US3629260A - S-triazolo(4 3-a)pyrazine derivatives - Google Patents

S-triazolo(4 3-a)pyrazine derivatives Download PDF

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Publication number
US3629260A
US3629260A US694816A US3629260DA US3629260A US 3629260 A US3629260 A US 3629260A US 694816 A US694816 A US 694816A US 3629260D A US3629260D A US 3629260DA US 3629260 A US3629260 A US 3629260A
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Prior art keywords
pyrazine
parts
triazolo
methyl
derivatives
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US694816A
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John Anthony Maguire
Francis Leslie Rose
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Imperial Chemical Industries Ltd
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Imperial Chemical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to new pyrazine derivatives which prevent bronchospasm and which are therefore useful in the treatment of diseases which involve spasm or constriction of the bronchial musclature, for example asthma or bronchitis.
  • R and R which may be the same or dilferent, stand for alkyl radicals, and X stands for an amino, hydroxy, formamido or acetamido radical.
  • pyrazine derivatives of the present invention have a skeleton ring structure of the formula:
  • R or R is, for example, an alkyl radical of not more than 4 carbon atoms, for example the methyl or n-propyl radical.
  • a preferred group of pyrazine derivatives of the invention comprises those compounds wherein R and R stand for alkyl radicals which together contain not more than 5 carbon atoms.
  • a suitable cyanogen halide is, for example, cyanogen chloride.
  • the above interaction may be carried out in the presence of a diluent or solvent, for example water, ethanol or ethylene dichloride, and it is preferably carried out at about ambient temperature, for example between 10 C. and 30 C.
  • a diluent or solvent for example water, ethanol or ethylene dichloride
  • the interaction is also preferably carried out at a pH of between 4 and 9 in the presence of an acid binding agent, for example an alkali metal salt of a weak acid, for example sodium hydrogen carbonate, sodium carbonate or sodium acetate.
  • a suitable cyanogen halide is, for example cyanogen chloride, and the interaction may be carried out in a diluent or solvent, for example water or ethanol, or a mixture thereof.
  • the interaction is preferably carried out about ambient temperature, for example between 10 C. and 30 C., and it is preferably carried out at a pH of between 4 and 9.
  • R and R have the meanings stated above, with an acylating agent derived from formic or acetic acid.
  • acylating agent for example, acetyl chloride or acetic anhydride, or acetic acid or formic acid together with a condensing agent, for example dicyclohexylcarbodi-imide.
  • R and R have the meanings stated above, with a reactive ester or halogeno compound derived from carbonic acid, followed, if necessary by treatment of the initial product with a base.
  • a suitable reactive ester or halogeno compound derived from carbonic acid is, for example, a lower alkyl ester of chloroformic acid, for example ethyl chloroformate, or carbonyl chloride.
  • the pyrazinylhydrazine derivatives used as starting materials in the above processes may be obtained by the interaction of the corresponding halogenopyrazine derivatives, for example the corresponding chloropyrazine derivatives, with hydrazine, and the halogenopyrazine derivatives themselves may be obtained by the interaction of the corresponding hydroxypyrazine derivatives with a phosphorus oxyhalide, for example phosphorus oxychloride.
  • the pyrazine derivatives of the invention may be used in the form of pharmaceutical compositions and therefore according to a further feature of the invention we provide pharmaceutical compositions comprising at least one pyrazine derivative of the invention together with a pharmaceutically-acceptable diluent or carrier.
