832
rd ul.>5have reported that inhibitors
i i f ~i~oii(~a~iiiiie oxidase piissess pronounced anticonvulsant properties. 4-.4minoquiiioline has heeri showii to be a potent inhibitor ( i f this enzyme, as mmparecl to 4-aniinopyridine which was almost devoid of such inhibitory On t h e basis of these observations we have synthesized 2,3-disubstituted qninaxolones froin aminopyridines and 5nminoquinoline follon-ing the method of Bogert, et nl.'
Experimentals" 2-(2-Thenoyl)diphenyImethane. A.- -iz Grignard reagent was prepared from 7.2 g. (0.30 g.-at,orn) of niagnesium and a solution of 50 g. 10.30 niole, 3 0 nil.) of 2-broinothiopherie iri anhydrous ether. After cornpletioii of reaction, most of the ether was distilled while 47 g. (0.24 mole) of 2-cyanodiphenylinethane dissolved in anhydrous benzene \v:w added. The mixture was heat,ed under reflus for 18 hr. mid n-orked-up in the usual way. Experimental* The product was it visrous oil, t1.p. 1!13-195" (0.5 m i d , 59 g. Molar proportions of acetantiirauil (n1.p. 78-80') and the ap( , S f i c ; ). It was cymta1lize.d froin rth:tnol, 11i.p. 43-44'. propriate amines were mixed together iri a round-bottomed flask. A n a l . Calcd. for CI,H,;OS: C'. 7 i . 6 6 : IT, 5.07; S, 11.6'2. The contents of the flask 7%-erefirst heated i ~ na low flame and Found: C, 77.53: H, 4.97: S, Il..i%. then on a full flame. On woling, the jelly-like mass which sep:iThe product w:is oxidized quant3it~atively using sodiuni dichrorated out crvstallized yielding 2,::-disilt)stitiited quinazoloiie8 in mate in glacial aretiv ai,id t o give 2-[2-theno?.l)beiizophenorie, good yield. m,p. 135-136' (from rthaiinl'l. The various Dyridine derivatives used were 2-tiniiiio-, :3-anh~i-, -1?m1. Clahd. f o ~ (, " I \ I - T I ~ ~ (', ? S :Z$.94; If, 4.14. Found: C, arid 4-arriinopyridines, aiid 2--ariiiiio1iiethyl-, 3-ami~ioiiiethyl-, Z3.60; H.4.24. and 4-amiriomelh~lp~ridi1ies.I n adtiitiorij S-aniirioquinolin~~ B . --A ~ Griparcl rwgeiii \$-:is prep:ircd froin 37 g. (0.15 i i i i j l r was aho used for the preparation of :i quinazolone. .$I1 (pino f 2-broiiiotliplirii~~liiiett~:tii~~ and 3.9 g. (0.16 g.-atom) of niaga d o n e s were crystallized from :i riiisture of ethyl alcohol and nesiuni in dry ether. .ifter most of the ningnesiuni had reacted, etlier (1 : 1) except the oiie fornietl f i . o r n 4-aiiiiiiopyridine which t h e et.here:tl solution of t l i ~Grignard reagent was transferred, was crystallized with niethj-1 alcohol oiily. The characterizatioii uitder iiitrogen, til a sr'p:tr:ttory funnel :tnd added slowly t o a of these 2,Misuhstituted quinazolones WIS done by their sharp boiling solution of 22 g. (0.15 mole) of 2-therioyl chloride in dry melting points :tnd also b!- analysis. The results are sunimarizetl benzene. Solvent ~ m rtJriioved s urii il the boiling temperature in Table I. was 66", :tnd the rriixturr \viis heated for 4.5 lir., t,hen decomposed 'i of product, identical with m d worked-up t o give 16 g. ( t1i:ti obtained by A . 2-(3-Thenoyl)diphenylmethane. A. This rciinpnund could not be prepared as WEIS the 2-isi)iiier, hut resort, hac1 t o be had i n the entrainment inrthod usiiig ethyl hroiiiide. 'The produrt, h.p. 180-185" ( 0 . 5 iiiin.), m x s :t btained in 58?:, :-ield. .InaZ. (I:tlcd. for ClsH,, .66; H, 5.07; 6 , 11.32. Found: C', 77.64: H, 5,flO; B. --The coriipiniriil wa. esseiit,ially as was the 9-Thien>-lanthracenes' 2-isomer. The prodiic,t 11.p. 127' (0.20 nini.) (spinning hand clolunin), was a. viscous oil o1it:tincvl in yield :377;,. 9-(2-Thienyl)anthracene.-A rnixturc of 34 g. [ 0.122 mole) methane, 12110 nil. of glacittl acetic avid, ohroinic~ai*idwas heated under reflux for :is i~ciciled, diluted with uttt.er, :tud refrigerated overnight giving 20 p. 16.jC&)of cryst:&, rii.11. 11:3-114°. Recryst,allization froin al)soluw et,h:trinl gave an analyticd sainplc :is yellow iieetlles, 111.1). 1 1:i..i 1 11.0", n-hic.11 fluoresced green under u1t)ravioletlight. A n a l . Calcd. for ( ' 1 5 1 f l oa; If, 4.65: s, 12.32. 'I'hc? title cwnipoulitls w e r e pre1i:tred :is part of a n air pollution I'orlntl: c, 82.81 : 1 1 . .&.!I:: study prograin t o make new pol! lie aromatic compounds ' h e sain(' prodric,t w i d ~i\~t:iiiied iisiiig }lhosphoruspelitosidr or available for carcinogenicity test The synthetic routes hydrogeri pheii!,l p'rioq)h:ttc~: ~ st,he :wid catalyst. t o these compounds involve exteiisions t t i useful reactions previThe product fi)rir~ctI:t tlrep viiiI(~11 : 2 adduct w i t h 2,4,7-triously recorded.4 i i i t rofluorerione, 1n.p 166 - 167". .4.~iuL C a l d for C:,,H,,S&S: C , 59.33; H, 2.4Y; N, 9.43: (1) 'Tiiis in\.estigatiun was supported b y research G r a n t AP-00088-06 P, 3.60. Found*: C, 5 9 . 2 i : H, 2.41: S,!).44; S,3.67. I "
