Jwrnal of Medicinal Chemistry, 1971, Vol. 14, No. 6 545
NOTES
I n summary, none of bhe compounds reported were as active as aminophylline. Experimental Sectionlo
8-Azatheophylline-7-acetic Acid Ethyl Ester (II).-To a s o h of 0.69 g (0.03 mole) of N a in 50 ml of MeOH was added 5.43 g (0.03 mole) of I. The reaction mixt was refluxed for 0.5 hr and to it was added 5.0 g (0.03 mole) of C1CH2C02Et. Refluxing was continued for 2 hr. The solvent was cooled to room temp, and the ppt was filtered and recrystd from MeOH-H20; yield 4.1 g (50%), mp 157-159". Anal. (C1~H13N~O~) C, H, N, 0. 8-Azatheophylline-7-acetamide (HI).-To a suspension of 9.2 g (0.1 mole) of chloroacetamide in 150 ml of HzO was added 18.0 g (0.1 mole) of I, and the reaction mixt was heated to 50" for a few min. Heating was discontinued, and a soln of 4 g (0.1 mole) of NaOH and 0.1 g of NaI in 25 ml of HzO was added. The reaction mixt was refluxed a t 90" for 2 hr and cooled to room temp. The ppt was filtered and washed with cold HzO. The product was recrystd (MeOH-DMF) to give 17.7 g (75%) of 111, mp 228-230". Anal. (CSH1ONe03) C, H, N. 8-Azatheophylline-7-acetamide derivatives (IV - VIII), listed in Table 11, were prepd by the following procedure. A soln of 0.01 mole of I1 and 0.01 mole of an amine in EtOH was refluxed for 4 hr. The reaction mixt was cooled to room temp. The pptd solid was filtered and recrystd from an appropriate solvent with charcoal treatment. 8-Azatheophyllinamine salts (XIV-XIX), listed in Table 11, were prepd by keeping a soln of 0.01 mole of I and 0.01 mole of an amine a t room temp for 4 hr. The solvent was removed in vacuo, and the residue was heated with E t 2 0 and MezCO. The resultant solid was crystd from the appropriate solvent.
Acknowledgments.-The author wishes t o express his appreciation to Dr. T . Darby, Rilr. L. Wiemeler, and N r . C. Shannon of the Pharmacology Department of Abbott Laboratories, North Chicago, Ill., for pharmacological investigations and permission to use their data. (10) Melting points were determined in open capillary tubes in a ThomasHoover melting point apparatus. I r spectra were determined in K B r disks n i t h a Beckman IR-8. Microanalyses were provided b y Orville Kolsto a n d Victor Rauschel and staff of the Abbott Microanalytical Laboratory, North Chicago, Ill.
Synthesis of I-Amino-2-hydroxycyclopentanecarboxylic Acid JOHNI). HUDDLE AND CHARLES G. SKINNER* Department of Chemistry, North Texas State University, Denton, Texas 76203 Received October 30, 1970
I n the search for effective chemotherapeutic agents, many amino acid analogs have been synthesized in recent years; several have been found to possess antitumor properties, and others inhibit the growth of certain bacteria and viruses.' 1-Aminocyclopentanecarboxylic acidZ (cycloleucine) has, for example, shown promise as a chemotherapeutic agent in the treatment of such diverse problems as acne3and l e ~ k e m i a . ~ Few specific antimetabolites of serine and threonine are known;' a-methylserine inhibits the growth of (1) W . Shive and C . G . Skinner, Metab. Inhzbitors, 1,53 (1963). (2) T. A. Connors, L. A . Elson, A. Haddom, a n d W. C. J. Ross, Biochem. PharmacoE., 6, 108 (1960). (3) B. Ciocca, P.Rovesti, a n d G. Roccheggiani, Parfum. Cosmet. Sauons, 3, 363 (1960); Chem. Abatr., 66,3004f (1961). (4) A. Goldin, J. M . Venditti, I. Kline, a n d N. Mantel, Cancer Res., 21, 27 (1961).