  • compositions may be in a form suitable for oral administration, for example tablets, capsules, syrups or linctuses, or they may be in a form suitable for parenteral administration, for example sterile injectable aqueous solutions.
  • These compositions may contain conventional excipients and may be manufactured by conventional techniques. It should be noted, however, that while the pyrazine derivatives of the invention are not themselves soluble in water, satisfactory aqueous 4 solutions may be obtained by adjustment of the pH of the aqueous phase. Thus, for those pyrazine derivatives of the invention wherein X stands for an acetamido radical, a satisfactory solution is obtained if the pH of the aqueous phase is adjusted to between 8 and 9.
  • the pyrazine derivatives of the invention may be administered to patients together with other compounds which are known to prevent bronchospasm.
  • Such other compounds are, for example, aminophylline which is administered orally or by injection, ephedrine which is administered orally, sympathomimetic amines, for example isoprenaline or adrenaline which are administered as aerosols, or those corticosteroids which are used to control asthma, for example prednisolone.
  • the pyrazine derivatives of the invention may also be administered together with a selective S-adrenergic blocking agent, for example 1-(4-acetamidophenoxy)-3- isopropylamino-Z-propanol, which will inhibit any sympathomimetic action of the pyrazine derivative on the heart but not affect the action of the pyrazine derivative on the bronchial musclature. Since the pyrazine derivatives of the invention possess only weak sympathomimetic activity, it is expected that administration together with a selective B-adrenergic blocking agent will only be useful when the pyrazine derivatives have to be administered at high doses.
  • a selective S-adrenergic blocking agent for example 1-(4-acetamidophenoxy)-3- isopropylamino-Z-propanol
  • EXAMPLE 4 A solution of 3.2 parts of anhydrous sodium acetate in 9 parts of Water is added to a solution of 2 parts of 2- hydrazino-S-methyl-3-n-propylpyrazine and 2 parts of glacial acetic acid in 25 parts of ethanol. The mixture is warmed until all the solid has dissolved, and then it is cooled to C. A stream of phosgeneis passed through the solution for 10 minutes, and the pH is maintained at by the addition of anhydrous sodium acetate. The mixture is then evaporated at 50 C., and the residue is suspended in 60 parts of 0.5 N-sodium hydroxide solution.
  • EXAMPLE 5 7.3 parts of 2-hydrazino-5-methyl-3-n-propylpyrazine are dissolved in a mixture of 50 parts of ethylene dichloride and 25 parts of water. A stream of cyanogen chloride is bubbled into the solution which is maintained at 25-30 C. The pH of the reaction mixture is kept at 7-8 by addition of solid sodium carbonate as necessary. The completion of the reaction is shown by the absence of a blue colouration when a sample of the reaction mixture is shaken in air with a mixture of aqueous sodium hydroxide and methyl alcohol. The pale yellow solid which forms is collected, and washed with Water and ethylene dichloride. After recrystallisation from dioxan there is thus obtained 3-amino-6-methyl-8-n-propyl-s-triazolo 4,3-a] pyrazine as pale yellow needles, M.P. l99-200 C.
  • EXAMPLE 6 4.1 parts of 3-amino-6-methyl-8-n-propyl-s-triazolo [4,3-a]pyrazine and 6.5 parts of acetic anhydride are heated at 90-100 C. for minutes. 10 parts of methyl alcohol are then added and the resultant suspension is filtered. Recrystallisation of the solid from n-butanol gives 3 aoetamido 6 methyl 8 n propyl s triazolo[4,3- a]pyrazine as colourless needles, M.P. 264-265 C.
