cluding those where the 5 substituent, Y , is amino, b u bst i t ut ed amino, hydroxy, alkoxy, mercapt 0, or niethyliiiercapto and where the 6 substituent, X, is chloro or hydrogen. S-Substituted aniidinopyrazinecarboxamidcs were prepared by the reaction of a number of mono- and 1 , l disubstituted guanidines with a few selected esters. Theoretically, a monosubstituted guanidine ( e . g . , niethylguanidine) could give rise to either or both of two isomeric products: (a) I1 (where R3 = H arid R 4 = CHJ or (b) the isomer in whirh the acyl and methyl groups are attached to the same nitrogen atom. That the former structure (a) is the more likely one is based on the following arguments: (1) an unequivocal synthe+ of S-(methylamidino)benzaniide has been reported2 and it has been shown to be identical with the coiiipouiid prepared from niethylguanidine and ethyl betizoated or benzoyl ch1oride;l (2) no reaction occurred
IC,+, R - C H 5, R = (CH I-NCH-CHC1 /N CONHC(=NHWHHjx(m=)c H i x Z J i H IIa-48
hn alternate synthesis of S-amidino-3-amino-5dimethylamino-6-chloropyrazinecarboxaniide (IIa-14) was devised which might have broader application (Scheme 111). Treatment of methyl 3-amino-.5,6-dichloropyrazinecarboxylate (Ib) with guanidine afforded the acylguanidine (IIc-82) which reacted with
SCHEMEI1
/
Ia-2
I
c
0 Ia-4
/
/
1
i
Y =H,N Y =HO Y =CH,O Y = (CH,),N Y = C,H,CH,NH
/
I L - ~ Y. =CH$ 2, Y = CH,O 3, Y =CjHiO 4 . Y =C,H-0 5, Y = (CH,),NCH~~H,O 6. Y = H S
with 1,2,3-trimethylguanidine and selected esters of type I ; and (3) steric and statistical probability considerations favor this structure. When the 5-phenoxy-6-chloro (IC-4) and the 5-(2-dimethy1aniinoethoxy)-6-chloro (IC-3) esters were heated with guanidine in 2-propanol, replacement of the 5 subbtituent with a guanidino group occurred with the forniation of IIa-48 (Scheme I). The 5-methylsulfinyl-6chloro (Ie-1) and 5-mesyl-6-chloro (Ie-2) esters (see Scheme 11) reacted with guanidine to give conipounds (11) with the expected properties, hut lack of stability prevented isolation of pure samples. (2) I. Greerinald, .I. .Im. C h c m . Noc., 4 7 , 1443 (102'3). (3) \\-. T r a u b e and 1 .; Gorniak, Z . A i n y e ~C. h e m . , 41, 379 (IU2!1).
Ig-1, 2, 3, 4, 5,
Ie-1, Z = SOCH, 2 , Z = YO,CH,
If'
dimethylamine in dimethylformaniide to give (IIa-14). The product was identical with that obtained from Id14 and guanidine. The intermediate esters were prepared by the methods outlined in Scheme 11. h key intermediate for thebe syntheses was I b which vas first made4 from methyl 3-aminopyrazinecarboxylate(Ia-1) and sulfuryl chloride. As expected, methyl 3-amino-6-chloropyrazinecarboxylate (Ia-2) and sulfuryl chloride gave the same product (Ib). With methyl 3-amino-&bromopyrazitiec.nrboxylnte (1:~-3)rcq~lacrmentof the bromine (4) R. J. Tull, J. t e n Broeke, a n d E. J . Crayoe, Jr., a r e responsible for the original synthesis of this compound and Dr. J . \-an d e l i a m p and his colleagues adapted the method f o r t h e i,reparation of the larger amounts of the material required in this study.
P
ployetl, only 111b v :LC iao1:itctl. H o ~ v e v t ~ ,hen tlic, reactiou wab cmiducted in a highly polar holverit surh 'I: diniethyl sulfoxide, diriiethylforni:inii(lc. dimethyl CUIfonc., or sulfolarie, the dehired eht c'r, mcthyl ;3,5-tliaiiii~io-B-chloropyraziriecarboliylate (Id-1 1 (Table I) \va< produced in good yields. I he rcx:ic.tion of I b with aroriiatic. :initn(~sgave the be't rcwilth when a mixture of t h r :miiic atid the aiiiint. hytlrochloride was 1 1 ~ 1 . lI(1thylhydraziiie theoretically c*oultl r ( w t with 11) to produce either (or both) of tmo t~oiiier\(Id-47 arid IT). However, it \vas proved that the product \yay the .5-(1inct hylhydrazi~io)c~oiiipon~id (Id-17) hy (lemonstrat ing that it rrwtccl with henzuldt.hydc to producc the liyclrazoiie (Id-18) (Schenir Tj. Siniil:trly, Parmi, ( / found that 2-h:iloalh;iiiuir w ~ d - rcxcat ctl \\ i t 11 I 7
11
69
TABLEI
COOCH3
N Id ,; H2
It I
Nu. 1C
I1
11
2
CH3
3 4 3 6
C2Hs CaH7 (CH3)rC H CaHs (CH3)KHCHr C?HsCH(CHz) (CH3)aC CrHii C3H;CH(CH3) ( C?Ha) 2 CH CsH13 CH3 C H3 C H3 CH3 C Ha CrH5 C2Hs CiIIS CrH5 C3H;
1% H
7 8 9 10 11 12 1:3 14 15 16 17 18
lY 20 21 22 23 24 23 26 27 28
- ( CH?)4-(CH?)oC H?=C HC H2 C H2=CHC HJ C Hr=C H C H?
