4 amino 4 aryl cyclohexanones - 1. modification of the aryl ring

8/4/2019 4 Amino 4 Aryl Cyclohexanones - 1. Modification of the Aryl Ring

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42 4 J . M e d . C h e m 1980, 23, 424-430

white solid (98%): mp 139-140 "C; [ u I z 5 ~1.2' (c 1.2, CH,OH).Anal. (CI6Hz2N2O7), H, N.

Acknowledgment. We acknowledge the Food andDrug Administrat ion (Grant F D 00590) for their supp ortof this investigation. M.K. than ks the Mitsubishi-KaseiInstitute of Life Sciences for enabling him to perform thiswork. We also tha nk Constance Mullin for her help inpreparing this manuscript .

L-Aspartyl-L-m,p-dimethoxyphenylalanine ethyl Ester(20) . The coupling reaction followed general procedure B. T h eresidue obtained from removal of th e solvent under reducedpressure wa s crystallized from isopropyl alcohol to give N-(ben-zyloxycarbony1)-P- enzyl-L-aspartyl-L-m,p-dimethoxyphenyl-alanine methyl ester as a white solid (61%): mp 154-155 "C; [0IED

$41.4" ( c 1.0, CHC13). Anal. (C31H34N20 9), H , N.The deprotection reaction followed general procedure D.

Removal of th e solvent under reduced pressure yielded 20 as a

4-Amino-4-arylcyclohexanones and Their Derivatives, a Novel Class of Analgesics.

1. Modification of the Aryl Ring

Daniel Lednicer,' Philip F. VonVoigtlander ,* an d D. E dw a r d E mme r t

T h e U p j o h n Com pan y, Research Laborator ies , Kalama zoo, Michigan 49001. Received Aug ust 7, 1979

Investigationof central nervous system activity of phenylcyclohexylamines wa s continued by preparation of "reversed"analogues. Following the unexpected finding of analgesicactivity with 1-(dimethylamino)-1-phenylcyclohexylamine,the SAR of the series was investigated. Synthesis starts by double Michael reaction of acrylate on arylacetonitriles.Following cyclization, decarboxylation,ketalization, and saponification, he geminally substituted acid is rearrangedto the isocyanate by m eans of (C6H50)2PON3.socyanates were then converted to the title compounds. Analgesicactivity is very sensitive to he nature and position of th e substituten t on the aromatic ring. The most potent compoundsin this series ( p - C H 3 ,p-B r) showed 50% the potency of morphine. Deletion of the ring oxygen abolishes activity.

Com poun ds related to 4-phenylcyclohexylamine haveproven a fruitfu l nucleus for the p reparati on of biologicallyactive compounds. Suitable modif ications of this m oietyhave provided several series of compounds which showneuro leptic activity;' subs titution of a carbon onto the ringato m bearing aryl leads to hypo tensive agent .̂^ One ofth e more interesting of the earlier series was tha t in whichth at same carbon bore an oxygen substituent.2 It was thusof some in terest to ascertain th e effect on biological activityof placing a nitrogen atom o n tha t apparently im portantposition. Specifically, we und ertook th e preparatio n of4-phenyl-4-(dimethylamino)cyclohexanone1 . Random

o3

6 H 5

/ t u \

C H 3 C c I 3

1

screening surpr isingly showed this com pound t o exhibitnarcotic-like analgesic activity. This was particularly un-anticipated because th e molecule departs so radically fromthe various SAR correlations proposed for centrally actinganalgesic^.^ We thu s unde rtook th e system atic investi-

gation of th e SAR in this ser ies. Th e present report dealswith th e effect on activity of modification of th e arom aticmoiety.

Chemistry. Our init ial approach t o these deceptivelysimple compound s rel ied heavily on the schem e we had

devised in con nection with th e earlier work for constructionof the su bstitu ted carboxylic acids (7 ) (Scheme I).3 T hi sroute offered the advantage that most of the requiredarylacetonitriles are commercially available (the p - t e r t -butylnitrile was obtained in a straightforward man ner fromth e benzyl alcohol) . Th e key to the sequence was the

(1) Address: Mead Johnson & Co., Evansville, Indiana 47721.(2 ) See, tor example, D. Lednicer, D. E. Emmer t , R. A. Lahti, and

A. D. Rudzik, J . Med. Chem. , 16 , 1251 (1973).( 3 ) D. Lednice r , D. E. Emmert, A. D. Rudzik , and B. E. G r a h a m ,

J . M e d . Ch e m. 18, 593 (1975).

( 4 ) (a ) 0. Schauman. Pharrnazie , 4,364 (1949); (b ) A. H. Beckettand A. F. Cases, J . Pha rm. Pharrnacol., 6, 986 (1954); (c ) P.S. ortoghese, J . Ph ar m Sc i . , 55 . 865 (1966).

0022-2623/80/1823-0424$01.00/0

Scheme I

C O z C H 3

A r C H Z C N - r < - r

2 C O z C H 3

4 , R' = CO,CH, ; R2 0

5 , R' = H; R2 03

2-

6, R ' = H ; R 2 = (

/ N \ D o r 7 0 : I14NCH3 - r 7 Q : IC H 3 C H 3 7 , R 3 = C O , H9, R4 = H

11 10, 4 = C H , 8 , R J = NCO

recently developed modif ication of th e Curtius reactionwhich allows this transformation to be carr ied ou t in th epresence of acid-labile group^.^ We mod ified this proce-dure yet further in tha t we substituted an inert high-boilingsolvent (an isole) for the alcohols used i n th e original work.I t i s a t r ibute to th e ext reme s te r ic hindrance about thequaternary carbon t ha t th e isocyanates (8 ) obtained by thisreaction sequence are usually stable to chromatographyon silica gel-the routin e isolation procedure. For reasonswhich are not immediately app arent, the produ ct from theacid containing th e 2- thienyl group as th e aromatic sub-

stit ue nt showed th e expected isocyanate reactivity; in thiscase, the reaction was run in ethan ol to afford the corre-sponding carbamate. Reduction of 8 by means of LiAlH,afforded the secondary amine (9 ) . T hi s w a s t he n me th -ylated by m eans of CHzO an d NaBHd6 the hindered na-ture of th e am ine again manifested itself in the ob servationth at at least one recycle was required to assure com plete

(5) T. Shioivi , K. Ninomiya, and S. Yamada , J . A m . Ch e m. SOC. ,94 , 6204 (1972).

