TABLEI I K D1Lmro.v STUDIES O F EPIMERIC ~-~-TUDKOX~.-~-PHE~YL~UINOLIZIDINES IN CHClp I r spectra, cm-'---------. Free hydroxyl absorp
% concn
NO.
Intrarriol H bonding
Interinol H bonding
33-50 (w) 3080-34!50 i s ) IIIa 360.5 (s) 20 3350 ( w ) 3080-34.50 (w) 10 460.i ( m ) IIIa IIIR 1 360.; (m) 3330 (x) None 3350 (w) None 360.5 ( m ) IIIn O.O.i3 I\'R 20 360.5 ( h ) Sone 3073-34.50 (s) Xone 3073-34.50 i w ) 10 360.i (m) IT k IT7% ) :." Fractions 12-17, eliited with CCl,, yielded 405 mg of biphenyl and iinsatiirated phen!-lcliiiiiolizidiiie. Fiwtionr 18-21, eluted
TABLE I11
ESTERS OF
~~YDROXYPHENYLRUINOLIZIDI~ES
C6H5why OCOR
Ester position
Phenyl position
Yield, 52 2 (a) 49 IIIb CH3 2 (e) 2 (a) 63 IIIc C,H, 2 (e) 2 (e) 66 11% CH, 2 (a) 54 I T-c C2H; 2 (a) 2 (e) r1-1 CH, 1 (e) 1(a) i0 VI1 CHI 1 (a) 1 (e) 30 Hydrochloride, recrystallized from l I e r C O ; analyzed for C, H, C1, S . from EtOH; analyzed for C, H, N. R
NO.
servations in other ~yqtems.' This characteristic shift of the methyl signals also occurred in the corresponding epimeric acetates (TI, VII) of l-hydroxy-l-phenylyuinolizidines (Table 11). Since the latter structural characterirtics are known,i this provided further evidcnve for structures I11 and IT'. The esters (Table
&
CH3&
C85
CHJOO
VI
VI1
111) were prepared readily from the corresponding alcohols using an excess of the appropriate anhydride in pyridine. The compounds described in this study were tested (7) R . U Lemierix, R K. Kullnig, H J. Bernstein, and W. G . Schneider .I. AmPr. ~ h p mS o r , 79, inn5 (19.571, 80, 60% (~wB).
BP, "C ( m m )
Mp.
oc
120 ( 0 . 1 ) 110-110 ( 0 . 1 ) 120 (0.1) 122 (0.1.5)
*
204-2056 198-199a l68-17On 20*3-206" ... 1.i8-160b 183-184b ... C : calcd, 66.7; found, 67.4.
with CCL, yielded 78 mg of iinsaturated phenylquinolizidine, identified by its ir spectrum. Fraction 22, eluted with CCl,, yielded 99 mg of unreacted 2-ketoqninolizidine, identified b y its ir spectrum. Fraction 23, eluted with CCL, yielded 6.56 mg of IVa. The ir spectrnm showed weak C=O absorption indicating the preseiice of a small amount of inireacted 2-ketoquinolizidine. Fractions 24-34, eluted with CClr, yielded 9.614 g 1 2 4 7 ) of IVa. l~ecrystallizatioii from petroleiim ether yielded 6.27 g (8) G. C. Helsley, J. -1.Richman, C. D. Lunsford, H. Jenkins, R . P. Mays, \I-. H. Funderhurk, and D. X. Johnson, J . .Wed. Chrm., 11, 4i2 (1968); P. Xilsen, Acta Pharmacal. T o z ~ c o ~ 1 8. ,, 10 (1961). (9) All melting points were taken on a Thomas-Hool-er Uni-Melt melting point apparatus and are corrected. I r spectra \yere determined on a Perkin-Elmer Model 257 ir spectrophotometer and were corrected against t h e 5.138-p absorption band of polystyrene film. T h e nmr spectra. were taken on a Varian Model -1-60.1 instrument (TMS). Where analyses are indicated only by symbols of t h e elements, analytical results ohtained were of~t h e theoretical values. within ~ t 0 . 4 7 (10) R . E. Counsel1 and T. 0. Soine, J . A m . Pharm. Assoc., Sci. Ed., 49, 289 (1960). (11) L. F. Fieser, "Organic Experiments," n. C . Heath and Co., Boston, Mans., 1864, p 89.
