Ytericliiies.
V.' Some Analogs of .l.,7-Diamino-Z-phenyl-6-ytericiillecarbo~an~i~le~
A scries (it' 4,'i-di~miiio-ti-pteridirie~ar~~~)xaniide~ were prepared either hj- reactii)ii of the appropriate 2-3uhtituted 4,6-diamiiio-j-iiitrosopy~imidine with the required Y-wbstituted cyaiioacelamide 0 1 ' by aminolysis of ethyl 4,'i-diamino-2-pheriyl-6-pteridinecart~oxyl~~te,The ester waq prepared from ethyl tlia1nino-~-nitroso-2-pheii~lpyri~iidirie aid alho iinexpec.led1.v ohtaiiietl when the treated with diphenyl sulfoacetate, cyaiioac rea, ur c ~ ~ - a i i o a c . e t ~ l u ~ ei ltl hrhc : i i ~prehe A series of 4-amino-i-h3.droxy-~-phenyl-6-p iiiecahosaniide arialog' wa.k prepared f ezter.
Introduction to Papers V-XI1 of This Series.--Thi\ paper is the first of seven in n hich some of the medicirial chemistry related to the diuretic agent triamterenc i. reported. A chronology of thi\ project waa presented :it the Third Interriatioiial Symposium 011 Pteridines. In the previous papers iirw syntheses of 6-alkyl-i:tminopteridinrs were presented as w l l as the prep:mtions of triarntererie &oxide and the 7-phenj 1 isonicv of triamtercne. The first papers in the current group complete the discussioii of chemistry :riid the 1a.t article presents the diuretic structure-wctirit\ relatiomhips of the compounds reported. l'hr discovery of the iiitere4iig diuretic activitj, of 1,T-diamino-2-pheIiyl-Ci-pteridiIiecarb(~xamide(I) in our l:ibor:itory? during the courw of investigating the diuretic activity it1 :L wide variety of pteridines prompted us to prepare a number of related compouiitls i l l order to explore the itructure-acti~ity relationships iri thin 511*eu. This paper reports a portion of this worL.
NH1
'l'hc most direct preparation of -i,i-diainitio-(j~~teridinccxrboxamides proceeds cia t'he base-cat'alyzed condensat'ioii of cyanoacetamides n-it'll J-amino->iiitrosop~rirnidiries.~ This method was successfully applied to the preparation of the compounds shown in Tables 1-111. Polar solvents such as dimet,hylforniamide (DAIFj, capable of dissolving t'he sometimes poorly soluble iiit~rosopyrimidiiies, gave relativcly rapid aiid clean reactions. Thc tiecessarj- 4,6-diamirio->-riitrosopyriinidiiies were, in general, prepared b>-the thermal isomerization of' thc iao~iitrosomalonoriitrilesalt of the appropriate aniicliric or gut~nidine.~The amidines were prepared I 1 1 Previous paper- in tiiis series: (a) I Pacliter and P. E. Nernetl;. ./. Ow. C i i e n . , 28, 1187 (1968); (I>) I. J. Pacliter, i b i d . , 28, 1191 (1963); ( e ) I. .I. l'acliter, P. 5;. Kemeth, and 3 . J. Villani, ibid., 28, 1197 (1963): (d) I. .1. I'acliter and P. E. Nernetli, i b i d . , 28, 1203 (1963). ( 2 ) A portion of this work was presented a t t h e Third International Symposium on Pteridines. Stuttpart, Germany, 1962, a n d reported in preliminary form liy J. \Yeinstock and Y. D. Kiebeliiaus in "Pteridine Chemistwv," \V. PHeiderer a n d E. (2. Taylor, bhi., Pergamon Press, Oxford, 1964.
1, :i;. i : i ) .i. \\-rinst,ock, U.h. I ' a t m t 2 , $ m j , - i Z(1!160j; 'T. S. Osdene rmd I:. 'l'aylur, C . 9. Patent 2,975,180 (1961). I t ) T. S. Osdene and C:. AI. Timinis, .f. Ciienc. Soc., 2086 (19%). (:j) 0. Vuxl and E. C. 'Taylor, J . .lm. C'hcm. Soc.. 79, 1518 (1957).
