8/8/2019 J.Med.Chem.1969.12.473-477

1/5

M a y 1969 ~-I'HEXYLCYCLOALKYLAIV~INE D E E l V A T l V E S 47 31 Phenylcycloalkylam ine Derivatives. II.',2

Synthesis and Pharmacological ActivityA. KALIR,H. EDERY, . PELAH, . BALDERMAN,ND GILA PORATH

T h e Israel Instztute f o r Uzoloyzcal Reseal ch , Sess-Zzona , IsraelKeceaued .-luyust 28, 1968

lievzsed Ilan?iscrzpt Receaeed J a n u a r y 6, 1969A series of S ,K- sub sti tut ed 1-arylcycloheuylamines was prepared mainly by the reaction of an arylmagnesiunihromide and 1-dialkylaminocyclohexanecarbonitrile. As the cyclopentyl analog could not be obtained by this

way, condensation of 1-phenylcyclopentylamine ith pentamethylene dibromide in DIIF was tried with success.These compounds were tested fo r their psychopharmacological pro perties. 1-[l-(2-Thienyl)cyclohesyl]piperidine(16)was found to be the most active.Th e pharmacological propert ies of 1-( -phenylcyclo-hexj 1)piper idine (7 )3 p h e n y l ~ y c l i d i n e ~ - ~ ) ,or which a tthe time of this investigatioii only one synthesis has

beeii st imu lated th e exploration of possiblepreparative routes applicable also to other members ofthe series.

5 7 27S'ar iocs a t tem pts were made to prepare 7 . Piperidinedid not sub sti tute th e halogen a tom in pheiiylcyclohexylchlor ide, but caused dehydrohalogenation; also themethylelie group in I -benzylpiFeridine proved unreac-t ive for co,idei ,sat ion with pentamethj ene bromide inthe preseiice of K a H .By a no the r me thod , based o n the ear ly work ofB r uj l a ~ i t s , ~series of' T-alkylated l-phenylcyclohexyl-

amines mere ot ta i i ied (Table I) f rom th e correspondingalk j laminocj clohexacecarboaitr iles (Table 11). T h emechanism of tLe BrLylants reaction has been the sub-ject of inaiiy ill\ estigations,6ss-11which revealed thatpiperidiiiocj clohexanecarbonitrile (27) w i th PhMgBrg i t e s 7 , whereas wi th PhLi the expec ted produc t ,1-pipericiinocyclohexyl phenyl ketone is obtained.The format ion of 3 f rom 5-ethylcyclohexaiiecar l io-nitr i le (25) and 3 moles of PhLi sugges ts th a t the reac-tion proceeds th rough S - c j clohexylidenethj amine asan in te rmedia te . This view is suppor ted by the factt h a t M a d d o x, e t aZ.,I2 obta ined the above amine f romS-cyclohexylidenethylamiiie n d 2 moles of PhLi . Thecyclopentyl analog of 7 could no t be prepared this way,8bu t as descr ihed hi th e Experime ntal Section. An alter-

( 1 ) Part I: A . Kalir and Z. Pelah, Zsrael J . C h e m . , 5, 223 (196i).( 2 ) Presented in par t at the 34th Meetin g of th e Israel Chemical Societj-,

Jerusalem, Dee 1964; Israel J . Chem. , 2, 312 (1864), and at th e Meeting of theIsrael Physiological and Pharmacological Society, Rehovoth, .Ipril 1966.

