Synthesis and analgesic properties of N-substituted trans-4a-aryldecahydroisoquinolines - J. Med....

8/4/2019 Synthesis and analgesic properties of N-substituted trans-4a-aryldecahydroisoquinolines - J. Med. Chem., 1988, 31

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J. M e d . C h e m . 1988,31, 555-560Synthesis and Analgesic Properties of N-Substitutedtrans-4a-Aryldecahydroisoquinolines

555

De nni s M. Z i m m e r m a n ,* B u d d y E. C a nt r el l , Joh n K. S wa r tz e ndr ube r , Noel D . Jone s , La ur a G. M e nde l sohn ,J. Da vid Le a nde r , a nd R o dne y C . N ic ka nde rL i l l y R esearch L abora tor ie s , E l i L i l l y and Com pan y , L i l l y Corpora te C en t er , I nd i anapol i s , I nd i ana 46285.Received June 12, 1987

A respresen tative series of N-substituted derivatives of the morphine-based trans-4a-aryldecahydroisoquinolinewere synthesized and evaluated fo r opioid analgesic activities. Compoun ds with pote nt analgesic activity and highaffinities for th e ~1 an d K opioid receptors were discovered. The effect of varying the N-s ubstitue nt in the t rans-4a-aryldecahydroisoquinolinearalleled, to a certain extent, previous findings with other morphine part structures.Replacement of the N-methyl with a phenethyl group significantly increased analgesic potency. Th e N-cyclo-propylmethyl analogue wa s found in rod ents to have mixed agonist-antagonist properties; however, its antag onistactivity was far weaker than those reported for th e N-(cyclopropylmethy1)morphinan nd -benzomorphan derivatives.Resolution of the stereoisomers and determination of their absolute configuration by X -ray crystallography showedthat th e opioid receptor effects were predominantly found with the 4aR,8aR isomer, the same relative absoluteconfiguration of morphine. Unexpectedly, the 4aR,8aR N-cyclopropylmethyl analogue (compoun d 30), which inroden ts had mixed agonist-antagonist propertie s similar t o those of pentazocine, was found in rhesus monkeys tobehave as a full morphine-like agonist.One ap proa ch for the discovery of new ana lges ics has

been to synthesize portions of the mo rphine molecule andunder take s t ruc ture -ac t iv i ty re la t ionship s tudies wi ththese par t s t ruc tures . In genera l th is s t ra tegy has beenqu ite successful, leading to t he d iscovery, for example, ofthe m or ph ina n ' a nd be nz om or pha n2 se ri e s. Whi l e i t i sbe l ieved th a t the new m orphine-based s t ruc tures wil l r e -tain signif icant analgesic activity, of ten the overall anal-gesic prop erties of th e new series vary especially in regardto heir relative agonist and antagonist activities an d theirreceptor se lec tiv it ies . The se di f fe rences have led to th ediscovery of opioid analgesics with improved clinical use-fulness.One m or ph ine pa r t s t r uc tu r e th a t ha s r ec eived l i t tl ea t t e n t ion i s t he trans-4a-aryldecahydroisoquinoline,3which, as seen in Figure 1,has a c lose re la tionship to boththe m or ph ina n a n d the be nz om or pha n s t ruc tu re s . P r e -viously we have descr ibed a d i rec t approac h for th e syn-thes is of the decahydroisoquinol ine s t ruc ture and ana-logues of it.485 We now repo r t the sy nthes is an d phar -macological ac tiv i ty of a nu mber of N-sub st i tu te d trans-4a-aryldecahydroisoquinolines.Th e op io id r e c e p to r a f-f inities are discussed, an d the structure-activity relation-ships observed wi th th is new ser ies a re comp ared to tho sealready reported for the m orphin an and the benzomorphanseries.Chemistry. We have recent ly descr ibed a h igh-yie ldfive-step synthesis to th e trans-aryldecahydroisoquinoline1 f rom the N-ethyltetrahydropyridine3 (Scheme I).6 T h esynthe t ic sequence involved the use of the m eta la ted en-a m i n e 4 to genera te th e bicycl ic enamin e 5. C o m p o u n d5 was electively reduced to th e trans-isoquinoline 6, whichw as N - d e a lk y l a te d by u s in g v i ny l c h l o r ~ f o r m a t e ~ia th e(1) Hellerbach,J.; Schnider, 0.;Besendorf, H.; Pellmont, B. Syn-thetic Analgesics, Part II a, Morphina ns; Barton, D. H. R., vonDoering, W., Eds.; Pergamon: New York, 1966.(2) Eddy, N. B.; M ay, E. L. Syn thetic Analgesics, Part IIb, 6 ,7 -Bentomorphans; Barton, D. H. R., von Doering, W., Eds;Pergamon: Ne w York, 1966.(3 ) Weller, D. D.; Rapoport, H. J . A m . C h em . S O C . 976, 98,6650-6657 and references cited therein.(4) Evans, D. A.;Mitch, C. H. ; Thomas, R. C.; Zimmerman, D. M.;Robey, R. L. J.A m . Chem. SOC. 980,102, 5955-5956.(5) Zimmerman, D. M.; Robey, R. L. U.S. atent 4 236009,1980;Chem. Abstr . 1981,94, 121345t.(6) Zimmerman, D. M.; Cantrell, B. E.; Reel, J. K. ; Hemrick-Luecke, S. K.; Fuller, R. W. J . Med. Chem. 1986, 29 ,1517-1520.

