878 Journal nj Xedicinal Chemistry, 1971, T'o/. 14, S o . 0 Firefly larvae tp-ts were carried out by Professor A. 1). Carlson Nant*y Littell, Ilepartmeiit of Biological Sciences. State 1liiiversit:i- of Xew York, Stony Brook, S . E'. Light oiitpiit from ernittiiig cells was monitored by a phototitbe diiriiig espowiire to a solii of test conipdZ* (Table IS;. Rate Studies.-Sohi of 2V-ethyl-2,3-dirnethylmaleimidei i i 0.5 J I phosphate biiffer (stable for >24 hi.) were degassed by alternate espociue to vaciiiim airtl S , (6 cycle.). The buffer aiid
(24)
22.
I). Carlson, J . Exp. Biol.. 48, 381 (1968); 49, I95 (1968).
HARDTMANK, et ai. was then poured into a side arm coiitg the appropriate arllt, of GSH. After shaking briefly to ensure soli?, the cell contg the reaction s o h wah placed in the light path of a Cary JIodel 1 1 ipectrophotonieter. Reaction was follou-ed firit a t 3050 X. then b y mmplete spectroscopic cwveh. Optical deniitieh at different times nt 303.0 nm were men3iired and the rate colistaiits cromputed with the aid of a second-order rate eqiiation and 3 (;enern1 Fzleclric Computer. .\ complete de>cription of the kinetic propertie.. of .\'-alkylnialeiniides will appear iii :I flittire art i cle.
Tetracyclic Quinazolinone Derivatives GOETZE.
HARDTMBNN,*
BRUNO8. HUEGI,
Department nf Chemical Research
JOHK H. GOGERTP, LOUISC. IORIO,
AND
H. WILLIAMBARNES
Phurrnacnlogy Section, Department nf Binlogical Research, Sanclnz Pharnzaceutzcrrlr. Division of Sandnz-Wander, Inc., Hunover, S e w Jersey 07.936 Received Sovember 30, 1910 The preparation of 1,6,7,8,O,c3a-hexahgdro-4-methyithio-2~-p~~rido[1,2-c]p~rimidine and l,5,6,7,8,8a-hexahydro-3-methylthioimidazo[l,j-a] pyridine and their reactiona with iaatoic anhydride and with anthranilic acid are described. The pharmacology of the reaction products is discussed.
Recently Ziegler and COM orkers' investigated the reaction of isatoic anhydride n ith 2-methylniercaptoiniidazoline. We nom nould like t o describe the reaction of 2 novel bicyclic mercaptomethylureas n ith a variety of isatoic anhydrides and anthranilic acids and discuss the pharmacological properties of the reaction products. The first saturated imidazo [l,Z-a]pyridine, namely, the urea 1, was reported by Winterfeld and Schueler.2 When n-e allowed pipe~olylamine~ to react with CSI4 the thiourea 2 was obtained, which on reaction n i t h Me1 yielded 3. Analogously the homolog 4 wab prepared from 2- (2-aminoethyl) piperidine .5
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SCH , 3, .HI 3a
When equimolar amounts of t'he free base 3a and of isatoic anhydride (5) n-ere allowed to react at 100" in dioxane, 2 nen- products n-ere formed. One was identified as thioanthranilic acid 5'-Ale ester (6)6 and the other was the expected tetracyclic material 7. Compd ( I ) E. Ziegler, IY. Steiger, and Th. Kappe, .Ifonateh. Chem., 99, 1499 (1968). (2) 1;. Tyinterfeld and H. Schueler, A r c h . Pitarm., 298, 203 (1960). (3) ,J. 1%. Norton, 21. -1. Benson, R . -1. Seibert, and F. IT-. Bergstroem, .I. A m e r . Chem. Soc., 68, 1330 (1946). (4) 11. Behringer and H. hleier, Jzcrtus Liebigs .Inn. Chem., 6 0 7 , 67 (IU5i).
in) 11.Freifelder
a n d G. R. Stone, J. O r g . Chem., 26, 3802 (1961). (6) Tliis material is probably formed by reaction of liberated methylmercaptan ivitli unreacted 6.
