Pyrazine Diuretics. 111. 5- and 6-Alky1, -Cycloalkyl, and -Aryl Derivatives of N-Arniclino-3-aminopyrazinecarboxaniide~
I I I the evalLmtioii a h diuretivs of the N-amiclirin-:~-:iriiitrv~~raaitiec:t~t~o~aiiiid~~, :t series i l f 5- :tiid ti-alkyl, -rycloalkyl, and -aryl derivatives KVRSsyrthesized ailti stitdied for effects on renal electrolytr esc*retioti. Several rompoilrids reverse the electmlyte exc.ret>ioiieffect,.. (Jf deoxq-corticosterone acet,ate in the xdreiialectornized r a t , the most highly active heiiig T - ~ i i i i t l i i i o - ~ ' , - ~ i r 1 i i 1 i r ~ - 6 - i i i e t h ~ l ~ ~ r ~ z i ~ i e ~ ~ ~ r ~ i ~ ~ ~ ~ ~ 1 n i d ~ .
An extensive program of syiithc of S-:miidino-:3:tniinopyrazinet.arboxnmidcs ha> b i (wried out iu these lnboratories since the discio\.ery that cw,taiii roim pounds of this class po tluwtic and aiiti1;:iliuret ic activity in animals ar i.1s2 'l7iis papw is coiicwned with the syiith d diuretic actiyity of Saniidino-;3-aniiiiopy.raxiIlec.arboxamides Ivit'h alkyl; vyc~loall;yl,or aryl substituents at t'he 5 aiid ti positions of the Ijyrazine ring arid with s c ~ c r a lof their halogeiiated derivatives (11).
I
OH
111
VI
I1
Chemistry. --The substitutcd S-amidino-3-aminopyrazinecarboxamides (11) were prepared by the reaction of substituted niethyl 3-aniinopgraxinecarboxylates (I) (Table I) with guanidine and are listed i l l Table 11.
C'ompd no. 2ch 3r 4cc
7c 8c IOC
llr 12c 13cd
14c
15c 18c
RI H H II CHI CoHa CzHa c-CaHa
tonvt. (11')
1% erc' -tartiiig materials for both syiithctic routes. -\lethod A , that of Weijlard, et d.,' ~iivolvc~l the reaction of IV with 4,5-diaminouracil followed by alkaline liydrolysi- of the resulting lurnazines (I7) llethod B, devised by Tog1 and coiisistetl of the reaction of 11' I\ ith anii~ionialoiiuriiidamidirie followed by alknliiie hydrolysis of the resulting 8-ainirio-
It 2 CIIa C-CGfIII
C'dIs c16115 C " d
11 €1
c-CsI€ll
II
CBH6 p-CICsII4
If I€
H
Far -(CHz)4-
a A, water; B, acetonitrile, E. King and P. C. Spensley, J .
The key intermediates for t h e syiit,hesis of the csters (I) were the substituted 3-miinopyrazinecarboxylic. acids (111) prepared by either of the two methods illustrated in Chart 1. Substituted glyoxals or a-dike-
~iyr~ziriec.nrl-,ox:~niidFs ( V l ) . A c~onvcnicnt >yiltIicsi> of i~riiiriomaloiiniiiiduiiiidiiie dihydrochloride" iiivolviiig
(1) J. B. Bicking, J. W. hIason, 0. 1V. !\-oltersdorf, J r , , .I. IF. Jones, S . I ' Kwong, C. M. Robb, and E. ,J. Cragoe, J r . , .I. M e d . Cham., 8, 638 (1965). (2) E. J. Cragoe, Jr., 0. \V. M-oliersdnvf, ,Jr., .I. 13, Rirkinir, S. I-. l i n < , ~ ~ i r . and J. 11. Jones, Ibzd.. 10, 66 f l Q 6 7 ) .
I S ) .i. \\eijiariI AI. ' I ' ~ l ~ l e -and r , '1. 1:. t:rickson, . f . A l f l z . (.'t'PNl. , i o # ' . 67, E 0 2 [ICl~Li). 1 4 8 0. Vu-I and 1:. ( ' , 'i'a>lor, ! l > i d . , 81, 2,172 (t!I:i'~lJ, 1.i) I:. sila,, allli I ) . \\.cjc)iic-y, J . 181,8!1 ~ I : I ~ < , I
catalytic hydrogtmlly
\v.
of p1ieiiylasomsloii:tniidami-
r ~ u ., ~ , ,
July 1967
U
PYRAZINE DIURETICS.I11
599
16a
PYRAZINE DIURETICS.111
July 1967
601
HzO (3.66 1.) with 269 g of 57; Pt,-C catalyst was hydrogenated dose of each compound which will produce a 50% rea t room temperature under ail initial pressure of 2.5 kg/cm2 of versal of the electrolyte effects of a 12-pg dose of DOCA hydrogen. The theoretical 4.38 moles of hydrogen was absorbed has been codified and the score is listed in Table 11. in 6 hr. The catalyst, was removed by filtrat,ion, the filtrat,e The only highly active (+2) compound of this series was extracted with five 2-1. portions of ether, and the aqueous is N-amidino-3-aniino-6-methylpyrazinecarboxamide solutioii m s coiicentrated by distillation at, 2-4 mm to 300 ml. Concentrated IlCl (32.7 nil) and then isopropyl alcohol (2.92 1.) (sa), which is equipotent with the analogous 6-bromo were added to cause the product to precipitate as an oil which compound' but less active than the 6-chloro analog' soon crystallized. There was ohtailled 275 g (66%) of product, (+ 3). The strong dependence of DOC4 inhibitory mp 217" dec. activity on structure is seen in the marked reduction in 3-Amino-6-ethylpyrazinecarboxamide(loa).--Aminomalonamidaniidiiie dihydrochloride (52.5 gj 0.28 mule) was added to a activity when the methyl group of 9d is replaced by solution of ethylglyuxal (28.5 g, 0.335 mule) in I 1 2 0 (450 ml) at hydrogen or ethyl or shifted to the 5 position of the 5'. Coiiceiitrated SH1011 (65 nil) was added to make the solupyrazine ring. tion basic. After 20 hr a t So,the precipitated product was Substitution of the 5 position of 9d or of the analcollected aiid recrystallized from isopropyl alcohol to obtain 17.5 g (38%) of loa, rnp 160-167'. A mnple recrystallized ogous &bromo compound with methyl (to give 6d and from isopropyl alcohol has mp 165.5-16S.5°. 19d, respectively) reduced inhibitory activity markedly.
