DE2161586A1 - 5-nitrofuryl triazolopyridazines - microbicides, active against urinary tract infections - Google Patents

Abstract

Compounds of formula (I) where X = O or S; Het = triazolo- 4,3-b pyridazine; n = 0 or 1; R1 and R2 = H, cycloalkyl(5-7C) or satd. or unsatd. hydrocarbon opt. substd. by aryl, OH, SH, lower alkoxy, lower alkyl mercapto, morpholino, furyl, amino, alkylamino or acylamino; or R1 and R2, together with the N atom, may form a piperidine, piperazine, pyrrolidine or morpholine ring, opt. subst. by OH, carboxy, alkyl or hydroxyalkyl. Microbicides, esp. useful in urinary tract infections. 2.32g. (II), X = O, n = 0, Hal = Cl was suspended in 25 ml. dioxan and 25 ml. methanol. 12.4g. (III) R1 = C2H4OH, R2 = Y = H was added and the mixture refluxed for 1 hour. After cooling the mixture was filtered and the residue recrystallised from aqueous dioxan to give 0.85g. (I) m.pt. 284-285 degrees C.

Description

Nitrofuryl-triazolo [4,3-] pyridazine derivatives Addition to the patent application File number P 21 13 438.3 From DOS 1.670.095 are nitrofuryl-triazolo [4,3-b] pyridazine derivatives known which are substituted by an acylated amino group are and antimicrobial properties, especially antibacterial activity im.urine. It has been found that the urinary activity of nitrofuryltriazolo [4,3-b] pyridazine derivatives can increase to an unexpected and surprising extent for the person skilled in the art, if the above-mentioned amino group is substituted with variable alkyl radicals.

The main application relates to NitrOfuryl-fTiazolo t4, 3-b-pyridazine derivatives of the general formula 1 in which X is an oxygen or sulfur atom, n is the number 0 or 1, Het is the triazolo [4,3-b] pyridazine system and R1 and R2 is a cycloalkyl radical having 5-7 carbon atoms or a saturated or unsaturated lower hydrocarbon radical, which is optionally substituted by hydroxyl -, mercapto, lower alkoxy, lower alkyl mercapto, orpholino, furyl or optionally alkylated amino groups can be substituted, the two radicals R1 and R2 together with the nitrogen atom also optionally by a hydroxyl, carboxyl, alkyl or hydroxyalkyl group substituted piperdine, piperazine, pyrrolidine or morpholine ring and where optionally one of the radicals R1 and R2 can also be hydrogen, their physiologically acceptable salts, storage for the production of the same, and their use for the production of medicaments with antimicrobial effect. The main application also relates to medicaments containing compounds of the general formula 1.

The triazolo (4,3-b] pyridazine ring system is preferred in formula I substituted in the 3- or 6-position.

According to the invention, the compounds of the main application have particular properties interesting antimicrobial properties, especially against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Proteus mirabilis. Because these connections surprisingly have an extremely high antibacterial activity in the urine, they are ideal for treating urinary tract infections.

In the embodiment of the inventive concept of the main application was now found that those compounds of formula I also have a good antimicrobial Have effect in which the hydrocarbon radicals R1 and / or R2 by longer Are substituted by alkyl, aryl or acylamino groups.