vinyl formamide 7. Use of the N-ethyltetrahydropyridine3 in th is sequence over the N-m ethy l ana logue 2 is urgedbecause compound 2, which is the 3-methoxy der iva t iveof th e parkinsonism-causing agent MP TP,8 was found , likeM P T P , to be h igh ly ne ur o tox ic. 6 Howe ve r, t he N - e thy lM P T P d e ri va ti ve 3 was not neurotoxic in mice even a tdoses 8 t imes those of MPTP.6T h e methylisoquinoline 8 was synthesized by reductionof the vinyl formam ide 7 , a nd the e na n t iom e r s of 8 we r esepa rated by fractional recrystall ization of their mandelicac id sa l ts . An X-ray c rys ta l s t ruc ture de te rmina t io n of 9as its D-mandel ic sa l t revealed th a t com pound 9 , the (+)isomer, has the 4aR,8aR absolute configuration. Trea tme ntof the trans-(3-methoxyphenyl)isoquinolines 1an d 8-12)with HB r in acetic acid gives th e 3-hydroxy derivatives inhigh yie ld . Th e N-su bst i tu ted decahydroisoquinol inederivatives 19 were prepare d either by alkylation w ith anappr opr ia te ha l ide or by acyla tion wi th an ac id chlor idefollowed by reduc t ion of the result ing amid e . Th e com-pound s ob ta ine d f rom 18 a l l ha d the (-) optical rotationan d th e 4aR,8aR configuration, which is the sa me relativeabsolute conf igura t ion found in morphine .X-ray Analysis of Compound 9. C om poun d 9 c r ys -tallized from 2-propanol/acetone/water s colorless prismsin the space group P222, Z = 4, with u nit cell dimensionsof a = 6.831 (5) A, b = 17.681 (12) A, c = 20.456 (14) A.T h e c a lc ul at ed d e n s it y w as 1 .2 03 g ~ m - ~ .total of 1973unique ref lections with 20 less tha n 116.0 were measu redon an auto mat ed four -c i rc le d i f f rac tometer us ing mono-chromatic copper radiation. T he structure was solved byu s i n g t h e R a n d o m T a n g e n t m e t h o d ( R A N T ) of t h eSHELXTL program library (G.M. Sheldrick, 1981) and wasrefined by the least-squares meth od w ith anisotropic tem-pera ture factors for all a toms except hydrogen. Hydrogenatom s were included with isotropic temper ature factors atcalculated positions. Th e fi ia l R factor was 0.0747 for 1571observed ref lec t ions . F igure 2 shows an OR TE P plot ofthe molecule .Pharmacological Results

Th e analgesic activity of these compounds in the m ousewrithing a nd th e rat tail heat tests is given in Table I. T h eprocedures for these tes ts have been previously d e~ cr ib ed .~

(7 ) Olofson, R. A,; Schnur, R. C.; Bunes, L.; Pepe, J. P. Tetrahe-dron Let t . 1977, 1567.( 8 ) Markey, S. P.;Schmuff, N. R. Med . Res. Rev. 1986,6,389-429.0022-2623/88/1831-0555$01.50/0 0 1988 American Chemical Society


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556 Journa l of Medi c i na l Chemi s t ry , 1988 , Vol. 31 , N o. 3 Z i m m e r m a n e t a l.Tab l e I. Structures of the 2-Substituted trans-4a-Aryldecahydroisoquinolines nd Their Activity in the Mouse Writhing and the RatTail He at Analgesia Te sts

R'Q

mouse writhing: rat tail heat:compd isomer R, RZ EDSO,"w/k , c EDz,,,,* mg/kg, sc3.5 (2.1-5.8) 8.8 (3.0-15.6)1.2 (0.9-1.5) 3.3 (3.0-4.0)0.5 (0.5-0.6) 0.4 (0.3-0.5)2.1 (1.1-3.1) 1.6 (1.1-2.1)14 (+ I OH CH3 0.4 (0.3-0.5) 0.3 (0.2-0.3)20 OH CH&H=CHZ 1.0 (1.0-1.3) 1.4 (0.9-1.8)22 (+ I OH CHzCH=CHz

19 (*I H CH38 (ht) OCH, CH313 (*I OH CH315 (-1 OH CH321 (-) OH CHzCH=CH,23 (*I OH CHZCH, 18.2 (15.8-20.9) > l oo25 (+ I OH CHzCH326 OH CHZCHZCH, 1.5 (1.1-1.9) 1.3 (0.8-1 .7)27 (-1 OH CHZCHZCH,29 (*) OH CHZ -C-C~H, 3.3 (2.4-4.5) 5.6 (3.9-7.4)30 (-1 OH CH ,,C -C ~H , 2.2 (1.8-2.8) 3.0 (1.9-4.3)32 OH CHZCH=C(CH,)z 1.0 (0.8-1.3) 1.5 (0.9-1.9)33 (.t) OH CHzCHzPh34 (-1 OH CHzCHzPh35 (+ I OH CHZCHzPh36 (*Imorphine 0.9 (0.7-1.1) 0.7 (0.5-0.9)cyclazocine 0.07 (0.02-0.2) -nalorphine 0.7 (0.4-1.1) > l o opentazocine 2.0 (1.4-2.9) 2.6 (1.8-3.7)

28 (+ I OH CHzCHzCH331 (+ I OH CH Z-C-C ~H~ >50 >50

0.3 (0.2-0.3) 0.08 (0.03-0.19)OH CH,-c-C,H, 0.6 (0.2-1.1) -

Th e ED,, value (95% confidence limits) is defined as the dose required for 50% reduction in frequency of writhing. *T he value(95% confidence limits) is defined as the dose required for a 2-s increase in reaction time.

