573
AIay 19tis trituration with ice water yielded 3.4 g of 2-phienyl-4-chloro6,s-diaminopyrimido[5,4-d]pyrimidine. This (2.9 g) was treated with liquid NH3 (25 ml) in a bomb a t 150' for 6 hr. The solid residue was washed (H20, EtOH). It was recrystallized from l>MF-lIeOH yielding 0.8 g (317,) of crystals: mp 354-336" dec: Rr 0.69 (system 1); ?A: HCooH 248 mp (log e 4.44), 294 (4.27), 336 (sh) (3.83), 334 (sh) (3.72). Anal. (CI2HnK7. O..iHsO) C , H, S .
2-Phenyl-4-piperidino-6,s-diaminopyrimido[5,4-d]pyrimidine. -2-Phenyl-4-c hloro-6,8-diaminopyrimido [5,4-d]p j rimidine (1.O g) and piperidine (60 ml) were refluxed 16 hr. The mixture was filtered and the filtrate was concentrated t o dryness in vacuo. The residue was dissolved in hot aqueous AcOH, decolorized, and filtered, and then the solution n-as made basic with concentrated SH40H. The pale yellow solid was collected (0.4 g) and recrystallized from h2eOH-Hz0 to give a solid, mp 215', h'r 0.55 (system 2 ) . .Inal. (CliHlgKi) H ; C : calcd, 63.33; found, 64.00. Methyl 5-Amino-2,6-dihydroxypyrimidine-4-carboxylate.Methyl 2,6-dihydroxy-5-nitropyrimidine-4-carboxylate (5.0 g, 0.027 mole) \vas added t o a solution of 12.1 g 10.07 mole) of sodium dithionate a t 10" and then stirred a t room temperature for 15 min. A solid precipitated which was washed with hot LlcOH (2.85 g, 66%) and recrystallized twice from DMF to give pale yellow crystals, mp 254-255' dec. A n d . (CsHiN304) c, H, s. 2,6-Dihydroxy-5-nitropyrimidine-4-carboxamid~~.--A mixture of methyl 2,6-dihydroxy-5-nitropyrimidine-Pcarboxylate(35 g, 0.16 mole), MeOH (720 ml), and liquid S H s (72 nil) was heated at 100" for 6 hr in an autoclave. On cooling a solid was obtained ivhich was recrystallized from 540 ml of HzO to give 21 g (60y0) of a yellow solid, mp 269-270°, which on analysk proved to be the ammonium salt of the desired product. Anal. (CjHiNbO5) c, 11, x. -4portion of the above wari treated with aqueous acid and re-
Pteridines.
X1I.l
crystallized from AleOH t u give crystals, nip 2b3" dec. dna/. (CJG"06) C, H, N. 2,5,6-Triaminopyrimidine-4-carboxamide.-A suspension of 5.3 g (0.027 mole) of 2,6-diamino-5-nitropyrimidine-6-carboxamide and 300 mg of PtO2 in 200 ml of glacial AcOH was shaken under 2.8 kg/cm2 of H2 for 2.5 hr. The catalyst was removed by filtration and the solvent was evaporated under vacuum. The residue was washed with RleOH to give 3.8 g (837,) of product which was dissolved in dilute ",OH and treated with charcoal, and the solution was filtered. Chilling gave 1.2 g ( 2 6 % ) of white needles, mp 285' dec. -4sample was boiled with JleOH to give yellow needles, mp 286-288" Anal. (C&N&) C, H, N. 2,6-Diamino-5-nitropyrimidine-4-carboxamide.-~4 suspension of 18 g (0.071 mole) of methyl 2,6-dichloro-5-nitropyrimidine-4carboxylate in 720 ml of lOy0 MeOH-KHa was heated in a steel bomb a t 100' for 2 hr. The product was dissolved in excess MeOH, filtered, and taken t o dryness under vacuum. The residue was washed (H20) and recrystallized (MeOH) to give 3.2 g of prisms, mp >285'. Anal. (C&N&) C , H, N. 4,6-Diamino-2-phenylpyrimidine.-A mixture of 3 g (0.013 mole) of 4,6-dian\ino-2-phenylpyrimidine-5-carboxamideand 9.9 g (0.13 mole) of thiourea was heated a t 180" for 5 hr and cooled. Addition of 90 ml of 5Yc NaOH and u arming caused the separation of a yellow-green solid, mp 180-188". This was dissolved in hot H2O and acidified with HC1 t o give a yellow solid, mp 258-260", which is the hydrochloride of the product. This \yas dissolved (HtO), treated with charcoal, and made basic with xH4OH to give white crystals, mp 193-195". Repeating the acid-base cycle gave 0.45 g of crystals, mp 194.5-196', whose ir spectra were identical with that of an authentic sample, lit.18 mp 195-196'. Bnal. (ClOHlOXd) C, H, N. (18) G. 1.H o n a r d , B. Llthgoe, a n d A. R. Todd, J. Chem. Soc., 476 (1944).
