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 n 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).
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 9 897
NOTES
TABLEI PHYSICAL PROPERTIES A N D Locar, ANESTHETIC ACTIVITY OF N-DIETHYLAMINOACETYL DERIVATIVES OF NAPHTHYLALXYLAMINES Local anesthetic act. Compd
RI
R
Struo-
Yield,
ture
%"
(mouse), M P , '(2
60 I 57 7 85 NHCOCHzN (C2H;)2 H 50 I 19 180 NHCOCH~N(CZH& GC3H7 40 I 36 90 C H ~ N H C O C H ~ ( N C Z H ~ I Z H 60 100 $53 I CH2NHCOCH2N (CZH:)~ CHI 80 110 I 37 3 C H ~ N H C O C H ~ (C2Hs)z N 5 CzHs 30 130 I 48 2 C H ~ N H C O C H ~(CzHs)% N n-C3H7 6 70 14: 46 I C H ~ N H C O C H ~ N ( C Z H B ) Z i-C3H7 7 10 110 48 I CH2NHCOCHzN(CzHs)2 n-C4Ho 8 60 120 45 I CH~NHCOCH~N(CZH;)Z i-CaHs 9 60 140 55 2 I CH~NHCOCH~N(CZH;)~ sec-CaHo 10 30 120 12 6 I C H ~ N H C O C H ~ K ( C ~ H ~ ~ 11 (CH3)zN(CH2)2 80 143 34 6 I CH~NHCOCH~X(CZH:,)Z i-C3H7 12 60 148 I 46 CHzNHCOCH2N(C2H>)z sec-CdHQ 13 30 103 40 6 I CH~XHCOCH~N(C~H;)~ 14 i-C3H7 30 135 64 5 I CH~NHCOCH~N(C~H:)~ 15 SCC-C~H~ 60 235 39 8 I (CzHs)zX(CHz)z CHzNHCOCH2N (C2Ha)z 16 20 125 31 4 I CH~NHCOCH~N(C~H& n-C3H7 17 80 150 64 I CH~NHCOCH~N(CZH~)Z i-C3H7 18 30 130 66 I CHzNHCOCHzN (C,Hs)2 19 n-CaH9 30 145 I 38 8 CHgNHCOCH2N(CzHs)z 20 i-CaHo 10 135 59 4 I CH~NHCOCH~N(C~H~Z 21 sec-CpHo 90 110 66 1 I CH2NHCOCHzN(CzHs)z 22 H so 140 Fj3 6 I CH2SHCOCH& (CzHd)2 23 CH3 80 150 36 I CHzNHCOCHzN ( C Z H ~ ) ~ 24 C2Hs 40 160 75 I CH~NHCOCH~N(C&), i-C3H7 25 40 160-162 60 2 I CHzNHCOCHzN (C2H:h 26 i-CaH9 90 140 67 6 I CH~NHCOCH~N(CZH:)Z sec-CaHg 27 90 24,i 63 5 I CHzNHCOCHzN (C?H:)2 e 28 80 105 55 3 I CH~NHCOCH~N(C~H& H 29 30 160 45 I CHzNHCOCHzN (CzHs)? 30 CHI 90 160-163 I 76 CHzNHCOCH2N (CPHD)? 31 CiHs 50 170 I 79 CHzNHCOCHzN(C2Hj), i-C3H7 32 0 155 72 2 I CH2NHCOCHsN (CzH5)z i-C?Ho 33 60 130 30 I CHzNHCOCHzN (C*Hs)z SCC-C~H~ 34 10 85 32 I 35 (CH3)2N(CH2)3 CH2XHCOCH2X(CJL)2 20 95-100 70 I C H ~ N H C O C H ~ N ( C ~ H B ) Z sec-CaHo 36 80 140 61 2 I CH,NHCOCH,N ( C Z H ~ ) ~ i-CBH7 37 70 110 77 I CHzNHCOCHJV(CzH:)2 sec-C4Ho 38 10 140 66 I CHzNHCOCH&'(C2Ha)2 sec-C4Ho 39 70 130 31 7 I CHzNHCOCHzN (CZHBIZ s~c-C~H~ 40 60 110 58 7 I CH~NHCOCHZN(C~H& 41 i-C3H7 10 125 I 50 8 CH~NHCOCHZN(CZH:)Z 42 sec-C4Hg 30 109 31 5 I CH2NHCOCHJV"CzHb)z i-CBH7 43 10 155-160 76 4 I CHZNHCOCHzN ( C P H I ) ~ 44 SCC-C~H~ 30 100 IT 47 5 CHtNHCOCHJ'J(C2H:)2 45 i-C3H7 100 130 71 I11 CH~NHCOCHZN(GH~)~ 46 i-C3H7 30 129 74 2 I11 CH2NHCOCH2N(CzH5)z 47 sec-C4Hp 100 Lidocaine. HCl b All compounds were dihydrochloride salts except where noted; they were analyzed for C, H, N and the a Crystallized product. anal. values were within +0,4% of the theor values. c The compounds were tested subcutaneously a t a concentration of 10 mg/ml [C. Bianchi, Brit. J . Pharmacol., 11, 104 (1956)l. d 2-(l-Pyrrolidinyl)ethyl. e 2-Piperidinoethyl. 2-Morpholinoethyl. 0 3-(l-Pyr3-RIorpholinopropyl. 1 4-(1-Pyrro1idinyl)butyl. 4-Piperidinobutyl. 1 4-hlorpholinobutyl. rolidiny1)propyl. 3-Piperidinopropyl. Trihydrochloride salts. 1 2 3 4
$'
the new residue was distd to give 15.8 g of 38 as a viscour and colorless oil, bp 220-224' (0.1 mm), which was converted with dry HCI in EtzO into a cryst hydrochloride, mp 110'.
R. Perego for performing the microanalyses, Rfr. G. Bietti for assistance in preparing the COmPOUndS, and Miss C. Bacci and Miss L. Tomasi for carrying out the pharmacological tests. "
Acknowledgment.-The
authors wish to thank Dr.
_