(6) R. L. Sondergam, J. Hentchoya , H. Charle, an d G. Charles,Tetrahedron L et t . , 261 (1973).

C 1980 American Chemical Society



4-Amino-4-arylcyclohexanones

Tab le I. Analeesic Act iv i tv

Journal of Medicinal Chemistry, 1980, Vol. 23 , No. 4 425

“0./ N \

C H 3 C H 3

analgesic ac t . := ED,,, m g lk g b

no . Ar X f l ick p inch screen wri the an ta g

1 a1 0 al l b10 bl l c1 cl l d1 0 d1 e1 0 el l f1 0 fIlk!

l o gl l hl l i1Oil l j

l O jI l k1 0 k11 1101l l m1 0 ml l n1 0 n110

1 0 01 l P1 9 P1 1 ql o a

C6H5

C6HS2 - th i en y l2 - th i en y l

1 - n a p h t h y l1 n a p h t h y l

o -CH C, H,o -CII C, ,

m-CH,C,H,m-CH,C,H,p - C H 3 C 6 H 4

p - C H 3 C 6 H 4

m - ( C H 3 0 ) C , H ,m -(CH,O)C,H,p-(CH30)C6H43,4-(CH30)2C6H33,4-(CH30)2C6H3

P-FC,H,p - F C 6 H 4

o-ClC,H,0-ClC,H,m-ClC,H,

p-ClC,H,p-ClC,H,

m-ClC,H,

p-BrC,H,p -Br C, H,3>4- (C 1)2C 6H3

3,4-(Cl),C,H,2 ,4 - (Cl ) ,C ,H,

0OCH,CH,O0OCH,CH,O0OCH,CH,O0OCH,CH,O0OCH,CH,O0OCH,CH,O0OCH,CH, 000OCH,CH, 00

OCH,CH,O0OCH,CH,O0OCH,CH,O0OCH,CH, 00OCH,CH, 00OCH,CH,O0

7 1

> 10 06 32 4

> 1 0 0>10 0

6 3>100

7 1> 10 0

13

> 1008119

> 2 58 74 4

3522

7 1> 1 0 0> l o o

8443

6 3> 1 0 0> 10 0

6 6>100

6 347

> 1 0 0> 1 0 0

63> l o o

7 9>100

42

7 12 92 0

> 2 57 14 4

13357 1

>100>100

9353

6 3> 1 0 0>100

>1 0 0>1 0 0> 1 0 0> 1 0 0> 10 0> 100> 10 0> 1 0 0> 10 0>1 0 0>50

> 2 5>100

> 1 0 0> 25> 2 5

> 100> 5 0

> 2 5> 100> 10 0>10 0> l o o>2 5> 25

> 1 0 0> 100>1 0 0> 100>1 0 0

4 4

> 1 0 03 22 2

> 100> 10 0

6 32256

> 100

32

471 719

> 2 57 110

1 52 07 1

> 1 0 07 1

3

421

> l o o> 1 0 0

7 1

>100>100>100> 1 0 0>100> 1 0 0> 100> 100> 1 0 0> 1 0 0>5 0> 2 5

> 100>100

> 2 5> 2 5

> 100>5 0

> 2 5> 100> 100>100

> 100> 2 5> 2 5

> 100> 100> 1 0 0> 100> 100

2;4-(Clj;C,H; OCH,CH, 0 2 5 2 5 > 100 10 > 10 0

p-[(CH3)3ClC6H4 0 > l o o > 1 0 0 > l o o >10 0 > l o op-[(CH3),CIC,H, OCH,CH, 0 >1 0 0 > 10 0 > 100 > 10 0 > 1 0 0

meper id ine hydrochlor ide 2 2 2 9 > l o o 1 5 >10 0m o rp h in e su l f a t e 1 . 5 1 .6 > 100 0 .6 > 1 0 0

p en tazo c in e l ac t a t e 7 6 > 5 0 4 > 5 0T h e u p p e r a n d l o w e r 9 5 % conf ide nce in tervals ( ref 10) w e r e n o t m o r e t h a n 2 a n d 0 . 5 t im e s t h e ED,, respectively.

See Ex p er im en ta l Sec t i o n an d r e f 8 for descr ip tion of method s.

reaction). Finally, prolonged exposure to acid gave the freeketals. It is of interes t in this connection th at th e fearedelmination of the tertiary benzylic amine was never ob-served under th e admittedly m ild condit ions used.

In order to ascer tain the role of the oxygen at the 4position, th e deoxy counterpart (13) of th e lead compo undwas prepare d in a straightforward manner by displacem entof the cyano group from the P-aminonitrile of cyclo-hexanone (12) by means of phenylmagnesium bromide(Scheme II).7 Th e necessity for the arom atic portion wastested by replacing this group with a cyclopentyl ring.

Th us , alkylat ion of th e anion from 14 (LDA) with cyclo-pentyl bromide gave 15 in workable yield. T he ester wasthen saponif ied and the ac id taken on to th e dimethyl -amin e analogue 20 by th e same sequence as tha t used inthe m ain ser ies.

Results

T h e EDh0values for these compou nds are recorded inTable I. Th e ketals and ketone analogues were of similarpotency. Substi tut ion on th e aromatic ring has a pro-nounced effect on activi ty in th is ser ies. A substantialenhancement of potency is seen by inclusion of a sub-

( 7 ) C . R. Hauser and D. Lednicer, J. Org. Chern., 24 , 46 (1954).