ROBERTA. WILEY.4m ,JEKHYII. C'OLJ~ISS '1'1111.E I \.
of white needles, m p 117--178', bringing the total ,yield of I\'& to 16.27 g ('39.6r~i). Fixctiona 36-46, eluted with 5 0 :50 lle2CO-aiihydrous Et,O, gave 7.31 g (19c-i) of prodiict, m p 114-116°. T h e sample was tallized frum petroleum ether t o give 5.6 g (14.57:,) of 2(r)-hydroug.-L'ia)-pheiiylqriiii(~lizidiiie (IIIa), rnp 11~)-120". Adniixtiire of the material with IVa showed a sigiiifirant melting l x ~ i i i tdepression (90-95'). Anal. IClaH,,NO) C, IT, S . Esters of Hydroxyphenylquinolizidines (Table III).--.i solution 01 0.01 mole of the appropriate epimeric. li!(~rox!phenylqi~inolizitliiir. in 10 in1 of ArrO or propionic anhydride and 40 ml of pyritliiit. !vas refliixed for 18 tir. T h e mixtiirr w a s coo1r.d to room temperaturcl arid trcated with (wished ire :tnd excess solid RrCOZ, respectively. The aqiieoiis mixture was extracted w i t h two 250-nil portions of Et2(). The etherex1 solution w a s evapo-
Phosphorus Analogs of Nitrogenous Drugs. 11.' 10H-Dibenzo[l,4]thiaphosphorins as Central Nervous System Depressants
I n a n effort to delineate the electronic properties of the tricyclic niicleus which are important to chlorprornazinetype biological activity, 10-(3-dimethylaminopropyl)-1OW-dibenzo[ 1,4]thiaphosphorin, its oxide, and three analogous oxides, substitilted a t the 2 pwition with CI, P l l e , aiid O l I e groups, respectively, have heeii synthesized. Ultraviolet spectral data are presented to show that extensive deloralizaiion o f the :;p elertroiis CIII the pho,sphorus atom i n the phosphine would be expected. T h e compounds are shown t o depress spoiitaneoii' activity in mice i n the 30-50-mg/kg dosage range, and a p,o>sihle correlatioii between biological activity niid elechoriic properties of the nucleus, a: revealed by iiv spectral data, are disciiswtl.
The important biological properties associated n-it h t h e phenothiazine tranquilizers, of which chlorprornazine ih the prototype, are well known and have been rrviewed extensively.* I n a n initial attempt aimed a t definition of optimum stereoelectronic properties in the tricyclic nucleus the title compounds, of which 1 is the prototype, in which phosphorus replaces the ring nitrogen have been synthesized arid submitted to preliminary hiological evaluation. Several related oxides 2 have also been prepared aiid tested. We elected to insert phosphorus into these systems because its close chemical relationship to nitrogen Lvould be expected to affect the chemical properties of the aromatic nucleus in a very yubtle manner. These small changes should be observ( t j ( a ) Part I : R. A . IYiley and H . N . Godwin, J . I'harm. Sci., 54, 1063 1!16J). (I>) J. IT. C. was a Predoctoral Fellow of t h e Public Health Service, (c) T h e authors gratefully acknowledge t h e assistance of D r . ('. li. J3rickson in the biological studies. (2) (a) AI. Gordon in "Psychopharmacological Agents," Vol. 2. 31. Gordon, Ed., Academic Press, %-em York, S . Ti., lY67, p 1; (b) I(. Stach and LV. Poldinper, Fortsch. Arziieimittel/orsch., 9, 129 (1Y66): ( c ) P. M. Mradley in "Physiological Pharmacology, h Comprehensive Treatise." Vol. 1, XY. 8. Knot a n d F. Q. Hofmann, Ed., Academic Press, New York, iX. Y., 1963, D 417. I
11183-1967.
able chemically, by observing the spectrowopic propc~ties of the s p t e n i , as well a i biologically. Peruwl of the uv ypectral data for the first \i\ conipounds in Table I will show that the unshared electron* of nitrogen adjacent to an aromatic .yzteni iritrract n i t ti the aromatic a electronb to cause :i h:cthochromic shift in the Am,, and :L pronounced increa.e in the tIIIaX. The effect i:, more pronounced in I'h2SH than in l'hSH2, but reduced i n l'li,X(CHs)3SlIe2. perhap" tier:iu*c> the alkyl chain interfere< with coplaim-ity of the t n o benzenoid ring\. The 3p orbital accommodating t Iw unbhsred electrons of phosphorus is much larger t l x i i i the corresponding 2p orbitaI of nitrogen and, iri * o n i c l \ituations, thi. results in striking chemical diffrrencv betweeri analogou:, nitrogen and phosphorus conipoundg. For example, the phosphoru.; a n d o g of pyridine is not l i r i o \ v ~ i ,apparently ~ becaube i n this \p2honded system the overlap of the 3p phosphorus elcctrons with those i n the carbon 2p orbitals is so poor th:tt little or no r'ewiiance stabilization is afforded. HOKever, i n the prc>tent case, the uv data for 1'11,J' in I
( 9 ) R. F Hiidx,n structure and Mechanism in Or~anoplios~,iioriIr hemistry," hcaderiiir Press New York, N. Y . , 1965, p 3.
