US3903086A - Nitrofuryl-triazolo{8 4,3b{9 pyridazine-amide compounds and bacteriostatic compositions - Google Patents

Nitrofuryl-triazolo{8 4,3b{9 pyridazine-amide compounds and bacteriostatic compositions Download PDF

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Publication number
US3903086A
US3903086A US316198A US31619872A US3903086A US 3903086 A US3903086 A US 3903086A US 316198 A US316198 A US 316198A US 31619872 A US31619872 A US 31619872A US 3903086 A US3903086 A US 3903086A
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United States
Prior art keywords
pyridazine
triazolo
compound
nitro
compounds
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Expired - Lifetime
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US316198A
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English (en)
Inventor
Herbert Berger
Rudi Gall
Max Thiel
Wolfgang Vomel
Winfriede Sauer
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Roche Diagnostics GmbH
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Boehringer Mannheim GmbH
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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

  • R is hydrogen or a saturated or unsaturated aliphatic hydrocarbon radical containing 2 to 5 carbon atoms
  • bacteriostats are outstandingly effective as bacteriostats and are particularly useful in the treatment of bacterial infections in the urinary tract.
  • the new nitrofuryl-triazolo[4.3-blpyridazine-amide derivatives according to the present invention are compounds of the formula:
  • R is hydrogen or a saturated or unsaturated aliphatic hydrocarbon radical containing 2 to carbon atoms,
  • R can be alkyl. alkenyl. alkynyl of from 2 to 5 carbon atoms.
  • the new compounds (I) according to the present invention have surprisingly high antibacterial activity in the urine and are. therefore, especially well-suited for the treatment of infections of the urinary tract.
  • Some of the new compounds (I) show. in vitro and in vivo. inhibiting values which, against Eschcric/u'u (u/i. S[up/1ylocuc'cus uureus. Pseudo/norms urugiimxu and Proteus miruhilis. so significantly exceed that of the hitherto most effective commercially available urinary antiseptic. nitrofurantoin. that they represent a valuable advance in the art of medical practice, especially for combating dangerous chronic infections of the urinary tract. for example. pyelonephritis.
  • the new compounds (I) according to the present invention can be prepared. for example. by one of the following methods:
  • derivatives of the acid of formula (ll) there can be used all compounds which react with amines to give amides.
  • the nitrile can be converted into an amide directly or via an amidine.
  • acid halides especially acid chlorides, which can be obtained from the carboxylic acid by reaction with a halogenation agent, for example, thionyl chloride or phosphorus oxychloride.
  • a halogenation agent for example, thionyl chloride or phosphorus oxychloride.
  • examples of other reactive derivatives include acid esters, for example the ethyl ester. and acid imidazolides.
  • the reaction generally takes place easily in aqueous solvents and with good yields.
  • the acid itself can be reacted with amines in the presence of carbodiimides.
  • the earboxylie acid (ll) used as a starting material can readily be obtained by hydrolysis of the corresponding nitrile which. in turn, is obtained by the oxidative cyclization of 6-cyano-3-[ 2-( 5-nitro-2- fufurylidene)-hydrazino]-pyridazine.
  • the oxidative cyclisation of the above-mentioned starting material. as well as of the compounds (lV), can be carried out at a slightly elevated temperature, preferably in trifluoroacetic acid or glacial acetic acid or in a mixture thereof.
  • Lead tetraacetate has proved to be especially useful as oxidation agent.
  • the components can be simply heated in an inert. high boiling point solvent. for example diethylene glycol dimethyl ether. By the subsequent addition of water, rendering alkaline and extraction with an organic solvent. the products of the process can be isolated.
  • an inert. high boiling point solvent for example diethylene glycol dimethyl ether.
  • the nitration of the compounds (VI) takes place in conventional manner, for example, with nitric acid and acetic anhydride in the cold.
  • the starting materials (VI) can be obtained, for example, by the cyclisation of 6-cyano-3-( Z-furfuryIidene-hydrazino )-pyrida7.ine and reaction of the reaction product obtained therefrom, in a manner analogous to process 1.
  • amidrazones of general formula (VII) used as starting materials can be obtained by the condensation of -nitro-2-furan-imidoethers with appropriate 3- hydrazino-pyridazine derivatives.
  • the cyelisation of the compounds of general formula (VII) can be brought about simply by heating in an inert solvent.