Structure-Activity Relationships of Some Pteridine Diuretics
JOSEPH WEISSTOCK,'"JAMES W W I L S O NVIRGIL , ~ ~ D. WIEBELHACS,~~ ALFREDR. ~ I A A s s , * ~ SOSNOWsK12b FRLk;vcIS T. BRESKAN, A N D GENEVIEVE liesearch and Developinen1 Divisio,z, Smith Kline and French Laboraturies, Philaclelphza, Pennsylvania
Received January 6, 1968 The diuretic activity of pteridines related to 2,4,7-triamino-6-phenylpteridine(triamterene), 2,4-diamino-6,7dimethylpteridine (I),and 4,?-diamino-2-phenylpteridine-6-carboxamide(11)was studied in the saline-loaded and sodium-deficient rat. A limited number of related pyrimidopyrimidines were similarly studied. Some of the compounds related to triamterene and I not only cause S a + excretion but also conserve K +. All of the P-phenylpteridines we have studied which are active natriuretic agents also cause IC+ excretion. In the triamterene aeries, replacement of any of the amino groups by either a large amine or a nonbasic group other than hydrogen leads to reduction of diuretic activity. Replacement of the phenyl by a small, nonbasic group gives active diuretic agents, but an aromatic (or heteroaromatic) group seems desirable for highest activity. Some variation in the substitution pattern on the pteridine ring is permissible as demonstrated by the activity of the triamterene isomers. The 7-phenyl isomel. is outstanding as a blocker of K + excretion.
The presently known diuretic pteridines3 may be grouped into three principle classes based on st'ructural features and electrolyte excretion pattern. I n order of their discovery these are (1) the 2,4-dialnino-6,7-dialkylpteridines, (2) the 2-aryl-4,7-diaminopteridine-6c arboxamid es, and (3) the 2,4,7- t riamino- 6-arylp teri(1) Previous papers in this series: (a) I. J. Pachter a n d P. E. Nemeth. J . O w . Chem., 2 8 , 1187 (1963): (b) I. J. Pachter, i b i d . , 28, 1191 (1963); (0) I. J. Pachter, P. E. Nemeth, a n d A. J. Villani, ibid., 28, 1197 (1963): (d) I. J. Paohter a n d P. E. Nemeth, ibid., 28, 1203 (1963); (e) J. Weinstock, R. Y . Dunoff, and J. G . Williams, J . M e d . Chem., 11, 542 (1968); (f) J. Weinstock, R. Y. Dunoff, B. Sutton. B. Trost, J. Kirkpatrick, F. Farina, a n d A. S. Straub, i b i d . , 11, 549 (1968); ( g ) J. Weinstock, I. J. Parhter, P. E. Nemeth, and G. Jaffe. ibid., 11, 557 (1968): (h) J. Weinstock, 3 . Graboyes, G . .Jaffr, I. J. Pachter, E;. Anader, C. B. Karash, a n d R. Y. Duncrff, ibid., 11, 560 (1968); (i) J. Weinstock a n d R. Y. Dunoff, ibid., 11, 51% (1968); (j) H. Gralioyes, G. E. Jaffe, I. J. Pachter, J. P. Rosenhloom, 4 . .I. Villani, J. W. Wilson. and J. Veinstock, i b d , 11, 568 (1968); (k) J. Weinstock, R. Y . Dunoff, J. Carevic, J. G. Williams, a n d A . J. Villani, ibid., 11, 618 (l#X). (2) (a) Xedicinal Chemistry Section. (b) Biochemistry Section.
