Journal of Mdicinal Chettiistry, 1.970, Vol. 13, KO.6 1009
.a
crystd from DMSO t o give the Sn salt as prisms, mp 340-342'. Anal. (CI8H8Cl4S~S2Sn) Sn. Sodium 5,7-Dichloroquinoline-8-thiolate.-The above Sn salt (1 g ) was stirred in a solution of XaOH (1.5 g) in HzO (25 mlj overnight. The E a salt was filtered, washed with HzO, and dried. Recrystallization of the dried residue (0.55 g) from EtOH gave the sodium salt as yellow needles, mp 280' dec. 5,7-Dichloro-S-quinolylDisulfide.-To a solution of XaOH (1.5 g) and Is (0.25 g j in HzO (100 ml j was added finely ground tin 5,7-dichloroquinoline-8-thiolate (1.4 9). The mixture was stirred overnight and then filtered and the residue was thoroughly washed with H20. Recrystallization of the dried residue from dioxane gave product (0.30 g) as yellow prisms, mp 219-220'. Anal. (C,8H8C14S~Szj C , H, N. 5,7-Dichloroquinoline-8-thiol.-To a stirred suspension of the above disulhde (0.25 g ) in oxygen-free MeOH (25 mlj were added successively, solutions of KaOH (0.65 g) in HzO (5 mlj and glucose (0.65 g ) in HzO (3 ml). The mixture was stirred and heated under reflux for 3 hr, before evapn of the AIeOH. The mixture wa5 filtered and the residual Na salt was dissolved in HzO (25 ml). C o t was passed through the solution for 10 min, and the white ppt was filtered and dried in omuo. Recrystallization from MeOH gave the thiol (0.1 g) aa needles, mp 102-103'; pmr spectrum as expected. Anal. (CsHsC12SS) C , H, N.
4cknowledgment.-The authors thank Mr. L. S. Bark (University of Salford) for a Sn analysis on tin 5,7-dichloroquinoline-S-thiolate.
Structural Modification Studies of 3-Piperonylsydnone. 2. Synthesis of Piperonyl-Substituted Hydantoin, Thiohydantoin, Thiazolidinedione, Rhodanine, Imidazolinone, and Related Compounds* N ' I L L I . 11, ~ BURTON, WILLIAML. BUDDE,ASD C. C. CHENG Jiidwest Research Institute, Kansas City, Missoiiri 64110 Received February 16, 1Y?O
The antimalarial activity of a mesoionic compound, 3-piperonylsydnone (I), against Plasmodium beryhei was reported. Preliminary structure-activity relationship studies?vJ revealed the importance of the piperonyl moiety for the antimalarial activity for compounds of this type. The mode of action of I is still u n l a o n n . One possible explanation for the many interesting biological acthities exhibited
I
by t h e sydnones4g5is that these compounds may interfere with the biocheiiiical role of amino acids. It is certainly not inipivbable for 3-piperoii?ls\.dilolie to act as an amino acid ant,agonist since the compound itself was prepared from an N-substituted amino acid (N-piperonylglycine) . Consequently, syntheses of certain piperonyl derivatives containing a hydantoin (IIa), (1) This investigation was supported b y Contract DA-49-193-MD-2749 with t h e U. S. Army Medical Research and Development Command. This paper is Contribution N o . 767 from t h e .Irmp Research Program on malaria. ( 2 ) jV, 11. Nytierr and C . C . t h a n g . .I. J f e d . Chenr.. 8 , 581 (19651. (31 S. G . Hoots and C. C. Clieng, J . Heterocycl. Chem.. 4, 2 i 2 i l O G i ) . (41 L. I3. Kier s a d E. R . Roche, J . Phrirm. Sci., 56, 1.19 (1Y67). (5) E. Ackermann, Pharmazie, 22, 537 (1967).
thiohj daiitoiii ( I l b ) , thiazolidinediorie (Ilc), rhodaiiirie (IId), and an imidazolinone (IIe) moiety, :tq well as other related compounds, were studied. Thest, conipounds. on i/t 11itro or iri itiro hydrolysis, may yield rithrr a p-hubstituted alanine or other analogous derivat ive i:.
I \' Ila. X
NH; Y = 0 h,X=NH: Y=S c.X=S;Y = o d , X, Y = S t'. X.Y = NH
Condensation of piperonal with 2-thiohydantoin and with rhodanine in &OH, according to the general I)rocedurr of Granacher, et ~ l . readily , ~ yielded the I)iperonylidene derivatives, I I I b and IIId, respectively. Similar preparations of the corresponding hydantoin arid thiazolidinedione compounds (IIIa and IIIc) required the presence of n large amount of SaOAc. Thti yield of I I I a by the direct condensation method was gencrally low. This iiiterniedi:itc can be obtained in hetttt.r yield through the desulfurization of 5-piperoiiyl idt~rie-2-tliiohyd:intoiri (IITb).
