EP0000200B1 - 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 PDFInfo
- Publication number
- EP0000200B1 EP0000200B1 EP78100264A EP78100264A EP0000200B1 EP 0000200 B1 EP0000200 B1 EP 0000200B1 EP 78100264 A EP78100264 A EP 78100264A EP 78100264 A EP78100264 A EP 78100264A EP 0000200 B1 EP0000200 B1 EP 0000200B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- diamino
- amidino
- methyl
- reaction
- pyrazinoate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 0 CC1C(*)CC(O)=C(*)*1 Chemical compound CC1C(*)CC(O)=C(*)*1 0.000 description 3
Classifications
-
- 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 new N-amidino-3,5-diamino-6-substituted-2-pyazinecarboxamides and process for preparing same.
- N-Amidino-3,5-diamino-6-substituted-2-pyrazinecarboxamides particularly the N-amidino-3,5-diamino-6-chloro-2-pyrazinecarboxamide which is commercially known as amiloride are described by the general formula in Column 1 of U.S. Patent 3,313,813. All of the compounds disclosed in U.S. Patent 3,313,813 possess diuretic and natriuretic properties; they selectively enhance the excretion of sodium ions without causing an increase in excretion of potassium ions.
- the present invention also relates to several novel N-amidino-3,5-diamino-6-substituted -2-pyrazinecarboxamides. These compounds are also useful because they possess diuretic and natriuretic properties and selectively enhance the excretion of sodium ions without causing an increase in excretion of potassium ions.
- the potassium loss which is caused by most 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.
- 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 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 hexamethylphosphoramide or dimethylformamide.
- the reaction temperature is not critical and the reaction can be run at anywhere from 25-100°C.
- the length of time the reaction is carried out is not critical either and can be run anywhere from 0.1 to 10 hours.
- 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 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 methyl-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 methyl- 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-pyrazinecarboxamide 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 HCI and cooling one obtains 1.43 g. of N-amidino-3,5-diamino-6-cyano-2-pyrazinecarboxamide hydrochloride m.p. 350°C.
- 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 (MgS0 4 ). After evaporation of the CHCI 3 , the residual oil was treated with hexane to give 75 mg. of methyl 3,5-diamino-6-cyano-2-pyrazinoate hemihydrate melting at 284-5°C.Elemental analysis for C 7 H 7 N 5 O 2 ⁇ 1/2 H 2 0;
- Step A Methyl 3,5-diamino-6-trifluoromethylthio-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 CHC1 3 , the CHCl 3 layer washed with water, dried (MgS0 4 ) then concentrated to give an amber oil.
- Step B N-Amidino-3,5-diamino-6-trifluoromethylthio-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-diamino-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 0 (20 ml.) is added to the reaction mixture to precipitate 390mg. 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 ⁇ H 2 O;
- Step A Methyl 3,5-diamino-6-trifluoromethylthio-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-trifluoromethylthio-2-pyrazinoate
- Methyl 3,5-diamino-6-trifluoromethylthio-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 trifluoromethyl- thiomercaptide in situ.
- N-Amidino-3,5-diamino-6-trifluoromethylthio-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 trifluoromethylthiocopper in place of cuprous cyanide.
- Step A Methyl 3,5-diamino-6-phenylthiopyrazinoate
- Step B N-Amidino-3,5-diamino-6-phenylthio-2-pyrazinecarboxamide hemihydrate
- Guanidine hydrochloride (5.2 g., 0.055 mole) is added to an 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-phenylthiopyrazinoate (2.5 g., 0.009 mole), heated on a steam bath for ten minutes then poured into water (200 mi.) to give 2.2 g. N-amidino-3,5-diamino-6-phenylthio-2-pyrazinecarboxamide hemihydrate which melts at 238°C. after being washed with methanol.