Morphine ""'0,D N

Hoq6,7-Benzomorphans

aH

Morphinans

Htrans~4aPhenyldecahydroisoquinolines

Figure 1.I n the m ouse wr ith ing t e s t , c om pound 13 , the racemicN-methy l-3-hydroxy derivative, has an analgesic potencyc om pa r a b le to th a t o f m or ph ine . The r e wa s a s t epwiseincrease in ac t iv i ty by a l te r ing the subs t i tu t io n a t the3-phenyl position from hydrogen to metho xy to hydroxy.R e p la c e m e n t o f t he N- m e thy l w i th a phe ne thy l g r oup ,c om pound 33 , increased analgesic potency twofold. Bot h

(9) Zimmerman, D. M.; Smits,S. E.; Hynes, M. D.; Cantrell, B. E.;Leander, J. D.; Mendelsohn, L. G.; Nickander,R. Drug AlcoholDepend. 1985 14 , 381-402.

b.1160

HZbl

H2C lFigure 2.c om pounds 13 a n d 33 produced a pa t te rn of behavioraleffects similar to those ob served with mo rphin e, includingStr aub tail and increased locomotor activity. Compoundssubs t i tu ted a t the ni t rogen w i th a l ly l , propyl , cyc lo-propylmethyl, cyclobutylmethyl, and dimethylallyl groupswere also po ten t analgesics. Com parison of th e individuale na n t iom e r s (1 4 a n d 15 ) of compound 13 in the wr i th ingtes t showed tha t wi th th is N-m ethy l der iva tive the ana l-gesic ac tiv i ty res ided p redomin ant ly in the 4aR,8aR n-a n t iom e r 14; owever, the other s te reoisomer (15) sti l lproduced signif icant analgesia. W ith the N-cyclopropyl-methyl derivative 29 th e analgesic activity was selectivelyin the 4aR,8aR somer , compound 30 .


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N-Substituted trans-4a-Aryldecahydroisoquinolines Journal of Medicinal Chemistry, 988, Vol. 31,N o. 3 557Scheme 1'

/q3.f\OC H = CH2

7

CH38

9, ( + - 4aS,8aR) Isomer10, (-)-(4aR,6aS) Isomer

H1, Racemate11, (+)-(4aR,8aS) Isomer12, ( - ) - 4aS,8aR) Isome r

8,9,10 13, Racemate14, (+)-(4aS,8aR) Isomer15 , ( - ) - 4aR,8aS) Isom er

cH300'0-Q3'HR- X *Method A

0II1. R-C-CI2. LiAlH4Method B +

16, Racemate1,11,12 17, (+)-(4a R,8a S) Isomer18, ( - ) - 4aS,8aRl Isome r19

aFor the sake of clarity, only one enantiomer is depicted.In general the re la t ive analgesic potencies of the

trans-decahydroisoquinolines n t h e r a t t a i l h e a t t e s tpa ra l le l those obse rved in the mouse wr i th ing te s t . Th e(3-hydroxyphenyl)-N-phenethyler ivative again was themost po tent , having activity as the racemate approximately3-4 t imes tha t of morphine . Th e N-a l ly l and N-cyc lo-propylm ethyl der ivatives had analgesic potencies s imilarto th at of pen tazocine , whereas nalorp hine fails to increasereac t ion t ime by 2 s in th i s te s t even a t a dose of 100All r acemic mix tures o f the t r ans-decahydro iso-quinolines were evaluated for their abil i ty to antagonizeth e ana lgesic re sponse of morph ine (5 mg/kg , sc ) in thera t ta i l heat test . Th e procedure has been previously de-sc r ibed? Among th e r acemates , on ly th e N-cyc lopropyl -meth yl derivative 29 showed significant antagon ist activity,and this ac t ivi ty was fou nd se lectively in i ts 4aR,8aR ste-r eo isomer , compoun d 30 . Figure 3 s h o w s t h e m o r p h i n ean tagonis t ac t iv i ty o f compound 30 c o m p a r e d w i th t h e

m g / k g .

an tagonis t ac t iv i t ie s o f pen tazoc ine and na lorph ine .Co m p o u n d 30 antagon ized th e analgesic effects of mo r-phine in the ra t ta i l heat test with doses as low as 1mg/kg ,sc . Und er s imilar condit ion s, i t required 10 mg/kg ofpentazocine and 1 mg /kg of na lorph ine . At tem pts todetermine a dose tha t would reduce th e analgesic responseof morp hine by 50% (AD,,) with compo und 30 were un-successful because , as the dose of 30 was increased, i tsagonist ef fects became increasingly apparent .Co m p o u n d 30 was a lso able to antagonize the mor-phine-i nduce d Stra ub tail reaction an d increased locomotoractivity in mice. Th e experim ental details of this test haveb e en p r ev i ou s ly d e ~ c r i b e d . ~ he dose tha t caused a 50%red ucti on of th e effects of 40 mg/kg, sc, of morph ine (ADm)was 10.5mg/kg , sc. In th i s te s t , the ADso%or pentazocineand nalorphine were 16.9 an d 0.45 mg/kg, sc, respectively.Co m p o u n d s 31 ( the opposite enantiomer of c o m p o u n d 30)a n d 20 ( the N-allyl racemic mixture) w ere inactive in thistest .


