DE3108068A1 - N-Methanesulphonic acids and alkali metal N-methanesulphonates of sisomicin, gentamicin and their derivatives, process for their preparation, pharmaceutical compositions containing these compounds, and their use as antibiotics - Google Patents

Abstract

The invention relates to N-methanesulphonic acids and alkali metal N-methanesulphonates of the broad-spectrum aminoglycoside antibiotics sisomicin, gentamicin and their derivatives, to a process for their preparation and to their use as antibiotics.

Description

N-methanesulphonic acids and alkali-N-methanesulphonates of

Sisomicin, gentamicin and their derivatives, processes for their preparation, Medicines containing the new compounds and their use as antibiotics The invention relates to new N-methanesulphonic acids and alkali-N-methanesulphonates broadly effective aminoglycoside antibiotics sisomicin, gentamicin and their derivatives, a process for their production and their use as antibiotics.

Aminoglycoside antibiotics of the sisomicin or

Gentamicins are important drugs for effective control bacterial infections. However, under treatment with these substances you can in isolated cases, side effects of the kidneys and auditory nerves occur.

It has already become known that antibiotics such as neomycin, Dihydrostreptomycin, Kanamycin and 3 ', 4'-Dideoxykanamacin B with formaldehyde and Sulfur dioxide or formaldehyde and sodium bisulfite or with sodium hydroxymethanesulfonate after several hours of reaction time into the corresponding N-alkanesulfonic acids or

Let transfer N-alkanesulfonates, which improve serte Show compatibility: German Auslegeschrift 1 216 280, German Offenlegungsschrift 1,418,452, The Journal of Antbiotics, Ser. A, 12, 114 (1959), The Journal of Antibiotics, Ser. A, 12, 117 (1959), The Journal of Antibiotics, Ser. A, 14 170 (1961), German Auslegeschrift 2 641 388. As these antibiotics, however, oppose a large number of resistant bacterial strains are ineffective, it is desirable for treatment bacterial infections broadly effective antibiotics with high tolerance own.

It has now been found that the broadly effective antibiotics sought are present with high tolerance in the compounds of the formula (I), where Me stands for sodium, potassium or hydrogen, R1 for methyl or ethyl, R2 for NH-X2, N-alkyl, N-hydroxyalkyl, N-hydroxyalkyl x2 x2 x2 2 len-NH, NH-CO-O-alkylene-NH-X, NH-CO-O-hydroxyal- 2 kylen-NH-X², NH-CO-O-alkylene-N-hydroxyalkyl, NH-CO- Hydroxyalkylene-NH-X where X2 has the meaning given above, R3 and R4 are different from one another and are hydrogen or hydroxy and R5 is a radical of the formulas where X1, X2, X3, X4 and X5 are identical or different and are CH2-SO3Me or hydrogen, at least one of the radicals X1 to X5 not being hydrogen.

It has also been found that the new compounds of the formula (I) are obtained if a compound of the formula (II) where Pos1, R3 and R4 have the meaning given above, R2 'stands for amino, alkylamino, hydroxyalkylamino, aminohydroxyalkylamino, aminoalkyloxycarbonylamino, aminohydroxyalkyloxycarbonylamino, hydroxyalkylaminoalkyloxycarbonylamino, aminohydroxyalkylcarbonylamino, and R5' stands for a radical of the formulas is, with HO-CH2-SO3Me 'or a mixture of formaldehyde and Me'HSO3 or a mixture of formaldehyde and Me2XS205 or a mixture of formaldehyde and SO2 in aqueous solution, where Me' stands for sodium or potassium.

In particular, alkyl in R2 stands for C1-C4-alkyl, hydroxyalkyl in R2 for C2-C5-hydroxyalkyl with 1 to 4 hydroxyl groups, hydroxyalkylene in R2 for C3-C6-hydroxyalkylene with 1 to 4 hydroxyl groups and alkylene in R2 for C2-C6 -alkylene.