\'
Treatmerit of p i p e r o i i y l d i t ~ i i ~ c a r b ~ n i4a t1~ (1.1) with ClCH?C'02H'', should thtloretically > ield ; (T'III), :ti1 isomer of 5-1)i~)rronj Irhodnnine. Ho~vcvrr. preparation of V I :iceording t o the general method of Dains, et u / . , ] j gave instead I)iperoiiylammonium N-l,iperonyldithiocarbaiiiat (, (VII). Swertheless, when VI1 was treated with C1CH2C'02H.thc tlr4red :~-piperoii>-lrhodaniii~ YIII was obtainrd.
. obtained by either catalytic or chrmical reduction' of IIIst. Other analogs (IIb-d), owing to tBhrpreseiicr of' sulfur in the molecules, canriot be prepared by ordinary cat'alytic reduction of the corresponding unsaturated compounds (IIIb-d). Sa-Hg treatment of I I I b and IIIc gave 3-~~i~)eronj-l-l'-tliioli~~da~itoiti (IIb) and >-pi~ ~ t ~ i ~ o i i y 1 - 2 , ~ - t h i a z o l i c l i i i (TIC). t ~ ~ i o i i respectivelj-. ~ ill gooci yields. --Imuch lowtlr j-ield of I I b was obtairird ~ I wduction I of' l I I b with eittirr Sn a n d ethanolic HCIY,9 or HI.8 Application of the nforenientioried methods to t,he piperonylidene derivative of rhodanine (IIId), however, result,ed either in failure or in substantia1 hydrolysis of the rhodanine portion of the molecule. Synthesis of 2-amino-5-piperonyl-4-imidaxolinonr (IItt, ws t,he imino form) was accomplished as follows: (;ranaclier. 11. Ge . O f n r r . \ , KIupfensieiIi. ani1 IC, 11d1,. Chim. d c t u , 6, 458 (19 17) .\nalysis of ir spectra is iraeful i n c l i a r a c t e r i h g the condengatiun Iroduots I I I a and I I I h as well as the reduced derivatives IIa a n d 1 1 1 3 . Tlie i i n i d ~function in lieterucyclic rings gives t ~ v oahsorptions in t h e C--0 r e K i m . I n the e w e of f - p i i ~ e r ~ ~ ~ ~ y l i r l e n e h g . d a(nI It uI ai ~) ,~the absorytion at 1TOO c i n 1 is aruigned t o C--0 a t the 2 position and tile other a t 1740 c m - 1 t o C=O a t the 4 position (cJ'. L. .J. Bellamy. " T h e Infrared Spectra of (:omplex i\Iolecules." 2nd ed, IViley. Sex\- Tork, S . Y.. 1958, p 221). Rerliiction of IIIa to I I a caused these absorption8 t o shift t o 1730 and 1775 cm-1, respectively. This shift. is consistent with a higher CO band order (a shift of 80 c m - l t o higher energies) as conjugation with t h e C=C bond 11640-1650 om-1) is eliminated. 181 I C . I . . \Vlit.eler, (.. Hoffirran anti '1'. I:. . l ~ > l 1 i i s u n. I, . .Bid. C ' l , ~ r c , 10, 11; 11!111 , ! I 'I' 1:. ,l,,l,!l.,,,, illl,l \\ 1 : l ) ' l \ r , , . l l i l ) , , i 12, 2 0 ; 81!112l. llii
Xb
>;a
('.
4 s procedureYcould 110 t bti applied for the preyaratioii of IX from thv corresponding thiohydantoin IIb, due to the insolublitj of the latter ill acid medium. Hydro13 >is of 5-piperonj lidenerhodaiiirir (IIId) in KaOH gay(' (10) J . C . Shivers and (>. H . Haiiser, J . d m e r . Cheni. S u c . , 69, 1264 (1947). ( 1 1 ) F. C . Uroxm, C. li. Bradsher, E. C. Morgan, hf. Tetenbaum, m i l P.N'ilder, Jr., ibid.,78, 384 (1956). (12) R. Andreasch, Monatsh. Chem., 29, 399 (1908).
13) F. B. Dains, R. Q. Brewster, a n d ('ollecteri Vol. I . 1941. 11 14;.
(.',
P. Olander. "Orailnir S?II-
I !IPW-.''
,11,
\- I ) v i i l ~ ~ f mw ii i t l .I. l t r , i i , l i \ . v ,
% . l ' h ! , ~ ~ df ' l.t v r t , . , 211, 1
, l!l:+2>.
