Narch 1965
239
CYCLOALKANESPIRO-5’-HYDANTOISS
The Chemistry and Pharmacology of a Series of Cycloalkanespiro-5’-hydantoins W. OLDFIELD’ T h e Distillers C o m p a n y Ltd., Research and Development Department, E p s o m , Surrey, England ASD
C. H. CASHIX~
T h e Disiillers C o m p a n y (Biochemicals) Lid., Pharmacology Departmeni, Speke, Liaerpool, Laneashire, England Received October 26, 1064
A number of substituted cycloalkanespiro-5’-hydantoins have been prepared and tested for toxicity, for gross effects on behavior, and for anticonvulsant and analgesic activity in mice. Indications of sedative activity were obtained by ability to potentiate hexobarbital anesthesia. A limited number of compounds were tested for antiinflammatory activity in rats. Cyclopentanespiro-j’-hydantoinsshowed a low toxicity and low sedative activity. Certain cgclohexanespiro-5’-hydantoins showed analgesic and antiinflammatory activity. Some cycloheptanespiro-5‘-hydantoins exhibited anticonvulsant activity, while the few cyclooctanespiro-5’-hydantoins tested possessed properties reminiscent of the barbiturates but with lower potency.
Numerous cycloalkanespiro-5’-hydantoinshave been tested2a-k for anticonvulsant activity, but little has been reported relating to other types of pharniacological activity in these compounds. Although 1- and 3-substitut’ed hydantoins have been widely investigated,3-5 few 1’- andjor 3’-subst’ituted cycloalkanespiro-5’-hydant’oins have been described. These include 1’- and/or 3’-1nethyl~-~ and 1’-phenylg derivatives, 3’-iiiorpholinomethyl and 3’-piperidinorriethylcyclohexaiiespiro-5’-hydantoinsarid their corresponding 1’-methyl analogs, lo 1’-(2-diethylaminoethyl)- and 3’- [ 2-(4-pyridyl)ethyl ]cyc$lohexanespiro-5’hydantoins,” and ccrtain 3’-pheriylcyclopciitarlcspiro5 ‘-hydant oins. It was of interest therefore to synthesize a number of novel 1’- and/or 3’-substituted cycloalkanespiro-5’hydantoins and their known parents so that they could be tested for several types of pharmacological activity. Chemistry.-Cycloalkanespiro-5’-hydaiitoins (Ia) were conveniently prepared using the Bucherer synthesis. l3 It is apparent that when R is a group other than hydrogen then two geometric isomers are possible. One isomer (a-form) has been observed to predominate when the Bucherer synthesis is used to prepare the hydantoin from the substit’uted cycloalkanone, whereas (1) Lilly Research Laboratories Ltd., Bromborough Part, K e a Ferry, Wirral, Cheshire, England. (2) (a) R. Tiffeneau and hI. Beauvallet, Presse mBd., 61, 417 (1943); (b) H. R. Henze. R. C. Wilson, and R. JV. Townley, J . Am. Chem. Sac., 66, 963 (1943): (c) E. S. Rothman and A. R. Day, ibid., 76, 111 (1954); (d) G. W. Smith and A. R. Day, ibid., 77, 3541 (1955); ( e ) J. A. Faust, L. H. Jules, L. Yee, and XI. Sahyun, J . A m . Pharm. Asaoc.. Sci. Ed., 46, 118 (1957); ( f ) L. H.Jules, J. A. Faust. and JL Bahyun, U. S. Patent 2,716,648 (1955); (a) H. C. Brimelow and C. H. Vasey, British Patent 807,679 (1959); (h) W. Reppe, 0. Schlichting, F. Westphal, and A. Amann, U. S. Patent 2,732,380(1956); (i) W. 6 . Waring, British Patent 796,069 (1958); (j) H. C. Brimelow and C. H. T’asey, British Patent 807,678 (1959); (k) W. J. Close and AI. 4. Spielrnan in “Jledicinal Chemistry,” Vol. 5, W. H. Hartung, Ed., John Wiley and Sons, Inc., h-ew York, N. Y., 1961,p. 1. (3) E. Ware, Chem. Reu., 46,403 (1950). (4) M.Tiffeneau, B. Tchoubar, XI. Saiaslambert, and S.LeTellier-DuprB. Bull. SOC.Chim. France. 445 (1947). (5) K.Schlogl, F. T e s s e l y , 0. Kraupp, and H. Stormann, J . Med. Pharm. Chem., 4,231 (1961). (6) H.C. Carrington, J. Chem. Soc., 681 (1947). (7) H. C. Carrington, ibid., 684 (1947). ( 8 ) H. C. Carrington and W.S. Waring, ibid., 354 (1950). (9) H.C. Carrington and W. S. Waring, British Patent 817,745 (1959). (10) 0. 0. Orazi and R. A. Corral, Tetrahedron, 16, 93 (1961). (11) E. Schipper and E. Chinery, J . Org. Chem., 26, 3597 (1961). (12) L. Kcole and L. Berlinguet, Can. J . Chem., 40,353 (1962). (13) H. T.Bucherer and V. A. Lieb, J . prakt. Chem., 141, 5 (1934).