Suitable radicals R2 are, for example: -NH-CH2 -503Na, -NH-CH2-S03K, -NH-CH2-S03H, -NH-CO-O-CH2CH2 -NH-CH2 -S03Na, The compounds according to the invention and their pharmaceutically usable salts are distinguished by a strong antibacterial activity and a considerably increased tolerance compared to the underlying aminoglycoside antibiotics.

The aminoglycoside antibiotics are preferably used as starting materials of the formula (II) Sisomicin, netilmicin, 3 "-N-ethyl-3" -N-desmethylsisomicin, 1-N- (2-aminoethyl- oxycarbonyl) -sisomicin, 1 -N- (3-amino-2-hydroxy-propyloxycarbonyl) -sisomicin, 1 -N-L2- (2, 3-dihydroxypropylamino) -ethyloxycarbonyl7-sisomicin, 1-N - / (R, R, S) -2,3,4,5-tetrahydroxypentyl7-sisomicin, 1 -N- (4-amino-2-hydroxybutyl) -sisomicin, 1-N- (4-amino-2-hydroxybutyryl) -sisomicin, 1-N- (S-3-Amino-2-hydroxypropionyl) -sisomicin, 1-N (/ S, S7-4-Amino-2,3-dihydroxy-butyloxycarbonyl) -sisomicin, 5-episisomicin, the gentamicins B, C1, Cola 'C2, 1-N- (S-3-amino-2-hydroxypropionyl) -gentamicin B.

When carrying out the process according to the invention, 1 Moles of a compound of the formula (II) with 1 to n moles of HO-CH2-SO3Me 'or with one Mixture of formaldehyde (as paraformaldehyde or 1,3,5-trioxane) and Me'HS03 or a mixture of formaldehyde (as paraformaldehyde or 1,3,5-trioxane) and Me'2S205 or a mixture of formaldehyde (as paraformaldehyde or 1,3,5-trioxane) and Sulfur dioxide in aqueous solution, where n is the maximum number of basic Means amino groups contained in the compound of the formula (II).

The reaction is generally carried out at temperatures of about 0 ° to 1000C, preferably between about 100C and about 500C.

The reaction can be carried out under normal pressure, but also under increased pressure will. In general, normal pressure is used.

To produce the substances according to the invention, reaction times are required which can range from less than a minute to 20 hours. The reaction time depends on the type of raw material used. So, according to a particular embodiment of the present invention surprisingly a mixture of sisomicin or gentamicin or their derivatives and the sodium salt of hydroxymethanesulfonic acid Use immediately after dissolving in water for an injection, as the implementation expired in less than a minute. In contrast, one needs for the reaction of sisomicin with sodium disulfite or sodium hydrogen sulfite with the poorly soluble Paraformaldehyde or 1,3,5-trioxane in water have longer reaction times.