29 30
ACH'
H
yield" 91 88
13ecrystn
solventh .\
P
89
P
,O
P P P P P U-\I C PE He P
__
H H H H
io 91 51
H
38
-_ 15
n
72
H H H CH3 C2Hs C3H; ( CHa) r C H CaHs C?Hr C3H; (CH3)CH C4H9 CaHs
40
81 70 97 73
11
Mu, "C 212-213 221-222 149-150 138-140 125.5-126.5 140-142 113.5-115.5 106-108 t 8-108 100.5-102 5 T4.5-75.5 82.5-84.5 72.5-75.5 145.5-146.5 102-104 83,5-85.5
Formula
--Carbon, Calcd 35.5i 38.81 41.66 44.18 44.18 46.42 46.42 46.42 46.42 48.44
48.44 48.44
50.25 41.66 44.18 46.42 4d.42
58
P P
i8
P
-(2.5-77.5
i4
P YE PE
5Y.5-61.5 99-101 80.5-83.5
48.44
77.5-79.5
50.25 51.91 46.78 50.61 44.54 46.i8
54 65
46.42 48.44
[hFound 35.80 38.74 42.11 44.21 43.82 46.39 46.:34 46.46 46.31 48.27 48.65 47.96 50.27 41.73 44,16 46,55
Calcd 3.48 4.19 4.81 5.36 5.36 5.84
4 6 . TO
5.81 6.28 5.84 6.28
48.60 46,T5 48.39
5.84 5.84 5.81
6.28 6.28 6.28 6.68 4.81 5.36 5.84
I'ound 3.38 4.22 5,05
5.39 5.18 5,77 5.80 6.04
5.72 6.09 6.50 5.iO
6.60 4.52 5.24 5.75 5.97 6.22 5.i9 6.3i
Calcd 27.65 25.86 24.29 22.90 22.90 21.66 21.66 21.66 21.66 20.54 20.54 20.54 19.54 24.29 22.90 21.66 21.66 20.54 21.66 20.54
Found 28.01 25.49 24.24 22.89 22.62 21.67 21.64 21.65 21.25 20.45
lY.45 18.54 21.86 19 60 23.12 21.7 3 20.44
20.57
20.40 19.45 24.21 22.81 21.io 21.46 20.54 21.45 20.40
i5d
91 59 95
-_
PE PE P P
€1 CHV C?Hr
6Y
P
TO 54
P P-\T
168-171 109-111 105-106.5 90.5-92 43.5-45.5
H
98
P
16i-169
CsHnClKdO?
44.54
44.63
4.57
4.52
23.09
23.09
11
i8
P
132-133
ClaHiaClK;aO*
46.78
46.93
5.10
5.18
21.83
21.92
98
P
119.5-121.5 CiiHiaClSaOi
48.80
48.91
5.58
5.39
20.70
20.5Y
84
11 P P
C1aHlaClNaO? 53.34 ClrHisClNaO? 54.81 C13HliClFNa02 50.25 CI~H~?C~~NPO~ C~hHlaClNaOn 54.81
53.46 55.24
4.46
50.05
4.48 4.93 3.89
4.08
19.14 18.2i 18.03
19.22 18.20 18.06
10
45.5-47.5
6.68 7.04
5.10 5.58
5.08
48.80
4Y.81 52,OO 47.01 50.54 44.46 46.85 48.iO
5.40
lY.54 18.63 21.83 19.68 23.09 21.83 20.70
5.10 6.02 4.57
6.28 6.94 4.95 5.79 4.61
59
P
15i-158 112.5-114.5 171-174 137-138 115-119
55.25
4.93
4.88
18.2i
18.13
81
I'
148-169
C~iHiiClNaOa
4 6 . i3
46.14
3.Y2
4.08
19.82
lY,5i
97 76 1ood
\\
153-154 CsHsClFaNaOz 124.5-125.5 155-157 257 172-175 171,5-174 206.5-207.5 144-146 186-188 136 5-138 5 179 5-180 5
33.76
34.10 36.46
2.88 3.3i
3.08 3.22
1Y.W
36.19
18.76
19.57 18.i 0
38.72
39.25
5.52
5.55
22.58
22.33
51.71 46.02 38.95 46.23 36.29 52.58
51.33 45.96 38.41 46.36 36.54 52.25
3.98 3.22 4.50 5.64
412 3.10 4.33 5.49
4.35 4,41
4.39
20.10 1i.89 22.72 24.51 30.23 21.90
20.30 17.86 20.50 24.02 30.82 21.72
66 84 93d
40 60d T1 89 68 88 67
...
