I
>I e
K! IIa. RI = K,= H h. R, = R1 = Me c, R: = H;R? = hle d. R; = Me: RI= H
J
li
k.
IIIa. R, = R2= R, = H l\’:i, b . R , = R ? = H ; R,=C,;H; 11, c. R,= RL= Me; R,3= H c‘. d. R, = H; R2= Me; R3 = H e. R, = H; R2 = Me: R,3=C,,Hf , Rl = Me; R,= R,= H
It, = R1 = H; R,,= SHI K , = R , = H ; R;=SH R = R,= Me: R, = NH, K = M ~R,;= H: R ; =
ePiiL1
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Glu =
Antineoplastic Research. 1. Pyrazole and Pyrimidine Derivatives of Dehydrocyclohexirnide Analogs’
Cycloheximide? (I),a product of S f r e p t o m y x s yi.iseus cultures, is well known for its ability t’o inhibit protein biosynthe~ie.~This biological action as well as that of emetine, anisomycin, and others is att,ributed to the stereochemical relationships between the S mid 0 atoms of the n i ~ l e c u l e . ~It has also been demonstrated that this relat’ionship can be affected by a change in the substitution pattern or stereochemistry at many of the other positions in the molecule.3 11) This work was aided Iiy Grant T-474 from t h e .\nierican C‘ancrs Society a n d Grant 6i-16 from its Illinois Division. (2) .‘ictidinne@. ( 3 ) For recent reports see 13. S. 13aliga. .\. IT. P r o n c z u k . a n d FI. S . Munro, .I. B i d . Chem., 244, 4480 (1969); 1.Geller, F. Robustelli, 6 . H. Barondes. €5. D. Cohen, a n d .\I. E.Jarvik. E a y c h o p h a r m n c o l o g i n , 14, 371 (1969): .J. A. I3urdman a n d L. J. .Journey, .I. .\‘eurochem., 16, 493 (1969); S. D. J. Y e l l a n d AI. Shils, Biochem. f’harmacd., 18, 1919 (1969). (4) ‘1. 1’. Grollrnan, Science, 157, 81 (1967): Proc. S a t . - < r ( i d . 56, 1867 (1966). ( 5 ) 11. I). Sisler and AI. 11. Siegel. in “.\ntih a n d 1’. I). Slmn.. Ed., Springer-Terlag. S e n Ilor
In order to estab1i.h lurthcr points about the structure-activity relationfhips of thefe molecules we have undertaken :t program directed toward the yynth several modified glutarimide antibiotic*. Durir courqe of the.? itudies we had occasion to prepare :I :I few dehydroc) cloheximide type compounds I1 which could :ilm be converted into a variety of heterocyclic compound,. through the 1,:S-diLetone system. € 3 7 ~ 1 1 though we would be destroying the essential iteroochemical feature-, the combination of the salient part. of cycloheximide with heterocjdic \ > . h t e r n \ :ippe:irod attractive for it- biological potential. Thc required 1,3-dihetone. I1 and 1’ n ere preparetl from the rnaminr~ of the appropriatelj 5ubstitutid ketont. :ml the :icid chloride of 2-(P-glutariniido)ac~,tic acid :iceording to the ac:.latioii procedure dewloped h j ,Johnion, rf al. ,fi in their elegant total \ynth+ih of c) cloheximide Though Struck :ind c0workt3r3~ h:d pr(1pared dibetone. I1:i.c.d by :I similar method, v t’ fourrtl the ,Johri~onmodific:ition. generally g a v ~much bettt.1 yields. Uehydrocyclolieximidr (IIb) was more prepared by the ,Tone\’ oxidation of cycloheuimi at ambient tenqxrature.’ The p? raxole derivative. 111 :ind V I were i > : i + i l ~ . formcd by t h r wtion of hydrazine and phenylhydrazint. o n the 1,3-clil\c.toiw- Although we have indicated the r l , u \ a h j \ C I’atun, a n d \ \ C’arlyon J 1866) T\ e h a \ e asslgned t h e ztereocllemi‘ti i a t C -2 a s depicted hecauqe of t h e argiiirient5 presented h \ these n o r h ~ r 5 (71 I1 F Struck. F1 3 scliaeffer r A Krauth, R T Kernp 1 I hlieali, a n d J \ A l o n t y o m e n , J W e d Chem , 7 , 646 (1964) (8) l i e l d s n e r e generallj 70-80V0 decidedl\ better t h a n t h e CrOs-I10 \c niethod ongmall) used h g h C. Iiornheld I1 G Jones, a n d T 1 P a r k e [I $ m e r Chem SOC 71, 1 5 0 (194911
Journal of Xedicinal Chemistry, 1970, Vol. 13, -Yo. $.