dines. I n this paper we will discuss the structureactivity relationships within each of these classes and compare these classes to each other. I n addition we will discuss the diuretic activity of some related pyrimidopyrimidines. The prototype for the first class is 2,4-diamino-6,7-dimethylpteridine(I), for the second class, 4,7-diamino-2-phenylpteridine-~-carboxamide (11), and for the third class, 2,4,7-triarnino-Ci-phenylpteridine (triamterene, 111). (3) For a brief discussion of t h e discovery of useful diuretic activity in t h e pteridines see J. Weinstock and V. D . Wiehelhaus in "Pteridine Chemistry," IV. Pfleiderer and E. C. Taylor, Ed., Pergamon Press, Oxford, 1961, p 37. For discussion of other biological properties of pteridines and related compounds see (a) elsewhere in the above reference: (b) "Chemistry and Biology of Pteridines." G . E. W. Wolstenholme and 11. P. Cameron. Ed., Little, I3rown and Co., Iloston, Mass., 1954; (c) 8. Kaufman, A n n . Rev. Biorhem., 36. lil (1967); (d) G. H. Hitcliings and J. J. Uurchail. .Iduun. Enzymol., 27, 4 1 i (1965).
I
I
NH,
"2
I
I1
NH, LII
Biological Methods.-Three t l pe. of diuretic ~ L W J .; \\ere used to characterize the activity of the pteridines. The orallj doied saline-loaded rat nab employed a s the> first Rase line data obtained in this protocol \sith st:mdard diuretic agents indicated that urine volunic I\ as a rcasonablj- reliable indicator of natriuresis. 111general oiily thoso compounds reasonably active i i i thii teit were itudied in more detail. The orall? doicd sodium-deficient rat p4 meayured t h e natriuretic potency of the conipound- in aiiiriials in :istate of :Ivid sodium retention due, :it least in part, to high Icvels of endogenous iiiiiieralocorticoid~. Finally, renal c1c:ir:mce experiment s in salinc-loaded, 9-a-fluorohylrocortisone treattd dog.;' (refrrred t o hereafter :IS the saline-SaI'HC dog) provided more detailed data on the cff wts of the (.ompoutids oii Sa-, Iry pH, and glorncrular hltratioti rate. SII ice t l i c ~ ct 11r w t e i t + xi1 e:i i i i re di teriis, correlation betn-ern the-e te d, although in general thc compoun it1 t h rat \vc>re idso active i i i the dog, while the comlioundi it h 1)oor :ictiyit). iii the .:dine-loaded rat n ere a1-o ~)oorIy:ictivc i t 1 t h e sotlium-deficient rat :uid t h e dog reiinl clenrance-. 111?':ihlei I -XI17 thr \:ililic-lo:id~drat data 1~e1.c r:lt(d ;I- ~ 0 1 1 0 \ ~ - , Thv U I volunit, ~ w i s cspressed :ii :L 1)cr ( w i t oi t hc origiiiiil viliiic 1o:id. aiid t h e ;.t:itidard control ((XIc of t l i v d i n e lwd) suhtrncted iiom this gave the dic\ct duct to drug. Siiice 229, over control is the point of h f : t t istical iigiiihcitricc (9.75 confidence limit.), respotim t1i:iii 22@%n(w r;itcd : i s 0. Rcil)oiiye- of 22-4.F I o w r cwritrol were rated :is 1 , 4(i-W?; o w r caotitrol :is 2, ; I I I ~>fisY; o~ CY control :I- :3, T h e gre:ite.t res~)oiiw :it :MI\ d o ~ c(u~ii:tIl~ either 1.7 or 30 mg kg) I i o i , t Iiv rating. Lllthough Z C , over controls is t h c h i)oint ot .titi iiticul .igiiific:iiicc> thiq cut-off i. of liniitcd 1 1 1 ~t :i ~ iI Ig h c w t h t ru I\ 1I i t ere5t I I ig coni 1mu I id u-(1