P-\\ M e
P A P P E
4.99
4.08
The compounds in this table were prepared by method E-3 in the Experimental Section unless otherwise specified. * A, acetonitrile; D, dimethylformamide; E , ethanol; He, hexane; 31, methanol: P, 2-propanol; PE, petroleum ether (Merck's Benzin, bp 30-60"); W, water; E t , ethyl acetate; Ac, acetic acid: S,dilute methanesulfonic acid; H, dilute HC1: N, dilute NaOH; H-N, Ac-N, and S-N indicate that the compound was purified by dissolving in the indicated dilute acid and precipitating with dilute This compoimd was used in the next step without purification. e Isolated S a O H . c This compound was prepared by method B-2. as the hydrochloride salt. f This compotind was prepared by method B-4. 8 This compound was prepared by method B-5. * Derived from D-glucamine. a
c, cyclohexane;
corresponding &halo derivatives and the easy nucleophilic displacement of the halogen atom also has been accon~plished.~ Bromination of methyl 3,s-diaminopyrazinecarboxylate (Ig-1) afforded the 6-bromo derivative (Ih-1). Analogously, with iodine and mercuric acetate in aqueous dioxane the 6-iodo compound (Ih-2) was obt:tined. Structure-Activity Relationships.-Each of the Kamidino-3-ainino-5-substituted 6-halopyrazinecarbox(i) J. 13 liiihiny, t o be puhlidied
amides (11) syntheiized were assayed for their deoxycorticosterone acetate (DOC.1)-inhibltory activity using the adrenalectomized rat according to the method described earlier.' 8 The compounds routinely were administered subcutaneously, but similar results were obtained with representative compounds when the oral or intraperitoneal routes were employed. X scoring systemgsimilar to that already described' waq iised and the results are recorded 111 Tables 111-V. (8) 11 b Glitler and S L Steelman, .Vature, 212, 191 (1966) (9) See footnote y, Table 111, for a descnption of this b\ stein
70
..
71
Jnliuury 19ti7
Hecrys1II
c/c
NU.
1 2 3 4
5 6 7
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
111 11 Clla C?E1s C3Hi (CHs)?CH CaHs (CHajsCHCHs CzHsCH(CH3j (CH3)xC CsHii C~H~CH(CHJ) (C9Ha)?CH C6H13 CIf3 CHa Clla CfIa Cllr C2IIL CzHa CcHa CiHs CsH; -( CH1)4- ( CH?) 6C'Ilr=CHCI!: H CHz=CHCI.lr c 11d CHg=CHCHj C!HL
-solyieid5 ventb 93 14-N 89 11-5 63 H-K 93 Ll-rV 75 >I-\\65 P 76 AI-\\ 74 M - \ V 84 >I-\\ 70 P 69 1' 82 I' 100 A I - \ \ H:l 13-N 92 H - 4 9 7 AI-\\70 AI-\\
IIU, OC 240 5-241.5 238-239 2 17-2 18 221-222 215 219.5 221 208-209 222-223 2 15-2 16 186.5-188.5 2008-211 lY4 5-190.5 21+21i
C ' a hJII,
X
Calcd Found 31.38 81 59 :34. .io 3 4 . 1 9 3 7 . 29 37.35 39. 78 39.75 39 78 3 9 . 8 0 42 03 42.26 42.03 41.81 42.0:3 4 2 . 0 2 42.03 42.20 44.07 44.01 44 O i 44.34 44.07 44.02 45.9:3 45 95 37 . 2 9 37 24 3 9 . 78 3 9 . 9 9 42.03 4 2 . 3 1 42.03 42.40 4 4 . 0 7 44.34 42.03 42.00 4 4 . 07 4 4 . 2 5 44.07 4 3 . 9 1 4 5 . 9 3 46.06 4 i . 6 2 47.60 42.33 42 34 46.22 46.55 40.08 40.41 42.33 42.59 4 4 . 3 7 44.51