H
I
4a did not react with 5 under similar conditions, but the desired 8 (see Table I) was obtained when 5 was replaced by anthranilic acid. I n the same manner, 4,5dimethoxyanthranilic acid and several other anthranilic acids (see Experimental Section and Table I) could be treated ryith 3a and 4a. Pharmacology.-In the course of preliminary investigations on the pharmacological activitieb of a series of tetracyclic quinazolirione derivatives, it was noted that these substances provided a profile of CKSdepressant activity not unlike that obtained n i t h standard sedative-hypnotics. Each of the present series of compds v a s submitted to a battery of behavioral and drug-interaction tests 111 mice, with %elected compds being further investigated in behavioral tests in squirrel monkeys. The results LTith the test compds nere compared to those obtained n i t h methaqualone, glutethimide, and, or phenobarbital. All substances (suspended in 0.5% carboxymethyl cellulose soln) were submitted t o a preliminary screen in mice to determine effects on behavior.78 Initial btudies on lethality of a few selected compds (following ip administration to mice) indicated that a general ( i ) 9 I r n i n ' h m a l and Clinical Pharmacologic Techniques in Uriig L>aluation, ' J H Kodine and P E Slegler E d , Year Book PubIlslier% Chicago, I l l , 1964, p p 36-34 (8) G Chen, Sump Sedatzte H y p n Drugs, 1953, 4 5 ( 1 9 2 % )
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 9 879
TETRACYCLIC QUINAZOLINONE DERIVATIVES
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880 Journal of Medicinal Chemistry, 1971, Vol. 14, h'o. 9
HARDTMANN, cf ai.
dosage range of 12.5-200 mg/l-. This latter effect became more obvious with lower doses of the test comyd providing a dose-response curve often observed with sedative-hypnotic substances or antidepressants. X1though 7e, 8, and 8a were shon-n to be anticonvulsnrits, t'hese activities were considered a t best weak and did not' appear t o coiltribute to possible structure-activitjrelat,ioriships within the present series. Probably the most significant activity demonstrated by compds within the series u-as that relating to reinduct anesthesia following hexobarbital. Although no ture-activity relationships could be described, 7 vided activity in this test comparable t o those obtained e 11). T o further with standard substances ( activity, 7 and 7a monkeys on a conwere administered orally to
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(9) X-Suliamoylazepine l.$--S.%),synthesized a t Sandoz, Hanovcr, S . .I.. has been found t o produce a convulsive a>-ndrome in mice or rats >!-liicli is similar t o t h a t obtained v i t h pentylenetetrazol (PTZj. I n addition t o its '+ being slightly more active t h a n P T Z , X-S.1 also provides more reproduci0le results t h a n does t h e standard. For these reasons, K-S.% is used in these 3 laboratories t o replace PTZ. (10) J. E. P. Toman, E , .i, S\\-inyard, and L. S. Goodman, J . S e u r o 2 physiol., 9 , 231 (1964). h & (11) ~ . n - . D u n h a m a n d T . S . l l i y a J, , P h n r m , S c i . , 4 6 , 2 0 8 ( 1 9 5 ~ j . '4 (12) C . F. Winter, J . Pharmacol. E z p . Ther., 9 4 , 7 (1948). (13) Locomotor activity in mice was measured using mice (5:proup) placed in darkened circular actophotometers (manufactared b y Koodward 2 Research Corp., Herndon, T'a.). Compds \yere administered i p 15 min previous t o ip injection of 5.0 mg/kg of dl-amphetamine sod. Activity \vas then measured (by t h e animals interrupting photocell beams) for G consecutive 10-min periods. (14) R . E. Tedeschi, D. H. Tedeschi, -4, l l u c h a . L. Cook, P.A . LlatLis. and E. J . Fellon.s, J . Pharmacol. E z p . Ther., 125, 28 (1959). (15) RI. Sidman, S c i e n c e , 118, 157 (1953). e
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TETRACYCLIC QUINAZOLINONE DERIVATIVES
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 9
by the ability of substances t o antagonize amphetamineinduced stimulation of locomotor activity in mice. I n this respect, compds in the present series separated into two categories: those potentiating amphetamine (7 and 8) and those antagonizing amphetamine (7a, 7d, and 7). Because amphetamine antagonism has been used in the past as a measure of potential tranquilizing activity, 7d was further tested in the fighting mouse test.14 As can be seen from Table I, 7d provided antagonism of shock-induced fighting in mice st doses below those showing antagonism of amphetamine. The results presented in these studies indicate that certain pyridoimidazoquinazolinones and pyridopyrimidoquinazolinones possess CNS-depressant activities with profiles demonstrated over a broad range of testing procedures, suggesting that the compds are sedatives and/or tranquilizers.