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558 Journal of Medicinal Chemistry, 1988, Vof.31, No. 3Table 11. Affinity of the 2-Substituted tnms-4a-Aryldeeahydraisoquinolinesor th e p and x Opioid Receptors

Zimmerman et af.

r3HINAL binding assay (w receptor) VHIEKC binding assay ( 8 receptor)% displacementn 9o displacement-

compd Ki, nM 100 n M loo0 n M K # , M 100 nM loo0 nM15 8.9 43314 0.96 6122 15 42 2 1621 1.3 22.828 43 83 427 473 12 4fi. ._ ..25 34 70 0 1524 29 52931 4 35 5 3230 4.2 2.534 0.23 8935 19 74 8 53cyclazocine 1.2 1.3nalorphine 6.5 15morphine 5.7 167pentazocine 6.9 75

'Percent stereospecific displacement of either [SHINALor I3HIEKC run in triplicate at the concentration indicated.

Figure3. Antagonismofmorphine analgesia by 30, pentamcine,and nalorphine in th e rat tail jerk test. The analgesic effect ofmorphine sulfate (MOR) 10min after the sc administration of5 mg/k g wax determined in am bin ati on with either saline (SAL),compound 30,pentamcine (PEN ), or nalorphine (NAL). Th e testantagonists were administered at the sc doses indicated 60 minbefore test.

Th e a f f in it ies of the individual enant iomers of severa lof th e trans-4a-aryldecahydroisoquinolines or the p a n dI opioid receptors are given in T a b l e 11. p receptors werelabe led by us ing [3H]na loxone (Nal) wi th ra t bra in hom-ogenates. K receptors were labeled by using L3H]ethyl-ke tocyc lazoc ine (EKC) and homogenates f rom guinea pigc o r t e x i n t h e p r e s e n c e o f f e n t a n y l a n d ~ - A l a ~ - o - L e u ~ -enkephalih to block the p a n d 6 receptor binding of EKC .T he de ta i ls of both procedures have been previously de-scr ibed? Severa l of th e isoquinol ines wi th th e 4aR,8aRabso lute configuration have high affinity for th e p receptor,and except for the cyclopropylmethyl derivative 30, all hadsubstant ia l ly lower a f f in i ty for the I receptor . The N-methyl der iva t ive 14 has an a f f in i ty for the p receptor 6t ime s th a t of morphin e whi le the a f f in ity of t h e N - p h e n-e thyl ana logue 34 is 25 t im e s tha t o f m or ph ine . The r eappeared to be a good correlation of the relative aff initiesof these comp ound s for th e p receptor and the i r ana lges icpo tenc ie s in bo th the m ouse wr i th ing a n d r a t t a il he a tanalgesic tests. Both N-m ethyl stereoisom ers (compou nds14 and 15) have sign ificant affinity for th e p receptor . Theaffinity of th e 4aR,8aR (compo und 14) isomer is 8-10-foldh igher tha n t ha t o f t he 4aS,8aS i somer (compound 15) .With the N-allyl an d N-cyclopropylmethyl derivatives, theaff inities of the 4aR,8aR somers (21 and 30) for the preceptor were substant ia l ly grea te r tha n those of the i ropposi te s te reoisomers (22 and 31). Of a l l the N-subst i -

tu t ed isoquinol ines , only compound 30 had high a f f in i tyf o r t he I receptor .Discussion

In genera l, the changes in ana lges ic ac t iv i ty th a t occurwith modif ica t ion of t h e trans-4a-phenylisoquinolinemolecule para l le led those previously repor ted wi th th emorp hinan ' and benzomorphanz ser ies . A t t he 3 - phe ny lposition, activity increased from h ydrogen to m e thoxy tohydroxy. Subst i tu t ion of phene thyl for the N-methylgroup increases potency, an d ana lges ic ac t iv i ty was re -ta ined wi th t he N-cyc lopropylmethyl and th e N-a l ly l de-rivatives. As i s t he c a se in th e m or ph ina n a nd be nz o-morphan se r ies , the N-(cyclopropylmethy1)isoquinolineanalogue has antag onist activity; however, i ts antagon istac t iv i ty i s weak com pared t o th e antagonis t ac t iv i t ies oft h e N-(cyclopropylmethylmorphinan (cyc lorphan) and-bemo morp han (cyc lazoc ine) der iva tives . F ur the rmo rethe N-allylisoquinoline d erivative does not have m orphineantagonis t proper t ies , whereas th e N-a l ly l der iva t ives inthe m or ph ina n a nd be nz om or pba n se r ie s ar e po te n t a n -tagonists. Resolution of the tram-4a-phenylisoquinolinesshowed th a t t he ana lgesic act iv i ty and a f f in i ty for opioidreceptors resided predomina te ly in the 4aR,8aR i somer ,th e sam e absolute conf igura t ion found for the ac t ive iso-mers of the mo rphinans, benzomorphans, and morphine; '$however , unl ike N-methylmorphinan and -hemo morph ander ivat ives , th e (4aS,8aS)-N-methylisoquinolinesomer(compound 15) has s ignif icant ana lges ic ac t iv i ty and a f -f in i ty for the p receptor .Compo und 30 was found to have mixed agonist-antag-onist properties similar in potency to tho se of pentazocinein both rats and mice. Such a profde of activity is normallyindicative of a reduced dep endence l iabil i ty n ot only inrodents bu t a lso in other spec ies . Compo und 30 wasevaluated for its physical dependence and abuse liabili tiesunder th e auspices of the C omm ittee on Problems of DrugDependence at th e University of M ichigan and the MedicalCollege of Virginia. '" Surp rising ly, in sing le dose su p-p r es s ion s tud ie s in m or ph i ne de p e nde n t r he sus m onkeysundergoing spontaneous wi thdrawal , compound 30 sup-pressed w ithdrawa l an d was more poten t and longer lastingth an morphine . Fur th ermo re , pr imary physica l depen-dence studies showed tha t chronic administration of com-pound 30 produced a marked physica l dependence more(10) Personalcommunication as reported in the Proceedings of the39th Annuol Scientific Meeting, Committee an Pr ob l ems ofDrug Dependence, Cambridge, MA , J u l y 6-9.1971.