S c h e m e I1

M e 2NcD-c6H5>0e 2 N

1 5 , R = C,H,1 6 , R =

1 4

0

yo(]- Y o 0N \

1 7 . R = N CO C H 3 C H 3

208;R = N H C H ,1 9 , R = N(CH,) ,

stituent in th e para position. Ortho and meta substitutiongive agents with moderate activity. At first sight, the rankorder of activity (CH3 y Br > C1 > CH,O > F > H ) issuggestive of som e steric effect; it is of note in th is con-nection th at th e p- te r t-bu tyl compound is iner t in this



426 J o u r n a l of Medicinal Chemist ry , 1980, Vol. 23, No. 4 Lednicer , VonVoigt lander, Ernrnert

T a b l e 11. D i m e t h y l 4-Aryl-4-cyanopimelates'

E,,? jj c r d i n e 1F i g u r e 1.

assay at the top screening dose. I t is of note, too, tha t al l

compounds reported in Table I are devoid of sedative(screen) as well as m orphin e antag onistic (antag ) activity.Two compounds (13 a n d 20 ) not l isted in Table I wereinactive on all five of the end points.

Fu rthe r work on selected analogues shows these agentsto be classical opioids.R Effects of these com pounds c an,for example, be reversed by administration of naloxone.We consider this a t least presumptive evidence th at theseinteract w ith th e same receptors as do classical narcotics.This observation is at f irst sight surpr ising, since thecompounds in q uestion differ markedly from the connec-tivity posited by Beckett an d Casey. Closer examination,however, shows topological similarity to the prototypenarcotic meperidine. Com parison of Dreiding models of1 and meperidine, wherein th e phenyl groups are axial lyd i s p ~ s e d , ~llows direct su perposition of carbonyl oxygensand nitrogen (N o 0 distance is 5 8, n each compound).It is of note t ha t th e aromatic r ings wil l the n occupy thesam e plane with about 0.5 8, eparation (Figure 1). Whileit is temptin g to ad duce physical signif icance to this ob-servation, more detai led data is needed regarding themolecular pharmacology of these compoun ds. Th e topo-logical coincidence does, howev er, serve to rationalize th eactivity of the above agents.

Experimental SectionAll melting points ar e uncorrected and reported as observed

on a Thomas-Hoover melt ing poin t apparatus . The au thors areindebted to the Department of Physical and Analytical Researchof T he U pjohn Co. for spectral and elemental analyses. Analytical

results indicated by eleme nt symbols were within f0.4% of theory.p-tert-Butylphenylacetonitrile.A solution of 5 mL ofthiony l chloride in 10 mL of benzene w as added to 10.0 g (0.061

mol) of p-tert-butylb enzy l alcohol in 85 mL of benzene. Following30 min of stirring a t room tempe rature, the m ixture was heatedto reflux for 4 h. Th e mixture was allowed tocool, and the solventwas removed un der vacuum . Th e residue was disti l led a t 0.05mm to afford 10.14 g (92 %) of product, bp 62-65 "C.

A mixture of 9.64 g (0.053 mol) of the ben zyl chloride obta inedabove, 10.13 g of p otassium cyanide, an d 0.10 g of p otassium iodidein 71 mL of water an d 150 mL of methanol was heated at refluxfor 1 h. Th e bulk of the metha nol was removed under vacuumand the residue extracted with ether. Th e organic layer waswashed with water and brine an d taken to dryness. Distil lationof th e residual oil at 0.03 mm afforded 6.38 g (70%) of product.bp 7 S 8 4 "C. Anal. (C12H21N) , N; C: calcd, 83.19; found , 82.56.

D i m e t h y l 4 - A r y l - 4 - c y a n o p im e l a t e s T a b l e 11). A mixtureof 0.10 mol of th e app ropriate a rylacetonitri le, 47 m L of methylacrylate, and 60 mL of tert-b utyl alcohol was broug ht to reflux.Th e source of heat was removed and the re was added quickly 15.2m L of Tri ton B in 23 mL of tert-b utyl alcohol. Following 4 h ofheating a t reflux, the m ixture was allowed to cool and diluted w ithwater a nd benzene. Th e organic layer was separated, washed withwater an d brine, and taken to dryness. Th e residue was disti lledf i rs t at 40 mm to remove excess reagent; the pressure was thenreduced and the product allowed to distill over. These esters were

(8) D. Lednicer and P. F. V onVoigtlander, J . M e d . Chern.. 22 ,1157 (1979).

(9 ) The phenyl ring in a closely related compound has been de-termined by NM R and X-ray diffraction to oc c upy the axialposition. D. Lednicer and D. J. DuChamp, J . Org. Chern. . 39,2311 (1974) .

____

C O z C H 3

C O Z C Y 3

yield ,no . Ar % b p ( m m H g ) , "C

3b 2-th ienyl 73 162-180 (0.05)3d o-CH,C,H, 37 168-175 (0.03)3e rn-CH,C,H, 66 165-174 (0.04)

3f p -CH,C,H, 73 170-180 (0.07)3g m -(CH,O)C,H, 56 180-187 (0.08)3k o-ClC,H, 73 170-183 0.08)31 m-CIC,H, 64 175-181 0.04)3n p -BrC,H, 7 0 183-193 (0.04)30 3,4-( l), C,H, 70 187-196 (0.04)3P 2 144Cl), c, H, 66 183-184 (0.04)3q p-[(CH,) ,C]C,H, 70 180-199 (0.05)

a All products w ere v iscous o i l s ; non e were subjected toco m b u s t io n an a ly ses.

characteristically very viscous oils and were, as a rule, notcharacterized further.4-Aryl-4-cyano-2-carbomethoxycyclohexanonesT a b l e

111). Solid potassium te rt-buto xide (22.5 g, 0.20 mol) was addedto a solution of 0.10 mol of the cya nopim elate in 700mL of THF.Th e mixture was heated a t reflux for 5 h, cooled in ice, and treatedwith 170 mL of 2.5 N acetic acid. Th e organic layer was separated,diluted with benzene, and washed in tu rn with aque ous sodiumbicarbonate, water, and brine. Th e solid which remained w henthe organic solution was taken to dryne ss was recrystallized. Inthose cases where th e p roduct failed to crystall ize, i t was useddirectly in the next step.