(3 ) Numbers refer t o Tables I an d 11.(4) A . J. Catenacci, Fed . Proc., 17. 357 (1958).(5) E. F. Domino, Znt. Rev . Neurobiol., 6 , 303 (1963).(6) Z. 15-elvart. C . R. .Icad. Sei., Paris, 250, 1870 (1960).(i). Bruylants, Bull. Soc. Chim. Belgen, 33, 467 (1924).(8) . Sansoulet, C. Tackx, and Z. Welvart, C. R. .Icad. Sei., Paris. 250,4370 (1960).(9) G. Chauviere, B. Tchouhar, and Z. Velvart, Bull. SOC. him. P r . , 1428(1063).(10) (:I) J. Yoshimura, I-. hgo, and T. Sato, J . .4m, hem. Soc., 86 , 3838(1904); (b) Bull. Chem. SOC. apan, 38, 1809 (1965).(1 1) 3. Hermans, P. van Daele, C . van de Westeringh. C. van der Eycke n,J. Roey. an d 1'. A . J . Janssen, .i.Med. Chem . , 8, 851 (1965).( 12) H. Maddor , E. F.Godefroi, and E. E'. Parcell, ibid., 8 , 230 (1962).

i ia t ive route f rom 1-pheiiylcyclopeiitylainiiie aiid glutaricanhydride mas unsuccessfulExperimental Section

1-Piperidinocyclohexanecarbonitrile 27).---Piperidine (85 g,1.0 mole) was carefully niixed with 84 ml of concent rated HC lan d 200 g of ice-water, and the p H was adjusted to 3-4. To thissolution, 98 g (1.0 mole) of cyclohexanone was added, followedby 68 g of K C S in 150 ml of H?O without external cooling butwith efficient stirring . After '2 hr the solution was allowed tostand overnight, and the crystalline precipitate was collected,washed (cold H20), and dried. The yield was 169-182 g (88-95',),mp 63-3-68', Th is product was sufficiently pure for th e next step.Recrystallization from EtOH raised the melting point to 68-70 '.Other alkylaminocJ-cloalkanecarbonitriles, repared accord-ingly, are listed in Table 11.N,N-Dimethyl-1-phenylcyclohexylamine5).----A mixture of8.7 g of 1-phenylcyclohexylamine, 7. 8 g of 885; HC02H, and1'2.5 g of 3 j C ; CHrO was refluxed for 5 hr, cooled, and madealkaline. Th e base was extracted (E t?O ), he solution was driedand concentrated, and the product distilled.N-Methyl-1-plienylcycloliexylamine (1) Procedure A).---*\solution of 27 g of S-(phenylcyclohexyl)formamidel n C& wasslowly added to 16.0 g of 1,AH in 500 nil of Etz0. After 1 hr ofreflux the mixture was decomposed and the basic materialseparated and distilled.N-Ethyl-1-phenylcyclohexylamine (3) Procedure B).--A solu-tion of 76 g (0.5 mole) of 25 in 200 ml of Et 90 was added to Ph Li[prepared from 236 g (1.5 moles) of PhBr and 25 g of I,i r ibbon in800 ml of Et201 at such a rate that a gentl e reHux w-asmaintained.The mixture was heated and stirred 30 min, then filtered quickly,and the filtrate cautiously was poured on crushed ice. Theorganic layer was separated, dried, and fractionally distilled.1-( -Phenylcyclohexy1)piperidine (7) (Procedure C).--A solu-tion of 76.8 g of 27 in EtrO-C& was adde d slowly to P h M g B rprepared f rom 110 g of P hBr and 17.3 g of 11Zg in 400 ml of Et?O.A viscous precipitate formed and stirring hecame difficult. Afterthe addition was completed the mixture was allowed to standfo r 3 hr, the n poured into ice-SH4Cl. The Et20 layer wasseparated an d washed (HZO). The base was extracted withdilute HC1, liberated again with concentrated SHaOH, extractedwith EtzO, dried, and distilled. Th e distillate which solidifiedwas recrystallin8ed rom E tO H.1-Dimethylaminocyclopentyl Phenyl Ketone (19).13 --TUsolution of PhI d (f rom 118 g of P hB r an d 10 g of I,i in 400 ml ofEtyO) was added 34.5 g (0 .25 mole) of 31 in 100 ml of I

8/8/2019 J.Med.Chem.1969.12.473-477

2/5

47-1 \ ' ( ) I . I "

No."

