January 19iO
FLUOROTETRAHYDROAZEPIKO [4,5-b IINDOL-3 (2H)-YLBCTYROPHESOSES
23
(lOOo, 0.3 mm) to provide 38.7 g ( 6 9 5 ) of material, mp 244" dec. (63.9 g, 0.200 mole) was added to the deep red ylide solution and Anal. (C26H23BrIG2P.HBr)C, €I, Br. Upon standing in air this the mixtiire was stirred a t reflux for 2 hr. After cooling the resalt quickly absorbs 1 equiv of H 2 0 , which readily dissociates on action mixtiire to .lo, 100 ml of H2O was carefully added, then the vacuum drying. aqueoiis phase wai adjusted t o p H 3 with 3 A' aqueous HC1. cis-N,N-Dimethyl-S-{ 3- [4-(2-hydroxyethyl)-l-piperazinyl] The layers were separate and t,he aqueous layer was extracted propylidene ) thioxanthene-2-sulfonamide (20) Dimaleate.-A sowith two 250-ml portions of CsH, to remove unreacted ketone and lution of cis-19 free base (4.30 g, 0,010 mole) in 10 ml of anhydrous PhaPO. The aqiieous phase was clarified with Darco G-60, PIIeOH at 0" was treated with 1.0 ml of ethylene oxide under N1. neutralized with :3 -Yaqueoiis KOH, and extracted throughly with After heating the soliitioii at reflilx for 4 hr, the solvent was CeH6 to provide 46.3 g (54%) of 19, a 1 :1 mixtiire of geometric removed and the residue was treated with 2 equiv of maleic iwniers. acid in EtOH to afford the crystalline dimaleate salt. Two reThe c r a m isomer was isolated by conversion to t,he dioxalate crystallizations from X e C X and one recrystallization from EtOH salt in . 3 l c C aqueous EtOH. One recrystallization from the same provided 2.38 g ( 3 3 5 ) of piire 20 dimaleate: mp 126-128"; solvent pair afforded pure trans-19 dioxalate: mp 181-181.5' ir (KBr) 2.93 p (011); uv m a s (EtOH) 308 mp (log e 3.9). C, H, N. dec. .-lnal. (C2rH?i~302S2.2C2H201.H20) The free base from frons-19 dioxalate, when treated with maleic Anal. (c,4H,,~3o,s,.2C4H401) C, H, iY. trans-N ,N-Dimethyl-9-{ 3- [4-(2-hydroxyethyl)-l -piperazinyl] acid in I f e C S , provided trans-19 dimaleate: mp 150-153'; C ~ H ~ - thioxanthene-2-sulfonamide (21 ) dimaleate was uv max (EtOH) 302 mp (log e 3.9). Anal. ( C B H ~ ~ N ~ O ~ S Z . ~ propylidene) prepared by the same procedure in 60% yield: mp 180-182" 0 4 ) C, H, N. (EtOH), uv max (EtOH) 302 mp (log e 3.9). A n d . (CZ4H31N3The cis isomer was isolated by neutralization of the oxalate mother liqiior to pH 10 with 3 N aqueous KOH, extracting 0,&~2c4H404) C, H, K'. cis-4- [3-(2-N,N-Dimethylsulfamoylthioxanthen-9-ylidene)thoroughly with CHyC12, and treatment of the enriched free base mixtiire with p-toluenesiilfonic acid in hot, MeOH. A single repropyl] -N-methyl-1-piperazinepropionamide(22) Dihydrochloride.-A solution of cis-19 ditosylate (1.85 g, 0.002 mole) and crystallization from MeOH provided pure cis-19 ditosylate: mp 3-chloro-N-methylpropionamide~6 (0.49 g, 0.002 mole) in 5.0 207-208", iiv m a s (EtOH) 261, 310 mp (log e 4.2, 3.9). Anal. ml of DRIF under N2 was stirred a t 80' for 48 hr with 1.7 g of (C?:.Hpiru'aOiSz.2C~;H,O32) C, H, N . Methylation of f~~ns-l9.-A solution of the free base of trans-19 K2C03. Upon cooling the reaction mixture was filtered, the (172 mg) in 4 nil of 97% HC0,H and 4 ml of 3770 formalin was filtrate was diluted with 4 vol of H20, and the product was isolated with CHC13. The crude base was treated with dry €IC1 in iheated at reflux for 30 min. The residue was dissolved in CHzCl,, washed with 1 -Yaqueous KOH, dried (RlgS04), then evaporated PrOH and the precipitated solid was recrystallized from i-PrOH to ail oil which crystallized from i-PrOH, mp 119-121". One reto afford 0.69 g (87%) of 22 dihydrochloride: mp 244.5crystallizatioii afforded a product which was identical with 246' dec, ir (KBr) 5.92 p (amide I), uv max (EtOH) 310 mp trans-4. (log e 4.0). Anal. (C2sH,4N,O3S?.2HCl)C, H , S . Methylation of cis-l9.--In the same manner cis-19 (free base) Acknowledgment.