The present invention accordingly relates to nitrofuryltriazoloE41 3-bpyridazine derivatives of the general formula I ' in which X is an oxygen or sulfur atom, n is the number 0 or 1, Het is the triazolo [4,3-b] pyridazine system and R1 'and R2' is a cycloalkyl radical having 5-7 carbon atoms or a saturated or unsaturated lower hydrocarbon radical, which optionally can be substituted by hydroxyl, mercapto, lower alkoxy, lower alkyl mercapto, morpholino, furyl or optionally alkylated amino groups, the two radicals R and R21 together with the nitrogen atom also optionally by a hydroxyl, carboxyl, Alkyl or hydroxyalkyl group substituted piperidine, piperazine, pyrrolidine or morpholine ring and where optionally one of the radicals R11 and RZ 'can also be hydrogen, characterized in that the hydrocarbon radicals R1' and / or R2 by longer alkyl, through Aryl or substituted by acylamino groups and their pharmacologically acceptable salt Di.e new compounds 1 'are in an si Ch prepared in a known manner by a) compounds of the general formula II in which X, n and Het have the abovementioned meaning and Hal represents a halogen atom, with compounds of the general formula III in which R4 and R5 represent hydrogen or the radicals R1 and Rz 1 2, and Y can be hydrogen or a formyl group, and in the event that R4 and / or R5 is hydrogen, the amino group, if desired, then by one or two of the radicals R1 'and R21 substituted, b) compounds of the general formula IV in which X, n, Het, R1 'and R2' have the abovementioned meaning, nitrated, or c) compounds of the general formula V in which X, n, R1 'and R2' have the meaning given above and R2 represents hydrogen, a hydroxyl or an amino group, cyclizes, or d) in the event that n should be l, compounds of the general formula VI or VI ' in which R1 'and R2' have the meaning given, with aldehydes of the general formula VII, in which X has the meaning given above, or condensed with a reactive derivative thereof and, if desired, then converted into their physiologically tolerable salts.

The reaction of the compounds II with compounds III usually takes place in a polar organic solvent, preferably at an elevated temperature. In many cases, however, you can do without a solvent and the compounds React II in an excess of the amine III. As a polar solvent for example, a lower alcohol such as methanol or a cyclic one is used Ether, like dioxane.

If Y in the compounds III represents a formyl group, then these split off during the reaction so that this no longer occurs in the end product.

The primary or secondary amino group is substituted in the usual way1, for example, with the corresponding halides of the radicals R1 and R2t. In the event that R1 and / or R21 is to be a methylol radical, formaldehyde can also be used are used as alkylating agents.

Compounds IV are nitrated with concentrated nitric acid in the presence of a dehydrating agent such as concentrated sulfuric acid or acetic anhydride, if possible at low reaction temperatures. Possibly in the Acetyl groups introduced in the molecule can then be replaced in a simple manner by acidic Hydrolysis can be split off again.

The compounds of the formula V used as starting materials are obtained one, in the case that R3 is hydrogen, in the usual way by condensation of the corresponding aldehydes with 6-substituted-4.e 3-hydrazinopyridazines. The oxidative cyclization is effected by mild oxidizing agents, whereby Lead tetraacetate and iron (III) chloride have proven particularly effective. The reaction will in polar organic solvents such as glacial acetic acid or alcohol at room temperature or carried out with heating.

The compounds of the formula V in which R3 represents an amino group are obtained by condensation of the corresponding imido ethers with correspondingly G-substituted ones 3-llydrazino-pyridazines obtained.

The cyclization can in this case by simply heating in an inert solvent, or by treatment with aqueous mineral acids can be partially effected at room temperature.

The cyclization of compounds of the formula V in which R3 is a Means hydroxyl group is preferably obtained by heating.

with water-binding agents such as acetic anhydride or polyphosphoric acid carried out. In many cases, however, it can already be achieved by cooking in higher-boiling, inert solvents such as toluene or xylene. The compounds V, in which R3 represents a hydroxyl group, are obtained by acylation of the corresponding ilydrazinopyridazines with the corresponding carboxylic acids or with reactive derivatives thereof.

As a reactive derivative of the aldehydes used in reaction d) VII are used, for example, diacyl derivatives, preferably diacetates, which with the compounds VI, for example, can be converted into acetic anhydride.

As physiologically harmless salts of the compounds L come, for example the flydrochloride, sulfates, phosphates, tartrates, citrates or acetates in question, in a manner known per se (e.g. by neutralization with appropriate acids) getting produced. Compounds of the formula 1 which are in the radicals R1 'and / or R 1 contain carboxyl groups, form with the basic 2 groups of the molecule internal salts. In the event that the acidic groups predominate, however, these can for the production of pharmacologically safe salts with inorganic or organic Bases, such as g * Bt alkali or alkaline earth hydroxides or carbonates, or with amines be neutralized.

