Journal of Medicinal Chemistry, 1970, Vol. 13, N o . 5 994
the gallbladder with the salt than with the free acid. The side effects observed with N a tyropanoate in the clinic were less than those seen with iopanoic acid.18,20-22 A crossover study in man by 1IcChesney and Banks showed that 50% of a 4.5-g dose of Na tyropanoate is excreted in the urine in 108 hr while 37y0 of a 3-g dose of iopanoic acid was in the urine.23 AIcChesney and Hoppe reported that iopanoic acid and Na tyropanoate are metabolized in the cat arid man and that the biliary excretion is mostly as the glucuronic acid conjugates. 24-77 The suggested metabolite of S a tyropanoate is shown in 8.
%fl
0
Experimental Section *s
~~-Ethyl-3-formamido-2,4,6-triiodohydrocinnamic Acid (2),Na 3-Acetamido-~~-ethyl-2,4,6-triiodohydrocinnamate (3, Na Salt), (4, and Na or-Ethyl-2,4,6-triiodo-3-propionamidohydrocinnamate Na Salt).-The preparation of the first two of these compounds by the acylation of iopanoic acid5 is described elsewhere.'* The acid 4 corresponding to the last of the above compounds is also described.l4 The N a salt of 4 was prepared by the method employed for N a tyropanoate and was obtained as colorless crystals, mp 199-210". Anal. (CIrHl&NNaOa) C, H ; I: calcd, 58.66; found, 58.06. Tyropanoic Acid, 3-Butyramido-a-ethyl-2,4,6-triiodohydrocinnamic Acid ( 5 , Acid).-A mixture of 50.0 g (0.0875 mole) of iopanoic acid5 ( I ) , 28.6 ml (0.175 mole) of butyric anhydride, 310 ml of PrCO*H, and 5 drops of H2SOa was heated on a water bath a t 70-80" for 2 hr. A solution formed and was poured int,o H20. The solid which separated was collected and dried, 47.0 g (84y0) of tan solid, neutralization equiv, 637; calcd for ClbHl&?rTO3: neutralizat,ion equiv, 641. Recrystallization from EtOAc gave very pale t,an prisms, mp 182-184" (reported mp 172185.5Ol4); neutralization equiv 640; uv max (9570 E t O H ) 237 mp (e 33,900); ir (3/4% KBr disc) 1660 (CONH), 1690 (COOH), 2500-2670 (broad H bonding), 2940 (CH), and 3220 cm-' (NH). Na Tyropanoate, [Na 3-Butyramido-a-ethyI-2,4,6-triiodohydrocinnamate ( 5 ) ].-Tyropanoic acid ( 5 , acid) was converted into its Na salt by the addition of a slight excess of methanolic NaOH to a suspension of 5 (acid) in MeOH. A solution was otitained and a gumnij- material separated when E t 2 0 was added. The addition of fresh Et20 t o t,he residue aft,er the liquid layer W'HS decanted arid tritiiratioii produced a solid which was collected and dried. There was obtained a colorless solid, mp 208-210". dnal. (Cl:H171&NaO~)C, H ; I : calcd, 57.42; found, ,56.6. Other samples of S a tyropanoate were recrystallized from HzO and aq i-PrOH. Na a-Ethyl-2,4,6-triiodo-3-valeramidohydrocinnamate (6, Na Salt).-The reaction of iopanoic acidj with valeric anhydride in the presence of valeric acid and H2S04 in the manner described for tyropanoic acid ( 5 , acid) gave a-ethyl-2,4,6-triiodo-3-valeritmidohydrocirinamic acid (6). Recrystallization (EtOH) gave (23) E. \V, JIcChesnej- and \\-, F. I3anks, Jr., Proc. Soc. E x p . Biol. M e d . ,
119,1027 (1905). (24) E. W. hIcChesnes and J. 0. Hoppe, Arch. Intn. Phar?nacodyn., 99,127 (1954). ( 2 5 ) E. W. McChesney a n d J. 0. Hoppe, ibid.. 105, 306 (1956). (26) E. W. McChesney a n d J. 0. Hoppe, i b i d . , 142, 562 (1963). (27) E. W. RlcChesney, Biochem. Pharnacol.. 15, 1366 (1964). ( 2 8 ) When analyses are indicated only b y symbols of elements, analytical results obtained for those elements were within &0.4Y0 of t h e theoretical i nliics. Melting points \yere taken in a Hernhberg-type apparatus anti :ire rurrwted. T h e spectra Tverr determined on a Cary 1 3 ultraviolet spect r o i i l i o t w i e t e r and on a I'erkin-Elmer 21 inirared spectrophotometer.
colorless prisms, mp 189-190.5'. Anal. (C16H2013N03)neutralization equiv: calcd., 655; found 652. The Na salt of 6 was obtained as colorless solid, mp 212-217' dec, from 6 in the manner described for N a tyropanoate. Anal. ( C I ~ H I & N N ~ O ~ ) C , H ; I : calcd, 56.23, found, 56.75. Na ~-Ethyl-3-hexanamido-2,4,6-triiodohydrocinnamate (7).The reaction of iopanoic acid5with hexanoyl anhydride and H2SO( gave a-ethyl-3-hexanamido-2,4,6-triiodohydrocinnamicacid ( 7 ) a- colorless prisms (EtOH), mp 196-198'. Anal. ( C 1 ~ H 2 J 3 K 0 3 ) C, H : I : calcd, 56.90; found, 56.01. The Na salt of 7 was prepared from the acid in the manner described for X a tyropanoate ( 5 ) and was obtained as a colorless solid, mp 170-190". Anal. (CnH&NKaOd C,H, I.