('.
b>- animonol> ai;- ot the appropri:itc imino ctlier Iij-drochloride' except ill the ca-c of thc o-chloro and I ) meth? lbe~iznniidities. I11 thebe cases, probahlj. hccauw of steric hi~idrniico,thc iiitrile m a s recovered duriiig attempted imino ether formation. However, thc iiitrilei reacted \\ it11 h> drosy1:imiiie uiider b:i conditiori~to give l~ciiz:~mido\;iiiies, which \vert h>drogenated7 under lov preqaure iri the presence of Iiariej nickel to give the 01tho-substituted berizarnidiiies. Thc required 4-substituted ~ , ( i - d i a r i i i ~ i o - > - i i i t r ~ ~ ~ o ~ ) y r i i ~ i idines \yere ni:tdr~ from ~,~j-di:imino-4-niethj 1~uercapto-.?-iiitro~op~ri~i~i~lirie by tlisplacemciit with the appropriatc anline. .hi alternate route for tlie prepnratioii oi 4,7-cIiaiiiiiio~-pl~eriyl-t~-ptcridiiiecarhox:tmitles (TI) in which thc~ aiiiide nitrcigeii is substituted coiisists 01 treatiiig etti! I 4.i-diainiiio-'.'-pht~1ij1-6-pteridiiiecarboxyl:1tc (Tj wit I 1 :til appropriate nriiiric. 111 order to verify tlie course of thi5 reaction, VI (R1 = = ('H3) rwctioii -1 from l , ~ i - d i a ~ n i ~ i o - ~ ~ - ~ i i t r o ~ o - ~ - ~ ~ h e i i ~ ~ l j ~ H,h'
x&'yC"" +
I
CjH,02C
R,R,NH
-+
NH-
v
",
6 VI
543
PTERIDINES. V
;\lay 196s
TABLEI
+
HINOCCHzCN
I NHZ
+
H,NOC NH, -Ultraviolet Solvent" Amax,
%
Itecrystn solvent"
>300
91
A
b
3-CHsCeH4
>310
83
A
b
2-CHsCsH4
>300
89
A
b
4-ClC~I14
>300
75
A
b
>300
80
A
b
>300
60
A
b
>300
86
A
b
>300 >300
9s 23
A F
a
Yield
Mu,
2-ClCaHa
4-Cl-3-NHzS02CeHab
H
o c
C
>300
77
A
b
mectra--
Log
e
240 4.358 273 4.470 386 4.328 24 1 4.336 272 4.493 385 4.297 239 4.318 272 4.461 380 4.220 236 4.629 272 4.741 378 4.571 239 4.420 272 4,585 383 4.461 239 4.590 272 4.731 380 4.438 24 1 4.338 27 1 4.362 323 4.111 387 4.417 Insoluble 270 4.398 374 4.068 246 4.305 370 3.964 233 4.134 272 4.407 373 4.117
Cliroinatogmpliy System'" Rt
1
0.73
1
0.76
1
0.85
1
0.75
1
0.80
1
0.86
1
0.61
2 1
0.65) 0.54
1
0.34
0.76 J 221 4.533 269 4.314 37 1 4.267 A b 1 0.69 CeHjNH >300 CiaHlzNsO 22 1 3.813 66 270 3.566 378 3.637 A 1 0.48 e >300 87 242 4.686 283 4.360 400 4.425 Recrystallization solvents: A, DMF-H,O; B, EtOH-H&; C, JIeOH-H20; D, DIIF; E, EtOH; F, AcOH; G, 50% aqueous AcOH; H, precipitate from aqueous BcOH with TU"4OH; I, dissolve in EtOH, filter, evaporate to dryness, and triturate residue with EtzO. The uv spectra were determined in the following solvents: a, 4.37, HCOOH; b, 0.1 S HC1; e, 1 X YaOH; d, 0.1 S NaOH; Prepared by Mr. A4rnoldKrog. The details of the e, EtOH. For the paper chromatography systems, see the Experimental Section. preparation of the required nitrosopyrimidine will be published. c 5': calcd, 31.50; found, 30.84. d All compounds were analyzed for 334-3s5 >300
20 72
G D
b
C, H, N.
