ASTIALDOSTERORE 2.3,3-TRlPHE~~LPROP~L.~~lISES
September 1989
87 3
TABLE I11 LOCALANESTHETIC L4CTIVITYBND DURATION O F ACTIOX
--
No."
R
9%
NR'R"
Local anesthetic a"c-.t yo equimolar concnC
Duration,
70
hLD50. mg/kg iv
Lidocaine 100 100 100 31.5~~ 1 CHs MezN 4 4.4 9 102.0 3 CH3 CjHioN 36.2 44 42.4 67.0 7 C2Hs CjHioN 86.7 11O d 81.8 55.0 EtJJY 10 n-CsH7 47.5 67.7 63.2 41.7 hIe2N 17 n-C4Hg 26. ,5 31.9 42.4 38.5 EtzN 113.5 148d 121.2 6.7 18 n-C4H9 C4HgNO 20 n-C4H5 27.2 37.6 72.7 40.0 21 n-C4Hs RlezN 15.5 24.9 69.8 40.0 n-BuNH 23 n-C4H5 82.8 llOd 75.6 17.5 24 n-C4H5 i-PrNH 64.8 83 97 42.5 a Hydrochlorides, except 21, which is a methiodide. Quantitative local anesthetic activity determined by method of Bulbring and Wajda.lB Activity and duration are expressed as per cent of equal concentrations of lidocaine. c As per cent of lidocaine activity based on equimolar concentrations. Moderate to marked erythema observed in the test wheal within 24 hr. e LDjo reported by C. D. Barnes and L. G. Eltherington, "Drug Dosage in Laboratory Animals," University of California Press, Berkeley, Calif., 1966, p 131.
ten compounds, all ester derivatives, exhibited a local anesthetic action. Structural analysis reveals that local anesthetic potency was generally related to the length of the 2-alkoxy substituent as six of the ten active compounds contained the 2-butoxy group. Among the compounds with this butoxy grouping, potency seemed to be enhanced in those with a monoalkylamino substituent (KRR'), although the most intense local anesthetic action was found in 18 which contains a diethylamino substituent (Table 111). In some cases, local anesthetic action was observed in compounds with alkoxy groups of lower molecular weight in position 2 . This activity disappears in compounds with an OH group in position 2 and when the CO-0 group is replaced by the isosteric CO-KH group (Table 11). It is of interest that 21, a quaternary methyl iodide
salt, exhibited local anesthetic activity. This is in contrast to the findings of Sador, et aZ.,l7 and Lofgren and Fisher,18 who reported a loss of activity after methyl quaternization of active compounds. Three compounds, 7, 18, and 23, displayed a local anesthetic potency greater than that of lidocaine. However, tissue necrosis, defined by moderate to marked erythema, occurred within 24 hr after administration. The erythematous area covered most of the wheal site. I n general, the compounds became more toxic as local anesthetic potency increased. Although many of the compounds exhibited vasodilator action in mice, only 5 , 6, and 16 displayed activity at sublethal, nontoxic doses. Their effect on dog blood pressure was negligible. ( 1 3 K. Nador, F. Herr, G. P a t a k s , and J. Borsy, S n t u r e , 171, 788 (1953). (18) S . Lofgren a n d I. Fislizr, Suensk K e m . Tidskr., 58, 219 (1916).
Synthesis and Antialdosterone Activity of Substituted 2,3,3-Triphenylpropplamines BENJAMINBLANK,WILLIAM A. ZUCCARELLO, SUZANSE R. COHEN, GERTRUDE J. FRISH~IUTH, ASD DANIEL SCARICACIOTTOLI Research and Development Division,S m i t h Kline and French Laboratovies, Philadelphia, Pennsylvania Received March 21, 1969 Several 2,3,3-triphenylpropylamineswere prepared and studied as specific inhibitors of aldosterone biosynthesis. All the compounds caused a significant natriiiresis in a rat antialdosterone assay. Two compounds (IVa and j ) completely inhibited the in vitro biosynthesis of aldosterone without altering deoxycorticosterone or corticosterone levels.