ti:,7

16:i1717:LI711

ISI X l II !I

8/8/2019 J.Med.Chem.1969.12.473-477

3/5

May 1969 ~-PHE~YYLCYCLOALKYLANISEERIVATIVES 475

NO. n25 526 527" 52s 529 530 43 1 432 433 4

TABLE1~-ALKYL.IMISOCYCLOALKANEC.IRBOSITKILES

R' R"H CzHs-(CH2)4-

Yield, % Bp (mm) or mp, "C92 116 (26)72 94-96 (0.9)24-26151-15263 58-5949 * 143-145 ( 2 5 )53 99 (26)89 99 ( 2 5 )79 125 (24)85 145 (30)

Analyses 7l D (1, " c )1.4653 (25)c, H

c, Hc,HC, H, SC, H 1.4560 ( 2 6 )s 1.4541 (27 )c , H 1.4802 (261.4882 (27), H, S

a Picrate. h small amount of a by-product, mp 200-201 dec, was identified as S,S'-his( 1-cyanocyclohexy1)piperazine. dnal.(ClSH2694) C, H .TABLE11

COSDITIOKEDI.OID.LNCERESPOSSERATS),AND DIGGIXGc r r v I r Y (GERBILS)b;FFECTS OF P F I E N C Y C L I D I S E A N D I T S A N I L O G S O X F O H C E D A I O T O I l A C ' T I V I r Y ( A I I C E ) ,Ger bil digging---N o. of animals out of 4 which did

no t pass the sand barrier after,---- Forced motor act. (rotarod)-- r CAK- 7

redn in performance after % reductionNo . Dose, mg/kg 30 min GO min Dose, mg/kg in response Dose, mg/kg 30 min 60 minl a 52 103a 125 676a 234

4808912147030

76

000430170046

7a 4 65 407c 15 0 08a 10 10 09a 10 0 0loa 10 0 0

1 a 10 0 013a 3014 2016a 23418 5

81519 1020a 1021 10

0010

589801543000

00034

68000000

8.0 g of anhydrous KzCO3, and 50 ml of dry DMF was stirredand heated. .4t 50-55" a n exothermic reaction occurred and thetemnerat ure rose to 95-100". The content was heated 1 hr ona water bath and poured into cold H20, and the product wasextracted with EtzO, distilled, and recrystallized.N -( 1-Phenylcyclopenty1)glutaramicAcid.-1-Phenylcyclopen-tylamine (5.1 g) was mixed wit h 3.52 g of glutaric anhydride.The reaction was exothermic and after short heating at 180-200"th e product was cooled and recrystallized (EtOH); yield 7.8 g(89\;), mp 172-173". Anal. (CI~H?ISOS), H. The productdid not cyclize when heated to 230-250" but decomposed t o1-phenylcyclopentene.Pharmacological Tests. Methods.- Saline solutions of th ecompounds were adjusted so that a volume of 0.1 m1/10 g wasadministered subcutaneousl y to mice and gerbils, a nd 0.2 m1/100 gto rats. Monkeys were injected (0.25 ml/kg) into the saphenavein. In ca ts the maximal volume injected was 0.2 ml. In allcases the animals used were of either sex. Hydrochlorides of

5101834683

1010101010101012

6044

100760100250000000

25100

510125723121057

1010510101012

302414041302410020124

102302141401200020223

5 6 5 2 28 7110 0 10 0 010 0 10 0 010 0 10 0 02, 5, an d 14 were prepared by dissolving the materials in diluteHCl and the solutions were then neutritliaed with phosphatebuffe r before injection.Conditional Avoidance Response: -1nl)red albino r:tts, weighing200-300 g, were trained to jump in a shuttle to avoid a65-\- electric shock. The condition w as :I photic stimulus of5-ser duration presented every 30 ser. ..\n animal was consideredfully trained when at least 80' 0 o f the possi1)le rurrect responseswere made in a period of 25 min. Four fully trained animalswere administered each dose level : ~ n dested 1 hr after injection.Forced Motor Activity (Rotati ng Rod): --liandoni-lired alllinomice, 20-25 g, were trained t o remain o n a rotating I ( J ~hichturned five times per mi1iute.1~Six trailled animals were injectedwith each dose level of th e c ~ i n i p o u ~ ~ d st i i t l tested :io n i i c i (io m i l l