Leuconostoc mesenteroides P-60, but other bacterial strains are unaffected; the higher homologs of threonine, 2-amino-3-hydroxypentanoicacid and 2-amino-3hydroxyhexanoic acid, are also reported to inhibit the growth of certain bacteria. The title compound possesses a cyclopentane ring which is present in cycloleucine and also contains the combination of a-amino and ,&hydroxyl groups found in serine and threonine. Several routes for the synthesis of 1-amino-Zhydroxycyclopentanecarboxylic acid were explored, for example, ammonolysis of a halohydrin produced from 1-cyclopentenecarboxylic acid. Procedures utilizing HOC1 to form a halohydrin, which had proved useful in other ~ y s t e m s , failed ~ , ~ to produce the desired intermediate; however, it was obtained by the action of monochlorourea (in AcOH) on l-cyclopentenecarboxylic acid, utilizing a procedure which had been reported for the synthesis of tr~ns-2-chlorocyclopentanol.~ Upon ammonolysis of this chlorohydrin, the only amino acid isolated was 2-amino-1-hydroxycyclopentanecarboxylic acid.8 This result is consistent with some previous studies where it was reported that several 2-chloro3-hydroxy-substituted acids produced the corresponding 2-hydroxy- 3-amino derivatives on a m m o n ~ l y s i s ~ ' -~ presumably through the mediation of an epoxide intermediate. Ultimately, the synthesis of 1-amino-2-hydroxycyclopentanecarboxylic acid was accomplished by a route similar to the method for the preparation of serine and threonine. l Z , l 3 1-Cyclopentenecarboxylic acid was converted into an acetoxymercurimethoxy adduct which, upon bromination, yielded 1-bromo-2-methoxycyclopentanecarboxylic acid. Ammonolysis of this material gave the corresponding aminomethoxy derivative which mas finally hydrolyzed with 49% HI to produce the desired amino acid analog. The ir spectrum of this compound was consistent with that of an a-amino-phydroxycarboxylic acid. The nmr spectrum of 1-amino-2-hydroxycyclopentanecarboxylic acid indicated the absorption of C H (adjacent to OH) a t 6 4.54; whereas, in the spectrum of 2-amino-1-hydroxycyclopent anecarboxylic acid, the C H (adjacent to "2) absorbs a t 6 3.80. These data are comparable to those observed using model compounds, serine and isoserine, with absorptions a t 6 4.18 and 3.48, respectively, and are consistent with the greater deshielding effect expected for the more electronegative OH. The C H of 1-amino-2-methoxycyclopentanecarboxylic acid was found to absorb a t 6 4.20. Gas chromatographic analysis of the trimethylsilyl derivatives of 1-amino-2-hydroxycyclopentanecarboxylic acid indicated that these compounds are present in approximately equimolar mixtures of cis and trans isomers. This would be anticipated since the replacement of the BrHg group with Br is known to proceed with
(5) C . Hedgecoth a n d C . G. Skinner, Biochem. Prep., 10,67 (1963). (6) G. Braun. J . Amer. Chem. Soc., 52, 3185 (1930). (7) H.R. Donahoe a n d C. A. Vanderwerf, "Organic Synthesis." Collect. Vol. 4 , U'iley, New York, N. Y.,1963,p 157. ( 8 ) B. F. Burrows and W. B. Turner, J . Chem. Soc. C , 255 (1966). (9) E . Erlenmeyer, Ber., 13, 1077 (1880). (10) P.Melikoff, {bid., 13, 1265 (1880). (11) 1'1.. J. N. Burch, J . Chem. SOC.,310 (1930). (12) H.E.Carter and H . I). West, "Organic Synthesis," Collect. Vol. 3, 1955,774. (13) Ref 12,p 813.