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- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Dentistry (AREA)
- Plant Pathology (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Liquid Crystal Substances (AREA)
- Cephalosporin Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US05/811,011 US4196292A (en) | 1977-06-29 | 1977-06-29 | 6-Substituted amiloride derivatives |
US811011 | 2004-03-26 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000200A1 EP0000200A1 (en) | 1979-01-10 |
EP0000200B1 true EP0000200B1 (en) | 1982-03-24 |
Family
ID=25205286
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78100264A Expired EP0000200B1 (en) | 1977-06-29 | 1978-06-28 | New n-amidino-3,5-diamino-6-substituted-2-pyrazinecarboxamides and process for preparing same |
Country Status (12)
Country | Link |
---|---|
US (1) | US4196292A (ja) |
EP (1) | EP0000200B1 (ja) |
JP (1) | JPS5412389A (ja) |
AT (1) | AT362795B (ja) |
DE (1) | DE2861684D1 (ja) |
DK (1) | DK290278A (ja) |
ES (1) | ES471244A1 (ja) |
FI (1) | FI781966A (ja) |
HU (1) | HU178302B (ja) |
IT (1) | IT1105454B (ja) |
NO (1) | NO782230L (ja) |
PL (1) | PL119097B1 (ja) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4362724A (en) * | 1980-05-19 | 1982-12-07 | Merck & Co., Inc. | Method of treating edema and hypertension and pharmaceutical composition therefor in which the active ingredient comprises a novel substituted pyrazinyl-1,2,4-oxadiazole and a kaliuretic diuretic |
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 |
US6858615B2 (en) | 2002-02-19 | 2005-02-22 | Parion Sciences, Inc. | Phenyl guanidine sodium channel blockers |
US6858614B2 (en) * | 2002-02-19 | 2005-02-22 | Parion Sciences, Inc. | Phenolic 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 (es) | 2011-06-27 | 2014-01-22 | Parion Sciences Inc | 3,5-diamino-6-cloro-n-(n-(4-(4-(2-(hexil(2,3,4,5,6-pentahidroxihexil)amino)etoxi)fenil)butil)carbamimidoil)pirazina-2-carboxamida |
CA2895512C (en) | 2012-12-17 | 2021-10-19 | Parion Sciences, Inc. | Chloro-pyrazine carboxamide derivatives useful for the treatment of diseases favoured by insufficient mucosal hydration |
MX2015007797A (es) | 2012-12-17 | 2015-10-05 | Parion Sciences Inc | Compuestos de 3,5-diamino-6-cloro-n-(n-(4-fenilbutil) carbamimidoil) pirazin-2-carboxamida. |
US9102633B2 (en) | 2013-12-13 | 2015-08-11 | Parion Sciences, Inc. | Arylalkyl- and aryloxyalkyl-substituted epithelial sodium channel blocking compounds |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB286896A (en) * | 1927-03-29 | 1928-03-15 | Arthur William Howarth | Improvements in smokers' pipes |
US3305552A (en) * | 1965-11-22 | 1967-02-21 | Merck & Co Inc | 3-aminopyrazinoic acids and process for their preparation |
US3507865A (en) * | 1967-04-27 | 1970-04-21 | Merck & Co Inc | 3-hydroxy- and 3-mercaptopyrazinamidoguanidines the corresponding ethers and thioethers and processes for their preparation |
US3573306A (en) * | 1969-03-05 | 1971-03-30 | Merck & Co Inc | Process for preparation of n-substituted 3,5-diamino-6-halopyrazinamides |
-
1977
- 1977-06-29 US US05/811,011 patent/US4196292A/en not_active Expired - Lifetime
-
1978
- 1978-06-20 FI FI781966A patent/FI781966A/fi not_active Application Discontinuation
- 1978-06-22 IT IT49984/78A patent/IT1105454B/it active
- 1978-06-22 HU HU78ME2174A patent/HU178302B/hu unknown
- 1978-06-27 PL PL1978207947A patent/PL119097B1/pl unknown
- 1978-06-28 EP EP78100264A patent/EP0000200B1/en not_active Expired
- 1978-06-28 NO NO782230A patent/NO782230L/no unknown
- 1978-06-28 DK DK290278A patent/DK290278A/da unknown
- 1978-06-28 ES ES471244A patent/ES471244A1/es not_active Expired
- 1978-06-28 AT AT0469078A patent/AT362795B/de not_active IP Right Cessation
- 1978-06-28 DE DE7878100264T patent/DE2861684D1/de not_active Expired
- 1978-06-29 JP JP7924078A patent/JPS5412389A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
ATA469078A (de) | 1980-11-15 |
US4196292A (en) | 1980-04-01 |
FI781966A (fi) | 1978-12-30 |
DK290278A (da) | 1978-12-30 |
ES471244A1 (es) | 1979-10-01 |
IT7849984A0 (it) | 1978-06-22 |
EP0000200A1 (en) | 1979-01-10 |
PL119097B1 (en) | 1981-11-30 |
DE2861684D1 (en) | 1982-04-29 |
IT1105454B (it) | 1985-11-04 |
NO782230L (no) | 1979-01-02 |
PL207947A1 (pl) | 1979-10-22 |
AT362795B (de) | 1981-06-10 |
HU178302B (en) | 1982-04-28 |
JPS5412389A (en) | 1979-01-30 |
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