SUMMARY AND BACKGROUND OF THE INVENTION
[0001] This invention relates to a novel process for preparing N-amidino-3,5-diamino-6-substituted-2-pyrazinecarboxamide
particularly the N-amidino-3,5-diamino-6-chloro-2-pyrazinecarboxamide which is commercially
known as amiloride. Also included are several novel N-amidino-3,5-diamino-6-substituted-2-pyrazinecarboxamides.
These compounds are useful because they possess diuretic and naturetic properties.
They differ from most of the known, effective diuretic agents, however, in that the
compounds of this invention selectively enhance the excretion of sodium ions without
causing an increase in excretion of potassium ions. The potassium loss, which is caused
by known diuretics, often results in a severe muscular weakness. Since the compounds
of this invention are essentially free of this potassium depletion, they have this
decided advantage as diuretics. As diuretic agents, they can be used for the treatment
of edema, hypertension and other diseases known to be responsive to this therapy.
[0002] In some instances it may be desirable to make a salt of these compounds, using a
pharmaceutically acceptable acid, and these salts are to be considered as included
in this invention and in the scope of the claims.
[0003] The products of this invention can be administered to man or animals in the form
of pills, tablets, capsules, elixirs, injectable preparations and the like and can
comprise one or more of the compounds of this invention as the only essential active
ingredient of the pharmaceutical formulation or, as mentioned above, the novel compound(s)
can be combined in pharmaceutical formulations with other diuretic agents or, indeed,
other therapeutic agents.
[0004] The compounds of this invention are advantageously administered at a dosage range
of from about 5 mg./day to about 750 mg./day or at a somewhat higher or lower dosage
at the physician's discretion, preferably in subdivided amounts on a 2 to 4 times
a day regimen.
[0005] Particular compounds which can be prepared according to the process of this invention
are shown below in Formula I.

wherein X is Cl (this would be amiloride), CN, CH
3S, CP
3S or C
6H5S.
[0006] The novel process used to prepare these compounds is depicted in the following flow
sheet:

[0007] Generally the process shown as going from compound IV to II to I concerns the reaction
of N-amidino-5-diamino-6-iodo (or 6-bromo)-2-pyrazine- carboxamide shown in Formula
II and being described in the prior art particularly U.S. Patent 3,318,813 with Cu
X salts wherein X is as previously defined.
[0008] This reaction can be run in a solvent, particularly an inert organic solvent and
preferably hexamethylphosphonamide or dimethylformamide. The reaction temperature
is not critical and the resction can be run at anywhere from 25 - 100°C. The length
of time the reaction is carried out is ist not with and either and can be run anywhere
from

Isolation of the reaction product which is N-amidino-3,5-diamino-6-X-2-pyrazinecarboxamide
from the reaction mixture is performed by methods known in the art such as by adding
crushed ice and water to the reaction mixture to precipitate the desired product.
[0009] An alternative route to the compounds of this invention involves the reaction of
CuX wherein X is as defined above with lower alkyl (methyl)-3,5-diamino-6-iodo-(or
bromo)-pyrazinoate which in turn under similar reaction conditions as discussed for
the first reaction above will provide lower alkyl-3,5-diamino-6-substituted pyrazinoate.
This is shown in the above flow sheet as a reaction of IV to III. Compound IV is known
from the literature particularly U. S. Patent 3,313,813. The lower alkyl 3,5-diamino-6-X-pyrazinoate
(Compound III) can then be reacted with guanidine to yield the desired product Compound
I. This latter reaction is preferably carried out under anhydrous conditions with
or without a solvent such as methanol, ethanol, isopropyl alcohol or other solvents.
The reaction may be carried out at room temperature or by heating on a steam bath
for 1 minute to 2 hours or longer. The desired product usually is recovered from the
cooled reaction mixture by trituration with water. Purification frequently is carried
out by converting the product to a salt which can be recrystallized or the base can
be regenerated by addition of aqueous alkali.
[0010] The following examples illustrate but do not limit the preparation of the various
compositions of the invention.
EXAMPLE I
Preparation of N-Amidino-3,5-diamino-6-cyano-2-pyrazinecarboxamide
[0011] N-Amidino-3,5-diamino-6-iodo-2-pyrazine- carboxamide hydrochloride (3.50 g., 0.01
mole), cuprous cyanide (2.15 g., 0.024 mole) and hexamethylphosphoramide (30 ml.)
are combined and heated at 100°C. for 15 minutes. After cooling to ambient temperature
the reaction mixture is added to aqueous sodium cyanide solution (100 ml.), stirred
at 25°C. for 1/2 hour and the solid precipitate is collected by suction filtration,
washed with water, then chloroform. On dissolving the product in boiling water (50
ml.), treating with 6N HC1 and cooling one obtains 1.43 g. of N-amidino-3,5-diamino-6-cyano-?-
pyrazinecarboxamide, m.p. > 350°C.