881
CONTROL
Experimental Sectiont All compds were checked by ir and nmr spectroscopy (PerkinElmer 237 and Varian A-60, resp) and their spectra were found to be in agreement with the assigned structures. Melting points were determined with a Hoover capillary melting point apparatus and are uncor. No attempt has been made t o optimize the yields in the described reactions. 1,5,6,7,8,8a-Hexahydroirnidazo[1,5-a]pyridine-3(2H)-thione @).--A soln of pipecolylamine (37 g) in pyridine (250 ml) was slowly treated with CS2 (40 g). After the initial exothermic reaction had subsided the mixt was heated a t 100" for 6 hr. The solvent wa5 evapd, and the crude residue was crystd from Et+ ~) pentane (48.1 g, 95%), mp 81-85". Anal. ( C ~ H I Z NN,~ S. 1,5,6,7,8,8a-Hexahydro-3-methylthioimidazo [1,5-a]pyridine. HI (3).-A stirred soln of the thiourea 2 (108 g) in MeOH (500 ml) was treated with Me1 (110 g) and was allowed to remain a t room temp for 18 hr. The soln was concd in vacuo to 250 ml, treated with charcoal. and filtered. On addn of EhO, 117 e: (80%) of the reaction product 2 pptd, mp 153-156". Anal: ( C- ~ H S IS.) -_ ~-~ N IN. 1,6,7,8,9,9a-Hexahydro-4-methylthio-2H-pyrido[1,2-c]pyrimsoln of 2-(2-aminoethyl)piperidine6 (90 g) in idine -HI(4)-A pyridine (500 ml) was treated slowly with CSz (90 ml). The mixt was heated for 16 hr a t 110",cooled, and evapd to dryness. The crude residue (104 g) was dissolved in 500 ml of EtOH, Me1 (100 g ) was added, and the mjxt was refluxed for 1 hr. The solvent was evapd in vacuo. The residue was dissolved in EtOH, the soln was treated with charcoal, and the hydroiodide 4 (138 g, 70%) was pptd by addn of EtIO, mp 178-180". Anal. (CQHI7NISI) C, H, S, I. Free Bases (3a an4 4a) from 3 and 4, Resp.-3 (200 g) was dissolved in 2 N NcOH (250 ml), and the mixt was extd with CHzC12 (2 X 250 ml). The org phase was dried (Na2S04) and evapd in vacuo. The crude residue was used for further reactions. Compd 4a was prepd pnalogously from 4. 1,2,3,4,13,13a-Hexahydrg-11H-pyrido [l',2'. 3,4]imidazo [2,1b] quinazolin-11-one. HCI (7).-A soln of 3a (10 g) in dioxane (100 ml) was mixed with isatoic anhydride (12 g) and was heated for 4 hr a t 100'. The solvent was evapd, and the remaining oil (20.6 g) was chromatogd on silica gel (Merck AG, 0.05-0.2 mm). The head fractioqs were collected (14.4 g) and dissolved in MeOH (75 ml), and the s o h was satd with anhyd HU1. The pptd product w$s collected and recrystd (MeOH), yield 5.5 g 37% of 7, mp 307-310". Anal. (CldH1aN30.HCl)N, 0,C1. 8,9-Dimethoxy-1,2,3,4,13,13a-hexahydro-llH-pyrido[l ',2' : 3,4]imidazo [2,1-b]quinazolin-11-one (7a).-A soln of 4,5-dimethoxyanthranilic acid (4g) and 3a ( 3 g ) in DMAC (75 ml) was heated a t 130" for 20 hr. The mixt was evapd to dryness, and the residue was dissolved in CHzClz. This soln was extd with 2 N NaOH and with HzO. After drying (NazS04)the soln was satd with anhyd HCl and the pptd hydrochloride (3.4 g, mp 304") was removed by filtration. It wm dissolved in a min amount of H20 and the soln was made alk by the addn of 2 N NaOH. The resulting ppt was washed with HzO and dried ~
t Where analyses are indicated only by symbols of the elements, anal. results for these elements were within &0.4% of the theor values.