  • the splitting off of ammonia can also be carried out by treating the amidrazones (VII) with aqueous mineral acids at ambient temperature or possibly with heating.
  • nitriles used as precursors for compounds of the general formulae (II), (IV), (V), (VI) and (VII) can be obtained from the corresponding halogen compounds in a manner analogous to Kolbes nitrile synthesis.
  • Starting from the nitriles of the above-mentioned compounds there are first obtained, by boiling in alcoholic hydrochloric acid, the corresponding carboxylic acid esters which can then be saponified in aqueous formic acid, with the addition of methanesulphonic acid, to the carboxylic acids.
  • this carboxylic acid ester was now boiled under reflux for 2 hours with 21.2 ml. 90% aqueous formic acid, to which 2 g. methane sulphonic acid had been added, a further 1 ml. methane sulphonic acid was then added thereto and reflux boiling continued for a further 2 hours.
  • the reaction product i.e., the free carboxylic acid was precipitated out by the addition of water, filtered off with suction and washed with water.
  • baeteriostatie activity of the compounds in accordance with the invention was evaluated in vitro and in vivo.
  • the following comparison compound and compounds according to the invention were used in the tests:
  • the compounds were evaluated with respect to their bacteriostatic activity in the excreted urine of rats following oral administration.
  • the results of these experiments are set out in Table II.
  • the bacteriostatie maximum dilution of urine against Escherichia coli I06) was determined 22 hours after 20 milligrams of test compound per kilogram of body weight had been orally administered to the rats.
  • Six (nine) rats were employed for each experiment (test compound); the test results are calculated on the basis of 50(75) milliliter urine samples.
  • the compoundsof this invention are anti-microbials and have been found to be bactericidal to the pathogens found in surface infections, gram negative as well as gram positive. They additionally have utility as agents for routine treatment of acute and chronic bacterial infections of the urinary tract, including those caused by Proteus ap. Further they lend themselves because of their properties to use in the prevention or treatment of mixed surface infections or wounds, severe burns, cutaneous ulcers, pyodermas osteomyelitis, preparation of wounds and burns for skin grafting and prevention of infection of grafts and donor sites.
  • the compounds of the invention can be employed in the form of aqueous solutions or suspensions thereof, as for instance, in the form of an 0.01 to 0.05 aqueous suspension or solution; in the form of solutions in nonaqueous, hygroscopic liquid vehicles such as polyethylene glycol, for instance 0.] 0.5% solutions in polyethylene glycol; incorporation into a water-soluble ointment-like base (concentration 0.1 0.5%) or in a powder base composed for instance of water-soluble polyethylene glyeols (concentration 0.1 to 0.5%); or in a form suitable for ingestion.
  • a preferred form is a tablet containing to 200 mg. of active compound.
  • symptomatic and laboratory responses 100 to 400 mg. per day can be administered.
  • Another preferred form for orally administering the compounds of the invention is in the form of a suspension thereof in a water miscible flavored gel. Such gel can contain from 1 to I0 mg. of compound per cc.
  • the compounds (I) can be administered orally and parenterally in admixture with a liquid or solid pharmaceutical diluent or carrier.
  • a liquid or solid pharmaceutical diluent or carrier As an injection medium, it is preferable to use water which contains the stabilizing agents, solubilizing agents and/or buffers conventional for injection solutions.
  • Additives of this type include for example, tartrate and borate buffers, ethanol, dimethyl sulphoxide, complex-forming agents (for example ethylene-diamine-tetraacetic acid) and high molecular weight polymers (for example liquid polyethylene oxide) for viscosity regulation.
  • Solid carrier materials include, for example starch, lactose.
  • compositions suitable for oral administration can, if desired, also contain flavoring and/or sweetening agents.
  • the compounds (1) according to the present invention can also be used in the form of powders and salves; for this purpose, they are mixed, for example, with powdered, physiologically compatible diluents or with conventional salve bases.
  • R is alkenyl of from 2 to 5 carbon atoms.
  • R is alkynyl of from 2 to 5 carbon atoms having one triple bond.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US316198A 1972-01-21 1972-12-18 Nitrofuryl-triazolo{8 4,3b{9 pyridazine-amide compounds and bacteriostatic compositions Expired - Lifetime US3903086A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19722202744 DE2202744A1 (de) 1972-01-21 1972-01-21 Nitrofuryl-triazolo eckige klammer auf 4,3-b eckige klammer zu-pyridazin-amide