Hydrogen, 7; Kitrugen, % Calcd Found Calcd Found 3 . 5 1 3 . 4 3 4 2 . 7 0 42.85 4 . 1 4 4 . 2 8 4 0 . 2 4 39.02 4 . 6 9 4 . i 3 38.05 3 8 . 0 5 5.19 5 . 2 8 36.09 3 5 . 8 9 5 . 1 9 5 . 1 3 3 6 . 0 9 35.77 5 . 6 4 5 . 6 5 3 4 . 3 2 33.93 5 . 6 4 5 . 3 1 3 4 . 3 2 :?4.32 5 . 6 4 5 . 6 4 3 4 . 3 2 34.16 5 . 6 4 5 . 5 9 3 4 . 3 2 34.00 6 . 0 5 5 . 8 8 32.70 3 2 . 6 6 6 . 0 5 5 . 8 1 32.70 3 2 . 4 1 6 . 0 5 5 . 9 5 32.70 3 2 . 5 9 6 . 4 2 6.42 3 1 . 2 5 31.03 4 69 1 . 4 9 3 8 . 0 5 3 i . 8 3 5 . 1 9 5 , 1 8 36.09 3 5 . 8 3 5 . 6 4 5.94 34.32 34.40 5 . 6 4 5 . 7 0 a 4 . 3 2 34.05 6 . 0 5 6.08 32.70 32.38 5.64 5 . 5 2 3 4 . 3 2 3 L l 4 6 . 0 5 6 . 0 3 32.70 32.63 6.05 5.82 32.70 32.58 6 . 4 2 6 . 4 9 31.25 31.02 6 . 7 6 6 . i i 29.91 2 9 . 4 4 4 . 9 7 4 . 8 7 3 4 . 5 6 34.11 5 . 8 2 5 . 8 5 31.45 3 1 . 4 1 4 . 4 8 4 . 4 4 36.36 36.07 4 . 9 7 4 92 34.56 34.17 5 . 4 2 5 . 4 3 32.93 32.58
UOCA CliloriIie, l/a inllih Calcd Found scorer 15.44 1 8 . 4 2 +4 14 55 1 4 . 5 6 +3 1 3 . 7 6 13 76 +3 13.05 13 05 +3 133.05 1 2 . 9 7 +3 1 2 . 4 1 12.4T +3 12.41 1 2 . 3 5 +1 12.41 1 2 . 4 0 +1 rt 12.41 1 2 . 2 i 11.83 11.85 +1 1 1 . 8 3 11.75 +1 J 11.83 11.81 * 1 1 . 3 0 11 20 13.76 1 X i 8 +3 1 3 . 0 5 13.15 +4 1 2 . 4 1 12.56 +4 12 41 12.4.5 +4 11.83 11.94 +3 1 2 . 4 1 12.21 +3 11.83 11.82 r:3 11.83 11.68 +:3 +:3 11.30 11.34 A1 10.82 10 93 12.50 1 2 . 7 1 +1 J 11.37 11.18 13 1 5 13.25 +4 12 50 12.38 +:3 11 91 11.84 +3
U.5
AI-\\
92
P-\\'
229-2:30 2 14-2 13 207-208 "8-209 21.5 224-225 2Oi-208 200 5-201.5 2 15-2 17 2-11 5-245 5 221-225 218-214 207-208 208-209
I1
85
H-N
213-212
40.08
40.24
4,48 4.43
36.36
36.34
13.15
13.31
+:3
I1
95
AI-\\
220-521.2
42 33
42.57
4.97
5.14
34.56
34 47
12.50
lL57
+4
H
ti5
.\c-s
219-220
44.37
44.36
5.42
5 54
32.93
33 01
11.91 11.9i
zt
11 11 H H
I 4
11-K
48.83 50.37 16.22 44.08 45.41
48.83 50.16 46.40 44.01 48.20
4 . 4 1 4 . 4 9 30.67 4 . 8 3 4.77 29.38 3 . 8 8 3 . 8 2 29 03 3 . 7 0 3 . 9 5 27.68 4.63 4.71 26.48
30.44 29.31 28.82 25 94
...
42.65
42.80
9.7
-, a-
lf-\Y E-\\
92 .\ 70 .'I Y8 P 84 P 90 H-h49 E 8-I >I-\\
€1
5i 100 96 j7
€1-?i P-\Vc
206-209 216-217 2006-208 225-226 199-202
H
9'2
E
217-218
__
.I
11 H 1-1
. I .\
27.69
...
...
10.62 10.58 10.50 11.40 20.02 20.10
+1 +1 +1 J
...
f
3.91
3.89
31.66
31.37
11.45
11.50
+3
3 0 . 8 3 30.82 2 . 9 1 33.19 3 3 . 5 7 3 . 4 0 30.98 31.40 3 . 9 0 39.93 3 9 . 8 3 5 . 7 0 3 6 . 5 9 3 6 . 5 4 5 12
3.13 3.64 4.30 5.72 5.15
31.46 31.27 30.11 2 9 . 9 2 3 1 . 6 1 31 38 3 7 . 2 6 37.68 24.90 24.34
11.38 10.89 22.86 11 79 9.00
11.26 10.86 22.61 11.65 9 01
$1 +2 +1
Y8 68
282-233 .\ 221-222 5 €ic 272-273 13-S 192.5-194.5 &\I' 223-224
95 95 85 92 74 38
E S-N H-S H-X Hd1f Hd
47.15 42.36 35.11 32.50 34.25 24.40
47.13 3 . 9 6 42.08 3 . 2 6 35.23 4.42 32.85 4 . 2 9 33.91 4.97 24.62 3 . 5 1
4 09 3 48 4 28 4.65 5.08 3.57
32 07 28.8'2 35.83 43.32 29.05 36.58
31.65 1 1 . 6 0 2 8 . 2 3 20.88 36.05 12.95 4 2 . 0 8 13 7 1 2 9 . 4 5 27.58 36.41 30.87
l1.iO 20.32 13.03 13.88 27.09 30.52
ii
65 83
248.5-250.5 276-2i8 203.5-204.5 234 299-300 >340
3
IC2
*
+2 +l 0 0
Isolated a i the hydrochloride The compounds are prepared by method D-1 unless otherwise specified. * See footiiot,e b, Table I. salt. d Isolated as the dihydrochloride salt. e Derived from n-glucamine. f Prepared by method D-2. 0 The DOCA inhibition score is the dose (in micrograms per rat) producing 507; reversal of the DOCA K a / K effect: +4 = 800, 0 = no activity a t 800 pg. Althorigh 110 st>atisticallysignificant activity was noted at the last dohe, the possibility of activity at higher doses exists. Furthermore, most of the compounds which scored zero in this test were active diivetics in the normal rat assay. T h e animals weighed 130 i 3 g ; thus, t'he dose in milligrams per kilogram is approximately 0.008 times the microgram per rat value.