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N-Substituted trans-4a-Aryldecahydroisoquinolinessevere tha n th at of morphine . Therefore , in rhesus mon-keys compound 30 produced effects th at would be exp ectedof a poten t , long- last ing, morphine- l ike agonist .On t he basis of i ts rode nt ph armacology, this prof i le ofactivi ty with compou nd 30 in rhesus m onkeys was c lear lyunexpec ted , Th e op io id an tagonis t p rope r t ie s iden t if iedin rodents were absent in rhesus monkeys. Fur therm ore ,in rhesus monkeys, 30 was est imated to be 3-6 t imes morepoten t tha n m orphin e, which was significantly greater thanits potencies in the rodent analgesic tests . T he reason forthe appa ren t d i f f e rence in op io id prope r t ie s wi th com-p o u n d 30 between these species is unexpla ined.Experimental Section

Melting points were determined fcr all solids on a Thomas-Hoover apparatus and are uncorrected. Mass spectra were re-corded on a CEC 21-110 mass spectrometer for all compoundsand were consistent with assigned structures. NM R spec tra wererecorded on either a Varian T-60 or Brucker WM-270 spec-trometer a nd were consiste nt with assigned structures. Opticalrotations were determ ined on a Perkin-Elmer Model 241 auto-matic polarimeter and were run as a 1% olution in m ethanol.All compo unds had elem ental analysis within 0.3% of theoreticalvalue unless otherwise indicated. Where melting points are notindicated, the substance is a liquid at room tempe rature.2-Met yl-4ap-(3-methoxyphenyl)-l,2,3,4,4a,5,6,7,8,8aa-decahydroisoquinoline 8) . A solution of 76 1.55 g, 0.005 mol)in 25 mL of anhy drou s toluene was added dropwise to 2 mL ofRed-AI at room temperatu re under nitrogen. Th e reactionmixture was then heated a t 90 "C for 1h, the n cooled to roomtemperature, and poured into 1N HC1. The acidic layer waswashed one time w ith ether an d then made strongly basic with50% NaOH with ice cooling. Th e desired product was extractedinto ether, an d th e ethe r layer was washed two times with water,dried over K2C03, and concen trated un der reduced pressure t oyield 1.21 g (95 %). Th e hydrobromide salt was prepared andrecrystallized from isopropyl ether/ethanol (1:l):m p 168-170"C. Anal. (C1,H,NOBr) C, H, N.(+)-(4aR ,8aR -2-Methyl-4aB-(3-methoxyphenyl)-1,2,3,4,4a,5,6,7,8,8aa-decahydroisoquinoline9). Into 200 mLof 2-propanol were disso lved 39.3 g (0.15 mol) of 8 nd 26.1 g (0.17mol) of (-)-D-mandelic acid. T he solvent was remov ed by evap-oration under reduced pressure , and the resultin g solid was re-crystallized from 1900 mL of hot water. Th e precipitate (26.1g) was recrystallized from 260 mL of acetone and 626 mL ofisopropyl ether , giving 17.9 g of the resolved man delate salt: m p97-101 "C. Tre atm ent of the salt with excess 1 N NaOH andsub sequ ent ether extraction a nd evaporation yielded 10.25 g of9 as a viscous oil (52%): [a]365+41.9"; [ a ] D +6.8". Anal.

(-)-(4aS ,8aS -2-Methyl-4ab-(3-methoxyphenyl)-l,2,3,4,4a,5,6,7,8,8aa-decahydroisoquinoline10). Th e resultingfiltrate from t he above water recrystallization st ep was evaporatedto dryness under reduced p ressure to yield 39.0 g. Th e free aminewas liberated with base a nd distilled a t 109-112 "C 0.1 mm) t oyield 21.0 g of a clear viscous oil: [a1365 27.7". Th is 21.0 g (0.08mol) an d 13.9 g (0.09 mol) of (+)-L-mandelic acid were dissolvedinto 100mL of 2-propanol. Th e solvent was removed by evap-oration, an d the resulting solid was recrystallized from 245 mLof acetone and 578 mL of isopropyl ethe r to yield 23.0 g of th eresolved mandelate salt: m p 98-101 "C. Trea tme nt with excess1 N NaOH and subsequent ether extraction and evaporationafforde d 13.0 g of a viscous oil (66%): [a1365 -41.4"; ["ID -6.8".Anal. (C,,H26NO) C, H , N.(+)-(4aS,8aS -4ab-(3-Methox~~heny1)-1,2,3,4,4a,5,6,7,-8,8aa-decahydroisoquinoline11). A solu tion of 8.9 g (0.056mol) of phenyl chloroformate in 40 m L of dichloromethane wasadde d dropwise to 13.0 g (0.051mol) of 10at room temperatureunder a nitrogen atmosp here. Following a 4-h reflux, th e mixturewas cooled to room temperature and concentrated under reducedpressure. Th e resulting oil was treated with 100 mL of 1N NaOHand stirred w ith slight warming for 15min. Th e desired carbamatewas then extracted into ether, and the ether layer was washedwith 1N HC1 and water. Th e ether layer was dried over K2 C0 3and t he solv ent evaporated under reduced pressure, giving 20.6