DMF a t room temperature using an excess of the amine is quite clean, leading to products that are readily purified. The reaction is selective in that only primary aliphatic amines unsubstituted on the a-carbon react under these conditions. Thus, 2-amino-1-phenylpropane, IT-methylpiperazine, and aniline did not react under these conditions. Further evidence of this interesting selectivity was obtained when 1,Bdiaminopropane, 1,2-diamino-2-methylpropane,and l-aminoethylpiperazine gave only single products. The structure of the compounds obtained from these amines was assigned on the assumption that the reactions involved the primary carbinamine. The required V is best prepared by the reaction of 4,B-diamino-5-nitros~-2-phenylpyrimidine (VII) with
ethyl cyanoacetate in absolute ethanol using sodium cyanide as the catalyst. This procedure gave a 75% yield of ester uncontaminated by acid. Condensation of the same reactants in absolute alcohol using sodium ethoxide as the catalyst gave the ester in 40% yield along with a 30% yield of the sodium salt of d,7diamino-2-phenyl-6-pteridinecarboxylic acid (VIII) (Scheme I). The corresponding methyl and isopropyl esters were also obtained in approximately 45% yield by the reaction of the appropriate alkyl cyanoacetate in the corresponding alcohol using sodium methoxide as catalyst. In each case, a substantial amount of VI11 was also obtained. An attempt to prepare the isopropyl ester using sodium cyanide as the catalyst in 2-propanol was unsuccessful.
544
\
UN*N
o!.
II
I
IL",
SH
!I2
(i7
X .i
I
ST !I4
i0
I
ss >so0
(ii
...
>I
C6H502CCH2S0,C6H IX
+
-
I l l \ll,
VI1
I1
X
1
The ester T- was alba uiicxpectedly obtaiiied from the condensation of diphen) 1 sulfoacetate (IX) and \'I1 in ethanol usiiig sodium cyanide catalysis (Scheme 11). A possible mechanism for this reaction n i g h t iiivolvc the condensation of IX arid VII to give X, which is coriverted t o XI by the addition of cyanide ion followed by the elimination of phenyl sulfite anion. Normal base-catalyzed cyclization of XI arid transehtcrificntio~iof the ester a t sonic htage would lead to V. Another unanticipated synthesis of V occurred when \-I1 W Z ~ H condensed with ethylcyanottcetylurethaii ill alcohol i l l the prescrice ~f hodiuln cyaiiide. Sirnilady,
XI
V was isolated f'roiii tlic coiiderisatioii 01 V11 I\ it11 cyaiioacetylurcn iuider the same conditious (kklienic 111). Howevei , iii DMF using sodium methoside as the catalyst. retiction of 171 with the ur.eth:m gave 2I.'heiiyl--l.-nn~iiio-(j.S-dioso-(j,7,S,9-tetr:Lh?.tll.op? riinido[3,4-g]pteridine (XII) while the reaction of 1-11 with cyanoacctylurea iirider these coriclitioiis g i v e t lw birnple curboxaniicle 1 ill high yield.
May 1 W
V
~'TEKIDISES.
545
TABLEI I I ~ ~ b
H . N ~ ~ " z
+
ON
H,NOCCH2CN
-
HzNx;qy"z HzNOC
NRiRz Yield,
NRiItz
%
hIIJ,
>300
KIICII3
47
WRz Recrystn solvent
H
Formulad
CsHioNsO
-Ultraviolet spectraSolvent Amax, mp Log e
d
Chromatography System Rr
278 393 281 403 234 284 384 280 370 289
4.410 3 0.28 4.167 a 4.230 4.380 N(CHa)z >300 62" H Ci"&"O d 4.548 3 0.43 4.330 4.299 a 4.376 4.289 NIICJl5 >300 32 E Ci3HisNaO .0.5&,0 d 4.322 3 0.60 400 4.301 a 289 4.395 385 4.369 Reaction was a See footnote a, Table I. b We wish to thank Mr. Barry RI. Trust for assistance in preparing these compounds. run in DMSO using potassium t-butoxide as catalyst for 24 hr a t 95'. d See footnote d, Table I. SCHEMEI11
VI I
U
+
C,HSOpCNHCOCH2CN
,
7
NaCN
XI1
/am
:NHz
C,H,OH
HLNCONHCOCHZCN
NaCCHj
1
NHz XIIIa, R = NHCO,CzH, XIIIb, R- NHCONH2
These results can be rationalized by assuming that in each case the expected product (XIIIa or X I I I b ) was formed, and that in ethanol in the presence of cyanide the substituted amides undergo attack by solvent anion to give V and either urethan or urea anion. In the presence of a strong base in a nonprotonic solvent, X I I I a undergoes cyclization to give XII, and X I I I b cleaves at the urea carbonyl to give I. The free acid of VI11 was prepared in almost quantitative yield by reaction of VI1 with 2 moles of cyanoacetic acid in the presence of 4 moles of sodium ethoxide. This acid was decarboxylated by heating a t reflux in quinoline. Similar syntheses of 6-unsubstituted pteridines have been reported p r e v i o ~ s l y . ~ ~ ~ In order to obtain some representative pteridines in which the 7-amino group of I was exchanged for hydroxyl, ethyl 4-amin0-7-hydroxy-2-phenyl-B-pteridinecarboxylate (XIV) was required. It was prepared by reaction of diethyl oxomalonate with 2-pheny1-4,5,6triaminopyrimidine in refluxing alcohol (Scheme IV) . Treatment of XIV with ammonia and ethylamine gave (81 1'.6. Osdene and 0 . AI. Timmio, J. Chem. SOL., 2038 (1936).