NOTFS
stereochemistry of the heterocyclic derivatives a t C-2 to be the same as the corresponding ketone, the hydrazines could have isomerized the methyl moiety during the condensation reaction. Use of semicarbazone or thiosemicarbazone resulted also in pyrazoles. All of the pyrazoles IIIn,c,d,f and VI exhibited uv maxima a t 225-22'7 mg, which shifted to 231-235 mp in acidified alcohol. The phenylpyrazoles IIIb,e had a maximum a t 253 mp, which was not affected by acidification. No attempt waq made to ascertain the exact location of the phenyl ring. The pyrimidines IT.' were best prepared by melting an intimate mixture of the 1J-diketones and guanidine carbonate or thiourea. Use of the standard base- or acid-catalyzed condensation conditions resulted only in the destruction or the recovery of diketone. The aminopyrimidines had double maxima of 230 and 303 mp, which could be shifted by acid to 226 and 312 mp, respectively. Thiourea product IVb had peaks at 233 and 2% mp. Preliminary evaluation of IIIa-e, IVd, V, and VI in the leukemia 1210 systemg by .ingle- and multiple-dose injections indicated the compounds to be neither active nor toxic. I n the Walker 256 test system four doses of 400-mg total showed that IIIa,b decreased tumor weight only slightly. Survey of a few representative compounds as IIId,e, and V in the paw edema antiinflammatory test and for androgenic-anabolic activity disclosed no significant activity . Experimental Section Pyrazole Formation.-The appropriate 1,3-diketone and NHISHL.H~O or CsH6SHNH2 (1 mol equiv) in EtOH (30-35 ml/g of diketoiie) was refluxed for 6 hr. The soln mas cooled t o 5" for 16 hr, and the product then collected. If insufficieiit product crystallized. the volume of EtOH was reduced zn V ~ C U O and additional material collected. The product was then recrystd from the appropriate solvent t o give an analytical sample. Data for pwazoleq I11 aiid VI are listed in Table I.
TIHLE. I D I T I FOR ru'I 11 COWPOUSDS hZp
Compd
O C
'
Recristn sohenth
Iield,
L/'o~
Formula
Anal? s e d
254-23.5 A 89 Ci3HiiX302 C, H, Pi kl 204-208 .4 90 CLBH21X30A C, H, S c 199-202 B 60 C1,H~iS,O~ C, H, N d 117-118 A ii ClaHlsN,On C, H e 190-192 A 62 C?oH&,Oz C, H, N -f 183-186 .;1 a.) CiaHisNaOs C, H, N IVa 255-237' A Si ClaHl,?;40z N b 260-263 CiaHiiN3028 ?: C 69 c 198-200 rl 24 C ~ ~ H ~ N ~ C, O H, A S d 234-235 CiaHnoN402 N A 30 v iig-im D 20 CizHioK04 C, H, I\j VI 233-236 A 37 C12HlaN302 C, H, S a Melting points were taken on a Fisher-Johns apparatus and A, EtOH, B, 21eOH; C, H20: 11, CH2Clr. are uncorrected. c Yields are based on material which could be cryqtallized directly from the reaction and had mp 0-4" lower than the analytical sample. d Kew compounds had the expected ir spectra All analyses indicated by only the elemental symbol were within zk0.47, of the theoretical value. e 4 change i n crystal structure occim at 184-1'37'. IIIa
(9) W e wish t o t h a n k D r . H. B. Wood of t h e D r u g Development Branch, Cancer Chemotherapy National Service Center for providing t h e anticancer asseys.