-
\\(sr(' tlio5c' t x t d 2 01':; d ' i l h o , ionic' conil)oiitid\\ liicli \\ vro in:Lctivc at ( h e u-u:~l do+c+ i i ~ \v(>rc l (iiiit ;ictivck :it higher dohe. I h c . sodium-deficictit rat test 1'1111 1)) glvlllg cxch i x t 10 r i g of Sa7 -uhcutatieouilj immediatel? i)r>torc,dosiug w i t h drug T h e iiiwi :ii collected for (i111, aiid :i1i:il; zed i o i Sa- , t t ~ dI\The> ~ s l ) o 1 1\\:1.> ~ lc~cY)rd(d:L- mllllgl~alli-ot cxcreted p"" rat. Ill t Iiv t:it)l(>st h c iii:isiiiiuin ie*l)oiiw :it ~ u i y dose is reported :i- ~ o l l o \ ~ -!1 n1g 1 :. :3. u-\i:\Il>
(5
r 7
Structure-Activity Relationships.-- Thcl diuretic prc )perties of aii:Llogs oi I arc shcin 11 i ] ~Table\ 1 :itid 11. Lllthouglia ~iumberoi t liese 2,4-dianiiiiopteritliiies:ii (' activtl i r i thci s:iliric4o:tded r:it, oiily the (i,7-dimcith\ 1 (aoriipouiid 4 i o u a g(~0(1 activity itt thc .otliurii-tleficieiit i'at. ('huiigcs" ill th(. 2,4-diamiiii) porticin of the molecule o:iuw :I Ill(JI'(' draytic clccreaic of diuretic. activitj . 1.3,6,7-Tetranieth j IIuniazine is the only compouiid other than I in l'nhle I1 which is highly active iii the -diiie-loadcd iat; hi)\\ever, it is not active i n thv sodium-deficictit r:i I The diuretic activit! of' 11 is shonii iri 'l':~bIe I l l . I t i.: active in both tlic iuline-loaded rat :ind the sodiunidrficient rat. 111 addition, it is an active natriuretic :igeiit iri the idirie-!)olE'HC dog. However, in cotitra3t i o I arid triamtererir, I1 causes ,iubstaritial I t 4 loss i t ) hoth the .otliriin-~c.iic.ic,iit rat aiid the salirie-9aHPY' tl0q. i o \ \ i i thcl etfcct of varyiiig thc h i i h t i t in the 2 I)ohitioii oi 11. Substituentb i i i tlw pheiij I ot h c i th:iti inivt Iij I iii:irl,edly rcduccd :ic.tivitj-, i i t i t l iimt
TABLEI1
T.4BLE
6,7-DIMETHYLPTERIDINES
IT
4,7-1)IAMIN0-2-PHENYLPTERIDISE-6-C.ARBOX.4MIDES
HzN)44qyc6H5
RIR,N OC "2
Diuretic act.o Saline-loaded rat
0 0 0 3 1 0 0 1 1 0 0 (0) 0 0 0 (0) 3 (0) a Numbers in parentheses refer to sodium-deficient rat data. See note a, Table I, for rating scale. J. W. Daly and B. E. Christensen, J . Am. Chem. SOC.,78,225 (1956). Note b, Table I. B. Roth, J. 11.Smith, and &I.E. Hultquist, J . Am. Chem. SOC., 73, 2864 (1951). E. C. Taylor and C. K. Cain, ibid., 74, 1644 (1952). f D. J. Brown and N. W. Jacobsen, J . Chem. SOC.,4413 C. K. Cain, &I.F. (1961). 0 Gift from Professor A. Albert. Jlallette, and E. C. Taylor, J . 4 m . Chem. SOC.,68, 1996 (1946). A. Albert, D. J. Brown, and G. Cheeseman, J . Chem. SOC.,474 (1951). 7 F. F. Blicke and H. C. Godt, J . Am. Chem. SOC.,76, 2798 (1954). 1
Diuretic act., ratu Saline Sodiumloaded deficient
KRiRI
3 2 1 2 1 0 0 0 0 0 1 2
NHz (11) NHCHa N(CH3)a NHC2H.j NHCH(CH3)Z NHCsHs ?JHCH2C Hz0 H NHCHzCHzNHz XHCHZCH(CHB)NH~ NHCHgC (CH8)zNHz KHCHzCHzN (CH3)z KHCHzCHzK(CzHs)z NH(CHJJN
A
0
3 3 1 1 0
... ... 1
... ... 3 3
v
2
0
NH(CH,),Nnh'-CH, W
0
...
0
...
1
...
1
...
KH(CHZ)~X'(CH~)Z NHCH,CH,S"O NHCH,CH,N
v n
NH
v
KHCHzCHOHCHzX (CzH:)a 1 a See footnote a, Table I, for rating scale.