x IV
NH2 XV, R = H , CZH,, CH3NH
the corresponding amide and N-ethylamide. Reaction with methylhydrazine gave the corresponding pmethylhydraaide. The structure of this hydrazide was inferred from its failure t o react with benzaldeh~de.~ Pharmacology.-The structure-activity relations of a number of these compounds as diuretics is reported in an accompanying paper. lo Experimental Section" The paper chromatography was done b y the circular system using a cotton wick to bring solvent to the paper. The following (1) BuOH-AcOH-Ht0 (4: 1:5); (2) systems were used: DRIF-HCOOH-Hz0 (10:3:7); (3)BuOH-HCOOH-Hz0 ( 5 :1 : s ) ; (4) dip paper in 20y0 solution of castor oil-mineral oil (1:l) in acetone, allow acetone to evaporate, develop with EtOHH20 ( 2 : l ) ; ( 5 ) same as 4 using 20% mineral oil in acetone to pretreat paper; ( 6 ) BuOH-5.6 -1' ",OH (4:s). Melting points are uncorrected and were determined in open capillary tubes. I I a n y of the pyrimidines used as intermediates were prepared by known methods. Since these are summarized in a readily accessible manner,'* individual references are not given. (9) A mixture of t h e a- a n d @-methylisomers was obtained from t h e reaction of V with methylhydrazine. I n t h a t case, one isomer reacted readily with benzaldehyde, whereas t h e other did not react (E. C. Taylor a n d J. Weinstock, unpublished results). (10) J. Weinstock, J. W. Wilson, V. D. Wiebelhaus, A . R. hlaass, F T . Brennan, and G. Sosno\\ski, J. M P d . Chem., 11, 573 (1968), paper S I 1 of this series. (11) Where analyses are indicated only by symbols of t h e elements, analytical results obtained mere within 3 ~ 0 . 4 %of t h e theoretical values. (12) D. J. Brown, "The Pyrimidines," Interscience Publishers, Inc., New Tork, N. Y., 1962.
547
PTERIDINES. V
May 196s
TABLE IVQ
NH, %
Recrystn solvent
89
B
Yield, h l p , OC
>300
265-270
2"
Ultraviolet Ypectra Solvent Amax, mil Log
a C
NHCHzCHCHd
380-283
47
B
I
2"
XHCHZC (CH3)z
>300
73
B
1
a
272 385
C
250 385
a c
NIIp
27 1 385 250 385
272
385 250 385 271 386 272 385
XH(CHz)&(CH3)2
264-266
54
E
a
S H ( CH,),N (CnHa)s
262-265
86
B
a
KHCH2CHOHCHzN(CzHj)e
260-262
41
E;
a
272
C
386 251 387
248-252
63
C
a C
249-253
49
B
a
c 277-279
47
B
a C
248-250
75
B
a C
120
47
I
272 386
251 386 27 1 386 250 385 272 385 249 385 272 386 251 385 272 386
250 386
6
Chromatography System Xi
4.525 4.250 4.568 4.236 4.560 4.318 4.597 4.290 4.551 4.281 4.583 4.255 4.521 4.262 4.528 4.270 4.524 4.258 4.529 4.193 4,508 4.274 4.587 4.248 4.467 4.233 4.502 4.201 4.535 4.303 4.582 4.255 4.533 4.292 4.574 4.241 4.502 4.238 4.558 4.212
a See footnote a, Table I. Prepared by bubbling l l e , N H into a refluxing mixture of ester in 2-ethoxyethanol for 2 hr. for characterization. C: calcd, j6.79; found, 56.29. ?J: calcd, 31.48; found, 32.11. e See Table I, footnote d.
