617
1Tny 196s TABLE I 3-AMINO-2,6-DIHYDROPYRROLO[3,4-C]PYRAZOLES
\" LIP, o c
Yield, 70
119-1 2 5 156-157 195-199 159-162 177-179 176-179 163-166 184- 192 220-221 142-144 387-193
8 45 68 24 36 94 29 46 73 33 34
hIeOII-EtOH
C, H, N C, H, N H, N HI N C, H ; Tu'd H, N c, H, N H, N c,HI N C, H, X C, H, N
12
217-221
-J.)
9,i% EtOFl
C, IT, N
13
243-247
17
Me013
C, TI, N
14
298 dec
2 MF
C, 11, N
15
272-273
33
EtOH
c, H,N
16
282-284
88
DMF
C, 11, N
17
240-242
33
95% EtOH
IT, N; Ce
18
166-169
26
Aq EtOH
C, H, N
No.
1 2 3 4 5 6
7 8 9 10 11
Crystn solvent
Analyses
Aq RIeOH CaHa RIeOH Aq EtOH
c, c, c, c,
DlIF EtOH Aq EtOH Aq EtOH EtOH
EtOH
a Anal. 2H20: calcd, 14.6: found, 13.0. * Anal 0.2ijH20: calcd, 1.55; found, 1.7. X : calcd, 18.3; found, 17.8. 8 C : calcd, 64.6; found, 64.1.
Ann/. 1.2.iHzO: calcd, 6.51; foiiiid, 7.29
TABLE TI 3-ACYLAMINO-2,6-DIHYDROPYRROLO[3,4-C]PYRAZOLES
"CORl H 5 C 2 0 2 C - N -N @W
nI
NO.
26 a
MP, 'C
CH3 3,4,5-(CHIO)~COHZ CHI CF3 3,4,5-(CH30hCeHz CH3 CHI
19 20 21 22 23 24 2.?I
6
198-202 212-2 15 178-183 195-199 216-217 207-2 11 180-184
Yield, 70
62 44 48 44 42 54 48
CH,
0.31T20: calcd, 2.78; foiind, 3.09.
The acetyl derivative was also obtained by acetylation of 3 with AcCl and pyridine in CH2Clz. Compounds 19, 22, and 24-26 in Table IT were prepared similarly. Ethyl 34 Diacetylamido)-2-phenyl-2,6-dihydropyrrolo[ 3,4-c] pyrazole-5(4H)-carboxylate (=).--A mixture containing 1.8 g of 3, 25 ml of AcpO, and 1 ml of pyridine was heated (90") for 1.5 hr. The excess anhydride was evaporated and the oil was triturated with cold HzO whereupon the diacetyl derivative precipitated. It was recrystallized from 95yo EtOH to give 1.5 g (737,) of a product, mp 143-145". Tlc on silica gel wing 57,
-
MeOH in CHzC12 showed that the product was homogeneous. The ir spectrum in CHCL showed no evidence of NH absorption in the 3000-3500-~m-~region. In the nmr a single peak for six protons for the two acetyl groups was observed a t T 7.8. There was relatively no shift in the uv absorption for the diacetyl derivative [249 mp ( B 12,800)] as compared to the unsubstituted amino derivative 3 [246 mp ( B 13,830)]. Anal. (ClsHZ&402) C, H, N. Ethyl 3-(3,4,5-Trimethoxybenzamido)-2-phenyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (23).-A solution of 1.15 g (0.00S mole) of 3,4,5-trimethoxybenzoyl chloride in 5 ml of CH2C12 was added to another soliltion of 1.36 g (0.005 mole) of
The mixtiire 3, 0.4 IIII of pyridine, and 20 in1 of C11&12. Ytirrpd for 2.5 hr and evaporated to a rolid, which WRS r e t r y t n l l i ~ c v lfrom Et011 to give the desired prodrwt . ('oiiiporiiid 20 in Table I1 nn. prepaied b i i i i ~ l : t i l \ .
Acknowledgment. --The microanalyses were yerfornicd by A h . I,. AI. Brancone and his associates. The spectral clutn w r e ohtained from l r r . W. I~iilnior : L I hiq ~ associates.
Pteridines. XI.',3 Pteridines Related to the Diuretic, 2,4-Diamino-6,7-dimethylpteridine ,Jo5rwIr k v E I h S T O C K , 1 t O B E R P . I Y. l)LJ.VOFF, JOYCE E. .JUNE G. \VILLI ~ M S ,O D ASTHONY VILL\NI
\ILEVIC,
,J,
IZrsPorch and Devdopinent Division, Smith Kline and Frmcli LnboratoriPs, P h iladelphin, Pmnsyhnnio 19101
lZeceived Dccenzbrr $6, ltCW
Significant diuretic activity of a pteridine was first observed in our laboratory with 2,4-diamino-G,T-dimethylpteridine. In this note we will describe some \vorl; carried out in order to explore the structure xctivity relationships of compounds related to this lead. The Isay reaction,d which is the condensation of ti 4,&diaminopyrirnidine with a 1,2-dicarbonyl compound t o form a pteridiue, was used to prepare the compounds in Table I. When unsymmetrical dicarbonyl compounds are used it is often possible to direct the course of the synthesis by altering the pH of the reaction medium. The 5-amino group usually is the more rea('tive of the amino groups and it will react with the most reactive carbonyl group. However, at low pH it also ~)i*oton:ites first, and thus allows the less basic 4-amino group to react with the most reactive carbonyl group.4 I