3,4-methylenedioxy-a-thiolcinnamic acid (Xa). Examination of its ir spectrum revealed that the product is in equilibrium with its tautomeric form, 3-(3,4methylenedioxyphenyl)-2-thiopyruvic acid (Xb). Antimalarial screening results in r o d e n t ~ 'indicated ~ that none of the compounds synthesized were active against P . beryhei. I n mosquito screening tests using a standard strain of Aedes aegypti infected with P . qallinaceuin,15 it mas found that 5-piperonyl-2-thiohydantoin (IIb) resulted in complete suppression of sporozoite development at 0.1% concentration and 3-piperonylidenehydantoin (IIIb) gave a 7570 sporozoite suppression at the same concentration. In antifolic acid assay,'; 2-amino-5-piperonyl-4-imidazolinone (IIe) was found to be active against the growth of Streptococcusjaecalis. The effect can be reversed by the addition of 0.2 pg of folic acid. 3-(3,4-lIethyleneclioxyphenyl)-2-thiopyruvic acid (X) was active against the growth of Lactobaczllus casei, and the activity n a s not reversed by 0.1 p g of folic acid. Experimental Section A11 melting points (corrected) were taken 011 a Thomas-Hoover melting point apparatus. Absorption bands of uv and ir s p e c h have been t,aken and were as expected. Nicroanalyses were performed at Midwest Research Institiite. Where analyses are indirated only by symbols of the elements, analytical results obtained for those elements were within k 0 . 4 5 of the theoret'ical values. 5-Piperonylidene-2-thiohydantoin(IIIb).--h mixture of 75 g (0.5 mole) of piperonal, 58 g (0.5 mole) of 2-thiohydantoiq 2 ml of piperidine, and 400 ml of AcOH was refluxed for 5 hr, during which time yellow crystals gradually deposited from t,he reaction solution. The cooled mixture was filtered t'o give 100 g of crystalline solid, m-hich decomposed at 215-218". Recrystallization from T H F gave 87 g (70Yc yield) of analytically pure IIIb, dec at 282-284". Anal. (CllHsN20$3)C, H, N. 5-Piperonylidenerhodanine (111d).-A4 mixture of 30 g (0.2 mole) of piperonal, 26.6 g (0.2 mole) of rhodanine, and 200 ml of AcOH was refluxed for 5 hr and the product isolated by filtration of the cooled reaction mixture to give 33.9 g (64% yield) of ,tallhe solid, nip 293-294'. Recrystallization from DRIF gave analytically pure IIId, mp 298-300' (lit. 236-258" dec,lGU .,--o ",).) de@) Anal. (C1lHiSO,S,) C, H, 3 . A higher yield ( 8 0 % ) of IIId was obtained when 5 3 g (0.65 niole) of anhydrous NaOAc was added to the reaction mixture prior to reflux. 5-Piperonylidenehydantoin(IIIa). Method A,-A mixture of 4'L..i g (0.28 mole) of piperonal, 25 g (0.25 mole) of hydantoin, .50 g (0.61 mole) of SaOAc, and 200 ml of AcOH was refluxed for 4 hr. The resulting solution was cooled, diluted with 300 ml of sat>uratedaqueous KaC1 solution, and ext,ract#edwith four 300-ml portions of CH&. The AcOH-CH&L ext,ract was added t o .io0 ml of H20 to give 9.1 g ( 1 5 5 yield) of prodiict (which did not c-otitain the unchanged hydantoin), mp 248-250". Recrystalli/.ation from 95yoEtOH gave analytically pure IIIa, mp 251.5'Lt33' (lit,.mp 245'17). Anal. (C11HaN20a)C, H, N. Method €;.-A mixture of 18 g (0.073 mole) of IIIb, 45 g r0.18 mole) of chloroacetic acid, 150 ml of DMF, and 150 ml of flrO was refluxed for 2 hr. On cooling, 15 g (89% yield) of rrys!:illine solid was isolated by filtration. The product was found ! o he identical wit,h that prepared by method A. 5-Piperonylidene-2,4-thiazolidinedione (IIIc) was prepared in :I similar manner from 15 g (0.1 mole) of piperonal, 11.7 g (0.1 mole) of 2,4-thiazolidinedione, 41 g (0.5 mole) of anhydrous ?;:LOA(:,and 100 ml of AcOH to give 10 g (40q7,)of solid, mp 24721!4°. Kecrystallizatioii froiii THF gave aiialytical sample, mp 249-250". Anal. (CI1HiNO4S)C, H, N. ( 1 5 ) F o r detailed explanation of test procedures and interpretation of results. see protocols issued by Division of Medicinal Chemistry, Walter Reed Institute of Research, Walter Reed Army Medical Center, Washington, D. C. ilfil ( a ) l