( C ~ . I H Z ~ N O ), H, N.

Journal of Medicinal Chemistry, 1988, Vol. 31, No. 3 559g of colorless oil. This oil was then treated with 470 mL of ethan oland 118mL of 50% aqueous KOH at reflux for 66 h. Th e mixturewas cooled and concentrated under reduced pressure. Th e re-sulting alkaline concentrate was extracted two times with eth er,and the eth er extracts were concentrated under vacuum. Th eresulting oil was dissolved into 200 mL of 1N HC l and washedwith ether. Th e aqueous layer was then made strongly basic (pH>E )with 50% NaOH with ice cooling. Th e desired amine 11was extracted into eth er, and th e ether layer was washed, driedover K,C03, and concentrated under reduced pressure to yield10 g of crude 11. Vacuum distillatio n at 121-125 "C (0.1 mm )afforded 9.1 g of 11 as a clear viscous oil (74%): [a1365 +29.0;

(-)-(4aR 8aR -4ab- 3-Met oxypheny1)- ,2,3,4,4a,5,6,7,8,-8aa-decahydroisoquinoline(12). This compound was preparedas above from 9. Vacuum distillatio n at 119-123 "C (0.1 mm )afforded 7.3 g of 12 (67%): ["I366 -29.4"; [ a ] D -9.0".General Procedure for the Synthesis f the 3-Hydroxy-phenyl Analogues. Th e 0-demethylation of all 3-methoxyphenylcompou nds followed the p rocedure described below for 16.34 ~,3,4,4a,5,6,7,8,8a~-Decahydro-4a~-isoquinolinyl)phenol(16). Freshly distilled 1 (5.2 g, 0.02 mol) was treated with 40 mLof glacial acetic acid and 40 mL of 50% aq ueous hydrobromic acidat reflux temperature for 18h. Th e reaction mixture was cooledto room temperature and diluted with 200 mL of water. Th e pHwas adjusted to 10 by using 50% NaOH with ice cooling. Th edesired product was extracted into a 3:l 1-butanol/toluenemixture, dried over K,CO,, and concentrated under reducedpressure toyield 4.2 g (90%). The solid was recrystallized fromdimethylform amide: m p 212-214 "C. Anal. (C15H21NO)C, H,N. Compounds 17, 18, an d 13-15 were prepared in the samemanner as 16.(+)-(4aS,8aS)-3-( ,2,3,4,4a,5,6,7,8,8aa-Decahydro-4ap-iso-quinoliny1)phenol (17): prepared from 11 and recrystallizedfrom hex ane/e thyl acetat e (1:3) in 89% yield; mp 234-237 "C;

(-)-( 4aR,8aR )-34 ,2,3,4,4a,5,6,7,8,8aa-Decahydro-4ap-iso-quinoliny1)phenol (18): prepared from 12 and recrystallizedfrom hexa ne/e thyl a cetate (1:3) in 91% yield; mp 235-238 "C;3-(2-Methyl-1,2,3,4,4a,5,6,7,8,8aa-decahydro-4ap-iso-quinolinyl)phenol(l3): prepared from 8 and recrystallized fromacetonitrile/ethanol (4:l) in 55% yield; mp 202-204 "C. Anal.( C I ~ H Z ~ N O ), H, N.(+)-(4aR ,8aR -3-(2-Metyl- ,2,3,4,4a,5,6,7,8,8aa-deca-hydro-4a~-isoquinolinyl)phenol14): prepared from 9; e-crystallized from ethyl acetate in 68% yield; mp 213-215 " C . Anal.(Cl,Hz3NO)C, H, N. It was converted to the hydrobromide saltand recrystallized from ethyl acetate/methanol (9:l): [a1365+22.95'; [ a ] ~5.53"; m p 240-241 "c . Anal. (CI6Hz4NOBr) ,H, N.(-)-(4aS 8aS -3-(2-Methyl-1,2,3,4,4a,5,6,7,8,8aa-deca-hydro-4a~-isoquinolinyl)phenol15): prepared from 10 an drecrystallized from ethyl ac etate in 71% yield; mp 213-215 "C.Anal. (C,,H&IO) C, H, N. Th e hydrobromide salt was prepared