4 - A r y l - 4 -c y a n o c y c l o h e xa n o n e s ( T a b l e I V ) . A mixture of0.100 mol of the carbomethoxycyclohexanone, 310 mL of 10%aqueous sulfuric ac id, and 720 mL of acetic acid was stirred ona s team bath for 24 h. Th e mixture was the n allowed to cool,diluted with water, and extracted thoroughly with ether. Th eorganic layer was washed with water, aqueous sodium bicarbonate,and brine. The solid which remained when the e xtract was takento dryness was th en recrystallized.

In several cases the product crystallized on dilution of thereaction mixture. Th e solid was then collected on a fi l ter and

recrystallized.4 -Ary l -4 -cy an ocy c lo h ex an o n e E th y l en e K eta l s (Tab l e V ).

A mixtu re of 0.050 mol of th e cyano keto ne, 3.6 mL of eth yleneglycol, and 0.16 g of p-toluenesulfonic acid in 140m L of benzenewas stirred at reflux under a Dean-Stark trap for 6 h. Th e solutionwas allowed to cool, washed w ith aqueous sodium bicarbonate,and take n to dryness. Th e residual solid was then recrystallized.

4-Aryl-4-carboxycyclohexanonest h y l e n e K e t a l s ( T a b l eV I ) . A mixtu re of 0.070 mol of th e cyano k etal a nd 15.0 g (0.38mol) of sodium hydroxide in 150 mL of ethylene glycol was stirredat reflux for 18 h. The mixture was allowed to cool, diluted withice-water, and covered with ether. Hydrochloric acid was the nadde d slowly with continuous stirring until t he aqueo us layer wasstrongly acidic. Th e organic layer was separated, washed withwater and brine, and taken to dryness. The residual solid waspurified by recrystallization.

4-Aryl-4-isocyanatocyclohexanonet h y l en e Keta l s (Tab l eV I I ) . To a m ixture of 0.040 mol of the appropriate 4-aryl-4-carboxycyclohexanone ethylene ketal and 5.6 g of triethylaminein 100 mL of anisole was added 11.17 g of diphenyl phosphonicazide. Th e mixture was the n warmed to 90 "C in an ice bath(effervescence was noted a t 80 "C). A t the end of 2 h the solventwas removed by means of a mechanical vacuum pump. Th e totalresidue was chroma tographed as quickly as possible on silica gel.Th e isocyanate (urn= 2250-2270 cm-') th us obtaine d was recrys-tallized when a solid. Whe n an oil , the produ ct was reducedwithout further purification.



4-Amino-4-arylcyclohexanones

Tab le 111. 4-Aryl-4-cyano-2-carbometo x y c y c l o h e x a n o n e s

J o u r n a l of Medicinal C hemist ry, 1980, Vol. 23, No. 4 427

F O z C H 3

*J0

N C

no. Ar rx n so lv en t m p , "C y i e ld , % fo rm u la

E t ,O-PE

Et ,Ob

b

a

Me,CO-SSBEt ,Ob

CH , C1,-SSB

Et,O-PE

7 6 - 7 8 9 0 C13H13N03S

1 0 7 - 1 1 3 " 9 3

9 99 9

113 - 1 1 8 9 5

1 2 6 . 5 - 1 2 8 9 0 C16H17N03

1 2 3 - 1 2 5 7 6 C1SH14C1N03

1 6 4 -1 6 6 6 7 c SH 14Br N O 3

82- 87' 9 5 CIS Hl,C1,NO 3

9 5

1 0 8 - 1 1 0 7 8 C19H23N03

(I Could no t be sat i sfactor i ly recrystal l ized . A m o r p h o u s g u m . An aly t i ca l sam p le m el t ed a t 1 1 2 - 1 1 3 "C .

Tab le IV . 4 -Ary l -4 -cy an o cy c lo h ex an o n es

Ar

NC

rx n so lv en t m p , "C y i e ld , % fo rm u la

5b 2- th ienyl CH,Cl ,-SSB5d o-CH,C ,H, Et ,O-SSB5e rn-CH,C,H, Et , -P E5f P-CH,C ,H, Et , 0 -PE

5k o-C lC,H , CH, C1, -SSB5 g m - (CH,O)C,H, E t ,O

51 rn-clc, H,5 n a -BrC. H.

- -PECH,Cl,-SSB

1 1 7 .5 -1 1 986.5-895 1 -5 47 9 -8 27 2-7 6

1 0 6 -1 0 87 1 -7 3 .5

1 1 0 - 1 1 31 5 6 -1 5 7 .51 1 9 -1 2 2 .51 4 1 - 1 4 3

6 67 87 67 46 48 05 47 05 85 47 8

Tab le V. 4 -Ary l -4 -cy an o cy c lo hex an o n e E th y l Keta ls

N CArx3:ln o .

6 b6 d6 e

6f

6 g6k616n60

6P

6q" Cy clo h ex an e .

rx n so lv en t

C,Hl,"

PEC6H1,SSBC,Hn

Et , 0 -PE

Et ,O-PE

m p , "C y i e ld , % fo rm u la

9 0 .5 -9 265.5-68 .536.5-38

1 0 7 .5 -1 1 07 0 -7 29 8 .5 -1 0 16 8 -7 1

1 2 7 - 1 3 11 2 0 .5 -1 2 31 0 9 .5 -1 1 2

1 2 4 -1 2 5 .5

9 08 56 19 29 2899 19 69 69 1

8 9

R e a r r a n g e m e n t of t h e 2 -T h i e n y l A ci d 8 b i n E t O H . T o asolution of 2.68 g (0.010 mol) of 4-carboxy-4-(2-thienyl)cyclo-

hexanone ethylene ketal and 1.39m L of triethylamine in 40 m Lof ethanol there was added 2.75 g of diphenyl phosphonic azide.Following 5 h of heating the so lution at reflux, the bulk of thesolvent was removed under vacuum. Th e residue was dissolvedin water and ether-benzene. Th e organic layer was washed, inturn , with wate r, ice-cold 2.5 N hydrochloric acid-water, saturatedsodium bicarbonate, and brine and taken to dryness. Th e residualsolid was recrystallized from cyclohexane to give 1.58 g (51 %)of produ ct, mp 113-117 O C . Anal. (C1 5 H 2 1 N0 4 S), H , N .