546
Journal of Medicinal Chemistry, 1971, Vol. 14, S o . ci
racemization, even though the initial addition product is trans.14 Preliminary microbiological studies using 5 species of bacteria have been attempted ; however, no significant inhibition of bacterial growth has been observed. Experimental Section15 Intermediate Derivatives.-Cyclopentanone cyanohydrin was prepared from cyclopentanone in 865i yield,'S converted into 1-cyanocyclopeiiteiie in 8 6 5 vieldj1i and finally, the latter compd was hydrolyzed to yield i-cyclopentenecarboxylic acid i n 50% yield.18 2-Amino-1-hydroxycyclopentanecarboxylic Acid.--?Jumeroiis attempts to prep the desired analog via a chlorohydrin reactioii followed by amnionolysis failed, and the only amino acid iaolated from these reactions \vas the isomeric product. For example. a soln of monochloroiirea (40 ml), prepd from 5 . 5 g (0.77 8 g (0.13 mole) of urea, and 6.7 g (0.067 mole) of added to a mixt of 11.2 g 10.1 mole) of l-cyclopenteiie-1-carboxylic acid in the presence of 5 ml of HOAc and 2: g of crushed ice, and the resulting mixt waq htirred overnight with cooling in an ice bath. Attempt-; to iqolate the chlorohydriii were unsiiccesaful, and the impure material was mixed with coiicd S H 4 0 H (330 ml) and allowed to stand at room temp for a 7-day period. The re.;lilting aolii was coned in vacuo and desalted by a modification of the procediire reported by Piez, et nT.lg The amino acid was cryst,d from H20-EtOH; in13 293-298" dec:*O ir (KBr) 8.08, 3.37, 6.13, 9.0, and 12.6 M : nmr 6 3.80 ( t , 1 H , nietliine hydiogeii), 1.60 -2.64 (in, 6 H, C H ~ C H Z C H ~ Ana/. ). (CeHiiSOj): S." 1-Amino-2-methoxycyclopentanecarbocylic Acid.-The syiithesis of l-bromo-2-methoxycyclopenta1iecarboxylic acid was patterned after a previously reported route for threonine13 whereby a inixt of 56.2 g (0.3 mole) of l-cyclopentene-l-carboxylic wid, 139.3 g (0.5 mole) of Hg(OAc),, and 750 ml of MeOH was stirred at room temp for 7 days to yield 149.2 g of adduct, mp 19.i-200° (presumably 1-aceloxymerciiri-2-methosycyclopentanecarboxylic acid). This material was added in small portionr t o a s o h of 90 g (0.73 mole) of KBr in 300 ml of 1 1 2 0 , cooled l o lo", and exposed to direct sunlight, and a soln of 80 g (0.3 mole) of Br2 and 90 g (0.75 mole) of KBr i n 150 ml of HzO was added slowly with stirring. After extn with EtSO and acidification with 47%; HBr, there was recovered an amber oil (73.6 g, presriinably 1-bromo-2-met~hoxycyclopentanecarboxglicacid) which failed to give a satisfactory elemental anal. Anal. (Calcd for CiH11Br03): C , 37.69: H, 4.97. Foiind: C, 38.31, 38.6:;: sample of this material (44.6 g) was added to 1330 nil of coiicd "+OH (cooled to 10-1,?1~) and allowed to stand a t room temp for 13 days. The resulting dark reaction mixt was filtered and reduced to near dryne2.5 in uacuo, and the residue was covered with AIelCO t o induce solidification. Asrending paper chroniatograms indicated the presence of 2 ninhydrin-active componelit \ iiicluding a weak spot corresponding t o l-amiiio-2lopeiitanecarbosylic acid (Xi 0.4.5, n-BuOH-HO,X(.): however, the major prodtict \ - a s n ninhydriiiactive compd with a different Elf valiie ( E l i 0.68, ~-BUOH-I-IOA~H20, 3 : 1: 1 ). This material was diseolved in HIO, treated with decdorizing chiirc'oal, and recry,*td tn-ice from H2O-EtOH 1 0 ~
~
- ..~
~~~
-
(1.1) ,J. ('liatt, Chem. H e u . , 48,7 (1951). (15) .\I1 melting points were determined with a Tliomas-Hoover capillary
melting point apparatus. S m r spectra vere obtained on DiO soins containing a traceamount of HCI. Ttiespectra were detd using a Jeolco J N h I PS-100 instrument. I r spectra n-ere obtained on KDr pellets with a PerkinElmer 237 grating spectrophotometer. T h e gas chromatographic d a t a were n a Loenco Model 2300 Series Graghimatic gas chromatograph. C;. .\yeret a n d K . .J. Schofield, J . C h e m . Soc.. 4097 (1958). . 9.Rapson a n d R . Robinson, i b i d . , 1533 (1935). (181 .\, H Cook a n d R . P.Linstead, ibid.. 956 (1934). 119) I C . .I.Piez, E . 13. Tooper, and L. S . Fosdick, J . B i d . Chem.. 194, 669 (19.52). (201 Iiiirroivs a n d Turner (ref 8) reported a product which did n o t melt lielow 310'. I t is assumed t h a t the reported product resulted through
ammonolysis of a n epoxide intermediate a n d is likely the trans isomer since analogous ring openings have been observed t o produce this structural form r comparable conditions. ( 8 . TT-instein a n d R . R . Henderson, HeleroCompound,,, 1, 29 (1950). 1 ) Where analyses are indicated 1))- sj-ml?ol of the elements, the d a t a ohtainrd v e r r nithin & 0 , 4 % of the calcri \ d u e s .