Figure 1.
zn vacuo a t 80' (2.5 g, 47%), mp 163-164'. Anal. (C1FH19N30a) C, H,N. Using the above procedure 10,11-dimethory-2,3,4,4a,5,6hexahydro-lH,8H pyrido[l ',2' 3,4]pyrimidino[2,1-b]quinazolin%one (8a) (mp 208-209') was prepd in 31% yield from 4,5dimethoxyanthranilic acid and 4a. Anal. (C17H21N303) C, .: 1,2,~,4,13,13a-Hexahydro-8-nitro-11H-pyrido [1'?2 3,4]imidazo[%,l-b]quinazolin-11-one (7b).-A mixt of 4-nitroanthranilic acid (5 g) and 3a (6.0 E) in DMAC (50 ml) was heated for 1 hr a t 160 to 170". After cooling, the soln was poured onto ice and made alk (2 N NaOH). The mixt was extd twice with EtOAc, and the org phase was dried (NazS04) and evapd in vacuo. The remaining oil (11 g) was dissolved in CHC13 and chromatogd on silica gel (hlerck AG, 0.05-0.2 mm); 2.5 g of 7b, was eluted. The crude oil was crystd from CH2C12-EtOAc (2.0 g, 26%), mp 188-191". Anal. (C14H14N403) C, H, N, 0. Apalogonsly 1,2,3,4,13,~3a-hexahydr0-8-rnethyl-llH-pyrido[1',2'. 3,4]imi~azo[2,1-b]quinazolin-ll-one (7c) was prepd in 30% yield from 4-methylpnthranilic acid and 3a, mp 181-184'. Anal. (C15H17NaO) C, H, N. 9-Chloro-l,2,3,4,13,13a-hexahydro-llH-pyrido [1',2'. 3,4] imidazo[%,l-b]quinazolin-11-one .HCI(7d) was prepd in 3570 yield by the above prooedure from 3a and 6-chloroisatoic anhydride, C,CH, ~ ) C1, PI', 0. mp 290-294". Anal. ( C I ~ H M C ~ N S O . H
-
882 Journal of MLdicinal Chemistry, 19?1, V o l . 14, S o . .9
2,3,4,4a,5,6-Hexahydro-lH,8H-pyrido [1’,2’:3,4]pyrimidino[2,1-b]quinazolin-8-one HCI (8).-To a suspension of anthranilic acid (13.7 g) in dimethylacetamide (100 ml) 4a (20 g) was added, arid t,he mixt was heated t,o 150-160” for 3 hr. After cooling the solvent was evapd in V Q C U O , and the residiie was dissolved in CHCI,. The soln was extd with 2 .V S a O H and with H20. The org phase was dried (Na2S04)and evapd, and the residue was chromatogd on silica gel i;lIerck AG, 0.0:-0.2 mm). The product was eluted with CHC13. After evapn the residue was dissolved in EtOH (80 ml), and the s o h rras satd with aiihyd HC1. On addn of Et20 (300 ml) the hydrochloride crystd, it was removed by filtration (-5.9 g, 2 0 5 ) and dried in vacuo (0.1 mm) at 60°, mp 267-270’. Anal. (Cl.&,N30C1) S, 0, C1. Analogously 1,2,3,4,13,13a-hexahydru-7-methyl-llH-pyrido[1’,2’: 3,4]imidazo[2,1-b]quinazolin-ll-one(7e) was prepd in
