poiieiit, no startiiig material, a i d foiir minor component>. X azo10nes3 are reported to have similar activities. O u r 170-mg portion was dissolved in AleOH-HL) ( l : l ) $applied i n previous experiericc with S-arylpiperazine derivative, bands on five sheets of Whatnian No. 311hI filter paper, and subhaving sedative, hypotensive, and :mtiadrenergic jected to electrophoresis a t pH 3 The major band a t E H activities led us to study certain 3-w-(-l.-aryl-l-piper0.50 was eluted with water and lyop zed to yield 63 mg of white aziny1)alkyl-.'-methyl- (or ?-phenyl-) 4(SH)-quinazopowder: single spot on paper electrophoresis at pH 3.5 ( E H 0..3)and pH 6.5 ( E M 0.51); 011 paper chromatography, Ki lories (I) (Tableb I and 11). 0.74; ninhydrin and Pauly ; aiuiiio acid aiialysis; 1.d 1.00, These compounds were readilj- prepared by heatiiig T y r 0.57, Ile 0.91, His 1.02, Pro U.I)X, Phe 0.!)4. "methyl- (or 2-phenyl-) 4-oxo-4H-3,l-benxoxazine (11) c.!lcLo-(-Val-Tyr-Ile-His-Pro-Phe-). ---To a >tiired ,s-.oliitioiiiuf 16 111: (0.084 mmole) of l-eth~-l-8-i:~-diinethylariiinopropyl)c~ari~o- with appropriate primary amines (method A) or by tliimide hydrochloride i r i 2 in1 of I ) l I F was added dropwise over treating isatoic atihydride (111) with the amines to give 14 hr 53 nig (0.04 mmole) of ~al-'l'~r-Ile-Ilis-Pi~o-Phe dissolved o-amino-S-substituted benzamideh (IV) which wcrc i n 14 nil of UMF. After 24 hr at rooni ternperatwe in the dark, then benzoylated iiiid cyclized with A c 2 0 (method B) paper electrophoresis showed no starting material at, EH 0..30 (Scheme I). I (R' = CHZ) iz alm prepared by heating (pH 3.5), and in addition to yeveral minor spots, a aiiigle major IV in Ac?O. The detail5 of the preparative cliemihtrj ninhydrin -. The coniponent at Ea 0.40 (pH 3.5); Palily solvent a a s removed in vacuo and the residue was dissolved iii h:tve been tlewrihcxl iri :I r( MeOH, applied in bands on sheets of Whatniaii No. 3 X A 1 filter paper. Follom-ing electrophoresis, the band a t with water and lyophilized to yield 15 m g powder: single spot on paper elect,rophores 0,4:3; Pauly ninhydrin - ; amino acid T y r 0.91, Ile 0.89, His 1.01, Pro 1.04) €'he 1.08.
+
+,
+,
Acknowledgments.-Ke are grateful to Ilr. Kennetli 11. Kopple for samples of cyclic peptides, Drs. 1'. A. Lehmaii, T. C. Lee, arid G . \Yindridge for assistance bioassays, Ilrs. €3. Katzung and S. ,J. Feinglass aiice with computer programming, and Dr. D. Sitecki for her helpful discussions and :L sample of thn soluble carbodiimide derivative used in the cyclization rc:ictioti.
Method B:
Hypotensive, Antiadrenergic, and Antihistaminic 3-Substituted 2-Methyl(or &Phenyl-) 4(3H)-yuinazolones ~ H I ZH L Y io,
H. J. € I
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LV. G. STRICKLII
Therapeutics lleseui ch Diviszon, M d e s Laboratories, Inc., Elkhait, Indiana /t6'51.$ \\I)
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