  • EXAMPLE 7 A solution of 13.3 parts of dicyclohexylcarbodiimide in 120 parts of dry ethyl acetate was mixed with a solution of 4.1 parts of 3-amino-6-methyl-8-n-propyl-s-triazolo [4,3-a1pyrazine in 80 parts of dry ethyl acetate and 3 parts of anhydrous formic acid. The suspension thus obtained is stirred at 25 C. for 42 hours and then filtered. The solid collected is Washed with ethyl acetate. The combined filtrate and washings are evaporated to dryness and the pale yellow solid residue is stirred in 40 parts of water with the addition of sulficient sodium hydroxide to make the mixture strongly alkaline.
  • EXAMPLE 8 A solution of 3.5 parts of ethyl chloroformate in parts of ethyl acetate is added slowly to a stirred solution of 5.1 parts of 2-hydrazino-5-methyl-3-n-propylpyrazine in 50 parts of ethyl acetate. The reaction temperature is maintained at 20-25" C. After 1 hour, the resultant suspension is filtered. The solid is dissolved in 35 parts of water and neutralised by the addition of. sodium acetate. The yellow precipitate which forms is collected and recrystallised from cyclohexane to give 2-ethoxycarbonyl- 5-methyl-3-n-propylpyrazine, M.P. 97-98" C.
  • EXAMPLE 9 A mixture of 25 parts of 3-acetamido-6-methyl-8-npropyl-s-triazolo[4,3-a]pyrazine, 65 parts of. maize starch, 130 parts of calcium phosphate and 1 part of magnesium stearate is compressed and the compressed mixture is then broken down into granules by passage through a 16-mesh screen. The resultant granules are then compressed into tablets using the conventional techniques.
  • the pyrazine derivatives of the invention prevent bronchospasm as illustrated by their action in preventing the death of guinea-pigs exposed to a histamine aerosol. This action is commonly used as a standard test for such activity. [Loew, E. R., Kaiser, M. E. and Moore, V. (1945). J. Pharmacol. and Experimental Therapeutics, 83, 120].
  • the pyrazine derivatives also show bronchodilator activity when tested on an artificially respired, perfused guinea-pig lung preparation. [Bhattacharya, B. K. and Delaunois, A. L. (1955). Arch. int. Pharmacodyn., 101, 495].
  • the preferred pyrazine derivative of the invention also relaxes an isolated guinea-pig trachea which has been constricted by acetyl choline, 5'-hydroxytryptamine or bradykinin, and it has no specific antihistamine activity when tested on an isolated guinea-pig ileum constricted with histamine.
  • a well-known feature of asthma is spasm of the bronchial musclature which results in dyspnoea, and relief is aiforded by known drugs, for example aminophylline, which prevent bronchospasm. Accordingly, like aminophylline, the pyrazine derivatives of the invention are also useful for the treatment of asthma, but differ from aminophylline in being considerably more potent than aminophylline.
  • a typical dose of pyrazine derivative is in the range 25 to 200 mg. per man, preferably in the range 50 to 100 mg. per man, administered orally or by injection at intervals as required by the patient depending upon the risk of an asthmatic attack.
  • the dose of pyrazine derivative is conveniently administered orally in the form of tablets or capsules containing between 10 and 50 mg. of pyrazine derivative, or in the form of a measured amount of a syrup or linctus.
  • the dose of pyrazine derivative may be administered parenterally in the form of an injectable aqueous solution con taining between 100 and 200 mg. per ml.
  • R and R are alkyl of l-4 carbon atoms, and X is selected from the group consisting of amino, hydroxy, formamido and acetamido.
  • a pyrazine derivative as claimed in claim 1 which is 3 acetamido-6-methyl-8-n-propyl-s-triazolo[4,3-a1pyrazine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Paper (AREA)
US694816A 1967-02-03 1968-01-02 S-triazolo(4 3-a)pyrazine derivatives Expired - Lifetime US3629260A (en)