10ycyield by the above procedure from 3a and 3-methylanthiaiitlic acid, mp 129-130” Anal. ( C I ~ H I ~ SC, ~O H,) S . 1,2,3,4,13,13a-Hexahydro-8-meth0xy-llH-pyrido[l’,2’ 3,4] imidazo[2,1-b] quinazolin-11-one (7f).--A mixt of 4-methoxyanthranilic acid (6 0 g ) and 3a (G 0 g ) i n 25 ml of D X A C w a i heated for 4 hr a t l5O-16O0. The Qolvent \\a. evapd and the remaining solid ditsolx ed i n CH2CL The soln v a5 v ashed n ith 2 S a O H (50 ml) taice n i t h water (100 ml), diied (Sa,SO,i, dnd evapd In t u c u o The rebidlie cry-td from Et-0. 4 0 g (42‘; I. mp lq54-157’ Anal I‘CI~HI-X~O-) C H, U,0
-
Acknowledgment.-Wc \I ish t o tharili N r . Urs Stoecldi and A h . S a n c y Engstroni for running the ir and iimr spectra.
Notes have described the synthesis of a series of j’ esters of am-C and the superiority of some of these derivatives as antileulcemic and immunosuppressant d r u g ~ . ~ a Sanchez and Orgel have recently described a conl)U.\Nb: T. GISH, G.LRY L. NEIL, ,\YLl ~ I L L I . \ M J. W E C H T E R * venient synthesis of am-C utilizing %-amino-p-Darabinofurano [1’.2’: &j]-2-oxazoline (I) as the key Research Laboratories, The Cpjohn Company, intermediate.’O In this synthesis, cyanamide is treated Kalnmazoo, Michigran 49001 with D ( -)-arabinose to yield the sugar-oxazoline derivReceived .\larch 1.5, 1971 ative (I),d i c h is then condensed with cyanoacetylene to give the 02,0?’-anhydroderivative (11) of am-C. 11, l-p-D-Arabinofuranosylcytosii~e’a,l~ (cytarabine, ai’art ithout iqolation. iq hydrolyzed t o am-C. Utilizing cytidine, a m C . cytosine arabinoside, Cytosar), has this synthetic route, but substituting 2-amino-P-Lproven efficacious in the treatment of acute leukemias arabinofurano [I/.’ 4,,j]-2-oxazoline for the D isomer, and lymphomas2a-f and is an inhibitor of DS=l synt h e ~ i s , ~ aD - ~S h v i r u s e ~ . , and ~ ~ ~ ~rodent ) t8um~rs,5a-j we have prepared the L enantiomer of am-C and have tested it for biological activity. We have further deand inhibits growth of various manimalian cell line^.^"-^ vised a method for the isolation of the 02,02‘-anhydro A derivative of am-C. 5’-(l-adaniantoyl)-ara-C, has derivative I1 of D-CLJU-C, :t conipd that may prove to be been shown to possess superior therapeutic properties an intermediate for the prepar:ttion of a number of (compared to ara-C) in the treatment of L1210 leukemic derivatives of am-C itself. mice6 and to possess greater immunosuppressive activThe preparation of 02.0?’-anhydro-1-p-n-arabinofurity in this species’a’h and in the rat.713-5 Recent reports anosylcytosine n-as first reported by Walwick, et al.,’” (1) (a) J. H. Hunter, E. 9. P a t e n t 3,116,282, Dee 31, 1963; (b) E . It. who obtained this product in the form of its hgdroDekker, and \T. K . Roberts, Proc. C h e m . S o r . , L o n d o n , 84 chloride by the action of prostatic phosphatase on the 3’.5’-diphosphate of the nnhydro