, ,
,CO-NR’ (CHzhC \NR‘-CO R
uf
Ia, R 1 = b, R’ = c, R 1 = d, R’ =
I
R2 = H H alkyl aryl
the other isomer (p-form) predominates when the Strecker synthesis is used to prepare the amino acid from the cycloalkanone, and the amino acid is converted to the hydantoin.l2214-16 Physical evidence15 has indicated that the isomers have the following configurations. NHCO-hH CO
R&T~IZZ
R 0 -form
a-form
It was assumed therefore that I a (n = 3, R is other than H) was almost completely in the a-form. Hydantoins cannot usually be substituted directly in the 1-position3 and consequently the following method was used to prepare Ib.
IIa, R2=alkyl b, R2 = my1
I11
Ib
I I a (R2 = allyl, 2-hydroxyethyl, benzyl, or methyl) was prepared from the amine hydrochloride in aqueous solution,l7 whereas I I b (R2 = phenyl, p-methoxy, or p-ethoxyphenyl) was obtained from the amine in glacial acetic acid. The preparation of 111 (R2 = allyl, hydroxyethyl, benzyl, or methyl) was carried out in (14) H.C. Brimelow, H. C. Carrington, C. H. Vasey, and W. S. Waring, J . Chem. Soe., 2789 (1962). (15) L. Munday. ibid., 4372 (1961). (16) H. L. Hoyer, Chem. Ber., 85, 491 (1950). (17) E. Schipper and E. Chinery, J. O m . Chem., 26, 4480 (1961).
I \'
I (I
iaiitcd by hydrolysis oi ( yc~lolic~\aiicspiro-?'-liyclaiito i i i itli (io?; sulfuric acid. Pharmacological Methods.-'l'hc coinpoitiid> \\ foiniulated in aqueous solutioii or as suspeiisiolis 111 0.5( sodiuni carbosyiiietlnylcellulosc. 'They ('1 adiiiii tistcwd orally to groups oi albitio iiiice (Schoficltl I \\ c~iglinig 19-21 g. aiid t c b t d for to\ic,ity, f o r g i ~ cd%cts 011 belia~ior,for anticoii\ ulsaiit acti! it? , atitl foi aiialgesic properties. T h c ~ability of the conipouiitb i o potmtiatc hexobarbital nab iiivestigatrd and, i i i cwtaiii ( J f tlir conipounds, aiitiiriflaiiiiiiato1.v acativit y ld in iats (bee Tables I- T-11). te Toxicity.--Tlict aciitcl toyicity of o a r l i cwmpouiid ~ \ \ . ; t h dc~tcwiiitictl i i i giouph of fi\ 1' iiitc('. trcxated orally with ascciidiiig do-(+. .\lortalitic.s 11C I (' t (w)tdcd ovor 48 Iir. :uid any gloss I)c~lia\-ioritlc h i \\ h i c e h occnri c d pi ior t o U l d at lllgtl daws \\ llotcd. l,l)a" \ alur. \\ ( iiiiatid 1)y :I grap1ilc;~l inctliod when possibl(L. c~)iiiporiiidz h, \vet B. Anticonvulsant Activity --'l gi\ ('11 orally to gt'oups of ten i i i i w l aiid 1 h i . aftvr dosiiig t h c s imcc \ ~ c r cstimulated hy tlic i i . iiijcctiotl c3itlicr ot stiyc.hiiiiic> (6'13 y Lg.) ot oi priitylerietcirazol (100 tiig. 1,g.j or aitbjcctcd t o elei~trosliochseizure. I n ca(x1i case tlic pel cent luhlb~iioriof tonic esteii,sor cdondsions which occurred i n each group n-as iiotcd. C. Analgesic Activity.--lnalgesic activity was asTI hy the ability of the conipouiids to inhibit stretchFI
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