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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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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pyridazine
triazolo
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nitro
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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)

Abstract


WHEREIN R1 is hydrogen or a saturated or unsaturated aliphatic hydrocarbon radical containing 2 to 5 carbon atoms, ARE OUTSTANDINGLY EFFECTIVE AS BACTERIOSTATS AND ARE PARTICULARLY USEFUL IN THE TREATMENT OF BACTERIAL INFECTIONS IN THE URINARY TRACT.
Nitrofuryl-triazolo(4,3-b)pyridazine-amide compounds of the formula:

Description

'United States Patent [1 1 Berger et a].
[ 51 Sept. 2, 1975 [73] Assignee: Boehringer Mannheim G.m.b.H.,
Mannheim, Germany [22] Filed: Dec. 18, 1972 [2]] Appl. No.: 316,198
[30] Foreign Application Priority Data Jan. 2l, I972 Germany 2202744 [52] US. Cl 260/250 AC; 260/250 A; 424/251 [51] Int. Cl. C07D 237/00 [58] Field of Search 260/250 A, 250 AC [56] References Cited UNITED STATES PATENTS 3,l38.593 6/l964 Burch 260/250 A 3,483,193 l2/l969 Gull 2.60/250 AC 3,506,656 4/1970 Berger et al 260/250 AC 3,522,256 7/l970 Berger Cl ill 260/250 AC Primary li.\'unz inerDonald G Daus Assistant Examiner-David E. Wheeler Attorney, Agent, or Firm-Burgess, Dinklage & Sprung ABSTRACT Nitrofuryl-triazolo[4,3-b]pyridazine-amide compounds of the formula:
CO-NH-R wherein R, is hydrogen or a saturated or unsaturated aliphatic hydrocarbon radical containing 2 to 5 carbon atoms,
are outstandingly effective as bacteriostats and are particularly useful in the treatment of bacterial infections in the urinary tract.
8 Claims, N0 Drawings NlTROFURYL-TRIAZOLO(4,3-b)PYRIDAZINE- AMIDE COMPOUNDS AND BACTERIOSTATIC COMPOSITIONS The present invention is concerned with new nitrofuryl-triazolol4.3-b1pyridazine-amide compounds and with bacteriostatic compositions containing them.
The new nitrofuryl-triazolo[4.3-blpyridazine-amide derivatives according to the present invention are compounds of the formula:
l N 11 l wherein R is hydrogen or a saturated or unsaturated aliphatic hydrocarbon radical containing 2 to carbon atoms, Thus. R can be alkyl. alkenyl. alkynyl of from 2 to 5 carbon atoms.
We have found that 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:
1. Reaction of the acid of the formula:
COOH
N l O N or of a reactive derivative thereof. with an amine of the general formula:
(Ill
wherein R, has the same meaning as above.
2. Oxidativc cyclization ofa compound ofthe general formula:
c n L emu-mu- $-co-mi--n o n N in which R has the same meaning as above.
11 1mm CO-NH-R1 (v) wherein R has the same meaning as above.
4. Nitration of a compound of the general formula:
CO-NH-R wherein R, has the same meaning as above.
5. Treatment of a compound of the general formula:
I I OgiU- (F N-NR0 CO-NIb-R O N ---N 2 (VII) wherein R has the same meaning as above. with an agent splitting off ammonia.
As derivatives of the acid of formula (ll), there can be used all compounds which react with amines to give amides. Thus. for example, the nitrile can be converted into an amide directly or via an amidine. In the simplest case, there are used 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. 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 compounds of general formula (IV) can be readily obtained via the corresponding nitrile or other reactive carboxylic acid derivative in a manner analogous to process 1.
For the condensation of the compounds (V) with 2- nitro-furan-S-carboxylic acid. 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.
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.
The 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. However, 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.
The 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.
The following Examples illustrate the preparation of the compounds of the present invention:
EXAMPLE 1 Preparation of 3-( 5-N itro-2-furyl )-6-carbamoyl-s-triazolo[4,3- b]pyridazine 0.147 g. 3-( 5-nitro-2-furyl )-6-chloroformyl-striazolo[4,3-blpyridazine was stirred for I hour at ambient temperature with 1 ml. concentrated aqueous ammonia solution. Insoluble material was then filtered off with suction and washed with water to give 0.1 g. 3-( 5-nitro-2-furyl )-6-carbamoyl-s-triazolo[4,3- b]pyridazine, which is recrystallized from 4 ml. dioxandimethyl formamide (9:1 with the addition of charcoal. There was thus obtained 0.06 g. 3-(5-nitro-2- furyl)-6-carbamoyl-s-triazolo[4,3-blpyridazine as a bright yellow product; m.p. 274 276C. (decomp).
The 3-( 5-nitro-2-fu ryl )-6-chloroformyl-s-triazolo- [4,3-b]pyridazine used as starting material was prepared as follows:
230 g. 3-chloro-6-cyano-pyridazine were suspended in 2500 ml. ethanol, 198 ml. hydrazine hydrate were added, with cooling, at ambient temperature and the reaction mixture was thereafter stirred for 30 minutes at ambient temperature. The precipitated crystals were filtered off with suction, washed with ethanol, triturated with a little ice water, filtered with suction and washed with ice water to give 195 g. crude 3-hydrazino- 6-cyano-pyridazine; m.p. l86 192C.
19.5 g. 3-hydrazino-6-cyano-pyridazine were dissolvedin 365 ml. water and 192 ml. methanol, with heating. At 50C., there were added 20 ml. 2N hydrochloric acid and a solution of 22.3 g. S-nitrofuran-Z- aldehyde in 192 ml. methanol, followed by stirring for minutes at this temperature and then for 30 minutes at ambient temperature. The solid material was then filtered off with suction, washed with 5071 aqueous methanol and thereafter with ether. There were thus obtained 35.17 g. crude 6-cyano-3-l2-(5-nitro-2-furfurylidenc)-hydrazino]-pyridazine, which is boiled for 4 15 minutes with 220 ml. dioxan: after filtering off with suction at 50C., there were obtained 23.6 g. of the pure compound; m.p. 275 278C (decomp).