(14) D. Bovet, C. L . Gatti, and 31.Frank, c i. R e p l . 1 s t . S u p e r . Saniia, 1,(15) N . W. unham and T. 8 . AIiya, J . .imer.Pharm. . I s . , 46 , 208 ( 1 9 3 i ) .

12 7 (1961).

8/8/2019 J.Med.Chem.1969.12.473-477

4/5

r i l l s L VIIS ~ i u t l i e t lii :I f ie ld of l.i.5 X 1.i . i 1x1 divided into 36 equal~ i i u : t r r s , o r 2 mill. T h e following parameters were recorded::iniliul:itioii, rcwiiig, t iinen : tppro:whing the center iif the field,lirtwiitig, arid the iinm:)er i i f Iduser excreted (eniotioiial defeca-1 io n ). IriiretI li s described Iiy Briml!leciirnt)e.16 F(i11r:ii:iiii:ils tver(~ idministereii each dose level and teyted 1 h rt hwwlt c,r.t i i t l c i t o tlig Lvheri p l a i d o n sand. Itandom-bred gerbils of a nx l ~ i i t i i i t r : i i i i , l 7 weighing 30GhO g, were tested i n a [:age with t \ v or i i i i ip : t r t i i iei i tr; separa t ed I i t trough filled with sand. '* The: i i i i i n : i l w:is pl:tc*ed i n o n e i~~~mpar tmentrnin before th e test whileI hi > s:ititi w:w .ovPred. Then t tie cover was removed and digging: t i * [ vit). \ v : ~ilirerveti through :I mirror plared above the cagc.This :ir1ivit>. was c~tiec~kedour times pr io r t o an d on th e day oft l i t : erperiiiieiit , The yerliil~were rested 40 and 63 mill after:i(ltiiiiiistr:it ioii of t h r c~iiiiipoiinds nti i f they di d not,c r i w wit hiti$5 i n i n :iftcr remciv:il (i f t hc ('over, th e response was recorded as :i" i ' : ~ i Iu r i ~ . ' ' S:iliiie-injei~tr(tinini:ils r r i ) s sd th e sirrid iiarrier withinI L ' n i i n .Hehavior of M o n k e y s . ~.\clults h esu s monkey3 w r e kept inb p : i i i i ) u s r:tyw :ind their Iiehavitrr was followed up several hours: i l ~ e ridiiiinist ratioti of t tic 1-onipouiidr. .$ hehavior sheet similar10 h:it desc-ril)eti !,y S ~ r t o n ' ~as used for assessment. In mcisiI ~ : I S W four animals were admi nistered each dose level.Intracerebroventricular Injections: in cats a Collison c3anul:iNX S iinI)litiited i n t i 1 rhe left lateral ventricle under pentoliarhital: i i i w t hesia : i i i t i iiseptir cciiidiiions. Th e anirnals were used 1 week:1f1 ('r i i l w r a t ion.

Ciint ro l ra t 9 rewived saline.Digging Test. -The gerhil ( . l l o i o u ~ s r i s t ru v i i ) shci

8/8/2019 J.Med.Chem.1969.12.473-477

5/5

May 1969 SPASMOLYTICH. 477subs t i tu t ion in the phenyl r ing decreases the psycho-t rop ic ac t iv i ty . In contrast , thienyl instead of phenylpromotes ac t iv i ty . Th us 16a was considerably moreac t i v e t h an 7a when compared o n a weight basis .-\1so3 var iation of t he a min oa lkj 1 group a l t ers thephaimacological act ivi ty of the molecule. Fo r exam ple,

S -m e t h y l am i n o - ( l ) ,N,N-dimethylamino- ( 5 ) , and 4,4-dimethylpiperidino- (14) analogs were considerably lessact ive than th e N-ethy lamino der ivat ive (3 ) o r 7 itself.Quaternizat ion (7c) renders 7 total ly inact ive, evenwhen adm inis tered intracerebroventricularly in order toby-pass the blood-brain barrier.