In many cases it is advantageous to have the desired substituents only after preparation of the nitrofuryl - triazolo-pyridazine system from less sensitive To produce substituents.-For example, a hydroxyl group can be produced by hydrolysis an acyloxy group or a halogen atom or by diazotization and boiling an amino group. An amino group becomes preferable during the reaction protected by acetylation or subsequently by aminolysis of a halogen substituent introduced. Conversely, acylamino or acyloxy groups can pass through in the usual way subsequent acylation of amino or hydroxyl groups can be produced. Of the The easiest way to achieve alkoxy is by alcoholysis of a halogen substituent introduce.

The substances 3: 1 can be used in liquid or solid form, orally and parenterally be applied. The preferred injection medium is water, which is the usual additives for injection solutions such as stabilizers and solubilizers and / or contains buffers. Such additives are e.g.

Tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (like ethylenediaminetetraacetic acid), high molecular weight polymers (like liquid Polyäthyleno> * id) for viscosity regulation.

Solid carriers are e.g. starch, lactose, mannitol, methyl cellulose, Talc, highly dispersed silica, higher molecular weight fatty acids (such as stearic acid), Gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable Fat, solid, high molecular weight polymers (such as polyethylene glycols). For oral application If desired, suitable preparations can contain flavorings and sweeteners. For external use, the substances II according to the invention can also be used in the form are used by powders and ointments they are used e.g. with powdery, physiologically compatible diluents or

usual ointment bases mixed in the following examples the invention explained in more detail.

Example 1 3- (5-Nitro-2-furyl) -6- (ß-phenaethyl-amino) -s-triazolo [4,3-b] pyridazine A solution at 700 ° C. of 1 g of 3- (5-nitro-2-furyl) -6-chloro-s triazolo [4,3-bjpyridazine in 7 ml of dimethylformamide, 0.96 g of ß-phenylethylamine is added and 30 minutes touched. Then you cool down, add ice water, suck out the precipitated crystals off, washes them neutral with water and dries. After recrystallization from dimethylformamide with the addition of carbon, 0.9 g of yellow crystals which are uniform by paper chromatography are obtained of 3- (5-nitro-2-furyl) -6- (ß-phenylethyl-amino) -s-triazolo [4,3-b] pyridazine, (mp. 224-2260C).

Elemental analysis and spectrum confirm the stated structure.

Example 2 3- (5-Nitro-2-furyl) -6- (2-acetamino-ethyl-amino) -s-triazolo [4,3-b] pyridazine 8 g of 3- (5-nitro-2-furyl) -6-chloro-s-triazolo [4,3-b] pyridazine and 6.7 g of acetylethylenediamine are stirred in 65 ml of dimethylformamide at 700C. The solution from which after about Crystals precipitate for 15 minutes, after one hour the mixture is cooled, filtered off with suction and the residue is washed with dimethylformamide and water. After drying will be so 7.8 g of 3- (5-nitro-2-furyl) -6- (2-acetaminoethyl-amino) -s-triazolo [4,3-b] pyridazine (M.p. 280-2830C dec.). Recrystallized from dimethylformamide, increases the melting point of the yellow crystals no longer increases.

Elemental analysis and spectrum confirm the stated structure. B. e i s p i-e 1 3 3- (5-nitro-2-furyl) -6-octadecylamino-s-triazolo [4,3-b-pyridazine 1.5 g 3- (5-nitro-2-furyl) -6-chloro-s-triazolo [4,3-pyridazine and 3.3 g stearylamine are stirred in 30 ml of dimethylformamide at 70 ° C. for one hour. Then it cools down, mixed with alcohol, filtered off with suction and the residue boiled with methanol. To Recrystallization from dimethylformamide with the addition of charcoal gives 1.48 g of 3- (5-nitro-2-furyl) -6-octadecylamino-s-triazolo [4,3-b pyridazine in yellow crystals (m.p. 213-2140C), elemental analysis and spectrum confirm the specified structure.