S0Tb.R
yield white cryat free of the lower ninhydrin-active component which sublimes above 285'. Anal. (CjHl,?JO3.H,O): C , H, X . A n anhyd sample of 1-amino-2-methoxycyclopen tanecarboxglic: acid %as obtained by vacuum sublimat ion at 124-140' 10.13 n i r n j ; ir (KBr) 3.38, 6.12, 7.20, 7.50, and 8.83 M : nmr 6 4.20 ( 1 , 1 11, CH), 3.52 fs, 3 H, OCH,), 1.68-2.80 fni, 6 H, CH?C:I-I?C~H,~. .Inal. (C,H,,SO,j: C, H, K . 1-Amino-2-hydroxycyclopentanecarboxylic Acid.--A mixt 10.3 g of 4 9 5 HI and 0.7 g (0.0023 inole) of 1-amino-2-methoxy(~yclopeiitaiiecarboxylicmonohydrate (0.70 g ) was heated under refliis for 2 hr. The reaction mixt \vas c ~ ~ n ctoddryness in v a c ~ o , aiid the resiilting residue was dissolved iii ICtOH and reduced to dryness twiee t o remove excess HI. The clear, viscous residue was finally dissolved i n a small vol of EtOH, adjusted to pH 8-9 with coned NHaOH, and placed in the refrigerator. The pptd amino acid was filtered, and reeq-Ftd from H20-EtOH t o yield 0.26 g (46"; of theory) of l-amiiio-2-liydroxyeyclo~)eiitaiiec.arboxylic acid: nip 288-290" der; nimp with 2-amiiio-]-hydroxycyc1opeiitaiiecarb~)xylic. acid, 273-282" : ir (KBr) 3.35, 6.03.6.40, 7.20, 7..i.i, 9.13, 11.7, and 12.7 p : iinir 6 4.34 ( 1 , 1 H, CII), 1.60-2.80 ini, 6 H, C'II&H2CH~). A n a l . ( C J ~ I I S O , ) : C,', 13, S . Microbiological Assays.-ays n-ith Escherichia coli 9723 \Yere carried oiit in ii previ dium**and incubated a t S7' for d e r t w n 1'cum 8086, S t ~ p t ~ c o c c u , ~ Pctliococcus c.c~~~cc~isic~c 804%were casein niediiini.23 For P . c ~ ~ ~ ~ i ~the i cpuriiie i c , and pyrimidine siipplernent ww inoreased to 1.2 ml, 100 nil of ha-a1 media and the phohphat e coiic!~w:i\ increased fourfold. The phosphate c o n ( ~ i oiirfold with I,. dc.r~i~anict(m, and 0.1 ~g tiilie dded. The kit t er 4 iiiicroorg:iiii~~n.; were inciibated at 30" for aboiit 16 h previonsly reported nniirlo acid inediiini24 was utilized i n th J- with Lactobacillus arahinoc:ilcium p;iritothennte \v:t-. bated l i t 30" for 20 hr.
.4cknowledgment.-Wi: icidi t o thank tho Robert A , Wclch Foundation arid the Stniuel Roberts Soblc Foundntiori for their support of this research. (22) E , 11. .\nderson, I'roc. S r i t . .letid. Sci. [ - . S . . 33, 120 (1946). (23) E , h f . Lansford. J r . , ',T. 11,Hardinp, a n d \I-. Stiive, Arch. Bzochem. B i o p k y s . , 73, 180 (1958). (24) J . > I . Ravel, I,. \Voods. U. Felsing, and I\-, Shive, J . B i d . C h e n i . , 206, 3 9 1 (1954).
Antiviral Agents. 1. Benzothiazole and Benzoxazole Analogs of 2-(a-Hydroxybenzyl)benzimidazole
Since the discovery? of the antiviral activity of 2-(ahgdroxybenzyl) benzimidazole (HBB), many analogs have been synthesized in attempts to broaden and improve upon the antiviral The importance of the a-hydroxybenzyl group as well as a fused bicyclic ring7 has been emphasized. Some evidence was found (1) Postdoctoral h-.LTO Fellow, SHI.
( 2 ) .I.C . Hollinslieaii a n d .'1 I