4-Aryl-4-(methylamino)cyclohexanone t h y l e n e K e t a lH y d r o c h l o r i d e s ( T a b l e V I I I ) . A solution of 0.29 mol of the

4-aryl-4-isocyanatmyclohexanonethylene ketal in 140 mL of THFwas added to a well-stirred suspension of 1.67 g of lithium alu-minum hydride in 13 mL of THF. The m ixture was heated a treflux for 4 h and then cooled in ice. There w ere added, in tur n,1.7 mL of water, 1.7 mL of 15% aqueous sodium hydroxide, and5.1 mL of water. Th e inorganic gel was collected on a fi l ter andthe f i l t rate taken to dryness . A solution of the re sidue in etherwas then trea ted w ith a jus t sufficient am ount of 3 N etherealhydrogen chloride to precipitate all the am ine. Th e solid wasrecrystallized from methylene chloride-ethyl acetate. In thosefew cases where the free base was crystall ine, this produc t wasrecrystallized directly.4-Aryl-4-(dimethylamino)cyclohexanone t h y l en e Keta l s



42 8 J o u r n a l of Medicinal Chemist ry , 1980, Vol. 2 3 , *Vo. 4

Table V I. 4-Aryl-4-carboxycyclohexanone t h y l en e Keta ls

Lednicer , VonV oigt lander , Em me rt

no . Ar rx n so lv ent m p , "C y i e ld , % fo rm u la

7 bI d7e

7f7g7 k717 n7 0

7 P7 q

2 -t hieny 1

m -CH,C,H,

m - (OCH,)C ,H,

o - C H 3 C 6 H ,

P- ' H3 ' H4

o-C1C6H,m-ClC,H,

CH,Cl,-SSBCH,Cl ,-SSBCH,Cl,-SSB

CH,CI,-SSB

CH2C1,-SSBCH,C12-SSBCH,Cl,-SSBEt ,O-PE

CH,CI,-SSBE t O A c

1 2 5 -1 2 7 8 2 C , ,H, ,O,S174-17 7 63 C ,H;;O;1 5 2 - 1 5 4 8 4 C 16H2004

1 7 2 - 1 7 4 8 5 ' 6H2 0 '4

102-107 ' 99~~

195 -197 77 C,SHl ,ClO,

c 5H 7Br 0 ,

1 4 0 - 1 4 1 .5 7 9 C , s H , ,C I O , b9 27 6 - 1 7 8

1 1 9 - 1 2 1 . 5 8 0 C 1 5 H 1 6 C 1 2 '

1 9 2-19 5 .5 71 C 1 5 H1 6 C 1 2 '

198-2 00 74 C, ,H, ,O4

a Could no t be sat i sfactor i ly recrystal l ized . C : ca l cd , 5 2 .8 0 ; fo u n d , 5 3 .4 0 .

Tab le VI I . 4-Aryl-4-isocyanatocyclohexanone t h y l en e Keta ls

n o .8 a8c8 dBe8f

8g8h8i

ch ro m a o g r so lven t rxn so lvent m p , "C y i e ld , % fo rm u la7 . 5 E t O A c - S S B2Et OAC-CH , C1,2EtOAc-CH,C12

0.1OEtOAc-SSB1 SEtOAc-CH, C1,2 .5 E tOAc-CH2 Cl ,3 0 EtOAc-SSB1Et OAc-CH,Cl ,1 0 E t O A c - S S B

CH,Cl,

PE

a

Et ,O-SSB

aQ

a

SSB

a

a

Q

4 8 -5 0 7 5 C I S H l J O 31 1 1 - 1 1 4 6 0 19 19No

8 090

8 42 5

2 83 58 4

7 0 .5 -7 2 6 2 C 1 6 H 1 9 N 0 4

81 CH,Cl, Q 97

80 3 4 -(C1) c ,H 2 .5EtOAc-CH2C1, Q 7 1

8 P 2 , 4 - ( C 1 ) 2 C 6 H 3 1 .5 E tOAc-CH,Cl , E t , - P E 8 5 - 8 9 . 5 7 7 c S Hl,Cl2NO 3

8m p-C1C6H, 1OEt OAc-SSB PE 76 .5-8 0 43 C1SH16C1N03

8 n P - B r C , H , CH,CI, Et,O-PE 8 7 -8 9 49 I S H 16Br 3

8q P- [ (CH, )3 c]C, H , ~ E ~ O A C - C H ,12 SSB 103-1 05.5 7 1 C 1 9 H 2 5 N 0 3

a Oily p ro d u c t , ch arac t e r i zed b y I R o n l y (urnax 2 2 5 0 - 2 2 7 0 c m - ' ) .

Table VIII. 4-Aryl-4-(methylamino)cyclohexanone t h y l en e K eta ls

no . Ar salt mp, "C y ield , % fo rm u la

9 a C ,H5 HCl 2 4 3 -2 4 5 7 8 C , H, ,C lNO,9 b 2 - th i en y l HC1 2 1 1 -2 1 4 3 5 c ,H2,,ClNO,s9 c 1 - n a p h t h y l 1 2 0 - 1 2 3 .5 5 4 C l '4H23N02

9 d 0 c c H , H C l 2 3 1 - 2 3 3 6 0 C , b H , 4 C l N 0 , ~ 0 . 5 H , 0

9 e m -CH,C,H, HCI 2 1 9 -2 2 1 5 8 I 6 H24C1N ' 2

9f P-CH,C ,H, 56-60 57 C, ,H,3NO,

9 g m - ( C H , O ) C ,H , H CI 2 3 8 - 2 3 9 7 1 C16H24C1N03C

9 h P - ( C H , O ) C , H , p - T S A 2 0 6 - 2 0 8 88 C23H31N06S

9i 3 ,4 - (C H ,0 1 C ,H HI 2 00-2 01 57 Cl?H261N04

9J P-FC ,H, HC1 262 -26 3 56 ClSH,,CIFNO,9 k o -ClC,H I b 9 6

91 m-ClC, ,H, HCl 252-2 54 56 c 5 H,, c1,N O ,9 m P - C G H , 6 3. 5- 66 .5 91 C, H2,C1N0,