mole) of ethyl 4,7-diamino-2-phenyId-pteridiiiecarboxylate in 200 ml of warm DMF was treated with 0.04-0.20mole of the amine depending on the availabilit,y of the amine. The reaction mixture was allowed to stand a t room temperature 18-66 hr and either water was added to precipitate the product or the solvents were removed under vacuum to obtain the product free of the reaction solvent. The latter was required wit'h the more soluble members of the series. Recrystallizat,ion was accomplished using the solvents indicated in the table to give the products in the yields indicated. 2-Phenyl-4,5,6-triaminopyrimidine.-To tt refluxiiig susperision of 10.7 g (0.05 mole) of 4,6-diamirio-.5-nitroso-2-phenylpyrimidine in 500 ml of EtOH was added 3.75g (0.075 mole) of %yo hydrazine hydrate and 2 tablespoons of Raney nickel. The mixture was boiled 5 min (during which time the green color of the nitroso compoiind was discharged) and filtered hot, and the filtrate was concentrated t o give 8.73 g (87%) of a brown solid, mp 186-189". Recrystallization of a small portion gave yellow tals, mp 186-190",lit.I3 nip 186-189". The crude product was sufficiently pure to use for further reactions. Ethyl 4-Amino-7-hydroxy-2-phenyl-6-pteridinecarboxylate (XIV).-A solution of 4.12 g (0.12 mole) of 2-phenyl-4,5,6triaminopyrimidine and 3.9 g (0.0225mole) of diethyl oxomalonate in 100 ml of EtOH was refluxed for 2 hr. Cooling and filtration gave 4.8 g (77y0)of yellow crystals, mp 215-230'. Two recrystallizations from aqueous DMF gave yellow crystals: mp 234'; Rr 0.93 (syhtem I ) ; ::A;t HC"oH 283, 378 nip (log (13) R. M. Evana, P. G. Jones, P. J. Palmer, a n d F. F. BteylieIis, J . Chem. Soc.. 4106 (1956).
3
0.44
3
0.40
4
0.75
0.48 3
0.57
3
0.43
3
0.30
3
0.30
3
0.50
3
0.44
3
0.59
See Table I1
E 4.307,4.041); X',k\;'"OH 268,310,380 mp (log e 4.338,4.1.52, 4.021). A n d . (CijH13N503)C,H, K. 4-Amino-7-hydroxy-2-phenyl-6-pteridinecarboxamide (XV, R = H).-A stream of anhydrous XH3 was passed for 1 hr through a refluxing stirred suspension of 5 g (0.016mole) of ethyl 4amino-7-hydroxy-2-phenyl-6-pteridinecarboxylate in 200 ml of
EtOH. During the course of the reaction a clear solution was obtained from which a precipitate slowly appeared. The mixture was cooled and the solid was collect,ed. This was recrystallized from aqueous D l I F to give 0.91 g (2Oyc)of crystals: mp >300"; Rr 0.53 (system 4);::A: HCooH 285,378 nip (log E 4.534, 4.204); X',;~'"O~ 282, 418 mp (log E 4.660,4.2:30). d n d . (C13HlOS6OZ) C,H, K.