Earlier studies1p2from our laboratories demonstrated the effects of simple structural changes on the degree and nature of adrenal corticosteroid inhibition. One compound, 2-amino-l, l-diphenylpropane (VI), emerged from these studies as a potent, specific inhibitor of aldosterone biosynthesis. Its homolog, 2-amino-l, l-diphenylbutane, was less active than the propane.2 To further examine the effect of substituents on the alkyl side chain of diphenylpropylamines, 2,3,3-triphenyl(1) W.A . Zuccarello, B. Blank, G. J. Frishmuth, S. R. Cohen, D. Scariraciottoli, a n d F. F. Owings, J . M e d . Chem., la, 9 (1969). (2) H. Blank, W. A . Zuccarello, S. R. Cohen, G. J. Friqhmuth, and n. Scaricariiittoli, %Girl.,la, 271 (1969).
propylamine (IVa) mas prepared and evaluated in a rat antialdosterone assay. The marked natriuretic effect of IVa in this assay led us to prepare a number of similar compounds with a p u m substituent in either a 2- or 3phenyl group. Compound IVa has been prepared by Wawzonek and Smolin3 by the hydrogenation of 2,3-diphenylcinnamonitrile. I n our hands, the only product isolated under a variety of conditions was the corresponding unsaturated amine, 2,3,3-triphenylprop-2-enylamine(V) . However. IVa and the other amines listed in Table I1 werrl (3) S. \Vawzonek a n d E. M. Smolin, J .
Ow. Chem., 16, 746 (1951).
+$
11\11 \ , 1 1_ _ *
\
('I1 ( ' S
C , H C'HX
s = ('I 0 1 ' Rr
1.
C',H 6H-
C'H('.\ I11
C,H ~'H-CHC'H-SH.
IY prepared conveniently (Scheme I) by the reduction ot 2 .3J- t rip heny lpro pioiiit rile> (111). n-hie h , in t imi, T W ~ P rcadily nvailable from b r r i z h ; \ dry1 halide. (1) arid pheiiylncetonitriles (11). The reduction of 111to IT' was accomplished either catalyticall\ in the presence of Ranej Si (method A) or with IJA%H (method R). 2-(p-.hiriophenyl) - 3 , :~-diphciiylpropyliiluii ic ( 1Vj) 11 :it o t) t :tined simply by the :icid h\ d r o I y , s i - of the corresponding wet:mido derivative IT'i. . i t teiiipt. to prepare the .iilfon(J of Il'f ere u i i i i i c r ( 4 ' i i l . .\ltlioiigh IIIj c.ould be pwp:ircd w:idiI\ , it did i i o t prove 11-cful :i- :t precur-or ot the : i m i i i c > . ,\lteriint i v e l ~, the S-:icct> 1 cleriwtive of I I7f wa\ prepared :uid oxidized to :I d f o n c that nieltetl : ~ 162 t -1($4'. I'~ifortunatel>, neither t h r 4 f o i i e amide iior t h c x m i i i e derived i'ronn it c ~ ) u l dtie purihetl i u f i c.ic.ntl! to ohtaiii s i i t i h > t o r J ;iii:iIytir:Ll d i t :i.