Spasmolytics. I . 3-Tropanyl 2-Arylacrylates and 3-Tropanyl 2-Arylhydracrylates'HEXRY . CALDWELL,OSEPH. FINKELSTEIN,O R D G E RBAKOV, CAROL PELIKAN, AN D \v ILLIAlI G. GROVES

Research and Dezelopment Dzciszon, Srnzth Klzne Ce. French Laboratories , Philadelp hia , Pennsyli anznRecezved .Youember 18, 1968

Synthesis and biological activities of a series of 3-tropanyl 2-arb-lacrylates and a series of 3- t ropanyl 2-aryl-hydracrylates are described. Th e acrylates had spasmolytic activity without anticholinergic effect. In contrastthe hydracrylates did not show this separation.Since th e adv ent of synth et ic ant ichol inergic spas-moly t ic d rugs , there h as been an in tens ive ef for t todiscover agents with lessened ant ichol inergic (dryness

of the mouth, blurring of vis ion, urinary hesi t 'ancy)side effects . Tho ugh a papaverine-l ike or musculo-tropic kind of sp asmoly t ic act ion has been soug ht ' ,papaver ine an d i t s analogs have no t ' been very usefu lclinically becau se of the ir poor ora l efficacy an d cardio-vasc ular side effects. In 1958, Bachrach , summariz ingthe l i terature on ant ichol inergic drugs, concluded t 'hatnone of the synthet ic agents exhibi ted specifici ty foran y par t i cu lar o rgan funct ion or segment of the gas t ro-in tes t inal t rac t . Fu r t h e r , h e n o t ed t h a t t h e re w as n osingle anticholine rgic of choice for an y gastroin testin ald i s tu rbance un less it is at ropine or bel ladonna becauseof low cost . Five years later, Friend concluded th ata t rop ine a nd bel ladonna were in "no imm edia tedan ger of being replaced" by new s ynt'h etic agent^;^the s i tua t ion is l i t tl e changed today .A major ob ject ive of synthet ic work in th i s areahas been to separa te the s ide ef fec t s f rom the des i redant isecretory a nd ant ispasmodic effects. M an y dif-feren t s t ruct 'u ra l var ia t ions in bo th t he t rop ic ac id a ndtropine moiet ies have been made wit 'h atropine, but .none ha ve completely el iminated th e s ide effects .E'or t ,his s tud y we w anted to determine if this separa-t ion could be ach ieved by subs t i tu t ion in the benzenering of atropine. Th e interm ediate t ' ropic acids (Ta bleI) were prepared f rom the appropr ia te ly subs t i tu tedphenylacet ic acids by th e metho d of B licke, et al . ,4 nvarying yields . For th e est erif icat 'ion s te p avai lablel i t 'e ra ture suggested th at the known sequences l ead ingto a t rop ine gave on ly moderate y ie lds . For example ,p-fluoroatropine, the only report 'ed nuclear-subst i tutedat rop ine , was made in '267, yield by Berger, et al . , jusing a modified Wolff enstein an d l la m lo ck 6procedure.One possible reason for this lo^ yie ld was thought tobe the absence of a solvent in the esteri f icat ion s tep.

(1) Presented before th e Division of Medicinal Chemistry at the 166thNational Meeting of the American Chemical Society, Atlantic City, N. J. ,Sept 1968.12) W. . Bachrach. . Im. J . Dige s t . Diseases , 3, T43 (1958).( 3 ) D. G . Friend. C l i n . Pharmacol. T h e r a p . , 4 , 555 (1563).(4) . F. Blicke, H. Raffelson, and B. Barna, J . .Am. Chem. Soc., 74 , 25 3(I'J.52).( 2 ) I t . S. Berger, .1.E. Jacoliioii, and .1..1.Kondritzer, J . O r g . Ciiem.,

22 , 4.il (1 0 . 5 7 ) .(Ci) R . Wolfieiiateiii and L. hlamlork, Ctiem. Ber . , 41 , 7 2 3 ( leos).