TABLEI11
0
TABLE T'
4,7-DI.4MINO-6-PTERIDINEC~4RBOX.AMIDES 4,7-L)I.iMIKO-%-PHEKYLPTERIDINE-6-C.~RBOXYLIC
ACIDDERIVATIVES
NHz Diuretic act." Saline-loaded rat
3 (3) 3 (3) 3 (3) 1(1) 0 1 1 0 1 0 0
COOH COOCHa CONHKH2* CONHKHC&bJ CON(CH3)NHz CONHN(CHs)zh CONHNHCH(CHa)2d CONHNHCH(CHs)CHzC6Hsd
0
CONHNHCH(CH3)CH2CH(CHa)zd
0 0 0 3(1) Numbers in parentheses refer to sodium-deficient rat data. See footnote a, Table I, for rating scale.
replacement of the phenyl by other groups also decreases activity. The good activity of the 2-dimethylamino compound in the saline-loaded rat was not shown in the sodium-deficient rat. Variations of I1 in which the 4-amino group was replaced by 4-methylamino, 4-dimethylamino, or 4-anilino were inactive in the
Rg
1
Diuretic act., rat' SalineSodiumloaded deficient
0 1 1
...
1
1
2 1 1 1 0 1 1 1 2 2 2 2 1
0
... 0
0
... ...
... CONHNHCHZC~H~~ 1 CONHN=C(CH3)zd CONHN=C(CH3)CHzCH(CH3)e ... ... CONHN=CHCGH~~ 1 CON(CH3)X=CHCsHjd ... CNb 1 C (=XH)NHNHz* 0 C(=NH)NHCHsc 2 C (=")"OHe E. C. Taylor and a See footnote a, Table I, for rating scale. E. C. J. Weinstock, I:. S. Patent 2,963,480 (Dec 6, 1960). J. Weinstock, Taylor, U. S. Patent 2,963,479 (Ilec 6, 1960). U. S. Patent 3,111,520 (Kov 19, 1963). e13. C. Taylor, U. S . Pateut 3,012,034 (Dec :, 1961).
576
NH
"'q
l i -i
I I'il
!J
577
PTERIDINES. XIi
Nay 1968
TABLE XI1 TRIAMTERENE PTERIDME ILOMERS
TABLEX
,
2,4,7-TR1AMINO-6-SCBSTlTUTEDPTERIDINES
HP
,N
J
J
R b
f
Ny"2
(
"?A+N-J+bH5 ,N
N ,
N NH2 Diuretic act." Salineloaded rat
Re
H
Isomer
2 (3) 3 (2) 3 (2) 1 2 (2) 2 (2)
CH3 C& CH(CHa)z (CH:!)LXb (CHn)aCHaC
-3
Diuretic act.. rat" SalineSodiumloaded deficient
a
6-C& (111) 3 7-C& 1 2-CeHj 2 4-COH5 1 See footnote a, Table I, for rating scheme.
3 3 2
a
TABLEXI11
1
PYRIMIDOPYRIMIDINES
CHIC~H, 2 (2) 1 CHACH,CE,H, COCeH, 1 COOH 0 CONH, 0 (0) CONH(CH~)3N(C€L):! 0 a Numbers in parentheses refer to sodium-deficient rat data. See footnote a, Table I, for rating scale. b Prepared by Jlrs. R. Y. PreDunoff by method of ref lb. Anal. (CgH13N,)C, H, K.d pared by Mrs. 11. Y. Dunoff by the method of ref lb. Anal. (C1OH1~N~.l/gH~0) C , HI N.d Analytical results were within i ~ 0 . 4 7of~ the calculated values for the elements indicated by
R y X f H 2
Rj
NH2 Diuretic act." Salineloaded rat
3 (3) 0 0 2 0 3 0 3
TABLE XI SIMPLEAMINOPTERIDIXES
0 0
Re
H
Rl
Diuretic act.Q Saline loaded rat
Hb HC H* Hb Hd He
3 (2) 2 2 H 1 H 3 (0) 2 KHA H "2, 3 H ",I 2 (3) SII? NHzC 0 ?r", NH~Q 1(2) 1 S(CH3)i ?J(CH3)2' a Numbers in parentheses refer t o sodium-deficient rat data. See footnote a, Table I, for rating scheme. b Footnote i, Table 11. A. Albert, D. J. Brown, and G. Cheeseman, J . Chem. Soc., 4219 (1952). Footnote b, Table I. e A. Albert, J. H. Lister, and C. Pedersen, J . Chem. Soc., 4621 (1956). T. S. Osdene and G. 11. Timmis, ibid., 2036 (1955). 0 E.C.Taylor and W. R. Sherman, J . Am. Chem. Soc., 81, 2464 (1959). h Gift of Professor E. C. Taylor.