i\i-Aniidino-3-amiIio-6-phenylpyrazirlecarboxamide (13d) is less active than 9d but is still approximately equipotent with the DOCA antagonist spiro~iolactone.'~ Here again, a shift of the phenyl group to the 5 position reduced activity. Substitution of the 6 position of 9d with diniethylamino (to give 23d) reduced activity. In contrast, a similar substitution in the S-amidino-3-aniino-6-halopyrazinecarboxamide series enhanced DOC4 inhibitory activity .
Experimental 7-Cyelohexyllumazine (3a).-Cyclohexylglyoxal
hemihydrate (14.9 g, 0.1 mole) was added to a suspension of 5,6-diaminouracil hydrochloride (17.9 g, 0.1 mole) in 250 ml of HzO and the mixture was stirred and heated 1 hr a t 100". The solid precipitate obt,aiiied upoii cooliiig was collected, dissolved in hot dilute SaOH, and reprecipitated by acidification of the solution with IICI. Itecrystallizatioil from aqueous acetic acid gave 7.5 g (30'; ) of product, mp 217-227". A sample recrystallized from aqueous acetic acid had mp 229-231". *lnal. Calcd for ClJ-T,,NzOz: C, 58.52; H, 5.73; N, 22.75. Foiuid: C, 58.59; 11, 5.52;N, 23.02. 6-(or 7-)Methyl-7-(or 6-)phenyllumazine (7a)and 6- (or 7-) Phenyl-7- (or 6-) methyllumazine (Sa).-A mixture of 4,5dianiiiiouracil hydrochloride (103.6 g, 0.58 mole), l-pheiiyl-1,2propaiiedione (103.7 g, 0.7 mole), HzO (1500 ml), and concentrated NH,OII (300 ml) was st,irred and heated 1 hr a t 90". The mixture then was cooled arid neutralized with acetic acid to precipitate a yellow solid, mp 202-223" dec. Recrystallization from acetic acid gave a crop of crystals, mp 276-279' dec. The filtrate on standing yielded a second crop, mp 250-253'. liecrystallization of the high-melting product from acetic acid gave 82.4 g (5653) of crystalline product, mp 281.5-282.5" dec, desienated as 7a. Anal. Calcd for C13HloN402: C, 61.41; H, 3.96; S, 22.04. Found: C, 61.78; H, 3.91; N , 22.08. Recrystallization of the'low-melting product from acetic acid gave 32 g (22%) of crystals, mp 254.5-255.8' dec, designated as
Sa. rlnal. Calcd for C13H10N402: C, 61.41; 1-1,3.96; N,22.04. Found: C, 61.79; H, 4.09; N, 22.14. 6,7,8,9-Tetrahydroalloxazine (lSa).-5,6-I>iaminouracil hydrochloride (76 g, 0.428 mole), 1,2-cyclohexanedione (57 g, 0.51 mole), and NaI1C03 (57 g, 0.68 mole) were added to water (2 l.), and the solutio11 was heat,ed 0.5 hr oii a steam bath. The solution wab cooled, filtered, and adjusted to p H 2 by addition of 5 5 , HC1. The precipitated product weighed 104 g (go%), mp 329.5-330.5'. A sample recrystallized from aqueous ethanol had mp 331.5-332.5$. Bnal. Calcd for C I O H , ~ N ~ OC,~ :55.04; H, 4.62; N, 25.68. Found: C, 55.29; H, 4.70, N, 25.58. Aminomalonamidamidine Dihydrocb1oride.-Phenylazomalonamidamidine hydrochloride6 (530 g, 2.19 moles) suspended in -
(13) C. M. Kagawa, Endocrinology, 67, 126 (1960). ( 1 4 ) Melting points were taken in open capillary tubes and are corrected. (15) Xcroanalytical d a t a were obtained by Rlr. K. B. Streeter, Mr. Y . C. Lee. a n d their staff.
dnal. Calcd for C?H,,?;,O: S , 33.72. Fiiruid: Y , 33.83. 3-Amino.6-cyelopropylpyrazinecarboxamide (lla) was prepared analogously from cyclopropylglyoxal i i i 337; yield and has mp 185.5-187.5" (from isopropyl alcohol). Anal. Calcd for CsHloN40: C, 53.92; 11, 5.66. Found: C, 53.83; H, 5.43. 3-Amino-6-cyclohexylpyrazinecarbo~amide (12a)was prepared analogously from cyclohexylglyoxal hemihydrate in 27%, yield and has mp 185.5-187' (from ethanol). Anal. Calcd for C1lHl6S40: C, 59.98; IT, 7 . 3 2 ; N, 25.44. Found: C, 60.07; H, 7 . 3 : ) :S, 25.22. 3-Amino-6-p-chlorophenylpyrazinecarb0~amide (14a)was prepared analogously from p-chlorophenylglyoxal mollohydrate in 38% yield and has mp 246.5-24S.5' (from 95
