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EP0000200A1 - New N-amidino-3,5-diamino-6-substituted-2-pyrazinecarboxamides and process for preparing same - Google Patents

New N-amidino-3,5-diamino-6-substituted-2-pyrazinecarboxamides and process for preparing same Download PDF

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Publication number
EP0000200A1
EP0000200A1 EP78100264A EP78100264A EP0000200A1 EP 0000200 A1 EP0000200 A1 EP 0000200A1 EP 78100264 A EP78100264 A EP 78100264A EP 78100264 A EP78100264 A EP 78100264A EP 0000200 A1 EP0000200 A1 EP 0000200A1
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Prior art keywords
diamino
amidino
methyl
mole
pyrazinoate
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German (de)
French (fr)
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EP0000200B1 (en
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Otto William Woltersdorf, Jr.
Susan Jane Desolms
Edward Jethro Cragoe, Jr.
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/02—Acyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 7 H 8 N 8 O.HCl ⁇ 1/2 H 2 0:
  • 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 2 0, 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 7 H 7 N 5 O 2 ⁇ 1/ 2 H 2 O;
  • Step A Methyl 3,5-diamino-6-trifluoromethyl- thio-2-pyrazinoate
  • 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 2 0 and extracted with CHCl 3 , the CHC1 3 layer washed with water, dried (MgSO 4 ) then concentrated to give an amber oil.
  • Step B N-Amidino-3,5-diamino-6-trifluoro- methylthio-2-pyrazinecarboxamide hydrate
  • 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 2 O (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 7 H 8 F 3 N 7 OS ⁇ H20;
  • Step A Methyl 3.5-diamino-6-trifluoromethyl- thio-2-pyrazinoate
  • 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.
  • Step A Methyl 3,5-diamino-6-trifluoromethyl- thio-2-pyrazinoate
  • 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.
  • Step A N-Amidino-3,5-diamino-6-trifluoro- methylthio-2-pyrazinecarboxamide
  • 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.
  • Step A Methyl 3,5-diamino-6-methylthio- pyrazinoate
  • Step B N-Amidino-3,5-diamino-6-methylthio--2-pyrazinecarboxamide hydrochloride hydrate
  • 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 7 H 11 N 7 OS ⁇ HCl ⁇ H 2 O:
  • Step A Methyl 3,5-diamino-6-phenylthio- pyrazinoate
  • Step B N-Amidino-3,5-diamino-6-phenylthio-2-pyrazinecarboxamide hemihydrate
  • 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-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 6 H 8 ClN 7 O;

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Abstract

N-Amidino-3,5- diamino-6- substituted-2- pyrazihecar- boxamides and a process for their synthesis.

Description

    SUMMARY AND BACKGROUND OF THE INVENTION
  • 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.
  • 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.
  • 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.
  • 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.
  • Particular compounds which can be prepared according to the process of this invention are shown below in Formula I.
    Figure imgb0001
    wherein X is Cl (this would be amiloride), CN, CH3S, CP3S or C6 H 5 S.
  • The novel process used to prepare these compounds is depicted in the following flow sheet:
    Figure imgb0002
  • 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.
  • 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
    Figure imgb0003
    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.
  • 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.
  • 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
  • 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 C7H8N8O.HCl·1/2 H20:
    • 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
  • 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 CHC13. The CHC13 layer was washed with dilute NaCN solution, then with H20, and dried (MgSO4). After evaporation of the CHCl3, 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 C7H7N5O2· 1/2 H2O;
    • 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
  • 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 - H20 and extracted with CHCl3, the CHC13 layer washed with water, dried (MgSO4) then concentrated to give an amber oil. The oil is dissolved in ether, extracted several times with H2O, dried (MgS04) 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 C7H7F3N4O2S:
    • 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
  • 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- H2O (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 C7H8F3N7OS· 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
  • 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
  • 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
  • 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
  • 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 MgSo4 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 C7H10N4O2S:
    • 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
  • 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 C7H11N7OS·HCl·H2O:
    • 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
  • 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 C12H12N4O2S:
    • 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
  • 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 C12H13N7OS·1/2 H 2 0:
    • 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
  • 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 CHC13. On evaporating the CHCl3 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 C6H8ClN7O;
    • 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.