9 0 3,4-(C1),C,H 3 HC1 225 -22 7 46 C,5H,OCl,NO,

9 q P - [ (CH, ) ,C lC , ,H, 1 1 8 . 5 - 1 2 1 9 4 C 19H,, NO2

69 C, ,H, , BrClNO,n p-BrC,H , HC1 266-26 7

9P 2 ,44 C1), ,H HCI 2 0 1 -2 0 3 .5 6 8 C l ,H, ,C l3 NO ,~0 .3 3 H2 O

' r ee b ase . Am o rp h o u s as f r ee b ase o r sa l t . (' C : ca l cd , 6 1 .2 3 ; fo u n d , 6 0 .0 7 .

( T a b l e I X ) . A solution of 0.013 mo l of 4-aryl-4-(methyl-amino)cyclohexanone ethylene ketal (free base) and 18 mL of 37%formalin in 54 m L of me thano l was heated at reflux for 4 h. Themixture was then cooled in ice and treate d cautiously with 2.86

g of sodium borohydride over 10-15 min. Th e mixture was stirredat room tem perature for 2 h, and th e bulk of the solvent was thenremoved under vacuum. Th e residue was parti t ioned betweenwater an d methylene chloride. Th e organic layer was washed with



4 -A mi no-4-ary l cyc l ohexanones

T a b l e IX . 4-Aryl-4-(dimethylamino)cyclohexanone t h y l en e Keta l s

Journal of Medi c i nal Ch emi s t ry , 1980, Vol. 23 , No. 4 429

n o , A r sal t y ield , % fo rm u la

1 0 a10b1OC

1 0 d1Oe1 0 f

1 g10h1 i

lO j1 0 k10 11 0 m1 0 n100

1O P1 o q

C6H52 - th i en y l

1 - m p h th y lo-CH,C,H,rn-CH,C,H,

r n - ( C H 3 0 ) C 6 H ,p - C H 3 C 6 H 4

P-(CH3O C,H,3-(0CH3)2C6H3p - FC 6H4

o-ClC,H,

p-ClC,H,rn-ClC,H,

p -Br C H,3,4-(C1)2C6H32,4-(C1)2C6H3

p - [ ( C H 3 ) 3 C l C 6 H 4

HCl

H IHIHClHClHCl

HIHClH C lHCl

HCl

22 6-2 299 9 - 1 0 3

1 2 8 - 1 3 21 8 2 -1 8 3 .5214-215.522 8-2 291 8 4 - 1 8 5 . 52 0 3 -2 0 4

9 5 -9 8 .579.5-82

2 0 8 -2 1 3224-2272 6 1 - 2 6 2254-2 55 .5

7 7 - 8 12 29 .5 -2 321 0 3 . 5 - 1 0 7

6 818

4 037857 66 87 87 28 51 2 . 65 25 9515 14 09 0

16HWC1N02

I

Cz,H,sNO,

C1,H,61N02c ,H,,ClNO,

Cl,H,,NO,

C,,H,,IN0;0.5 Ha0

C17H26C1N03

C1,H26C1N03

C 1 6 H 2 2 FN 0 2

C ,H,,ClINO,

C, ,H, ,BrClNO,

C16H7.3C12N02

C16H23C12N02

l b H Z I C I Z

C , 6 H , , C 1 3 N 0 , ~ 0 . 5 H , 0C 20H31N02

T a b l e X . 4-Aryl-4-(dimethylamino)cyclohexanones~~ ~ ~~ ~ ~~ ~

C H 3 C H3

n o . Ar rx n so lv en t m p , "C y i eld , % fo rm u la

1 a C 6 H 5 Et ,O 98-99.5 69 Cl,Hl,NOl l b 2 -t h i en y l MeOH-H,O 1 0 2 - 1 0 3 64 CiaHi ,NOS

l l d o -C H ~ C ~ H , ' MeOH-Et ,O 1 6 2 - 1 6 5 3 6 c sH,,INO1 e rn-CH,C6H,a CH,Cl ,-EtOAc 1 7 2 - 1 7 4 . 5 7 5 c 5 H Z P Ol l f p -C H ,C ,H , P E 65-67 .5 55 Cl ,H,lNO1 l g r n- (C H , O )C , H , P E 5 7 - 5 9 4 5 c S H,lNO,l l h p-(CH30)C6H4 SSB 89-91 66 ClSH,,NO,

l l j P- C 6 H , E t ,O 1 2 6- 12 8 7 5 C 1 , H I P O

C l , H , , N 0 ~ 0 . 2 5 H 2 0C 1 n ap h th y l CH,Cl ,-SSB 1 4 9 -1 5 1 .5 2 5

1 i 3>4-(0CH3 ,C6H3 E t , O 9 7 - 9 8 .5 7 1 16H23N03

I l k o -C lC ,H , E t, O 81 84 26 C,,H,, ClNO111 rn-ClC,H, Et,O-PE 9 3 - 9 5 81 Cl ,H1 8 ClNOal l m p -C lC ,H , E t, O 1 0 8 -1 1 1 7 0 C , ,H,,C lNO1 n p - B rC 6 H , Me,CO-SSB 115-118 6 9 C 4 H sBr N0110 3 4-(Cl) ,c6 , E t , 0 -PE 8 8 .5 -9 1 7 2 c14HI,C12 NO1 l P 2 4 -( C 1) ,C 6 H 3 E t , O 1 1 6 .5 -1 2 0 6 8 Cl ,Hl ,C4NO1 l q P-[(CH3)3ClC,H, PE 82.5-8 7 6 0 C, ,HZ,NO

' : ca l cd , 6 6 .7 9 ; fo u n d , 6 7 .3 9 .

br ine and tak en to dryness . Th e residual gum was recycledthrough the above react ion condit ions and workup. The crudeproduct was dissolved in ether and treated with just sufficientethere al hydrogen chloride. Th e precipitated salt was recrys-tall ized from methylene chloride-ethyl aceta te. Whe n the freebase was a s olid, this was recrystall ized as such.

