t o give the diol a i a 11. substituted a t position 2 coloi1e+, [ n ] u -8.18" ( c 0.4%). A n a l . jC27H33S03'~ C, H, N. I I~-drogeti;i~iori of ( S ) - [ ~ -)-(3) theti gave ( S ) - i + )-salhutamol n-hich w:i7 purified R C its acetate i d t ) mononiethaiiolate: inp 1 4 , i . i ' : [..]I) +36.0" i c 0.2::); CII IC(I.%:-;) [B]?so 0 , [ 8 1 2 7 5 +683 f 1 i i x ) , [e]io0 . r l t m i . (CI6Hl9SO6j C, If, X .
(+
Acknowledgrnent.-TT-e
thnnli our colleagues Dr. J.
Huiit :~ndhis staff for the analytical and spectral data, a n d Di,. 11. T. Brittain and his staff for the results of the, pharr~iacologicaltests. W e are particularly grateful t o 1\11., A\I,T. Iliiviw of B D H (Research) Ltd., London, for t l i c ~optical rotatioris, Dr. 31. D.Arnistrong of the Fels 110) F ~ . u n i( + ) - i o r t a r i r acid see ( a ) .)1 -1,.i. I i i d d , J . Chrm. S o c . , 4675 c l i ) .\. Sroll and . 1 rnann. H e l r . Ciiim. Acta, 2 6 , 022 (1043). ' 1 1 ) 1 r o n i ~ - - : - t ; ~ r t a r ~ ~ SPP ,J. IT. ITunt, .I. C k e m . Soc., 1926 11957).
(l!J(il);
Experimental Section2 The intermediate amines were prepd as previously described.,: The S-diethylaminoacetyl derivatives of naphthylalkylaminesare listed in Table I, and tneir prepn is well illustrated by the following example. -Y- [4-Diethylaminoacetamidomethyl-4-( ~~-naphthyl)-5metkylheptyl]piperidine (38).-A4 solu of (BrCH2C0)20(14.33 g, 0.055 mole) in CHCI, (30 ml) was dropped at .iinto oa stirred s o h of S-[4-aminomethyl-4-( a-naphthyl j-5-methylheptyll piperidine (15 g, 0.042 niole) and AcOH (2.56 g , 0.042 mole) in CHCh (50 ml). The mixt was stirred for 1 hr at room temp, poured into excess Etr" (44.6 g), and stirred for an addnl 1 hr. The > o h was then evapd to dryness, and the residue was taken n p in EtlO, washed (H,O), and dried (R/IgS04). The solvent was evapd and ~~
(1) S.Casadio. G . Pala, T. Rruzzese, C . Turha. and E . Marazzi-Uberti. J . .\Id C h e m . , 1.9, 418 (1070). (2) hfelting points are corrected and iiere taken on a Ellchi capillar3- melting point apparatus. (3) G. Pala, A . Donetti, C. Turba. and 5. Casadio, J . M e d . Chern,. 13, 668 (1070).