an d recrystallized from ethyl acetate/methanol @:I): m p 240-241"c; [a1365 -23.84"; [ a ] D -5.85". Anal. (C16H,,NOBr) C, H, N.General Alkylation Procedure for Preparing N-Substi-tuted trans-4a-(3-Hydroxyphenyl)decahydroisoquinolines(Method A). Either 16, 17, r 18 (1.0 g, 0.004 m ol) was h eatedwith 0.005 mol of the appropriate alkyl halide and 0.55 g ofNaHCO, in 30 mL of DMF. After refluxing for 1h, the mixturewas cooled and poured in to 100 mL of water. Th e product wasextracted into 300 mL of ether. Th e ether layer was washed twotimes with w ater, dried over K&OB, and concentrated undervacuum. Th e products were purified by recrystallization eitheras a free base or a salt form.Compounds 20-28 and 32were prepared by this procedure andexhibited the following properties.342-Allyl- ,2,3,4,4a,5,6,7,8,8aa-decahydro-4ap-iso-quinoliny1)phenol (20): prepared from 16 and allyl bromideand recrystallized from ethyl acetate (64% );mp 146-148 "C. Anal.

(-)-(4aR ,8aR -3-(2-Allyl-1,2,3,4,4a,5,6,7,8,8aa-decahydro-4a~-isoquinolinyl)phenol21 : prepared from 18 and allyl

["ID +9.2".

[a1366 +26.8'; [a]D 8.4".

[@I365 -25.6"; ["ID -8.2".

(Ci&z5NO) C, H, N.


6/6

560 Journal of Medicinal Chemistry, 1988, Vol. 31, No. 3bromide and recrystallized from ethyl acetate (65 %);mp 170-171.5

(+)-(4aS,8aS)-3-(2-Allyl-1,2,3,4,4a,5,6,7,8,8aa-decahydro-4a@-isoquinolinyl)phenol (22): prepared from 17 and allylbrom ide and recrystallized from ethyl ac etate (72% ); mp 172-1723- ( 2 - E th y l -1,2,3,4,4a,5,6,7,8,8acu-decahydro-4ab-iso-quin olin yl)p hen ol(2 3): prepared from 16 and ethyl iodide. Th e

maleate salt was recrystallized from ethyl acetate/ethanol (6:l)(61%): mp 138-140 "C. Anal. (CzlH zeN0 5) , H, N.(-)- (4aR 8aR )-3- 2-Ethyl-1,2,3,4,4a,5,6,7,8,8aa-decahydro-4a@-isoquinolinyl)phenol (24): prepared from 18 and ethyliodide and recrystallized from ethyl acetate (73% ); mp 166-169(+ - 4aS 8 aS -3-(2-Ethyl-l,2,3,4,4a,5,6,7,8,8aa-decahydro-4a~-isoquinolinyl)phenol25): prepared from 17 and ethyliodide and recrystallized from ethyl acetate (78%);mp 167-169" c ; [a]g65" ; ["ID +4.4'. Anal. (C1,Hz5NO) C, H,N.3- (2-n -Prop yl-1,2,3,4,4a,5,6,7,8,8aa-decahydro-4aj3-iso-qui nol iny l)ph eno l(26 ): prepared from 16 by employing n-propyliodide. Th e maleate sal t was recrystallized from ethyl acetate(50 %) : mp 150-151 "C. A nal. (Cz2H3 ,N05)C, H, N.(-)-(4aR ,8aR )-3-(2-n-Propyl-1,2,3,4,4a,5,6,7,8,8aa-deca-hydro-4a@-isoquinolinyl)phenol 27): prepared from 18 andn-propyl iodide and recrystallized from hexane/ethyl acetate (2:l)

C, H, N.(+) - (4aS ,8aS -3- (2-n-Propyl-1,2,3,4,4a,5,6,7,8,8aa-deca-hydro-4a@-isoquinolinyl)phenol 28): prepared from 17 andn-propyl iodide and recrystallized from ethyl acetate (49%); mp123-124.5 "c; aI365 +14.8'; [a]D+&lo . nal. (ClsHZ7NO)c,H, N.3 4 2 43-Methyl-2-buteny1)- ,2,3,4,4a,5,6,7,8,8aa-decahydro-4a~-isoquinolinyl]phenol32): prepared from 16 and 4-bromo-2-methyl-2-methyl-2-butenend recrystallized fromchloroform (6 4% ); mp 113-115 "C. Anal. (CzoHzeNO) , H, N.Genera l Acyla t ion/Reduct ion Procedure for Prepar in gN-Subst i tu ted trans-4a-(3-Hydroxyphenyl)decahydroiso-quinolines (Method B) . T o 1.0 g (0.004 mol) of eithe r 16, 17,or 18 and 1.0 g of triethylamine in 30 mL of DMF was addeddropwise 0.01 mol of th e appro priate acid chloride at room tem-perature u nder nitrogen. After the reaction mixture was heatedfor 2 h a t 90 "C, the solution was cooled and poured into 100 mLof water. Th e desired amide was extrac ted into 300 mL of ether.The ether layer was washed two times with water, dried overK2 C0 3, nd concentrated under vacuum. The resulting amidewas dissolved into 75 mL of anhydrous TH F and a dded dropwiseto 0.75 g of LiAlH4 dispersed in 50 mL of anhydrous THF. Aftera 4-h reflux, the reaction mixture was cooled, and the excessLiAlH4was neutralized by the careful addition of 10 mL of ethylacetate with ice cooling. Satu rated NH4Cl solution was the n addedto precipitate the lithium salts. Th e solution containing thedesired product was separated, evaporated to dryness, and workedup in the st and ard manner. Th e products were recrystallizedeither as a free base or a salt.