4-Aryl-4-(dimethylamino)cyclohexanones T a b l e X). Asolution of 4 mmol of 4-aryl-4-(dimethylamino)cyclohexaneethylene ketal or its salt in 7 mL of 2.5 N hydrochloric acid and14 mL of methanol was al lowed to s tand at room temperaturefor 48 h. Th e bulk of the solvent was then removed under vacuumand the residue m ade strongly basic with 50% sodium hydroxide.Th e precipitate was extracted with ether. Th e organic layer waswashed with water and brine and taken to dryness. Th e residue,if solid, was recrystallized; f not, the compound was first convertedt o a hydrohalide salt and recrystall ized in this form.

N,N-Dimethyl-1-phenylcyclohexyl-1-amine13). T o asolutio n of 15.2 g (0.10 mo l) of N,N-dimethyl-1-(cyanophenyl)-cyclohexyl-1-amine in 100 mL of T H F there was added 50 m L(0.14 mol) of 2.85 M phenylmagnesium bromide in ether. Fol-lowing 18 h of standing at room tempe rature, the m ixture wascooled in ice and t rea ted wi th 75 mL of satura ted ammoniumchlor ide and 25 mL of water . Th e organic layer was sepa rated ,

washed with water an d brine, and taken to dryness. Th e residuewas dissolved in ether, and this solution was extracted with 5portions of 25 mL each 2.5 N hydrochloric acid. Th e acid extractswere allowed to stand a t room tem perature for 18 h, extracte dwith ether , and m ade s t rongly basic. Th e precip i tated o il wastaken up in ether an d this last solution treated with 1N ethereal

hydrogen chloride. Th e solid which separa ted was recrystallizedseveral time s from methylene chloride-ethyl ace tate to give 7.88g (33% ) of product, m p 164-165 "C, whose NM R spectrum is inconsonance with t he structure. M I calcd 203 (free base); MS m l e203. No satisfactory analysis could be obtained. Anal. Calcdfor CI4HnClN.0.5 CH2Cl2:C, 61.70; H, 8.21; N, 4.99; MI (free base)203. Foun d: C, 62.69; H, 8.59; N , 5.08; MS (M+) l e 203.

4-Carbethoxy-4-cyclopentylcyclohexanonethylene K e t a l(15). To an ice-cooled solution of 10.0 g (0.10 mol) of diiso-propylamine in 100 mL of THF under nitrogen there was added62 mL of 1.68 N butyllithium in pentane. The re were then ad deddropwise, in sequence, 21.4 g (0.10 mol) of 4-carbethoxycyclo-pentanone in 100 mL of T H F and a solution of 14.9 g (0.10 mol)of cyclopentyl brom ide a nd 17.9 g (0.10 mol) of hexam ethyl-phosphoramide in 50 mL of TH F. The mixture was s t i r red for3 h in the cold and 18h a t room temperature. Th e so lu t ion wasagain cooled in ice and trea ted w ith 75 mL of satura ted aque ous



430 J.Med. Chern. 1 9 8 0 ,2 3 ,430-43'7

ammo nium chloride and 25 mL of water and benzene. Th e organiclayer was washed with water and brine an d taken to dryness. Theresidual oil was distilled a t 0.2 mm to give 2.37 g ( 88%)of product,bp 116-124 "c. Anal. (C16H2604) , H .

4-Carboxy-4-cyclopentylcyclohexanonet h y l e n e K e t a l(16). A mixtu re of 10.0 g (0.035 mol) of the este r an d 2.10 g ofNaOH in 80 mL of ethy lene glycol was heate d a t reflux for 18

h. Th e mixture was worked up exactly as above an d the productrecrystallized (SSB) to give 7.22 g (51% ) of acid, mp 110-113 "C.Ana l. (C14H2204) C, H.

4-Cyclopentyl-4-(methylamino)cyclohexanone t h y l e n e

Ac etal H ydro chl or id e (18). The acid (16) obtained above wasrearranged to the isocyanate exactly as above [7.81 g , (C6H5-O),POH,; 3.95 mL of TH F] . Th e isocyanate (oil , v,,, 2280)obtained on chromatography was reduced by means of LiAlH,(1.0 9). Th e basic product obtained after th e usual workup wasrecrystallized as th e HC l salt to give 2.50 g (3 2% ) of crystals, mp179-182 "c . Anal. (C14H26ClN02) , H , N.4-Cyclopentyl-4-(dimethylamino)cyclohexanone t h y l e n e

Ke tal H ydr oc hlo r id e (19) . Th e f ree base from the above sec-ondary am ine hydrochlor ide was subjected to th e s tandard me-thylat ion procedure (CH20, NaBH,) twice. Th e product wasrecrystallized (CH2Cl2-EtOAc)as he HC1 salt to give 0.62 g (2 4% )of salt, mp 200-203 "C. Anal. (C15H2,C1N02)C , H , N.

4-Cyclopentyl-4-(dimethylamino))cyclohexanoney d ro -ch lo r id e (20). Hydrolysis of 1.14 g of th e a cetal as above affordedon crystallization (CH,Cl,-EtOAc) 0.63 g (66% ) of the keton e,hydrochloride salt . Anal. (CI3H2,C1NO)C, H , N.