Claims (5)

1. A compound of the formula:
Figure imgb0004
wherein X is CN, CH3S, CF3S or C6H5S.
2. A process for preparing compounds of the formula:
Figure imgb0005
wherein X is Cl, CN, CH3S, CF3S or C6H5S
which comprises reacting a compound of the formula:
Figure imgb0006
with CuX
wherein X is as previously defined and Y is I or Br.
3. A process of claim 2 wherein the reaction is. carried out in the solvent hexamethylphosphoramide or dimethylformamide at 25 - 100°c.
4. A process for preparing compounds of the formula
Figure imgb0007
which comprises
a) reacting a compound of the formula:
Figure imgb0008
with CuX .
wherein X is Cl, CN, CH3S, CF3S or C6H5S and Y is I or Br to produce a compound of the formula:
Figure imgb0009
wherein X is as previously defined and
b) reacting the product of step a) with guanidine to yield the desired compounds.
5. A process of claim 4 wherein the reaction of step a) is carried out in the presence of hexamethylphosphoramide or dimethylformamide at 25-100°C.
EP78100264A 1977-06-29 1978-06-28 New n-amidino-3,5-diamino-6-substituted-2-pyrazinecarboxamides and process for preparing same Expired EP0000200B1 (en)

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US811011 1977-06-29

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FI (1) FI781966A7 (en)
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Cited By (1)

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US4952582A (en) * 1982-01-04 1990-08-28 Beyer Jr Karl H Pyrazinoylguanidine and derivatives thereof having few polar substituents and being useful as hyperuretic agents
US4594349A (en) * 1982-01-04 1986-06-10 Beyer Jr Karl H Hyperuretic agents
WO1990009792A1 (en) * 1989-03-03 1990-09-07 The General Hospital Corporation Topical application of amiloride or analogues thereof for treatment of inflammation
US6858614B2 (en) * 2002-02-19 2005-02-22 Parion Sciences, Inc. Phenolic guanidine sodium channel blockers
US6858615B2 (en) * 2002-02-19 2005-02-22 Parion Sciences, Inc. Phenyl guanidine sodium channel blockers
US6903105B2 (en) * 2003-02-19 2005-06-07 Parion Sciences, Inc. Sodium channel blockers
US7745442B2 (en) 2003-08-20 2010-06-29 Parion Sciences, Inc. Methods of reducing risk of infection from pathogens
US20090253714A1 (en) * 2003-08-20 2009-10-08 Johnson Michael R Methods of reducing risk of infection from pathogens
US20070021439A1 (en) * 2005-07-25 2007-01-25 Parion Sciences, Inc. Methods of reducing risk of infection from pathogens with soluble amide and ester pyrazinoylguanidine sodium channel blockers
AR086745A1 (en) 2011-06-27 2014-01-22 Parion Sciences Inc 3,5-DIAMINO-6-CHLORINE-N- (N- (4- (4- (2- (HEXIL (2,3,4,5,6-PENTAHYDROXIHEXIL)) AMINO) ETOXI) PHENYL) BUTIL) CARBAMIMIDOIL) PIRAZINA -2-CARBOXAMIDE
EP2931712B8 (en) 2012-12-17 2018-05-23 Parion Sciences, Inc. 3,5-diamino-6-chloro-n-(n-(4-phenylbutyl)carbamimidoyl) pyrazine-2- carboxamide compounds
RU2015129065A (en) 2012-12-17 2017-01-25 Пэрион Сайенсиз, Инк. CHLORINE-PYRAZINCARBOXAMIDE DERIVATIVES THAT HAVE AN ACTIVATING BLOCKING OF EPITELIAL SODIUM CHANNELS
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AT362795B (en) 1981-06-10
US4196292A (en) 1980-04-01
EP0000200B1 (en) 1982-03-24
FI781966A7 (en) 1978-12-30
JPS5412389A (en) 1979-01-30
IT1105454B (en) 1985-11-04
DK290278A (en) 1978-12-30
ES471244A1 (en) 1979-10-01
PL207947A1 (en) 1979-10-22
NO782230L (en) 1979-01-02
DE2861684D1 (en) 1982-04-29
IT7849984A0 (en) 1978-06-22
ATA469078A (en) 1980-11-15
HU178302B (en) 1982-04-28

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