potency of individual nienibers of the series paralleled those recorded in the adrenalectomized rat test. Representative compounds were assayed in these two tests using the oral route of administration and found to be active. By each assay procedure, diuresis and saluresis is noted, while potassiuni ion excretion is either unaffected or repressed. The effevts observed in rats are somewhat more pronounced than in dogs when equivalent closes are used.
Several riienibers of this series have been tested in combination with certain other diuretics and found to produce additive or synergistic effects on saluresis while reversing the kaluresis caused by the ot,her agent. Selected compounds from this series are presently undergoing clinical trial." The observations in humans appear to correlate quite well with the nninial studies. (11) Preliminary reports include: N.W. XIoukheihir and \V. 31. Kirkendall, CZin. Res., 13, 25 (1965); T. B. Reynolds and H . C. Pelle, ibzd., 14, 184 (1966): R . J. Sperber and S. Fisoh, ibid., 14, 262 (1966).
I:,. /'I,
II II
.I
I,
-01,
1.111',
I
\\'
)
II '
I ' \\ I1 s I1 s
IT II I1
I' iI s I1 I' \\', I'
I1 II I1 II
s
II II
I'
I'
II
II
I1
I1
Ii
II ri
I' \\. II s
II
I1
I I" >' 11
II
II
I1
II
II II
I1
I1
II
II
II I'
s
I ' \\ I' I' I1 I) 1) I'
I' .\ I I: I' 1.:
Jaiiuury 19G7
7s
Calcd
1 ound
34.50 30.98 48.83 44.08 44.08 46,23 50. 37 48.07 ::6. 73 40.17 31 .60
34 30 48 44 44 46 50
6.i 56 89 12 2; 34 34 48 0 2 36 i . 5 d!) 9;i 32 Oh
4.14 4.22 4.41 3 . 70 3 . 70 3 . 88 4 83 4.61 3 08 3.11 5.21
4.04 4.51 4.02 3.91 3.95 3.89 4.76 4.69 3.24 3 . 06 5.23
27.68 27, 68 29 . 03 29 :is "8,03 23.07 2 3 . 22 28,1!l
39.91 31.36 30.56 27 18 27.7 3 28. 76 29.0; 27 . 5.5 22.88 24.91 27. SS
55.21
5.5 30
4.36
4.5s
26.51
26,:;s
50.37 50.37
50 22 50 67
4.83 4.83
4 62 4.86
29 :s 29.38
36.61
36 89
3.84
4.12
38.85 30.78 42.03 49.19 45,41 42.03 44, 07 36.57 53.11 44.37
39 30 42 49 45 42 44 36 53 44
05 74 02 01 22 28 35 55 59 50
4.01 4.84 5.64 7.08 4.63 5.64 6.05 ,;.5ti 5 . .57 5.42
46.22
46 40
5.82
Calcd
Fviinil
('aid
40.24 i31.62 30.6i
IC orin11
Calcd
... . . . . .. . . ... ...
l~Ol1lld
... . . .
...
... .. . . . ... ... ...
...
...
...
...
... ...
20 14 29.08
. . ...
...
28.47
28.14
...
...
4.12 5.00 5.45 6.94 4.48 5.53 6.04 5.28 5.31 5.25
24.40 31.41 34.32 28.68 26.48 34.32 32.70 27.15 27.10 32 . 93
24.32 31.41 34.14 28.86 26.16 34.14 :32.62 27.23 26.60 3 2 . 76
6.14
:31.45
31.34
,
...
22.72 12.41 10.37 ...
..
..
2 2 , SS 12.4!) 10,4:;
...
. . . ...
11 s:: ,
11.67
... . . 11 .!I1
... . . I1 S 3
...
. . .