H H
saline-loaded rat. Table IV shows the effects of substituents on the carboxamide group of 11. Bulky alkyl groups decrease activity, but, as also found by Osdene, et u Z . , ~ certain aminoalkyl groups lead to retention of activity in the rat and dog tests. However, like 11, the active natriuretic compounds in the (6) T. 8. Osdene, A. A. Santilli. L. E. McCardle, a n d M. E. Rosenthale. J . X e d . Chem., 10, 165 (1967).
NH2 Diuretic act.LL Salineloaded r a t
R8 n",
0
0 N 3 a Number in parentheses refers to sodium-deficient rat. See footnote a, Table I, for rating scale. b E. C. Taylor, R. J. Knopf, R. F. RIeyer, A. Holmes, and JL L. Hoefle, J . Am. Chem. Soc., 82, 5711 (1960).
TABLEXIV COYPARISON O F DIURETIC AGENTSI N
YAItIOCS D I T R E T I C ASs.iYS
Aigent-
7 -
Test Saline-loaded rat" Sodium-deficient rata Glucose-infused dogb N a (control/drug)c K (control/drug)c Saline-9crFHC dog6 X a + (control/drug)c K + (control/drug)c c
Chlorothiazide
Triamterene 3 3
3 3
3 3
2 1
13/13 33/3
9/6 7/3
6/69' 4/16e
3/57 7/37
91221 20/18
481475
59/475
21/27
11
10/481 16/70
I
a See footnote a, Table I, for rating scale. Average pequivlmin in urine. d 10 mg/kg sc.
15/106 b a
Spironolactone 0
I*
7/13 8/9
25 mg/kg PO. 25 mg/kg iv.
aminoalkylcarboxamides are also active as kaliuretics. Two carbons between the nitrogens appear to be optimal. The higher activity of the dimethylamino and diethylamino compounds in comparison to the primary amino and morpholino compounds is note-
wortti> . The dimethj lamiiioethj.1 compound is utiusual it1 that relatively speaking it is more active iii the sodium-deficient rat than i t i the dine-loaded rat. Ijecaiihe of the extensive interest it1 the morl)holiiioethj 1 co~iipourid,~ it is iiitereiting t o coriiparc its activitj. to that of the closelj. related diethylitminoethj I :malog iii the sodium-deficient rat. The former c:~used the excretion of 2.92 iiig of S:I :tiid 10.46 m g of Iaii outst:tiiditig compound. j i i the s:iline-Ioaded rat, :tiid iii the sodium-deficient rat riot only cau*e>a marl;ed excretioii of sodium. but simultxiieoud! decrea-e< I< cwretioti. also ieeii in dog5 and 111a11.~ 111conithiazide. huch a s Eldrochlorothiazide. it ~ i o to n l ~hloclis the I< + lo>,\ durx to the thiazide hut :tlso Imteiitiatei: the Sa+excretioti.) In oiic :ipl)ro:ich to studying the qtructure--nctivity relationships of coiii])ound~related to triainterer prep:tred com1)oundq which differed from the prot by oiilj, o i i c structural fe2itui.e. IIITable J71 are thobe conil)outids iii which one of the i)rimar\* amino groul)s Iias been rcplaced by niiother group. 1iel)lacemcJiit of : i i i j of thc amines b j u IOU er :ill,ylaiiiirie led to conq)ounds which retaiii triumterene-lik diuretic activitj . .\lore extensive cliiiiigeh generallj, led to suhstantiall! less active compouiids. I n Table T'III i b shon t i the diuretic activitl. of compouiids iii which the phetil1 of triaintereiie hny beeti rel)l:iced by a buhstituted p h c , t i j 1. Here :ig:Liri, oiilj ~ i i i n l change:, l are permissible if e v c ~ imodest diuretic x t i v i t j 1s to be retained. Thc 1)tictij1 :irid p-tol>-l compouiid- :ire illubtrativc. T h e /,-tolyl compouiid is only al)proxiinatelp om-half :iact i\ c' ; t i trimit eretie. 111 gotieral, ortho i.on1er.s seem to be mor(' active than the other iwmers. The p hydroxy :tiinlog'fl of triamt