Elemental analysis for C
7H
8N
8O.HCl·1/2 H
20:
Calc.: C, 31.65; H, 3.79; N, 42.18; Cl, 13.35;
Found: C, 31.36; H, 3.58; N, 41.26; Cl, 13 29.
EXAMPLE 2
Preparation of Methyl 3,5-diamino-6-cyano-2-pyrazinoate hemihydrate
[0012] Methyl 3,5-diamino-6-iodo-2-pyrazinoate (370 mg., 0.0012 mole), cuprous cyanide (215
mg., 0.0024 mole) and hexamethylphosphoramide (10 ml.) are combined and heated at
100°C. for 15 minutes. After cooling to 25°C. the reaction mixture is added to aqueous
sodium cyanide solution, stirred at 25°C. for 1 hour and extracted with CHC1
3. The CHC1
3 layer was washed with dilute NaCN solution, then with H
20, and dried (MgSO
4). After evaporation of the CHCl
3, the residual oil was treated with hexane to give 75 mg. of methyl 3,5-diamino-6-cyano-2-pyrazinoate
hemihydrate melting at 2
Elemental analysis for C
7H
7N
5O
2· 1/
2 H
2O;
Calc.: C, 41.59; H, 3.99; N, 34.64:
Found: C, 42.81, H, 3.99; N, 34.09.
EXAMPLE 3
Preparation of N-Amidino-3,5-diamino-6-trifluoro- methylthio-2-pyrazinecarboxamide
Step A.: Methyl 3,5-diamino-6-trifluoromethyl- thio-2-pyrazinoate
[0013] Methyl 3,5-diamino-6-iodo-2-pyrazinoate (3.70 g., 0.0012 mole), cuprous trifluoromethylmer-
captide (5.0 g., 0.0025 mole) and hexamethylphosphoramide (100 ml.) are combined and
heated at 100°C. for 15 minutes. The reaction mixture is added to crushed ice - H
20 and extracted with CHCl
3, the CHC1
3 layer washed with water, dried (MgSO
4) then concentrated to give an amber oil. The oil is dissolved in ether, extracted
several times with H
2O, dried (MgS0
4) then concentrated to an oil which solidifies on trituration with butyl chloride
to give 1.26 g.
' of methyl 3,5-diamino-6-trifluoromethylthio-2-pyrazinoate, m.p. 151-5°C.
Elemental analysis for C
7H
7F
3N
4O
2S:
Calc.: C, 31.35; H, 2.63; N, 20.89; S, 11.95;
Found: C, 31.04; H, 2.67; N, 19.65; S, 11.95.
Step B.: N-Amidino-3,5-diamino-6-trifluoro- methylthio-2-pyrazinecarboxamide hydrate
[0014] Guanidine hydrochloride (3.34 g., 0.035 mole) is added to a solution of sodium methoxide
(1.67 g., 0.032 mole) in methanol (20 ml.) with stirring at 25°C. After 15 minutes,
methyl 3,5-di- amino-6-trifluoromethylthio-2-pyrazinoate (1.85 g., 0.007 mole) is
added, and the mixture is heated on a steam bath for 15 min. Crushed ice- H
2O (20 ml.) is added to the reaction mixture to precipitate 390 mg. of N-amidino-3,5-diamino-6-trifluoromethylthio-2-pyrazinecarboxamide,
m.p. 195°C.
Elemental analysis for C
7H
8F
3N
7OS· H20;
Calc.: C, 26.84; H, 3.22; F, 18.19;
Found: C, 27.09; H, 3.18; F, 17.49.
EXAMPLE 4
Step A.: Methyl 3.5-diamino-6-trifluoromethyl- thio-2-pyrazinoate
[0015] Methyl 3,5-diamino-6-trifluoromethylthio-2-pyrazinoate is prepared from methyl 3,5-diamino-6-iodo-2-pyrazinoate
following essentially the same procedure described in Example 3, Step A except that
dimethylformamide is used as the solvent.
EXAMPLE 5
Step A.: Methyl 3,5-diamino-6-trifluoromethyl- thio-2-pyrazinoate
[0016] Methyl 3,5-diamino-6-trifluaromethylthio-2-pyrazinoate is prepared from methyl 3,5-diamino-6-iodo-2-pyrazinate
following essentially the same procedure described in Example 3, Step A except that
bis(trifluoromethylthio)-mercury and copper are used to generate cuprous trifluoromethylthiomercaptide
in situ.
EXAMPLE 6
Step A.: N-Amidino-3,5-diamino-6-trifluoro- methylthio-2-pyrazinecarboxamide
[0017] N-Amidino-3,5-diamino-6-trifluoromethyl- thio-2-pyrazinecarboxamide is prepared from
N-amidino-3,5-diamino-6-iodo-2-pyrazinecarboxamide hydrochloride by essentially the
same procedure described in Example 1 using trifluoromethylthio- copper in place of
cuprous cyanide.
