July 196s
913
NEW COMPOUNDS
TABLE I SUBSTITUTED ~ , ~ B E N Z O D I . U E P I N E S
Ar 3a-e
2a-e
Compd
K
Method
Recrystn solventa
Yield. hip, o c
6 %
.inalysesh
2a c, €I c1 I A-B 87-90 72.3 2b e1 c, €1 86-80 I A-B 40.5 2c Br C, H, ?; 103-106 I A-C 41.9 2d CF3 118-123 C, H , N 50.4 I A-C 2ec H I 3a e1 155-1 57 c, 11, ?i I1 F-C 3a.HI D 270-275 c, I1 40.3 3h c1 1L61.5-163 I1 E-F c. 11, N 3b. I11 C, H, ?; D-A 286-289 64.7 3c Br I1 F C, IT, S 178-18 1 3c.HI D 272-215 c, 11, s 34.5 3d CF, I1 F 179-1 8 1 c, 11, N 3d.HI D c, II 278-282 38.4 1% 3e c, 11, ?rT I1 A 143-145 3e. I11 D 293-295 52.3 C, H, N A = EtpO, B = petroleum ether (bp 30-60"), C = hexane, D = EtOH, E = C&, F = cyclohexane. Acceptable analytical results were obtained for the elements indicated. c The isolation of this compound gave a 40.47, yield of a n oil which was converted to 3e without characterization. Experimental Section6
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1 (3-Chloropropyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-ones Some 4H,12H-Pyrano[2,3-a]phenoxazin-4-ones (2a-e). Method I.-The appropriate 1,4-benzodiazepin-2-one ( la-e)6 was dissolved in a mixture of DRIF and T H F (1: 1) and S ~ T Y E N D R AK U M A R ~ this solution, under dry Nz, was treated with excess (10-25%) D e p a r t m e n t of C h e m i s t r y , Veerut College, J f e e r u t , India NaNH2. The mixture was stirred for 2 hr a t 50" and was then treated with a threefold excess of 1-bromo-3-chloropropane and Received December 6, 1967 nas stirred overnight. The reaction mixture was poured into ice water and extracted with CHZCILwhich was dried and evaporated to drynesb. The residue was chromatographed on Woelm Derivatives of phenoxazinez-5 and 7-pyroneo -11 are reported to neutral alumina (Activity 1) on which the product was always possess marked physiological activity. I t was thought desirable less strongly adsorbed than the starting material. to synthesize some 4H,12H-pyrano[2,3-a]phenoxazine-4-ones 1,2,3,5-Tetrahydropyrimido[1,2-a] [1,4]benzodiazepines which will incorporate both phenoxazine and ?-pyrone moieties in (3a-e). Method 11.--A mixture of the appropriate 1-(3-chloroits molecule, for biological evaluation. propyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one(2a-e), 1 equiv of K I , and excess NH3 in EtOH as heated at 75' for 10 h r with Experimental Section12 shaking in a sealed container. The reartion mixture was filtered, removing KI, and the filtrate was concentrated in vucuo to a reei8-Amino-7-hydroxy-2-methyIchromonewas prepared by redue uliich wa8 recrystallized from EtOH to give the product as ducing 8-nitro-i-hydroxy-2-methylchromone~3 wit.h sodium hythe hydriodide salt. These salts were neutralized in the usual manner to give the crystalline frec bases. 8-Chloro-6-(2-fluorophenyl)-1,2-dihydro-4H-imidazo [1,2(1) Cleveland Clinic, Cleveland, Ohio. (2) (a) ill. L. Crossley, P. F. Dreishach, C. hl. Hofmann. and R. P. a] [1,4]benzodiazepine (4).--.4 solution of 5.0 g (15 mmol) of Parker, J . A m . Chem. Soc., 74, 573 (1952); (h) M. L. Crossley, R. 3. Turner, 1-(2-aminoethyl)-i-chloro-l,3-dihydro - 5 - (2 - fluorophenyl) - 2HC. M. Hofmann, P. F. Dreishach, and R. P. Parker, ihid., 74, 578 (1952); 1,4-benzodiazepin-2-oneiin 100 in1 of EtOH was heated for 24 hr (0) AI. L. Crossley, C. bl. Hofmann, and P. F. Dreishach, ibid., 74, 584 at reflux. The solvent \vas removed in vacuo to give a gum which (1952); (d) B. Boothroyd and E. R. Clark, J . Chem. Soc., 1499 (1953). mas then triturated with cyclohexane to give 3.9 g (82.5y0)of (3) A. Ribbentrop a n d W.Schaumann. Arch. Intern. Pharmacodyn., 149, c r j stals, mp 174-17i". Recrystallizations from CHpCls-cyclo374 (1964). hexane gave pure product a8 colorless needles, mp 175-177'. (4) M. R. Lewis, P. P. Goland, and H. A. Sloviter, Cancer Res., 9 , 736 ilnal. (C1i1113ClFN3)C, H, X, C1, F. (1949). ( 5 ) P. N. Craig, U. S. P a t e n t 2,947,745 (1960).
Acknowledgments.-We are indebted to RIr. S. Traiman for the infrared spectrophotometric determinations and to Dr. A41 Steyermark and his staff for the microanalyses.