Acknowledgments.-Appreciation is expressed to 1Ir. John Romano, Mr. Chester Sapino, and Mr. Arnold Ludke for technical assistance. The authors wish to thank the Analytical and Physical Chemistry Departments a t Sterling-Winthrop Research Institute for the analytical and spectral data. We also wish to thank Dr. H. 1'. Drobeck and A h . L. Duprey for the acute toxicity studies.
Isoquinolines. 2. 3-(Dialkylaminoalkylamino)isoquinolines as Potential Antimalarial Drugs'sZ JOHN L.
?jEUMEYER3 -4ND
KLAUSK.
WEIh.H.IRDT
Arthur D . Little, Inc., Acorn Park, Cambridge, Massachusetts 02140 Received March I S , 1970
Because quinolines have played such an important role in malaria chemotherapy, we believed that the heretofore unexplored class of 3-aminoisoquinolines deserved further investigation. I n our previous report1 we presented the synthesis and biological activity of a number of 3-aminoisoquinolines which do not contain the usual dialkylaminoalkylamino side chain, a common feature of the active quinoline antimalarials such as chloroquine (Ia) or pamaquine (Ib). Q--NHCHCH&H~CH&"C~H~)Z AH3
Ia, Q Ib, Q
= =
4-(i-chloroqr1inoline) 8-(6-niethoxyquirioline)
This report will present the synthesis and biological activitjr of such isoquinoline derivatives. Chemistry.-The synthesis of the diamines (VI) was carried out by the sequence of reactions shon-n in Scheme I from the appropriately substituted aminoisoquinoline' (11). The attempted alkylation of the 3chloropropionamide 27 with N-methylaniline yielded only the elimination product, N-(3-isoquinolyl)acrylamide.4a Such an elimination also occurred when the ( 1 ) Paper 1: J . I.. Seumeyer and K. K. Weinhardt, J . M e d . Chem., l S , 613 (1970). (2) This work was supported b y t h e U. S. Army Medical Research and Development Command under Contract DA-49-193-AID-3023. Titis is Contribution No. 783 from the Army Research Program on Malaria. Presented in part a t t h e 155th National Meeting of the American Chemical Society, hliami, Florida, 1968, S-28. (3) T o whom inquiries should be addressed a t t h e Department of Medicinal Chemistry, College of Pharmacy, Northeastern Oniversity, Boston, Mass. 02115. ( 4 ) ( a ) This compound was described in t h e previous paper (ref 1 ) and \vas desinnated as compound 14; (b) This compound x a s described in t h e Previous payer (ref I ) and ma8 deaignateri a s compound 15.
1000 Journal of Xedicinal Chemistrg, 1970, L7d.ltj,
0. j
SCHEME I
K'
K'
I
S
a. S =Hi.:1' = SH.: li = H b. S = Hr: I' = NH.:I i = ('H c . S = €3: Y = S H . : R = 1 I d. S = HI.: Y = F:H = kI
S = R r oi' H R = H or O W R'. K" = H or M e R"'=alkyl
3-chlorobutyramide 28 was treated with N,N-dimethyl"-ethylenediamine in refluxing CHCL ; N- (3-isowas the product isolated in quinolyl)~rotonamide~~ 50% yield. We observed that fusion of the 3-chloropropionamide (27) and the 3-chlorobutyramide (28) caused an introrqolecular cyclization leading to the 3-0xo-l,2,3,4tetrahydropyrimido[2,3-b]isoquinolin- 11ium ~ y s t e m . ~ The butyramides V bearing a labile Br in the 1 position (42 and 43) could be prepared best from I1 by acylation with 4diethylaminobutyric acid hydrochloridee and DCC in DhIF. The reduction of the amides V with LAH' T K L ~ successful by using the inverse addition technique. Partial hydrogenolysis of the labile halogen atom at the 1 position occurred, resulting in mixtures of products. Reduction of the amides with diboraue in xi*b generally tt more satisfactory method. In ail attempt to prepare 3-amino-1- [ (2-diethvliiminuetli~l)aniirio1isoyuirioline (VIII) by- treatment of p-diethylaniirioethylamine with 8-amino-1-bronioiioquinoline (T'IIu) , the unexpected disubstitution product 51 was isolated arid characterized (Scheme 11). Halogen atoms a t the 1 position of isoquinoline can be easily replaced by nucleophiles such as P-diethylaminoethylamine,g ethoside,1° or methoxide.' The ( 5 ) J. L. Seumeyer and I