If sisomicin and the sodium salt of hydroxymethanesulfonic acid are used as starting compounds, the reaction can be represented by the following equation: 5 HO-CH2-SO3Na (H20; 200C) Examples of active ingredients are: sisomicin-penta-N-methanesulfonic acid, sodium salt sisomicin-tetra-N-methanesulfonic acid, sodium salt sisomicin-tetra-N-methanesulfonic acid, potassium salt sisomicin-tris-N-methanesulfonic acid, sodium salt sisomicin-di-sulfonic acid , Sodium salt sisomicin-mono-N-methanesulfonic acid, sodium salt 3 "-N-ethyl-3" -N-desmethylsisomicin-penta-N-methanesulfonic acid, sodium salt 3 "-N-ethyl-3" -N-desmethylsisomicin-tetra-N- methanesulfonic acid, sodium salt 3 "-N-ethyl-3" -N-desmethylsisomicin-tris-N-methanesulfonic acid, sodium salt 1-N- (2-Aminoethyloxycarbonyl} -sisomicin-penta-N-methanesulfonic acid, sodium salt 1-N- (2- Aminoethyloxycarbonyl) -sisomicin-tetra-N-methanesulfonic acid, sodium salt 1-N- (2-Aminoethyloxycarbonyl) -sisomicin-tris-N-methanesulfonic acid, sodium salt 1-N - (/ SIS7-4-amino-2,3-dihydroxy-butylox micin-tetra-N-methanesulfonic acid, sodium salt, 1-NL (R, R, S) -2,3,4,5-tetrahydroxypentyl / -sisomicinpenta-N-methanesulfonic acid, sodium salt 1-N - / (R, R, S ) -2,3,4,5-tetrahydroxyp entyl7-sisomicintetra-N-methanesulfonic acid, sodium salt 1-N - / (R, R, S) -2,3,4,5-tetrahydroxypentyl7-sisomicintris-N-methanesulfonic acid, sodium salt netilmicin-penta-N-methanesulfonic acid, sodium salt netilmicin- tetra-N-methanesulfonic acid, sodium salt Netilmicin-tris-N-methanesulfonic acid, sodium salt 1 -N- (4-amino-2-hydroxybutyl) -sisomicin-penta-N-sulfonic acid, sodium salt 1 -N- (3-amino-2- hydroxypropyloxycarbonyl) sisomicin tetra-N-methanesulfonic acid, sodium salt 1-N- / 2- (2,3-dihydroxypropylamino) -ethyloxycarbonyl7-sisomicin-tetra-N-methanesulfonic acid, sodium salt 1-N- (S-3-amino-2-hydroxypropionyl ) -gentamicinB-tetra-N-methanesulphonic acid, potassium salt 5-episisomicin-tetra-N-methanesulphonic acid, sodium salt Gentamicin-tris-N-methanesulphonic acid, sodium salt The active ingredients according to the invention are generally solid substance mixtures in which the introduced n N-methanesulphonate -Groupings are statistically distributed over the basic amino groups present in the starting product of the formula (II). Since the reactivity of these amino groups differs only very slightly from one another, no selective conversion occurs. For practical use, it is irrelevant whether the active compounds according to the invention are used as substance mixtures or as uniform compounds.

The active ingredients according to the invention show characteristic characteristics in the IR spectrum Absorption bands at around 3450, 1635, 1190 and 1035 cm 1. In the thin-layer chromatogram (TLC cellulose prefabricated plates, Merck, Darmstadt; mobile phase = n-butanol / pyridine / water / acetic acid 5: 5: 3: 2) they run as strongly polar sub- punch at lower Rf values than the output compounds. The compounds are diluted through Hydrochloric acid cleaved, with formaldehyde as cleavage products by reaction with Detect dimedone and the underlying aminoglycoside by thin-layer chromatography permit. There is also a cleavage to the underlying aminoglycoside if one the active compounds according to the invention in aqueous-ammoniacal solution for 1 day at room temperature hydrolyzed. In contrast, these compounds can be dissolved in aqueous solution without cleavage Heat up to 600 for 8 hours. After being metabolized by the mouse, the active ingredients are partly in the form of the underlying aminoglycoside and partly unchanged Excreted in the urine, which can be determined by electrophoresis or thin layer chromatography and subsequent bioautographic determination can be proven.

The compounds of the invention are antimicrobial agents with a broad spectrum of activity and particular effectiveness against gram-negative bacteria.

These properties allow them to be used as medicinal products, especially in combating diseases caused by bacteria in humans and animals. They are good for prophylaxis and chemotherapy by local and systemic infections, especially of the genitourinary system in human and veterinary medicine suitable that are caused by gram-negative bacteria, e.g. E.coli, Proteus, Klebsiella and Pseudomonas ver caused, suitable. Hemmhöfe in the A-rar hole test were for example against the following bacteria Sta at a concentration of 100 micrograms ml found: Pseudomonas aerug. 5737 Pseudomonas aerug. F 41 Klebsiella pneum. 2 Müncnen Klebsiella pneum. 1 Düsseldorf E. coli Münster E. coli Neumann The procedure for the treatment of diseases caused by bacteria is characterized by that the compounds according to the invention are administered to humans and animals to suffer from these diseases.