23.6 g. 6-cyano-3-[2-(5-nitro-2-furfurylidene)- hydrazinol-pyridazine (m.p. 275 278C. (decomp)) were dissolved in 320 ml. hot trifluoroacetic acid, diluted with 320 ml glacial acetic acid and 46.5 g. lead tetracetate introduced portionwise, at a temperature between 45C. and 50C., while stirring. The reaction mixture was then further stirred for 30 minutes at 50C., the small amount of undissolved material was quickly filtered off with suction and the filtrate was gently evaporated in a vacuum. The evaporation residue was triturated with ice water, there being obtained 19.7 g. crude 3-( 5-nitro-2-furyl )-6-cyano-striaz0Io[4,3-blpyridazine; m.p. 186 190 198C. After recrystallization from isopropanoldioxan (1:1), with the addition of charcoal, the compound melts, with decomposition, at 212 214C.
15.8 g. 3-(5nitro-2-furyl)-6-cyano-s-triazolo-[4,3- bjpyridazine were boiled under reflux with 369 ml. 19% ethanolie hydrochloric acid for 2 hours, then left to stand overnight at ambient temperature. 1.7 g. of solid material were then filtered off with suction and the filtrate evaporated to dryness in a vacuum. The evaporation residue was introduced portionwise in a saturated aqueous solution of sodium bicarbonate and the precipitated product was filtered off with suction, washed with water and recrystallized from 350 ml. dioxan-ethanol (6:4), whereby 6.4 g. 3-(5-nitro-2-furyl- 6-ethoxy-carbonyI-s-triazolo 4 3-b pyridazine we re obtained; m.p. 225228C.
For the purpose of saponification, 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. After cooling, 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. There were thus obtained 5.5 g. crude 3-(5-nitro-2-furyl)-6-carboxy-s-triazolo-[4,3-b]pyridazine (m.p. 268 273C.) which, after recrystallization from dioxan-dimethyl formamide (9: 1 with the addition of charcoal, melts, with decomposition, at 280- 282C.
The 3-( 5-nitro-2-furyl )-6-carboxy-s-triazolo[ 4,3-blpyridazine thus obtained was boiled under reflux for 8 hours with 55 ml. thionyl chloride. The solution was then evaporated to dryness and the residue thoroughly triturated with trichlorocthylene. There were thus obtained 5.6 g. 3-(5-nitro-2-furyl)-6'chloroformyl-striazolol4,3-blpyridazine which, in contradistinction to the free acid, is readily soluble in dioxan.
EXAMPLE 2 Preparation of 3-( 5-Nitr r2-furyl )-6-( N-n-butylcarbamoyl )-striazolo[ 4,3-b pyridazinc 0.88 g. crude 3-(5-nitro-2-furyl)-6-chloroformyl-striazolo|4,3-b]pyridazine was stirred at ambient temperature for 1 hour with 11 ml. 6'71 aqueous n-butylamine solution. The reaction product was then filtered off with suction, washed with water and recrystallized from 18 ml. aqueous methanol, with the addition of charcoal, to give 0.55 g. 3-(5-nitro-2-furyl)-6-(N-nbutyl-carbamoyl )'-s-triazolo[ 4.3-b ]pyridazine in the form of a yellowish-white substance; nip. l56 157C.
EXAMPLE 3 Preparation of. 3-( 5-Nitro-2-furyl )-6-( N-allylcarbamoyl )-striazolo[ 4.3-b pyridazine 0.8 g. 3-(5-nitro-furyl)6-chloroformyIs-triazolo- [4.3-b]pyridazir*e was introduced, with stirring. into a 67! aqueous solution of allylamine, stirring was continued for 1 hour at ambient temperature and the solid substance was then filtered off with suction. washed with water and recrystallized from 85 ml. 80% aqueous methanol, with the addition of charcoal, there being obtained 0.42 g 3-(5-nitro-2-furyl)-6-(N-allylcarbamoyl)-s-triazoIo[4.3-blpyridazine in the form of a yellow product; m.p. I83 [85C.
The 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:
Compound No. Chemical Name A N-( S-Nitrofuryliden 1 -amino- (Comparison hydantoine (sold under the Compound) trade name Furadantin" by Norwich Pharmacal Co.) l 3-( S-Nitro-Z-furyl )-6-carhamoyl-s-triazolol 4.3-h pyridazinc 3-( S-Nitro-Z-furyl )-6-( N-nbutyI-carhamoyl )-s-tr'iazolo- 14.3-b lpyridaiine 3 3-(S-Nitro-Z-furyU-fi-(N- allylcarbamoyl )-s-tria1olo- I 4.3-h lpyridazinc The absolute bacteriostatic minimal concentration in vitro of the test compounds, for six different bacterial species. is set out in micrograms of test compound per milliliter in the following Table I.
In addition 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. Each value reported represents the result of one experiment and is expressed in terms of the volumes of water with which one volume of the excreted urine sample could be diluted and still retain its bacteriostatic property, due to the presence of test compoundv TABLE 11 Maximum Bacteriostatic Dilution Volume Ratio) Compound No.
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. Thus, a preferred form is a tablet containing to 200 mg. of active compound. Depending on the conditions, 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. 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. mannitol, methyl- TABLE l ABSOLI'TE BACTERIOSTATIC ACTIVITY IN VITRO (MINIMAL CONCENTRATION IN ug/ml) Compound Streptococcus Escherichia Escherichia Proteus Proteus Pseudomonas- No. l'accalis I) coli l8) coli I06) Mirahilis(298) mirahilis(279) aeruginosa(7l A If X 4 256 I28 IZX l l.(l() (1.25 (1.03] 2 l 2 cellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (for example stearic acid), gela tine, agar-agar, calcium phosphate. magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (for example polyethylene glyeols). Compositions suitable for oral administration can, if desired, also contain flavoring and/or sweetening agents. For external use, 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.
It will be understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.
What is claimed is:
1. A nitrofuryl-triazolo[4,3-bl-pyridazine-amide compound of the formula o n-m wherein R, is hydrogen dekyl, alkenyl, or alkynyl of from 2 to 5 carbon atoms.
2. The compound as claimed in claim 1 wherein R, is hydrogen.
3. A compound as claimed in claim 1 wherein R, is alkyl of from 2 to 5 carbon atoms.
4. A compound as claimed in claim 1 wherein R, is alkenyl of from 2 to 5 carbon atoms.
5. A compound as claimed in claim 1 wherein R, is alkynyl of from 2 to 5 carbon atoms having one triple bond.