I n our work when dry pyr id ine was added th eproduct w as the corresponding acry la te I ; in con t ras t ,w h en d ry DJIF was used and then acid hydrolysis ofthe pro tec t ive 0-acety l g roup , it gave the expectedhydracry la te I1 (see Char t I) . This faci le dehy drat ion-deacetylat ion react ion in the related acylscopolamineshas been s tud ied in deta i l by G arre t t , ' who found th ati t occurred during basic, but not acid, hydrolysis .Th e pure hyd racry la tes (Ta ble 11) were ob ta ined inmodest yields . It is of i n t e r e s t t h a t Sch m i d t , et al.,shave modified this procedure using microquanti t ies oftropine hydrochloride and 0-acetyl t ropic acid chloride,to give pure atropine in reproducible yields of 7OyG,.

Experimental SectionWhere aiialyseh are indicated by elements only , the analytical

results obtaiiied for those elements were within &0.4%, of thecalculated values.Chemistry.-Melting points were determined in open capilla rytubes using the Thomas-Hoover Uni-Melt and are Iincorrected.Subst ituted Phenylacetic Acids.-2-Chloro-, 3-chloro-, and4methylpheiiylacetic acids were available commercially. 4-Chloro- and 4-bromophenylacetic acids were prepared from thenitriles by acid hydrolysis.9 2,6- I ) ich lorophei i~- lace t iccid wasprepared from the nitrile in 52Yc yield by saponification withKO H iii ethylene glycol. 4-t-Butylphenylacetic acid was pre-pared bl- cai,hoiiating the Grignard reagent of 4-t-butylbenzylchloridelo which was prepared from t-butylbeuzeiie.Tropic acids (Table I ) were prepared by adding CHZO to theIvanov reagent prepared from the appropriately substitutedphenylaceti c acid and i-PrSIgC1 according to Blicke, et2-(4-Trifluoromethylphenyl)-2-hydroxypropionic cid was pre-pared by the general method used by Skerrett and Woodcock."A Grigiiard reagent was prepared by adding 246.5 g (1.09 moles)of 4-bromobe1izotrif l~ioride o 26.6 g (1.09 g-atoms) of 3Ig inEt20 and 10 drops of 3 ,I1 EtS lgB r in 2 hr Tvith stirring. Thesolution was heated at reflux temperature for 1.5 hr and cooledwith ice water. PyrIivic acid (32 g, 0.365 mole) in Et 2 0 (100 nil)was added in 45 miu, and the mixture was heated at refluxtemperature for 20 hr, cooled to ,j0, nd decomposed with 105;;H2S04. After filtratioii through Filtexel, the organic layer wascollected and extracted with 10yc SaOH. Acidification %ithHCl and extraction ( E t Z O ) , ave after drying aiid evaporation ofthe E tD , a residue which, oii recrystallizatioii from CsHa-hexane,(T) E. R. Garrett, J . . l m . C h e m Soc., 79 , 1 0 T 1 ( 1 9 5 2 .( 8 ) G . C. Schmidt, T . E. Eling, and J. C. Drach, J . Pliaiin. Sci . . 56 , 231

( l ' J 6 i ) .(9 ) H. Gilman and A . H. Blatt, "Organic Sj-ntlieses," C'oll. Vol. I . 2nded , John V'iley & Sons, Inc., S r w Tork, X. T.,944, I,436.

(10) E. E. Royals and R . X. I'rasad, J . d m . Chem. Soc . , 7 7 , 1646 (3933).(11) E. J . Skcirctt and D. TI-oodcock, J . Chem. Soc., 2803 (1932).