6.42 31.25 45.93 45 95 6.50 30.81 ... 41 97 ,5. 63 34.13 12.41 1 2 .26 5.64 34.32 42.03 44.07 44 17 3 2 . 70 11.83 11.86 5.81 32.73 6.05 45.93 31.06 11.30 31.25 6.36 6.42 45 88 11.09 45,93 46 03 31.14 11.30 11. 3.5 31.25 6.11 6.42 We are indebted to 11r.C. 11.Itobb f u r the preymitioii of this coiiiporiiid. comporind was isolated as the hydrochloride hydrate salt. This comporind was isolated as the hydrochloride hemihydrate salt. See footnote g, Table 111. leum ether (bp 30-60') (300 ml), and dried yielding 888 g of red crystalline Ib, mp 228-230'. The crude prodiict, was diswlved in boiling acetonitrile (56 1.) aiid passed through a heated (708 0 " ) column of decolorizing charcoal (444 g). The coliimn was washed with hot solvent ( 2 5 1.) and the combined eluate was coricent,rated in uacuo (to about 6 1.) and chilled. The J-ield of yellow crystalline Ib was 724 g (66c;C). Additional recrystallizations from acetonitrile gave pure material (See Table 11). Route b.-Uiider anhydrous coiiditions, Ia-2l (9.35 g, (1.05 rnole) was treated dropwise with stirring with SOX12 (10 ml) diiririy a 10-miii period. hfter 4.5 miii, gas was evolved, the mixtiire became red, and heat was evolved. hfter st aiidiiig overnight at room temperatiire, the mixture was heated at i 0 " for 1 hr. The exces S02Cl2 as removed by evaporation at redliced presiire and the residue (11.2 g ) was re acetoiiitrile (300 nil) (iisiii (:3X'C) of Ib. Sribbeqiieiit Route c.--Upon heating and S02C1, (89 ml) for 1 miri o i i a steam bath, a vigorous reactioii occiirred. The reaction vessel was cooled atid then allowed to stand for 20 hr. T h e prodiirt was isolated aiid purified as described for method b to yield 1 g (12('() of piire It). Route d.---The s>.iitheteam b a t h f o r 1.i i r i i t i . wer~ stirred aiid refliixed for 24 t u . The priidiic,t whic,li -;eparalcd After c~~olitig, the prodiict whicah beparated M-:W reriicnml 1)). i i p o i i cwciliiig was removed by filtratioii :tiid dried; yield 1:3.!1 g K l t ratioii, washed with water, dried, and recrystallized. (89( ). Piirifiratiori was efterted hy re( tallizatioti f r o m aceto5. Methyl 3-Amino-5-(2-dimethylaminoethoxy)-6-chlorot ii t riI r. pyrazinecarboxylate (Ic-5).---A solutitiii of I h (11 . I g, 0.0*5 inolc~) I'hiiig aiiiliiie mid aiiiliiir hytlt~c)c.hl~iricie for p-i~~il~ir~iaiiiliti(~ i i i 2-dirnethylamiiioethaiir,l ( 5 5 ml) w:w heated oii a > t w i n 1i:iIli : i i i t l p-c~tiloroaiiiliiiehydrochloride i i i the :tbovr procediire g a v ~ :I for :I5 miii. After caooliiig overriight , 1 he soliitioii wws t l i l i i t c ~ t l 7 I ; yield of Id-43. with water, aiid the protliic~t which 5. Methyl 3-amino-54 l-methyl-2-benzylidenehydrazino)-6- hltratioii, w~tshedwith water, dried, chloropyrazinecarboxylate (Id-48)w a s prepai,ed for the htru(,tiitie 6 . Methyl 3-Amino-5-mercapto-6 proof of I d 4 i . Compound Id-47 (100 m g ) was diisolved i t i .k inistiire (Jf sodium sulfide rionahydrate (9.6 g, 0.4 mole), r u l f i i t . wai'rii c:thanol ( 2 nil), benzaldehyde ( 2 drops) was added, aiid t h e 1 IO g), and ahsolute ethaiiol (80 ml) was refluxed for :$I)miii : i i t t l ~ i i l u t i o i iwas cooled. The cryutals that r;ep:trated were removed viitiled t i l 2 5 " . After the addition of Tb (8.0 g, 0.04 r i i o k ) , t l r i ~ ]],I, filtratioii, washed with water, and dried. iolutioii was -tiired :it 25' for 1 hr, filtered, anti :iciilified wilii C . Methyl 3-Amino-5- (and 5,6-di-) substituted Pyrazine:ice1 ic :wid. The prodiic.t that separal ed was reniiivt~l 11). carboxylates (Table 11). 1. Methyl 3-Amino-5-methylthio-6tiltretioii aiid piiritiecl ti>- disiolviiig i i i S:tOIf wliilioii :iiid I i i v chloropyrazinecarboxylate (IC-1).- A sohit i o r i of methyl merr:rpc,ipitatiiig with :wetic*avid. t w i i10 g, 0.18 mole) i r i 80':; aqueous ?r'aC)I-I (17 ml) and meth7. Methyl 3-Amino-5-methylsul~nyl-6-chloropyrazinecar:triol ( IO0 nil) w:ts added during 10 miii to B boiling mixtu1.e of boxylate (Ie-1 ).