~
f r o m tile Division of . l i r Polliltion, Bureau of Rtate Services, Public Healtli Seri.ire. (2) Taken froin t h e 1)octorate ttieses of S. ( i . Quo a n d 1'. Polss presenierl to t h e Virginia Polytechnic I n s t i t u t e in 1959 and 1962, respectively. I ) . 1.;. .\. Fellow 1960-196:3. Emtillan Kodak Fellow 1Y6S -1Y64, .\. \'ingiello, S. (;, Qtio, imd J. Sheridan, J . Ofg. Chern.. 2 6 , %tjti!I (19fil).
BOOKREVIEWS
Xovember, 1964 9-( 3-ThienyI)anthracene.-This compound was obtained essentially as was the L2-isomer’above in 80% yield from the corresponding ketone using hydrobromic acid as the catalyst. Recrystallization from absolute ethanol gave an analytical sample as yellow needles, m.p. 122.0-122.5”, which fluoresced green under ultraviolet light.
833
Anal. Calcd. for CtsHl&3: C, 83.03; H, 4.65; S, 12.32. Found: C, 83.10; H, 4.76; S, 12.06. The black 1 :2 adduct with 2,4,7-trinitrofluorenone melted a t 167-168”. Anal. Calcd. for C 4 4 H d 6 0 ~ S :C, 59.33; H, 2.49; N, 9.43; S,3.60. Found*: C, 59.44; H,2.53; N,9.38; S,3.37.
Book Reviews The Neomycins and Related Antibiotics. By KENNETHL. RINEHART, JR. John Wiley and Sons, Inc., Kew York, N. Y. 1964. 136 pp. 12 X 18 cm.
H. J. Rogers considere tha structure and functions of bacteria
mammalian cells, and derives from these facts theories of action of the sulfonamides and antibiotics which affect the synthesis of the bacterial cell wall. In a well-written chapter, R. The antibiotic neomycin was discovered in 1949 and the fact Knox discusses theoretical aspects of the strategy and tactics of that its gross architecture and stereochemistry were not comantibacterial chemotherapy, from serendipity through in vitro to pleted until 1962 attests to the degree of difficulty this type in vivo requirements. D. J. Kushner writes about the resistance of problem presents. The chemical and medical literature has of bacteria to harsh and destructive environmental conditions desperately needed clarification in the neomycin field due to the such as heat, chemical concentrations, radiation, pH, heavy large number of similar and identical antibiotics which have been metals, enzyme inhibitors, surfactants, and disinfectants reported throughout the world. To this end Professor Rinehart Special topics include the chemotherapy with sulfonamides has done an excellent job and yeoman service in identifying and (L. Neipp) and the pharmacology of these drugs ( R . E. Bagdon ) correlating these substances. It was fortunate perhaps that two the nitrofurans (H. E. and XI. F. Paul), topical antibacterial, closely related antibiotics, kanamycin and paromomycin, appeared ( R . J. Schnitzer), and therapeutic agents for tuberculosis (G. Ps on the clinical horizon in the late fifties since techniques used in and A. S.Youmans) and leprosy (P. C. Ekman). These special. the degradative procedures of one aided progress in the others. chapters are searching and critical evaluations of available. The book offers many interesting examples in the application methodology and the meaning of the procedures, and should of periodate oxidation, Hudson’s rotational rules, and nuclear , satisfy the demanding reader as well as those who look for overmagnetic resonance to the elucidation of oligosaccharide strucall information on one of these subject,s. tures. In some instances, however, structures have been postuUXIVERSITY OF VIRGIKIA ALFREDBURGER lated by presumptive rather than conclusive evidence but are CHARLOTTESVILLE, VIRGINIA interesting nonetheless in that they offer the reader a mental exercise in sugar conformational analysis. Of particular interest is the novel use of cuprammonium rotation data to the determination of absolute configuration of monosubstituted deMetabolic Inhibitors-A Comprehenisive Treatise. Volume 11. oxystreptamines. A welcome addition to the chemical studies is Edited by R. X. HOCHSTER and J. H. QUASTEL.Academic a