Publications (1)

Publication Number Publication Date
US3903086A true US3903086A (en) 1975-09-02

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US316198A Expired - Lifetime US3903086A (en) 1972-01-21 1972-12-18 Nitrofuryl-triazolo{8 4,3b{9 pyridazine-amide compounds and bacteriostatic compositions

Country Status (13)

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US (1) US3903086A (xx)
JP (1) JPS4880596A (xx)
AT (5) AT319224B (xx)
AU (1) AU466339B2 (xx)
CA (1) CA1001628A (xx)
CH (5) CH577510A5 (xx)
DE (1) DE2202744A1 (xx)
ES (1) ES410659A1 (xx)
FR (1) FR2181673B1 (xx)
GB (1) GB1351921A (xx)
HU (1) HU164579B (xx)
NL (1) NL7300613A (xx)
ZA (1) ZA73419B (xx)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4308386A (en) * 1977-06-13 1981-12-29 Richt Er Gedeon Vegyeszeti Gyar Rt. Novel pyridazinylhydrazones and method of administering same
US9187484B2 (en) 2012-05-02 2015-11-17 Southern Research Institute Triazolopyridazine compounds, use as inhibitors of the kinase LRRK2, and methods for preparation thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3138593A (en) * 1962-04-02 1964-06-23 Norwich Pharma Co 4, 5-dihydro-6-(5-nitro-2-furyl)-as-triazinor pyridazin-3-(2h)-one
US3483193A (en) * 1965-07-02 1969-12-09 Boehringer & Soehne Gmbh 5-nitrofuryl and 5-nitrothienyl compounds
US3506656A (en) * 1966-10-22 1970-04-14 Boehringer Mannheim Gmbh Triazolo-tetrazolo-pyridazine derivatives
US3522256A (en) * 1966-06-18 1970-07-28 Boehringer Mannheim Gmbh 5-nitrofuran and 5-nitrothiophene derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1527537A (fr) * 1966-06-18 1968-05-31 Boehringer & Soehne Gmbh Procédé de préparation de nouveaux dérivés du 5-nitrofurane et du 5-nitrothiophène

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3138593A (en) * 1962-04-02 1964-06-23 Norwich Pharma Co 4, 5-dihydro-6-(5-nitro-2-furyl)-as-triazinor pyridazin-3-(2h)-one
US3483193A (en) * 1965-07-02 1969-12-09 Boehringer & Soehne Gmbh 5-nitrofuryl and 5-nitrothienyl compounds
US3522256A (en) * 1966-06-18 1970-07-28 Boehringer Mannheim Gmbh 5-nitrofuran and 5-nitrothiophene derivatives
US3506656A (en) * 1966-10-22 1970-04-14 Boehringer Mannheim Gmbh Triazolo-tetrazolo-pyridazine derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4308386A (en) * 1977-06-13 1981-12-29 Richt Er Gedeon Vegyeszeti Gyar Rt. Novel pyridazinylhydrazones and method of administering same
US9187484B2 (en) 2012-05-02 2015-11-17 Southern Research Institute Triazolopyridazine compounds, use as inhibitors of the kinase LRRK2, and methods for preparation thereof

Also Published As

Publication number Publication date
ATA1041373A (de) 1975-04-15
AT327185B (de) 1976-01-26
GB1351921A (en) 1974-05-15
NL7300613A (xx) 1973-07-24
ES410659A1 (es) 1976-01-01
AU466339B2 (en) 1975-10-23
CH577507A5 (xx) 1976-07-15
AT327184B (de) 1976-01-26
AT319224B (de) 1974-12-10
HU164579B (xx) 1974-03-28
ATA1041573A (de) 1975-04-15
ATA1041473A (de) 1975-04-15
FR2181673B1 (xx) 1976-12-03
CH577509A5 (xx) 1976-07-15
CH577510A5 (xx) 1976-07-15
CH577512A5 (xx) 1976-07-15
AU5134473A (en) 1974-07-25
FR2181673A1 (xx) 1973-12-07
DE2202744A1 (de) 1973-07-26
ZA73419B (en) 1973-11-28
CH577511A5 (xx) 1976-07-15
JPS4880596A (xx) 1973-10-29
ATA1041273A (de) 1975-04-15
AT327186B (de) 1976-01-26
CA1001628A (en) 1976-12-14
AT327183B (de) 1976-01-26

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