Applications Claiming Priority (1)

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GB5356/67A GB1146770A (en) 1967-02-03 1967-02-03 S-triazolo[4,3-a]pyrazine derivatives

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US694816A Expired - Lifetime US3629260A (en) 1967-02-03 1968-01-02 S-triazolo(4 3-a)pyrazine derivatives
US12534*A Expired - Lifetime US3594479A (en) 1967-02-03 1970-01-29 Composition and method for preventing bronchospasms using pyrazine derivatives

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US (2) US3629260A (enrdf_load_stackoverflow)
AT (4) AT278813B (enrdf_load_stackoverflow)
BE (1) BE710283A (enrdf_load_stackoverflow)
CH (1) CH504448A (enrdf_load_stackoverflow)
DE (1) DE1695298C3 (enrdf_load_stackoverflow)
DK (2) DK124825B (enrdf_load_stackoverflow)
ES (2) ES350118A1 (enrdf_load_stackoverflow)
FR (2) FR1580154A (enrdf_load_stackoverflow)
GB (1) GB1146770A (enrdf_load_stackoverflow)
NL (1) NL6801322A (enrdf_load_stackoverflow)
NO (1) NO119839B (enrdf_load_stackoverflow)
PL (3) PL80902B1 (enrdf_load_stackoverflow)
SE (3) SE337594B (enrdf_load_stackoverflow)
YU (1) YU32608B (enrdf_load_stackoverflow)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4183741A (en) * 1976-05-21 1980-01-15 Fisons Limited Herbicidally-active heterocyclic compounds
US4402958A (en) * 1981-11-19 1983-09-06 American Cyanamid Company Novel (substituted phenyl)-1,2,4-triazolo (4,3-A)pyrazines and novel 2-hydrazino-(substituted phenyl)pyrazine intermediates
US4438266A (en) 1982-05-17 1984-03-20 Merck & Co., Inc. Triazolopyrazinamines useful as adjuncts to radiation therapy
US5095018A (en) * 1989-06-06 1992-03-10 Burroughs Wellcome Co. 3-benzyl-1,2,4-triazolo[4,3-α] pyrazines

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4242344A (en) * 1979-01-22 1980-12-30 Merck & Co., Inc. Piperazinyl-imidazo[1,2-a]pyrazines
US6451796B1 (en) 1997-11-11 2002-09-17 Ono Pharmaceutical Co., Ltd. Fused pyrazine compounds

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4183741A (en) * 1976-05-21 1980-01-15 Fisons Limited Herbicidally-active heterocyclic compounds
US4402958A (en) * 1981-11-19 1983-09-06 American Cyanamid Company Novel (substituted phenyl)-1,2,4-triazolo (4,3-A)pyrazines and novel 2-hydrazino-(substituted phenyl)pyrazine intermediates
US4438266A (en) 1982-05-17 1984-03-20 Merck & Co., Inc. Triazolopyrazinamines useful as adjuncts to radiation therapy
US5095018A (en) * 1989-06-06 1992-03-10 Burroughs Wellcome Co. 3-benzyl-1,2,4-triazolo[4,3-α] pyrazines

Also Published As

Publication number Publication date
NO119839B (enrdf_load_stackoverflow) 1970-07-13
DE1695298B2 (de) 1975-01-23
DK124825B (da) 1972-11-27
SE353093B (enrdf_load_stackoverflow) 1973-01-22
BE710283A (enrdf_load_stackoverflow) 1968-08-02
ES351068A1 (es) 1969-06-01
PL80903B1 (enrdf_load_stackoverflow) 1975-08-30
GB1146770A (en) 1969-03-26
YU19168A (en) 1974-10-31
PL80902B1 (enrdf_load_stackoverflow) 1975-08-30
FR7424M (enrdf_load_stackoverflow) 1969-11-12
US3594479A (en) 1971-07-20
AT278813B (de) 1970-02-10
FR1580154A (enrdf_load_stackoverflow) 1969-09-05
NL6801322A (enrdf_load_stackoverflow) 1968-08-05
SE353092B (enrdf_load_stackoverflow) 1973-01-22
CH504448A (de) 1971-03-15
ES350118A1 (es) 1969-04-16
DE1695298C3 (de) 1975-09-25
YU32608B (en) 1975-04-30
DK123721B (da) 1972-07-24
AT278825B (de) 1970-02-10
AT278824B (de) 1970-02-10
DE1695298A1 (de) 1972-03-09
SE337594B (enrdf_load_stackoverflow) 1971-08-16
AT278826B (de) 1970-02-10
PL80904B1 (enrdf_load_stackoverflow) 1975-08-30

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