Claims (5)

P a t e n t a n s p r ü c h e 1. Nitrofuryl-triazolo [4,3-b] pyridazine derivatives of the general formula I ' in which X is an oxygen or sulfur atom, n is the number 0 of 1, Het is the triazolo [4,3-b] pyridazine system and R1 'and R2' is a cycloalkyl radical having 5-7 carbon atoms or a saturated or unsaturated lower hydrocarbon radical, which optionally can be substituted by hydroxyl, mercapto, lower alkoxy, lower alkyl mercapto, morpholino, furyl or optionally alkylated amino groups, the two radicals R1 'and R2' together with the nitrogen atom also optionally by a hydroxyl, carboxyl , Alkyl or hydroxyalkyl group substituted piperidine, piperazine, pyrrolidine or morpholine ring and where optionally one of the radicals Ri 'and R2 can also be hydrogen, characterized in that the hydrocarbon radicals R1' and / or R2 by longer alkyl, are substituted by aryl or acylamino groups and their pharmacologically acceptable salts. 2. Process for the preparation of nitrofuryl-triazolo [4,3-b] pyridazine derivatives of the general formula I ' in which X is an oxygen or sulfur atom, n is the number 0 or 1, Het is the triazolo [4,3-b] pyridazine system and R1 'and is not a cycloalkyl radical with 5-7 carbon atoms or a saturated or unsaturated lower hydrocarbon radical, which is optionally substituted by hydroxyl -, mercapto, lower alkoxy, lower alkyl mercapto, morpholino, furyl or optionally alkylated amino groups can be substituted, the two radicals R1 'and R2' together with the nitrogen atom also optionally by a hydroxyl, carboxyl, Alkyl or Hydro7aflylgruppe substituted piperidine, piperazine, pyrrolidine or Morplaolinring can form and where appropriate one of the radicals R1 and R2 'can also be hydrogen, and in the embodiment of the main. registration file number P 21 13 438.3 the hydrocarbon radicals R1 'and / or R2' are substituted by longer alkyl, by aryl or by acylamino groups and by their pharmacologically acceptable salts, characterized in that a) compounds of the general Formula II in which X, n and Het have the abovementioned meaning and Mal represents a halogen atom, with compounds of the general formula III in which R4 and R5 represent hydrogen or the radicals R1 'and R2, and Y can be hydrogen or a formyl group, and in the event that R4 and / or R5 is hydrogen, the amino group, if desired, subsequently by one or two of the radicals R1 and R2 'substituted, b) compounds of the general formula IV in which X, n, Het, R1 'and R2' have the abovementioned meaning, nitrated, or c) compounds of the general formula V in which X, n, R1 'and R2' have the meaning given above and R3 represents hydrogen, a hydroxyl or an amino group, cyclizes or d) if n should be 1, compounds of the general formula VX or VI ' in which R1 'and R2' the specified. Have meaning with aldehydes of the general formula VII, in which X has the meaning given above, or condensed with a reactive derivative thereof and, if desired, then converted into their physiologically acceptable salts. 3. Use of nitrofuryl-triazolo [4,3-b] pyridazine derivatives of general formula 3 :, 'as well as their pharmacologically acceptable salts for Manufacture of pharmaceuticals with antimicrobial effects. 4. Medicines with an antimicrobial effect consisting of a physiological compatible carrier and at least one compound of the formula I 'or one pharmacologically acceptable salt thereof. 5. Medicament according to claim 4, characterized in that the Carrier made from starch and / or lactose, mannitol, methyl cellulose, talc, silica, Fatty acids, gelatin, agar-agar, calcium phosphate, magnesium stearate, an animal or vegetable fat or oil or a solid high molecular weight polymer.