-We t'hank llessrs. HansrlTiederwas converted to cis-4, mp 14.5-147'. 3-(4-Methyl-l-piperazinyl)propyltriphenylphosphonium Bromann and Gerard n'int'eau for their capable technical mide Hydrobromide.-1-Methylpiperasine (10.0 g, 0.100 mole) assistance and M r . Martin J. Lynch for development' of was added carefully to a stirred slurry of 3-bromopropyltrit,he chromatographic isomer detection systems. We are pheiiy1phosphi)iiiiim bromidelj (46.4 g, 0.100 mole) in 100 ml of also indebted to Drs. A. Weissman and G. L. Ragle for i-PrOH. Xheii heated to refliix, a deep red solution was obtained. the pharmacological testing results. After 2 hr at reflux, the solution was chilled to 5'. T h e crystalline prodiict was filtered, washed with cold i-PrOH, and dried
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(1.5) It compound reqiiired t o give a total >mire (if 13 per group of six mice. Antagonism of Apomorphine-Induced Cage Climbing.--The ability of compoiinds to aritagoiiize the apiimorphiiie-iiidi~cedcage climbing phenomenoii was determilied iii groups of foiir mice. .%poinorphilie (2.5 mg/kg) wah injected iiitraperitoneally 30 min after admiiiistratioii of the test, conipoiind, and the mice were placed in a wire-mesh cage. Fifteen miiiiites later the number of secorids oiit of a 60-sec observation period that at, least three of the foiir mice were stailding upright or had climbed from the botiorn of the cage was recorded. I h e s of the test compounds were decreased in 0.3 log iiiiervali iiiitil no antagoiii~mof the cage cnlimbiiig respoiise \vas oticerved.' (6) (2. .\. Youngdale. I). 0 . Anger, IV. C. Antlionj-, J. P.Dei-anzo, 11. L. Greig. 11. Y. Heineelman. 11. €1. Iieaslint., and J . Szrnusrkovicz. J . X e d . C h r m . . 7 , 41.5 (1964). ( i i The effective dose (EDao) ]\-as calculated by t h e method of Spearman a n d l i a r h e r , see D. .J. Finney, "Statistical Methods in Hiologiral Assay," 21afne.r.I ' i i l i l i ~ i ~ i n (x' < > . ,Se!! 1 ( i r k . S.J. .. 19.52
Antagonism of d-Amphetamine-Induced Aggregation Toxicity. Thirty niiiiiites after :idniiiiistratioii of the te-t u)iiipoiiiid mice byere iiijected iiitinperit oiieally with a di).e of ~i-:irnplietainii~e (10 mg/kg) w1iic.h \vi)iild he lethal to all i,oriti,i,l aiiiinals i i i i d r t r the coiiditioiis I J ~this rsperinieiit. The riiic,e w i . e inimedintely aggi,egated in groiipr; of teii iii plartic ctige- n-il ti pei,foixted 1iw1:il top.. The cages measured 13 X 16 X 12 rni arid were krpt :it i i i i iiiteriial temperatiire of :j2" in a cabiiiet maiiitained at 2 - O . h f t e r 4 hr of aggregation the number ( i f dead mice wn.- recorded. The ciuse of test compound was decreased at 0.5 log iiiterva1.s.; Effect on Body Temperature.-The budy temperatiire of miw was measured 30 min after administratioil of the test compouiid. Body temperature wab measured with aii iiitrapei~itoiiealttic~i~n~ister probe on a Tri-R e roriic thermometer. Tlitl a temperature for groups of mice was calcdated. Chemistry.-Melting p( s, taken in a capillai,>. tiibe, :iw vorrected. The stnictiireh of all compounds were >~ippiiII rd b y ir, iiv, aiid iimr spectra. Skellysolve B is a comnirrcial hesaiie, bp 60-io", made by Skelly Oil Co., Kansas City, IIo. The d i c a gel iised for chromatography was ohtniiied frvni F:. .\[rick A.G., Darmstadt, Germany. 4'-Fluoro-4-(1,4,5,6-tetrahydroazepino[4,5-b]indol-3( 2H )-yl j butyrophenone (l).--.l stirred mixture of 1,2,3,4,5,6-hexah?.1~1.11aze~iiio[4,.j-b]iiidole" (1S.B g, 0.100 mole), 4-chloro-4'-llii111.1,htyrophenone (2h.0 g, 0.140 mole), aiihy 4-methyl-2-pentarioiie (1.15 1.): and a few fluxed under Nz for 13 hr, cooled, poured iiito € 7 2 0 , mid extracted was dried (K2C03) arid concentratrcl idue \vas chromatographed oil silicn gel OAc (2:98). The product thus obtainrd l o give 1:?.:3 g {:
