July, 1964
453
3-HYDROXY-3-PHEKYLPHTHALIRlIDINES
tion of 18.0 g. (0.04 mole) of 21-bromo-3ajl7cu-dihydroxypregnane11,20-dione9 and 1.685 g. (0.015 mole) of triethylenediamine in 200 ml. of dry ethyl methyl ketone was heated a t 50" for 4 days. The solution became cloudy and crystals separated. Filtration gave 10.3 g. of crystalline solid, m.p. 243-248" after sintering and darkening from 210'. Dilution of the filtrate to 1 1. with absolute ether gave 1.9 g. of additional compound. A sample dried a t 100" in a high vacuum overnight was found by Karl Fischer analysis to be anhydrous. However, it was hygroscopic and was difficult to analyze. Anal. Calcd. for C48H,aBraN*O8: C, 59.62; H, 7.71; Br, 16.53; N,2.90; 0,13.24. Found: C, 58.01; HI 8.29; Br, 16.52; N, 3.22; 0,13.59. A sample of this material vias boiled with about 2 1. of water. The cloudy solution was filtered through Supercel and the warm solution was decanted from a little gum which immediately separated. On cooling a flocculent gelatinous precipitate separated and after standing overnight in the refrigerator it was collected, washed with water, and dried giving 3.7 g. of near white solid, m.p. 242-246" dec. Samples allowed to equilibrate in air a t SOYo humidity were found by analysis to contain 2.5 molecules of water (Table I). The nuclear magnetic resonance spectrum supported the proposed structure. Triethylenediamine Mono-?J-oxide Dihydrochloride (17).To a solution of 22.4 g. (0.2 mole) of triethylenediamine in 400 ml. of absolute ethanol was added during 15 min. with stirring a t 20' 100 ml. of 30% aqueous hydrogen peroxide. After standing a t room temperature for 4 days the excess hydrogen peroxide was destroyed by cautiously adding an aqueous slurry of 0.5 g. of 30% platinum on charcoal. After stirring vigorously for 4 hr. the mixture was filtered through Supercel and the colorless solution was evaporated below 80" giving the free N-oxide base as a clear colorless oil. The oil was dissolved in 300 ml. of absolute ethanol and acidified with 75 ml. of 6 .V ethanolic hydrogen chloride. The resulting white precipitate was collected and dried giving 37.4 g. of white solid. I n the melting point bath it darkened a t 200-220" but was not all decomposed a t 310". This was dissolved in about 1.4 1. of methanol and concentrated on a steam bath by a stream of nitrogen to 800 ml. After cooling, the crystals were collected and dried giving 23.5 g. of white solid with melting behavior the same as above. rln additional 8.9 g. was obtained from the methanol
filtrate. The infrared spectrum was very different from that of triethylenediamine dihydrochloride and the potentiometric titration showed two breaks in the curve; neut. equiv. calcd: 100.6; found: 101.3. 1-Phenacyl-4-aza-1-azoniabicyclo [2.2.2]octane Bromide 4Oxide Hydrate ( 18).-Mono-Xj-oxide free base was prepared as above from 22.4 g. (0.2 mole) of triethylenediamine. The solution, after filtration from the platinum on charcoal, was cooled to 3" and a solution of 41 g. (0.21 mole) of phenacyl bromide was added. After standing overnight the solution as concentrated to 500 ml. The resulting crystals were collected, boiled with methanol, and cooled. After filtration from a small amount of white solid, the two filtrates "ere diluted with ether giving white solids which were combined and dissolved in 1.11. of 90% ethanol by warming. After filtration this was diluted with 2 1. of absolute ether giving 54.2 g. of white solid, m.p. 165-166" dec. (with some darkening from 145'). The infrared spectrum showed this to be a hydrate. 3~,17~-Dihydroxy-ll,20-diketopregnene-21-trimethylammonium Bromide.-To a cold solution of 25.6 g. (0.06 mole) of 21-bromo-3~~,17~~-dihydroxypregnane-l1,20-dione~ in 330 ml. of ethyl methyl ketone was added 6.2 g. (0.1 mole) of cold trimethylamine. The flask was stoppered, clamped, and allowed to stand a t room temperature for 3 days. A tan gummy solid separated and then white crystals separated from the supernatant solution. These crystals were twice recrystallized from a mixture of ethanol and ethyl methyl ketone giving 5.49 g. of white solid, m.p. 200-204'. The crystallized gummy solid proved hard to purify. Anal. Calcd. for C2aH83BrNOa: C, 59.25; H, 8.29; N, 2.88; Br, 16.43. Found: C, 59.23; H I 8.70; N, 2.79; Br, 16.37.
Acknowledgment.-The author wishes to thank the following people mho contributed to this work: Dr. Hugh H. Keasling, Mr. William Veldkamp, and Mr. Kurt F. Stern for the biological data, our Department of Physical and Analytical Chemistry for the spectral and analytical data, and Mr. R. F. Tripp for technical assistance.
Antihypertensive Agents. 111.' 3-Hydroxy-3-phenylphthalimidines JOHSG. TOPLISS, LEROY11.KONZELMAN, NATH-4X SPERBER, AND FRANKLIN E. ROTH Chemical and Biological Research Divisions, Schering Corporution, Bloomfield, i\Tozu Jersey Received January 14, 1964 3-Hydroxy-3-phenylphthalimidines, related structurally to the diuretic agent chlorphthalidone but lacking a sulfamoyl substituent, showed antihypertensive but not diuretic activity when administered intravenously t o anesthetized dogs. Structure-activity relationships in the series were explored.
I n 1961, a preliminary account was given2 of investigations concerned with the antihypertensive activity of conipounds related t o certain known diuretic sulfonamides, but lacking the free sulfanioyl group. Subsequently detailed accounts of work in the 1,2,4benzothiadiazine series were published. We would now like to report results obtained with some substituted phthalimidines. A noteworthy feature of ~hlorphthalidone~(I) is (1) Part 11: J. G. Topliss, L. >Konzelman, !I. E. P. Shapiro, N. Sperber, and F. E. Roth, J . M e d . Chem., 7 , 269 (1964). (2) A. A. Rubin. F. E. Roth. bI. 11. Winbury, J. G. Topliss, 31. H. Gherlock, N. Sperber, and J. Black, Science, 139, 2067 (1961). (3) (a) A. A. Rubin, F. E. Roth, R. RI. Taylor, and H. Rosenkilde, J . Pharmacol. Ezptl. Therap., 196, 344 (1902); (b) J . G. Topliss, M. H. Sherlock, H. Reimann, L. 11. Konzelman, E. P. Shapiro, B. W. Petterson, H. Schneider, and N. Sperber, J . M e d . Chem., 6 , 122 (1963); (e) ref. 1. (4) Von F. Reutter and F. Schaub, Schweiz. M e d . Wochschr., 89, 1158 (1939).
its close similarity in diuretic and antihypertensive effects with chlorothiazide (and related thiazides)6 in spite of major structural differences between the compounds. I n view of the enhancement of the antihypertensive effect and elimination or reversal of the diuretic effect obtained on removal of the sulfamoyl group in the thiazide s e r i e ~ ,we ~ , ~were prompted to examine the biological properties of 3-(p-chlorophenyl)-3-hydroxyphthalimidiiie (11).
It
0
I ( 5 ) N. A. David, Currenf Therap. Res., 6, 93 (19(j3),
11,
8I? -
i:
-..
.^.
i
.
%
i
July, 1964 TABLE 11 ~-BENZOYLBEKZOIC ACIDS
11.p
s H
H
IT H
H
€1
li
Ii H
H
M €I H H
3-c1
3-Cl 3-C1 4-OCH3
H 5-OCH3
$3
See ref lob.
e
H 2'-CHa
n
Recrystn. solventu
H 4'-CF3
4'-OCHs
-Carbon. %Calcd. Found
176-178 145-1-17
13-H
CibHgF303
Et-H
182-183
C-H
227-228
Et-H
CisHi?Oa 70.30 CI~H~C~?OS CirHaClrO~ CirH9C103 56.97 CirHnC1203 C16HiaC103 59.91 CisHiaClOa
41-U
4'-C1 H 4'-C1 4'-CH3 4'-C1
=
=
hexane.
This coinpound, when administered intravenously to anesthetized dogs at doses of 10 mg./kg., produced a fall in blood pressure of extent and duration similar to that brought about by diazoxide (7-chloro-3-methyl2H-l,2,4benzothiadiazirie l,l-dioxide).3 Also, on oral administration of the phthaliniidine (11) to salineloaded rats, an antidiuretic effect was observed of the saiiie order as that produced by diazoxidc6 Accordingly, other related phthaliiiiidiries were prepared and evaluated biologically. These are listed in Table I. .1 number of them were known compounds and were prepared according to procedures described in the literature. The new conipounds were synthesized from the corresponding 2-benzoylbenzoic acids (111) by conversion to the pseudo acid chloride (11') followed by treatment with aninionia to give the phthaliiiiidine (V). The phthaliniidine structure (T') was established from a consideration of the infrared
v
Empirical formula
-Hydrogen. %Calcd. Found
-Chlorine, %Calcd. Found
CirHgClOa CirHgC103
XI
chloroform. Et = ether. H See ref. loa. f See ref. 10d.
= benzene.
C
3'-C1 2" H €I 3'-Cl 2'-C1 H
"C'.
TI
SI
T
b
61.23
61.41 70.46
3.08 4.72
3.30 4 90
19.37'
19 30h
56.81
2.73
2.90
24.03
24.45
59.84
4.09
4.20
11.06
AI. S. Yewman, J . Am. C'henz. Soc., 60, 1368 (1938).
c
11.22
Fluorine.
zoic acid 26 (Table 11) was established by decarboxylation with copper powder in quinoline affording 2,4'dichlorobenzophenone. I n connection with some projected deinethylation experiments on niethoxyl-substituted 3-hydroxy-3phenylphthaliniidines we mere led to investigate the reactivity of 3- (p-chlorophenyl) -3-h ydroxyphthalimidine (11) towards refluxing 50Co hydrogen broiiiideacetic acid. The crystalline product which separated from the reaction mixture had the eleniental coniposition C14H11BrC1S02and appeared to be a hydrobromide salt since an immediate, copious precipitate formed with silver nitrate solution. The empirical forniuln of the product corresponds to the hydrobroinide of the starting phthaliniidine (11); however, treatment with hot sodium bicarbonate solution gave 2 - ( p chlorobenzoy1)benzoic acid (VIII), whereas I1 was stable under these conditions. Catalytic reduction of the compouiid in methanol solution in the presence of platinum oxide and treatment of the reduction product with sodium bicarbonate solution furnished 3 - ( p chloropheny1)phthaliniidine (IX) identified by comparison with an authentic These transformations established the structure of the initial reaction product from I1 as 1'11, X probable pathway for the formation of TI1 is shown in the accompanying reaction scheme.
Va
spectra of the products determined in pyridine solution. These show a single sharp carbonyl absorption band in the 5.8 p region indicative of the phthalimidine structure (Y)as opposed to the open-chain form 1-awhich requires two carbonyl absorption^.^ The benzoylbenzoic acids (111) (Table 11) were obtained from the phthalic anhydride (VI) cia a FriedelCrafts reaction or by reaction with an appropriate Grignard reagent. The struct Lire of the benzoylben-
VI
XM
(6) R. 1L.Taylor, Angiology. 14, 79 (1963). ( 7 ) IT. G r a f , E. Girnd, E. Rchmid. and !IG. . Rtoll, H d c . Chim. .4rta. 42, 1083 (19,551).
VI11
IX
(8) Synthesized by AI. €1. Sherlork and K. Muller-Kulenkampff, dcliering Corporation.
Pharmacological Methods."-'l'he test procwiure has in part I . 3 b The activities of tlic coiiip:)iuids are giveii iii 'rahlc I and arc r a t d acccirrliiig to cutcgorks dcfined in part 11.' Structure-Activity Relationships.-Kith t h c mi ~ p l i o i of i 7 aiid 8 all of the caonipouiids show -1g111hm i i t 1y greater antihyperteiisi\-c avtir4ty thaii (ahlorphthalidoiic ( 1 ) . 3-ITydro\v-~-pheiiylphthaliinidiiic. (3) t d i i h i t s inoderate aiitihypertelisive activity. 111t i o d i i r t i o i i of a chloriiic atoni iii t h e 4'-positioii ( 2 ) i w i i l t \ ill a marked iiic*reast i i i activit poiitioii- this wbqtituriit doe< i i o t higii activity (4, 5, aiid 11). I)icliloi*o coinpoiitids (9, 10, m i d 12) ai'(%iiiodrratc.ly activc. hiit not as active as the, -I'-illoilochloro co11q~)~uld (2) .\loi,e highly d ) b t i tuted coinpounds (13 a i d 14) art' 110 iiioi'e activc tliaii 3 ~vliicliha3 110 aroiiiatic ring whstituciits. Sonic, lo:,^ of activity i- ckviderit when tliv c*liloriiic atoni i l l 2 i:, I ciplacrtl 1iy a trifluoroiiiethyl group a i d activity i y practically abolished ivhcii thcx replacing gi oiip i i ~iic~tliylor iiictliouyl. Replaceiiic~nt of thr hydroxyl gi oiip of 2 t)y iiietlioq-I, pipcridyl, oi' hydrogcw 1on-oi.h acti\-ity. Soiie of the compoiiiids tcstcd shows sigiiifiw i l t diiircktic activity; yorncx ouliii>it aiitidiiuy3ticA prop1hi.ti c + I ) r ~ ~ dcscribcd ii
Experimental 3-Hydroxy-3-phenylphthalimidines.-These were prepared liy niodific:ttioii o f the method of Graf.' The requisite benzoylI)eiizoic :iritl (40.0 g.) in benzene (150 inl.) was niised wibh oxalyl c*hloridc ( 2 0 5 excess) and, after the initial reaction had s u t i sided, the reac%iori mixture \vas refluxed for 1 hr. Benzene arid csccss of osslyl vhloride were removed by distillrtion, the residue \v:ts c:iut,iously added to a solution of 287, nnimoniiini hydroxide (200 d . ):md ethanol (100 i d . ) , kept a t rooni temperature for l(i hr., and t,lie crude product was collected by filtration. I