4-Amino-N-ethyl-7-hydroxy-2-phenyl-6-pteridinecarboxamide (XV, R = C2Hs).--A mixture of 4.0g (0.0128mole) of ethyl 4amino-7-hydroxy-2-phenyl-6-pteridinecarboxylateand 40 ml of iOyGaqueous EtNH, in 150 ml of EtOH was refluxed for 2.5 hr. On cooling, a solid was obtained which was collected and dissolved in hot HzO. The solution was filtered, the p H was adjusted to 4.jwith AcOH, arid the yellow-orange product which separated was collected. Recrystallization of this from aqueous D M F gave a yellow product, mp 295-299"dec, Rr 0.67(system 4). Anal. (CijHi4N602) C, H, N. 4-Amino-N-( 2-diethylaminoethyl)-7-hydroxy-2-phenyl-6-pteridinecarboxamide.-A solution of 3.4g (0.011mole) of ethyl 4amiiio-7-h~droxy-2-pheiiyl-6-pteridinecarboxylateand 3 ml of diethylamiiioethylamiiie iii 30 nil of I)AIF was allowed to s t a i d for 18 hr at room temperature. The solutio11 was filtered and the solveiit was removed under reduced pressure t o give 4.4g of a gold solid, nip 98-180'. This was dissolved iii 500 ml of refluxiiig
ethyl acetate aiitl filtered, mid the solution was coilcentrated 10 1.50 nil. Chillirig gave a product which was re from benzene to give 1.7 g (4074) of crystals, m p (system 6). :lnal. ( C ~ ~ H d J K .O.%.iHZO) h C,11, S . 1 -(4-Amino-7-hydroxy-2-phenyl-6-pteridinoy~)-Z-methylhydrazine (XV, R = CHaNH).--To a stirred si)Iiition of 9.3 g (0.03 mole) of ethyl 4-amino-7-hydroxy-~--pheii?-l-B-pteritliiiein 125 ml of l).\IF a t 0-5" w a s atitled 20 g (0.42 thylhydrazirie dropwise. After 9 hr the reactiini tenipyrttt tire was allowed to come t o room t~emperatiilrwit,h cont~iiiiicd .inring: for 14 more hr. Addition of 125 nil of ~ i t k :r~ n dadjustrnetit ol' the pI1 to 3 with cwticeiitrated IfC1 giive it ye1 nllizxtion from aqueous 111 ' dec; R i 0.77 (system 1 ) : X (log B 4 2 W , 4.313,3.987). .Lnul. (CI 4,7-Diamino-2-phenyl-6-pteridinecarboxylic Acid. A.--A riiixttire of 6.45 g (0.03 mole) of io-5-ni troso-2-p heiiyletic arid, :and 3.36 g pyrimitliiie, 2.8 g (0.033 mole) ( (0.066 mole) of Na0CH3 in 230 F ~ a 2refhived : for 10 t n i t i . This gave a yellow solid whirh wa,$rollected Iiy filtratioii :md sliirrietl in aqiieoiis EtOlI, and AcOI1 was added to bring [he pII to 4.,5. The resulting solid \vas cdlectetl 117 filtration atid washed well with Et011 and theri ether to give 4.i g (3GC; j of briff crystals. This was dissolvrd i i i 7 1. o f 13f'i, XIl4OH atid filtered through Celite, and the filtrate was with 4eOIT. The product as collect,edand I' times frcim I f 2 0 using charco:tl t o ti g:ivc yellow needles, mp 256' dec, 1, 272, ;3s:i tnp (lug B 4.318,4.4!)4,4.255); Xr 0.60 -atom) of N a i t i 400 nil of redistilled ethoxyethaiiol was added a mixtiire of I7 g (0.2nlole) of cyanoacetic acid and 21.5 g (0.1 mole) of 4,6-diamino-3tiitroso-2-pheri?.lp?-rimidiiie. The rnixt Lire w i a refluxed for 2 rniri, cooled, and filtered to give the sodiiirn salt of the prodlirt. This was dissolved in 500 ml of € I & miti acidified (AcOH) to give 28.1 g (985;)) of a white solid, mp 26::" clec. The ir s p e c t r i m of this product was identical wit,h that, of the product obtained above. 4,7-Diamin0-2-phenylpteridine.~~--X siispensioii of 10 g (0.05:! mole) of 4,7-diamino-'L-phenyl-6-pteridi1iecarboxylk arid i i i 230 nil of redistilled quinoline was refluxed for 5 hr, cooled, aiitl tliliited with 600 ml of hexane. Filtration gave a light browti s~ilidwhich was stirred in 2 I. of 0.7 S K;If40H,collected by filtration, atid washed (II20). Recrystallization of this f r o m .io(, (14) IVe \visli t o thank hIrs. J. Careviu preparing this compound.
LLII~
11r. 11. 811ali for a a i D t a n i , e i u