Biolog y. M eth ods . Th e biological testing consisted of abattery of sta ndar d assays., Briefly, CF -1 female mice were dosedsc with a suspension (or solution) of th e test co mpound in 0.25%aqueous methylcellulose an d 15 min later subjected to a seriesof procedures to detect analgesia, sedation, and na rcotic antag-onism. Th e tail-flick, tail-pinch, and HC1 writhing procedureswere used to detect analgesia, whereas the inclined screen tes t

was used to measure sedation. After the completion of the te sts(about 45 min postinjection), 6.3 mg/kg morphine sulfate wasgiven subcutaneously and 15 min later th e mice were retested onthe tail-flick procedure to determine if the compound might havenarcotic antagonist properties. Blockade of morphine-inducedelevation of tail-flick latency was scored as antagonism . Six micewere tested a t each dose in this battery of assays. When m ultipledoses were examined, the ED50values were calculated by themethod of Spearman and K arber . lo

(10) D. J. F inney, "Statistical M ethod in Biological Assay", HafnerPublishing Co., New York, 1952.

Synthesis and Structure-Activity Studies of a Series of 7a-Halogeno

Corticosteroids'

Ho-Jane Shue , Michael J. Green,*

De p a r t me n t o f Na t u r a l Pr o d u c t s Re se a r ch

Joseph Berkenkoph, Margaret Monahan, Xiomara Fernandez, and Barry N. Lutsky*

De p a r t me n t o f Ph y s i o l o g y, S c h e r i n g -P l o u g h Re s e ar c h , S c h e r in g - P l o ug h Co r p o r a ti o n , B l o o mf i e l d , N e u J e r s e y 07003.Received June 7, 1979

The preparation and topical antiinflammatory potencies of a series of ' in-halogeno-16-substituted-prednisolone

derivatives are described. Th e 7a-Chl0rO,7aLu-bromo,nd 7a-io do corticosteroids were obtained by addition of hydrogenhalide to the 6,7-dehydro compounds. Th e extent of addition of HC l varied with substitution a t C-11, while noaddition of H F was observed at all . Th e 7n-flUOro corticosteroids were prepared by reaction of the approp riate7p-hydroxy compounds with N,N-diethyl(2-chloro-l,l,2-trifluoroethyl)amine.he 'IP-hydroxy steroids were obtained,in tur n, from the 6,7-dehydro compo unds via the 6P,7P-dihydroxy derivatives. Antiinflamm atory potencies weremeasure d in mice by the T onelli croton oil ear assay. Th e greates t effect of a 70-halogen was observed in the16a-methylpred nisolone series, where 7n-ch loro an d 7a-b romo subs titution increased potency 2.5- to 3.5-fold.Compounds 4b a n d 5b were equipotent to betameth asone dipropionate. 'In-Halogen substitution in other seriesproduced more variable effects and sometimes led to a reduction of antiinflammatory potency.

Since the pioneering efforts of Sulzberger and co-workersin the dermatological use of topical hy dr oc ~r tis on e, ~* ~an ychemical modifications of the natural hormones have b een

a t c16, and introduction of a 1 ,2 double bond.g Further-more, it was shown th at topical activity could be enhanc ed

made in attempts to impr ove existing therapy. Most Of

the impo rtant structural changes have involved halogen-a t ion a t c6 a n d / o r C9,*l5methylation6s7or hydroxylation8

(5 ) J. A. Hogg, G. B. Spero, J. L. Thompson, J. B. M agerlein, W.P. Schneider, D. H. Peterson, D. K. Sebek, H. C. Murray, J.C. Babcock, R. L. Pederson, and J. A. Campbell, Chem. Ind .

( Lo n d o n ) ,1002 (1958).

(1) Part of this material was presented in preliminary form at the5th Intern ational C ongress on Hormona l Steroids, New D elhi,India , Nov 1978, by M. J. Green, J. Berkenkoph,X. Fernandez,M. Monahan, H. -J. Shue, R. L. Tiberi, and B. N. Lutsky, ab-stract S. 1 ( 2 ) ; . Steroid Biochem., 1 1 , 61 (1979).

( 2 ) Trivial names employed are hydrocortisone (11@,17n,21-tri-hydroxy-4-pregnene-3,20-dione),etamethasone valerate (9a -fluoro-16~-methyl-ll@,l7a,21-trihydroxy-1,4-pregnadiene-

3,20-dione 17-v alera te), betamethasone dipropionate (9a-fluoro-16~-methyl-ll@,l7n,21-trihydroxy-1,4-pregnadiene-3,20-dione 17,21-dipropionate).

(3 ) M. Sulzberger and V. H. Witten, J. Inuest. Derrnatol., 19 , 101(1952); M. S ulzberger, V. H. Witten, and C. C. Smith, J . A m .M e d . Assoc., 151, 468 (1953).

(4 ) J. A. Fried, A n n . N .Y . Acad. Sci., 61 , 573 (1955).

(6 ) G. E. Arth, D. B. R. Johnston, J. Fried, W. W. Spooncer, D.R. H off, and L. H. Sarett , J . Am. Chem. Soc., 80, 3160 (1958);G. E. Arth, J. Fried, D. B. R. Johnston, D. R. Hoff, L. H.Sarett , R. H . Silber, H . C. Stoerk, and C. A. Winter, J . A m .Ch e m. Soc. , 80, 3161 (1958).

( 7 ) E. P. Oliveto, R. R ausser, A. L. Nussbaum, W. Gebert, E. B.Hershberg, S. olksdorf, M. Eisler, P. L. Perlman, and M. M.Pechet, J . A m . C h e m . S O C . , 0, 4428 (1958); D. Ta ub , R . D.Hoffsommer, H. L. Slates, and N. L. Wendler, ibid., 80,4435(1958);D. Taub, R. D. Hoffsommer, H. L. Slates, C. H. Kuo,an d N . L. Wendler, ibid., 82 , 4012 (1960).

(8) W. S. Allen and S. ernstein, J . A m . C h e m . Soc . , 78 , 1909(1956).

(9 ) S. Tolksdorf, M. L. Battin, J . W. Cassidy, R. M. McLeod, F.H. Warren, and P. L. Perlman, Proc. SOC. x p . Biol. M e d . , 92 ,207 (1956).

0022-2623/80/1823-0430$01.00/0 1980 American Chemical Society

4 amino 4 aryl cyclohexanones - 1. modification of the aryl ring

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