chapter on biosynthetic considerations. Although incomplete, Press Inc., New York, N. Y. 1964. xvii 753 pp. 15 X it should offer the microbiologist valuable information relative to 21.5 cm. $29.00. antibiotic precursor studies. We know that the multitude of natural metabolites in a given THEODORE H. HASKELL PARKE, DAVISAND COMPANY “living” system balance each other to produce the “normal” ANNARBOR,MICHIGAN condition of the system. A deletion of one or several metabolites upsets this balance. This situation may remedy itself by the establishment of a new balance in which an induced overproduction of a previously less active metabolite makes up for the Experimental Chemotherapy. Volume 11. Chemotherapy of deletion of the lost vital factors. Or else, an extraneous chemical, and Bacterial Infections. Part I. Edited by R. J. SCHNITZER a drug, or an internal chemical arising through an induced physiF. HAWKISG. Academic Press Inc., New York, N. Y. 1964. cal change of the biochemical environment may restore the upset xvii 614 pp. 16 X 23 em. $23.00. [For a review of Vol. balance, occasionally upsetting another facet in an undesired I, see J . X e d . Chem., 6,825 (196311. side effect. Whatever we insert into a biological system, be it a In almost all fields of chemotherapy the triumphs of the late nutrient or a corrective medicinal agent, will preoccupy enzymes, 1940’sand the early 1950’shave been dampened by the emergence tie up other natural chemicals, or cause them to react chemically, of drug-resistant organisms, and the flare-up of nearly forgotten and thereby temporarily or permanently remove them from the infections in less treatable, or even untreatable, forms. Moreintegrated biochemical scene. All these substances are metabolic over, systemic antibacterial therapy is mostly bacteriostatic antagonists. They range from the irreversible inhibitors to the rather than bactericidal, and as G. P. and A. S. Youmans put it kinetically most unstable antimetabolite systems; they interfere in the present volume (p. 394), “there is, therefore, a real need for with the biosynthesis of needed metabolites, or compete with the new and more eradicative drugs.” This should not detract from finished product for a reactive site of a macromolecular biothe magnificent achievements of the antibiotics and the synthetic catalyst. antibacterial agents which have contributed so much to increased The present volume, the second and the last one in this series, longevity and healthier living. Nevertheless, the appearance of a attempts t o cover the kaleidoscopic variety of all grades of antinew treatise on all aspects of bacterial chemotherapy is a timely metabolites which have not been discussed in Volume I [see event and should guide the investigator to future needs of reJ . Med. Chem., 6,828 (1963)]. Expert authors have been chosen searches in this field. for each chapter, and each appears to have done his level best t o The antibacterial dyestuffs, with emphasis on acridine derivasurvey critically, broadly, and with restraint his assigned field tives, are reviewed by C. H. Browning. This section is the only about which he knows so much. The editors must have had a connection to the early history of antibacterial agents in this hard task coordinating these interwoven and overlapping chapbook. It is to be regretted that space did not permit the inters. Just as even an experienced biochemist will be troubled clusion of many other older antibacterial agents which were tried by the relative lack of specificity of the vast majority of antiand discarded before the advent of decisively active drugs for a metabolites, thus the editors must have suffered from the overgiven infection. Many valuable “leads” are stacked away among lapping of chapters. However, this could have been corrected those forgotten compounds. In a time when radical departures had the editorial work been done more carefully. To take a from useful drugs are being sought to overcome problems of specific point, the well-presented chapter on mono- and polyamine bacterial resistance and persistence, some of those old studies may analogs by E. A. Zeller is followed by a survey of inhibitors of well have been unearthed again. catecholamine metabolism (T. L. Sourkes and A. D’Iorio) which us.
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