Experimental Section4 Benzhydryl Halides (I).~ ~ p - T r i f l i i ~ ~ r ~ ~ n i e t h ~ l t ~chloe~izh~-di~yl ride5 arid p-nieth?.lheiizh?-di~~i i * h l i l r i t i c ~\yere ~ prepared t i s i i i g i q o r t e d pt,ocediirw. p-~IethyIthiohei~xIiydr~l hi~oniick \ \ a < obtained b y t,reat,iiig p-niethylthic,beiizhydi,oli f 17.5 g, 0.075 mole) iri dry C6H6with g:iseoiis HBr. After 4 hr the 1nistiii.e w:is diliiied wit,h H 2 0 anti iIre la~.erhwere .*eparated. The orgaiiic layer was washed, dried, ;itid c~)iiceiitratetI. The reyidiial yello~voil
p-Acetaminophenylacetonitrile..- h i , Iaige-xile preparariuii-, ( h e following procedure proved itsefiil. Cornrnercial p-aminoI)l-ieiiylacetotiitrilehydrochloride ( 115 g, 0.63 mole) was dissolved i i i f L 0 , and .ir; Na2C03atid solid h'a2COr were added to pH S. .\fter 200 nil of THF was added to form a hotnogeiieoiis rjolutioii, :ioetyIaiiriii was uwomplished with : M I ml of A4c20. The sohitioil was stii,red for 2 h i . at 0°, aiid for 1 hr a t room temperatwe. After tliliiting with I f 2 0 , the TIIF \vas removed, and the resultirig ~
-~~~ ~
~
~.
14) Where analyses are indicated
only by symbols of the elements, analytical results obtained for these elements were within *0.4% of the theoretical values. .Melting points were taken in a Thomas-Hoover capillary melting point apparatus and are corrected. ( 5 ) 9.Rossi a n d W. Butta. Farmaco, Ed. Sci., 16, 326 (1961). ( 6 ) A. G. Davies. J. Kenyon, B. J. I.yons, a n d T. .i. Rohan, .I. C h ~ n i . S o r . . 3474 (1954). ( 7 ) A . Muatafa, i h i d . , 352 (1949).
875 TABLEI
34
2,3,3-TltIPHENYI,PROPIOhITIlILES
CGH,CH-CHCN R
NO.
IITX
El
70
Recrystn solvent
Mp or bp (mm), O C
yield
I€ I1 IT
H
99-100 5. 1IeOH 11 CITj 195-197 (2) SCZT8 128-130 CsHs-petr ether* tl CF8 I1 180-182 EtOH I1 CH3 58-89 Hexane C 104-105 hIeOHb f H SCH3 hIeOH 133-134 g H OCH3 hIeOH c1 123-125 h H 1 H NHCOCH3 232-234 EtOH j H SOzCH3 160-162 3leOH-H2O a E. P. Kohler, -4m. Chem. J., 35, 386 (1950), reported mp 102". b Initial purification gel column with CeH6-petroleum ether (bp 40-60') (1:1 and 2: 1 by volume). (a
\nnlvses
Formula
72 CziHi?S 4s CzzHigN C, H, S 13 CzzHigNS C, H, S , S 30 czzHi~F& c, H, N 33 CzzHigN C, H, ?; 47 CzzHigNS C, H, 5 , S 38 CzzHigNO C, H, K C, H, C1, S 65 CZIHIGCIN 61 C23H20x20 C, H, i Y 38 CzzHi9NOzS C, H, S , S was effected by chromatography on a silica
TABLEI1 2,3,3-TRIPHENYLPROPYLBMINES
R
R'
C,H,CH-CHCH,NH, MP, NO.
11-a
b
R
H CH3
R'
H
H
C
H
d e f g h i
H CH3 SCH3 OCHa
SCH, CF3 H H H H H j H Lit.3 mp 269-272".
c1
NHCOCHI NHZ * Hemihydrate.
OC
Method
70
Recrystn solvent
yield
87 EtOH-Et20 20 hIeOH-EtOAcpetr ether 25 n-BuOH-Et20 227-230 B 54 EtOAc-Et20 223-224 B 71 E t OH-Et20 2;j4-257 A 4 EtOH-EtzO 14OC B EtOH-Et20 70 230-232 B 59 n-BuOH-Et20 274-276 B 99 CGH&le A 216 93 EtOH-EtzO 300c,e f c With decomposition. Hydrate. e Uncorrected. 269-271a 236-238
A A
Biological Testing.-The natriuretic effects of the test compounds were determined in an antialdosterone assay." Three of the most interesting compounds, IVa and j and V, were evaluated in an in vitro assay' designed to study the effect of the compounds on adrenal corticosteroid biosynthesis.
Discussion ,411 compounds in Table I11 exerted a significant ( P