"c ; a 1 3 6 5 -45.8'; [ a ] ~14.8'. Anal. (C1sH25NO) c , H , N.'c; [a1365 +45.2"; [ID +14.6". Anal. (ClsH25NO) c, H, N.

"c ; a1365 -0.4"; ["ID -4.8'. Anal. (C17H2,NO) c , H , N.

(61%); mp 124-125 "C; [~~]%-15.6";a]D-8.7'. An d. (ClsHn NO)

Zimmerman et al.Com pounds 29-31 and 33-36 were prepared by this procedureand exhibited the following properties.3-[2-(Cyclopropylmethyl)-1,2,3,4,4a,5,6,7,8,8acu-decahydro-4a~-isoquinolinyl]phenol29): prepared from 16 and cyclo-propanecarboxylic acid chloride. Th e maleate salt was recrys-tallized from ethyl acetate/ethanol (9:l) (61%): mp 135-138 "C.Anal. (C23H31N05) , H, N.(+)-(4aS,8aS)-3-[2-(Cyclopropylmethyl)-1,2,3,4,4a,5,6,7,-

8,8aa-decahydro-4a&isoquinolinyl]pheno1(31): prepared from17 and cyclopropanecarboxylic acid chloride. Th e succinate saltwas recrystallized from 2-propanol (56 %): m p 161-162 "C;+13.9'; [ a ] D +5.3". Anal. (Cz3H3,N05)C, H, N.(-)-( 4aR ,8aR )- 3 42- (Cycl op rop ylm et hy1)- 1,2,3,4,4a,5,6,-7,8,8aa-decahydro-4a@-isoquinolinyl]phenol 30): preparedfrom 18 and cyclopropanecarboxylic acid chloride. The succinatesalt was recrystallized from acetonitrile (61"): mp 157-159 "C;3-[2-(Phenylethyl)-l,2,3,4,4a,5,6,7,8,8aa-decahydro-4a@-isoq uin olin yl]ph enol (33): prepared from 16 and phenylacetylchloride. The m aleate salt was recrystallized from ethyl acetate(51 %): mp 56.5-59 "C. Anal. (C27H 33N 06), H, N.(-)-(4aR ,8aR )-3-[2-(Phenylethyl)-1,2,3,4,4a,5,6,7,8,8aa-decahydro-4a@-isoquinolinyl]phenol(34): prepared from 18and D henvlacetvl chloride and recrvstallized from ethvl acetate

[ a1365 -14.9'; ["ID -5.8'. Anal. (C23H33N05) C, H, N .

(63%); m i 2101213 "c ; a1365 -8l.i"; [a]D 26.6'. Anal. (c23-H,,NO) C. H. N."(+)-(4a k , ga s ) -3 -[2- (Phen yle thyl) 1,2,3,4,4a,5,6,7,8,8aa-decahydro-4a@-isoquinolinyl]phenol 35): prepared from 17and ph envlacetvl chloride and recrystallized from ethyl acetate(54%);mp 210'212 "c ; a1365 +78.8"; ["ID +25.6". Anal. (c23-H,,NO) C, H. N.I3 42-(C yclobuty methyl) 1,2,3,4,4a,5,6,7,8,8a~decahydro-4a~-isoquinolinyl]phenol36): prepared from 16 and cyclo-butanecarboxylic acid chloride. Th e m aleate salt was recrystallizedfrom ethyl acetate/ethan ol (9:l) (20% ): mp 136-138 "C. Anal.( C J L N 0 5 ) C, H, N.Regis t ry No. (&)- l ,8637-24-4; (i=)-7 ,111635-65-5;(&)-8,51605-17-5; (&)-8.HB r,111635-66-6;9, 59908-28-0; 10,59889-34-8;

111819-33-1; 14.HBr, 83502-25-4; 15, 111819-34-2; 15.HBr,11, 111765-98-1; 12, 111765-99-2; (f)-13, 51605-18-6; 14,83502-24-3;(*)-16,58637-26-6; 17, 111766-00-8;18, 111766-01-9;(*)-20, 58637-29-9; 21, 111766-02-0; 22, 111766-03-1; (*)-23,111635-67-7; (*)-23.maleate, 111635-68-8;24, 111766-04-2;25,111766-05-3; &)-26 ,58974-76-8;(&)-26*m aleate, 8974-77-9;27,111766-06-4; 8,111766-07-5; *)-29,63843-35-6; (*)-29*maleate,63843-36-7;30,59889-36-0; 30*succina te, 0719-85-9;31,59889-38-2;31.succinate, 111819-35-3; (*)-32,58670-09-0; (*)-33 ,51605-27-7;(*)-33srnaleate, 111635-69-9; 34, 111766-08-6;35, 111766-09-7;(&)- 36, 63843-31-2; (& )-36 -ma leate , 3843-32-3; PhCH2COC1,

Sup plem ent ary M ater ial Available: Tables giving the at-omic coordinates, bond lengths, bond angles, and anisotropictemperature factors ( 5 pages). Ordering information is given onany current masthead page.

103-80-0;c - C ~ H ~ C O C ~ ,023-34-1; c-C,H,COCl, 5006-22-4.

Synthesis and analgesic properties of N-substituted trans-4a-aryldecahydroisoquinolines - J. Med....

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Transcript of Synthesis and analgesic properties of N-substituted trans-4a-aryldecahydroisoquinolines - J. Med....