EXAMPLE 7
Preparation of N-Amidino-3,5-diamino-6-methylthio-2-pyrazinecarboxamidehydrochloridehydrate
Step A.: Methyl 3,5-diamino-6-methylthio- pyrazinoate
[0018] A solution of methyl 3,5-diamino-6-iodo- pyrazinoate (14 g., 0.048 mole)and cuprous
methyl- mercaptide (12 g., 0.108 mole) in hexamethylphosphoramide (100 ml.) is heated
on a steam bath with stirring for 1-1/2 hours, poured into ice water (0.5 1) extracted
with chloroform, washed with water, dried over MgSo
4 and evaporated at reduced pressure. Treatment of the residue with hexane gives 2.0
g. of methyl 3,5-diamino-6-methylthiopyrazinoate which melts at 158-60°C. after purification
by chromatography on silica gel; eluent 50% benzene-ethyl acetate.
Elemental analysis for C
7H
10N
4O
2S:
Calc.: C, 39.25; H, 4.70; N, 26.16;
Found: C, 40.16; H, 4.93; N, 26.58.
Step B.: N-Amidino-3,5-diamino-6-methylthio--2-pyrazinecarboxamide hydrochloride hydrate
[0019] Guanidine hydrochloride (1.5 g., 0.016 mole) is added to a solution of sodium methoxide
(0.75 g., 0.014 mole) in methanol (25 ml.), stirred for five minutes and filtered
free of sodium chloride. The guanidine solution is evaporated to 5 ml. then treated
with methyl 3,5-diamino-6-methylthiopyrazinoate (0.6 g., 0.0028 mole) heated on a
steam bath for five minutes, treated with water (10 ml.) and acidified with hydrochloric
acid to give 0.6 g. of N-amidino-3,5-diamino-6-methylthio-2-pyrazinecarboxamide hydrochloride
hydrate which melts at 170°C.
Elemental analysis for C
7H
11N
7OS·HCl·H
2O:
Calc.: C, 28.42; H, 4.77; N, 33.15; Cl, 11.98;
Found: C, 28.62; H, 4.44; N, 32.91; Cl, 12.11.
EXAMPLE 8
Preparation of N-Amidino-3,5-diamino-6-phenylthio-2-pyrazinecarboxamide hemihydrate
Step A.: Methyl 3,5-diamino-6-phenylthio- pyrazinoate
[0020] A mixture of methyl 3,5-diamino-6-iodo- pyrazinoate (3.5 g., 0.012 mole) and cuprous
phenyl- mercaptide (2.3 g., 0.013 mole) in hexamethylphosphoramide (18 ml.) is heated
on a steam bath for ten minutes and filtered. The filtrate is poured into 300 ml.
of water, and the methyl 3,5-diamino-6-phenyl- thiopyrazinoate which separates melts
at 210°C. after recrystallization from 2-propanol.
Elemental analysis for C
12H
12N
4O
2S:
Calc.: N, 20.28; H, 4'.38;
Found: N, 20.17; H, 4.40
Step B.: N-Amidino-3,5-diamino-6-phenylthio-2-pyrazinecarboxamide hemihydrate
[0021] Guanidine hydrochloride (5.2 g., 0.055 mole) is added to a solution of sodium methoxide
(2.7 g., 0.50 mole) in methanol (40 ml) stirred for five minutes and filtered free
of sodium chloride. The guanidine solution is evaporated to a volume of 20 ml. then
treated with methyl 3,5-diamino-6-phenylthio- pyrazinoate (2.5 g., 0.009 mole), heated
on a steam bath for ten minutes then poured into water (200 al.) to give 2.2 g. N-amidino-3,5-diamino-6-phenyl-
thio-2-pyrazinecarboxamide hemihydrate which melts at 238°C. after being washed with
methanol. Elemental analysis for C
12H
13N
7OS·1/2
H20:
Calc.: C, 46.14; H, 4.52; N, 31.39;
Found: C, 46.15; H, 4.59; N, 31.41.
EXAMPLE 9
Preparation of N-Amidino-3,5-diamino-6-chloro-2-pyrazinecarboxamide
[0022] N-Amidino-3,5-diamino-6-iodo-2-pyrazine carboxamide (1.61 g., 0.005 mole), cuprous
chloride (1.19 g., 0.012 mole) and hexamethylphosphoramide (15 ml.) are heated at
100°C for 10 minutes. The mixture is cooled to 25°C. then added to aqueous sodium
cyanide solution and extracted with CHC1
3. On evaporating the CHCl
3 and triturating the oily residue with hexane there is obtained N-amidino-3,5-diamino-6-chloro-2-pyrazinecarboxamide,
m.p. 241°C.
Elemental analysis for C
6H
8ClN
7O;
Calc.: C, 31.38; H, 3.51; N, 42.70; Cl, 15.44;
Found: C, 31.59; H, 3.43; N, 42.85; Cl, 15.42.