(5) All melting points were determined on a hot stage microscope a n d are corrected. (6) Compound la: L. H . Sternhach a n d E. Reeder. J . O r g . Chem., 26, 4936 (1961); lb, e: L. H.Sternbach, R. I. Fryer, W.Metlesics, E. Reeder, G. Sach, G. Saucy a n d 9.Stempel, ihid., 27, 2788 (1962), lo: R . I. Fryer, R. A. Schmidt. a n d L. H. Sternbach, J . Pharm. Sci., 53, 264 (1964); ld: G. Saucy and L. H . Sternbach, Helu. Chim. Acta, 46,2226 (1962). (7) J. V. Earley. R. I. Fryer, L). Winter, and L. H . Sternhach. J . N e d . Chem., 11, 774 (1Y68).
(6) E. Kohlstaedt and K. H. Klingler, German Patent 1,018,874 (1957). ( 7 ) J. Klosa. J. Prakt. Chem., 22, 259 (1963). ( 8 ) R. H. Highhy, J . A m . Pharm. Assoc., 33, 74 (1943). (9) H . Nakamura, T. Ota, a n d G. Fukuchi, J . Pharm. Soc. J a p a n , 56, 68 (1936). (10) V. V. S. Murti, N. V. S. Rao, and T. R. Seshadri, Proc. I n d i a n Acad. Sci., M A , 22 (1947); V. V. S. Murti, L. R. Row, and T. R. Seshadri, ibid.. 27A, 33 (1948); T. R. Seshadri a n d N. Vishwanadham, ihid., 26A, 337 (1947). (11) P. DaRe, L. Verlicchi, and I. Setnikar, J . Org. Chem., 26, 1097 (1960). (12) hleltinn points are taken in capillaries and are uncorrected. Where analyses are indicated only by symbols of the elements analytical results obtained for those elements were within h O . 4 7 , of the theoretical values. (13) C. B. Thanawalla, 9. Seshadri, and P. L. Trivedi, J . I n d i a n Chem. Soc., 36, 674 (1959).
Book Rev ieuls Progress in Biochemical Pharmacology. Volumes 2 and 3. Drugs Affecting Lipid Metabolism. Parts I and 11. Edittd by I). l i i ~ r i ~ c r i s v s ~R. u ! I'AOLETTI,and I). RTEISRER(:. S. l 13are1, khvitzerland, 1967. sii 520 p p :inti 532 pp, respctctivcly. 17.5 X 24.5 rin. Y2!).80 c w h voliinics.
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I ~ r o r nt lit, title of this seric's, Progross in Bioclicniical Pharriiacology, on(' \?-auld expwt its content to constit,iitc ii rcview serios.
Sonic~whatsurprisingly, this pair of volunws edit,ed 1)y three notctl :ii:tlioriticxsi n thtb field of lipid metabolism is rathcr :I coinpilatioti ( ~ tf h v pnpers prwcrited a t the Sec~ondInternational Syniposiuni on Ilrrigs aftecting Lipid 3Ietaholism held in 3lilnn, Scpt ltXj5. 'I'1ii.q is consistent with the conterite of Volumes 1 and 4 ( i t 1 preparation) which cover Symposia on Itadioactivv 1)ruy.a and ;2ttic:roselerosis! respectively. Thc tahle of contents enunic~ratestitlw of 54 and 56 pqx:r*, ITspwtively, and the nzrnies of an array of distinguishrd rcienti 1 h c w p p r s am grotiped into categories of (Poluinc. '2) Cholert vrol and Atherosclerosis, Plasma Triglycerides and Lipoproteins. I )rugs Affccting l'lasnin Lipids, and (Volumc 3) F a t t y Acids. 1'rost:tgl:indins. Free Acid 3lobilizatiori. Free Fat -(-(:ride Transport, and Liposolut)l(b Vitaniir sey+ons is *~introdurccItiy i i p:ip(jr presenting rcwnt clvvc4opnicntr in basic t,ioclicniistr> L Imckground for sut)scqii(siit l ) : i p ( ~ soil tlriig effects." This providrr :in ( t o r y Eorniat. t)cc*uiiseof the p:irticular exwllcnce of t h e w discw4 o l i . T h o authors of these papers, IT.I,. Holmes, Y. IT.IliTullio, ( i . Svhcttler., X, F . Oliver, F. Lynen, 13. Saniuelsson, I). Rtc~inticrg,A. Himi, 8. G:irattini, and I>. S. Goodmail, are to l i t . congratulated for the p:rrticular t~xcellencoand lwidity of thtxir prtwnt:Ltions. X g c w s r d point w1iic.h nicrit s reflectiou and discussion k)y rps:cx:irc-h scxic.ntists is th(1 whole qiiestioii of wrc*hivzrl-typep l l b h C : l t i o t i ~f rymposiiiin proeerdings. .i complete, as opposed to :i Iwtivc,, r c y w t l of spwinl lecturer at t i symposinni comprising 3.11~ ) i x ~ i i i i : i t e l100 y papers ('an indeed gntlicr :i large amount of curwrit inforrn:ition on a specific sut)jec*t into one (,ompilation. I Io\vc~vt~r, thew I)resentations which arc o f t c m cited 1ntc.r in t h . r .
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