-A mixtui,e of Iv-I ( 2 3 . I I J i 17.7 g, 0.08 molr) and methaiiol t 1 1.). The mistiire \v:i:qiieoiis H y 0 2(:35 r i d ) , m i d wetic acid (300 refhiset1 for air additiuiial 15 miii aiid c.ided, and the prc1diic.t hr at room teinperatiire. T h e solid then 1 1 I2 g ) u-:is-eparated by filtration, dried, and recrystallized. lioii, wadled with acetic acid, dried, :tiid rec 2. Methyl 3-Amino-5-methoxy-6-chloropyrazinecarboxylate 8. Methyl 3-Amino-5-mesyl-6-chloro [Ic-2).--A boiling solution of Ih ( 1 . 1 g, 0.00:Z mole) in anhydrou(Ie-z).---A suspen-ion of IC-1 (7.0 g, 0 , 0 : 3 mole) iii wetic. :tiid inel h:iiiol (200 ml) was treated wit,h a. whitio~iof sodiiim methi!)O nil) aiid ;30('; aqiieoiifi H,O9 ( 1 0 inl) was .stirreti a t t ~ i ~ i i i i i iixitie prepared from N a ( 1 I5 nig. O.Oli5 g-atcmi) i i i aiihydroiis I I I o ? ( 2 nil) w w atided, trrnprrat iiw. A f t w O!I lir, more :+I)( riwthaiiol (20 t i l l ) . The pridiic.t, iI g ) whii.li srparated II~JIJII :iiiiI stirriiig wits i v i t i t i i t i i t d for :t t i l t s 1 reactioir time i d 160 hi,. i,tiolitig w a s rem(ived 1)y filtratioir. 1)y fiitriilioii, wwlieil witlt ;i(,etii>i i i * i ( l , riwt h:tiiol, :tiit1 fiiially dried arid rei 3. Ethyl 3-Amino-5-ethoxy-6-chloropyrazinecarboxylate 5-hydroxy-6-chloropyrazinoate [ IO. .I f IC-3).. - A I~oilitig~ s . o l u t i c ~ iof i 11) (2.2 g, 0.01 mole) i i i :thsolutc iiiisiiitx of Ie-1 i7.3 g, 0.O;l mole), : i i . c s t i(* :wid i i 5 rnl ), : i i i t i \v:~lcsr c,tli:itiol ('LOO nil) w i i b treated \\ ith :I Sa(.)C2H6w l i i t i o i i prep:iretl f I2 r i l l I \v:i\ licwted o i i :I stc':itn h a t l i f r i t , :; Iir. Thc, pi,iicliic,t grad-
i d l y crystallized froin the reaction R l k l lire diiriiig the heat iiig period arid continued after roolirig. This material was separated by filtration, dried, and recrystallized. Attempts to convert I b t o If by heating with XaOH soliitioiih led to the formation of T-a or 1%depending iipon the reaction conditions. Esterification of \ %to If was unsuccessfiil. 10. 3-Amino-5,6-dichloropyrazinecarboxylic Acid (Va).Compound I b (1.8 g, 0.0081 mole) was refluxed with a solutioii of YaOH (645 mg, 0.324 mole) iii water (120 ml) for 10 miii. The oliitioii was filtered and acidified with HC1 ttr give 1.5 g ) of \-a, mp 228.5" dec. a / . Calcd for C5H3C12h',02: C, 28.87; H, 1.44; C1, 34.09~ Foiiiid: C, 29.30: H, 1.65: C1, 33.44. 11. 3-Amino-5-hydroxy-6-chloropyrazinecarboxylicAcid (Vb). -A mixture of I b (4.0 g, 0.018 mole) aiid 5cL XaOH d i t i o i i (55 ml, 0.688 mole) Wac: stirred aiid heated on a steam bath for 2.5 hr. The resiiltiiig ~oliifi(iiiwas cooled and acidified wiih HC1. The precipitate was removed by filtratioii, wahhed with water, dried, aiid recrystallized twice from aqueous ethanol to give 400 mg (127;) of 1-b,mp 210' dec. .lna/. Calcd for C5H4C1N30a: C, 31.68; H, 2.13; X, 22.17. Foulid: C, 31.64; H, 2.22: N, 22.27. 12. Methyl 3,5-Diaminopyrazinecarboxylate(Ig-l).-A mixture of Id-1 (14.2 g, 0.07 mole), Pd-C catalyst (9 g), 1 l g O (4.0 g, 0.1 mole), and methanol ( 2 5 0 ml) was shaken iii air atmosphere of hydrogel1 for 18 hr at room temperature a t ail initial pressiire of 2.1 kg/cm2. The pressiire drop indicated an absorption of 0.07 mole of hydrogen. The mixtiire was filtered, and the solids were extracted with a boiliiig soliitioii of 2-propaiiol ( 5 0 0 ml) and water (250 ml). The methanol filtrate and the 2-propaiiol-water extract were Iiiiited and coiiceiitrated to a volume of 100 ml and cooled. The product whirh precipitated weighed 10 g (85%) and was purified by recrystallization. Four other esters, Ig-2,3,4,5, were prepared by a procedure similar to Ig-1 above, whereiii the appropriate ester was siibstitiited for Id-1; the data are recorded iii Table 11. 13. Methyl 3,5-Diamino-6-bromopyrazinecarboxylate (Ih-1). -A solution of bromine (2.1 g, 0.013 mole) i i i acetic acid (10 ml) was added to a suspension of Ig-1 (2.0 g, 0.012 mole) iii acetic acid (25 ml) at 50". The mixtiire was stirred for 10 miri at room temperatiire and the crystalliiie product that separated was collected on afilter. After recrystallization, the yield wad 1.2 g ( 4 1 5 ) . 