771
Pyrimidine Formation.--An intimately ground mixture of diketone and guanidine carbonate or thioiirea (1 mol equiv) was heated in an oil bath to 160-180". The mixture liquified, then solidified upon continued heating. This change was accompanied by the release of H 2 0 vapor. The solid was added to a few milliliters of boiling H2O to remove the unreacted urea. After collecting the H2O treated product, it was recrystd from EtOH or H8O t o give the desired pyrimidine. Yields and physical data for the pyrimidines IV are in Table I .
Halogenated 1-(4-Arninobenzplidene)indene~~~~ CARLTABBBAHNER, DAVIDBROTHERTON, JANECLIKE, H~ROL KIXDER, D A N D LYDI i MOORERIVES
Carson-Sewman College, Jefferson Czty, Tennessee 37760 Received December 12, 1969
1-(4-Dimethylaminobenzylidene)indene (I) and a number of its analogs have been found active against subcutaneous Walker 256 tumors, intramuscular Walker 256 tumors, and Lymphoma S . 3 , 4 5 Moreover, I appeared to cause mammary tumors, especially in female rats. I n order to determine whether halogen atoms ortho to the amino group mould reduce the carcinogenic activity, we have prepared the compounds listed in Table I and submitted then for testing. The results obtained indicate that most of the ortho-halogenated compounds have activity against the Walker tumors in one or both types of test. Some of the compounds seem more effective in the single dose test, possibly because they are slower in absorption or activation than the unhalogenated compounds. When compared on a niolar basis the bromo compounds appeared to be somewhat more effective than the fluoro, chloro, or iodo compounds. It is interesting to note that the 77%-chlorocompound was inactive. A similar effect of a halogen atom in this position has been observed in the 4-(4-dimethylaminostyryl)quinoline series. A halogen atom at the 2 or 3 position of the indene portion of the molecule also prevented antitumor activity. Base-catalyzed condensation of the halogenated aminobenzaldehyde with indene seemed to go smoothly, but isolation and purification of the desired products required patient attention, as did preparation of the halogenated aldehydes. Experimental Section Equal molar quantities of aldehyde and indene were dissolved separately in hot EtOH and then combined in preparing the halogenated 1-(4-aminobenzylideiie)indenes. After KOH in EtOH was added dropwise in excess until a color change occurred, the solution was allowed to reflux about 30 min, then cooled, and filtered. 3-Fluoro-4-dimethylaminobenzaldehyde was prepared from .\',S-dimethyl-o-fluoroaniline according to the method of Campaigne and Archer.6 3-Chloro-4-dimethylaminobenxaldehyde (1) This investigation was supported b y Public Health Service Research G r a n t s No. (2.2-03717-07, -10, a n d -11 from t h e National Cancer Institute. ( 2 ) Presented a t t h e Southeastern Regional Meeting of t h e American Chemical Society, Tallahassee. Fla., December 6 , 1968. (3) C. T. Bahner, H. Kinder, D. Brotherton, J. Spiggle, a n d L. G u t m a n , J. M e d . Chem., 8, 390 (1965). (4) R . M. Folk a n d M.A . Sheridan, Proc. Amer. Assn. Cancer Res., 9 , 23 (1968). ( 5 ) F. J. C . Roe, R . L. Carter, a n d N . A. Rarron, S a t u r e , 222, 383 (1969). (6) E. Campaigne and K.L. Archer, Ory. S y n . , 33, 27 (1953).