derivative. This di(2) (a) R.W. Carey and R . R . Ellison. Clin. Res., 13, 337 (1965); (h) E. S. Henderson and P. J. Burke, Proc. A m e r . A s s . Cancer Res., 6, 26 (1965): phosphate h:td been obtained by phosphorylation of ( e ) M . S e s b i t and J. Hartman, i b i d . , 8 , 50 (1967); (d) R . Papac, \V. .i. cytidine with polyphosphoric acid. Sagyvary preCreasey, P. Calabresi, and A . D. Welch, ihid., 6 , 50 (196;); ie) R . Talley and V. K . Vaitkevicius, Blood, 21, 352 (1963); ( f ) k;.P. Yu, J. P. Howard, pared t h e 3’-phosphate e\ter of the 02,02’-anhvdroand B. D. Clarkson, Proc. A m e r . A s s . Cancer Re?.. 7 , 78 (1966). nucleoside Lza a polytrimethyl silj-lated derivative of Fisclier, Bzochcm. Phnrmacol., 11, 423 (1962) ; (3) (a) M . Y . Chu and G cytidine 2”.3’-cyclic phosphate. The 3’-pliosphate can (b) 9. 9 . Cohen, PTOQT. .VzicZ. A c i d Res., 6, 2 (1966): (e) J. H. Kim and M . L.Erdinoff, Cancer Res., 26, 698 (1965); (d) A. W. Schrecker and % J. ‘I.be depho-jphorylated enzymatically. Doerr and Foxi2 Urshel, ibid., 28, 793 (1968); (e) S. Silagi, ihid., 25, 1446 (1965). h:td prepared this anhydro nucleosidp from “-deoxy(4) (a) D. A . Butliala, Proc. SOC.Exp. B i d . .Wed., 116, 69 (1964); (11) 2’-chlorocytidine. Sone of these methods offers a G. E. Undcrwood, ibid., 111, 660 (1062). ( 5 ) (a) J. H. Uurchenal, H. H. ,\dams, li. S.Sewell, and J. J. Fox, Cancer convenient procesa for the preparation of the nnhydro Res., 26, 370 (1966): (11) R . L. Dixon and R . H. Adamson, Cancer Chemother. compd. We have non- prepared 02,02’-anhydro-1-PR e p . , 48, 11 (1965); ( c ) J. 9. Evans and G. D. Mengel, Biochem. Pharmacol., 13, 989 (1964); ( d ) J . 9 . Evans, E . .L RIusser, L. Bostwick, and G. D D-arabinofuraiiosylcyto~inedirectly from the aminoMengel, Cancer Res., 24, 1285 (1964); (e) J . S. Evans, E . A . Musser, G . D . oxazoline. For this purpose, the aminooxazoline I was Mengel, K . R . Forsblad, and J. €1. IIunter, P T O CS.O CE. x p . B i d . .Wed., 106, converted to its hydrochloride and this was condensed 350 (1961); ( f ) I. Kline, M. Gang, T’. S. Waravdekar, and J . 1 2 . Tenditti, Proc. Amrr. A s s . Cancer R P S . ,8 , 38 (1967): ( g ) I. Kline, J. h1. Venditti, with cyanoacetylene to give directly 11.HCl. Nucleic Acids. 12. Synthesis of the L Enantiomer of 1-P-Arabinofuranosylcytosineand of 02,02’-Anhydro-1-P-D-arabinofuranosylcytosine
D. D. Tyrer, and A. Goldwin, ibid., 6, 36 (196.5): (11) I . Kline, J. hl. Venditti, D . D . Tyrer, and A Goldmin, Cancer Re?., 26, 853 (1966): (i) I. Wodinsky and C . J. Kensler, Cancer Chemother. R r p . , 43, 103 (1964); ( j ) I