Claims (8)

1. A NITROFURYL-TRIAZOLO(4,3-B)-PYRIDAZINE-AMIDE COMPOUND OF THE FORMULA
2. The compound as claimed in claim 1 wherein R1 is hydrogen.
3. A compound as claimed in claim 1 wherein R1 is alkyl of from 2 to 5 carbon atoms.
4. A compound as claimed in claim 1 wherein R1 is alkenyl of from 2 to 5 carbon atoms.
5. A compound as claimed in claim 1 wherein R1 is alkynyl of from 2 to 5 carbon atoms having one triple bond.
6. The compound as claimed in claim 1 designated 3-(5-nitro-2-furyl)-6-carbamoyl-s-triazolo (4,3-b)pyridazine.
7. The compound as claimed in claim 1 designated 3-(5-nitro-2-furyl)-6-(N-n-butyl-carbamoyl)-s-triazolo(4,3-b)pyridazine.
8. The compound as claimed in claim 1 designated 3-(5-nitro-2-furyl)-6-(N-allylcarbamoyl)-s-triazolo(4,3-b)pyridazine.
US316198A 1972-01-21 1972-12-18 Nitrofuryl-triazolo{8 4,3b{9 pyridazine-amide compounds and bacteriostatic compositions Expired - Lifetime US3903086A (en)

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* 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

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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

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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

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

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