14. Methyl 3,5-Diamino-6-iodopyrazinecarboxylate (Ih-2).A susperisiori of Ig-1 (1.7 g., 0.01 mole) in water (30 ml) was heated to i o " , then mercuric acetate ( 3 . 2 g, 0.01 mole) aiid a solution of iodine (2.5 g, 0.01 mole) in warm dioxane (20 ml) were added quickly. The mixture was stirred and heated on a steam bath for 5 min, then allowed to cool to room temperature aiid treated with an ayiieoiis solution of K I (50 ml of K I ) . The red soliitioii qiiickly depohited a cr which was separated by filtration, dried, and re D. N-Amidino-3-amino-5-substitutedPyrazinecarboxamides. Route a. 1. N-Amidino-3-amino-5-dimethylamino-6-chloropyrazinecarboxamide (IIa-l4).--Urider aiihydrou.; conditions, ;l'a ( 5 . 7 5 g, 0.25 g-atom) was dissolved in dry methanol (150 ml) and
Ss
the resultiiig wlutiuii was treated with dry guittiidiiie hydi.0chloride (26.3 g, 0.275 inole) and stirred for 10 mill. The NaCl which formed was removed by filtration under anhydroiis coiiditioris and the filtrate was concentrated in mcuo to 30 ml. The residue was treated with Id-14 (11.5 g, 0.05 mole), heated for 1 min on a steam bath, and then kept at room temperatiire for 1 hr. The product that separated was removed by filtration aiid washed well with water. This material was siispended in water dissolved by the additioii of a little HCI aiid precipitated by the additioii of dilute S a O H solution. After filtration atid washing with nater, the product was dried; mp 216-217'. B y sitbstitutiiig the appropriate ester for Id-14 and the desired giianidiiie hydrochloride for guanidine hydrochloride it>elf, the above method was used for the syiithesis of each of the compoiiiids which appear in Tables III-\-. With methylguanidine and dimethylgiiaiiidiiie, the siilfate salts were iised instead of the hydrochlorides. These required heating with rodiiim methoxide iii methanol for 4,5 mill to assure complete coiiversiou to the free giianidiiie. 111some cases it, was coiiveriieiit to i d a t e the prodiicts as the hydrochloride salts using a procedure analogous t o the following w e . 2. N-Amidino-3-amino-5-dimethylamino-6-chloropyrazinecarboxamide Hydrochloride.-A suspension of IIa-14 (2.0 g, 0.0775 mole) iri water (70 ml) was treated with sufficient HC1 t o effect solution. After filtration, coiiceiitrated HC1 ( 5 ml) v-ah added to the filtrate and the crystalline product which separated was removed by filtration and dried, yield 2 . 2 g (Sic;). ltecrystallization from a mixture of water (50 ml) and concentrated HC1 ( 3 ml) gave piire material, mp 298' dec. -4na2. Calcd for CsH,,ClrX;iO: C, 32.66: H, 4 . 4 j ; 33.33: C1, 24.11. Found: C, 33.03; H, 4.43: S , 33.10: CI, 23.M. Route b. Step 1. N-Amidino-3-amino-5,6-dichloropyrazinecarboxamide Hydrochloride (IIc-82).--Sodium (920 mg, 0.04 g-atom) was dissolved in %propanol (50 ml) under anhydrous conditions, giianidiiie hydrochloride was added (3.85 g, 0.04 mole) and, after stirring for 30 miii, the mixture wab filtered. To the filtrate was added I b (4.44g, 0 . 0 2 mole), arid the mixtiire was refluxed for 15 min and then cooled to 10". The solid that' ueparated was removed by filtration, dried, and recrystallized from a mixture of water (50 ml) and 6 HC1 ( 3 ml). Step 2. N-Amidino-3-amino-5-dimethylamino-6-chloropyrazinecarb0xamide.-To a solution of IIc-82 (100 mg) iii D1IF (,3 ml) v-aa added 2 5 7 aqueous dimethylamilie ( 1 ml). The mixtiire was heated for 1 hr on a steam bath and then diluted with water (25 ml). The product that separated was removed by filtration and purified by reprecipitation: mp 216-217". 3. N-Amidino-3-amino-5-guanidino-6-chloropyrazinecarboxamide Dihydrochloride (IIa-48).-.4 solutioii of guaiiiditie i t i 2propanol was prepared by dissolving sodium (2.3 g, 0.1 g-atom) in 2-propaiiol (80 ml) aiid adding giianidirie hydrochloride (9.6 g, 0.1 mole). Compoiind IC-5 (4.7 g, 0.017 mole) was added and the mixtiire was refluxed for 30 miii. After c(io1iiig iii ice, the prodiirt was separated by filtration aiid converted to the hydrochloride by recrj-stallizatioii froin diliite HC1. Similar results were ohtaiiied when IC-5was replaced by IC-4.