In general, the dose of the compounds to be administered depends de, invention of the age and weight of the living being, of the type of administration, of The type and severity of the bacterial infection. The dosage of the invention Compounds is usually similar to the dosage of the underlying aminoglycosides. The dosage range is from 20 mg / day / human to 2000 mg / day / human, preferably 100 mg - 500 mg / day.

The compounds of the invention can be administered orally. the Administration can take place in single doses or divided into several doses. she can also to- are administered in the form of ointments, Creams or lotions. Pharmaceutical carriers for these formulations include Water, oils, fats, polyesters and polyols.

As shown below, the process for making Medicinal products which contain the new derivatives, characterized in that the new compounds with pharmaceutically suitable carriers and / or additives mixed.

For oral administration of the compounds of this invention you can Tablets, capsules or elixirs are used, but the compounds can can also be added to animal feed.

In general, topical preparations contain approx.

0.1 to about 3.0 g of the compounds of the invention per 100 g of ointment, Cream or lotion. Topical administration takes place approximately 2 to 5 times a day.

The antibacterial agents of the invention can be in liquid form as solutions or suspensions for use on the ears and eyes or for parenteral use Administration in the form of intramuscular or intravenous injections. Injection solutions or suspensions are usually administered so that approx.

1 to 15 mg of active ingredient per kilogram of body weight in 2 to 4 doses per day in the infected organism reach. The exact dose depends on the type of infection, the sensitivity of the infecting germ and on the individual characteristics of the person to be treated.

Formulation 1 tablet 10 mg tab. 25 mg tab. 100 mg tab.

a) Compound according to Example 1 10.50 * mg 26.25 * mg 105.00 * mg lactose 197.50 mg 171.25 mg 126.00 mg corn starch 25.00 mg 25.00 mg 35.00 mg polyvinylpyrrolidone 7.50 mg 7.50 mg 7.50 mg Magnesium stearate 2.50 mg 2.50 mg 3.50 mg * 5% excess A slurry of the compound according to Example 1, lactose and polyvinylpyrrolidone, and these are spray-dried, man gives the corn starch and magnesium stearate and compressed into tablets.

Formulation 2 ointment compound according to Example 1 1.0 g of methyl paraben U.S.P. 0.5 g propyl paraben U.S.P. 0.1 g petrolatum per 1000 g Manufacturing (1) Melt the petrolatum; (2) the compound of Example 1 is mixed with methyl paraben and propyl paraben with about 10% of the melted petrolatum; (3) gives the mixture in a colloid mill; (4) add the remaining petrolatum while stirring and cool, until it becomes semi-solid. The product is filled into suitable containers.

Formulation 3 solution for injection Per 2.0 ml vial per 50 liter connection according to Ex. 1 84.0 mg * 2100.0 gm methyl paraben, U.S.P. 3.6 mg 90.0 gm propyl paraben, U.S.P. 0.4 mg 10.0 gm sodium bisulfite, U.S.P. 6.4 mg 160.0 gm disodium ethylenediaminetetraacetate dihydrate 0.2 mg 5.0 gm water, U.S.P. q.s. 2.0 mg 50.0 liters * 5% excess example 1 Sisomicin-tetra-N-methanesulfonic acid, sodium salt A solution of 1.34 g (0.003 Mol) sisomicin in 1 ml of water are mixed with 360 mg (0.012 mol) of paraformaldehyde and 1.14 g (0.006 mol) of sodium disulfite in 1 ml of water and shake after subsidence the exothermic reaction, the reaction mixture for 4 hours at room temperature. The next Day is filtered and the filtrate is poured into 25 ml of ethanol, whereby one receives two-phase solution. The lower phase is kneaded with a total of 60 ml of ethanol and the solid product obtained is dried in a high vacuum.

Yield: 2.15 g.

Example 2 Sisomicin-tris-N-methanesulfonic acid, sodium salt analogous to Example 1 1.34 g (0.003 mol) sisomicin, 270 mg (0.009 mol) paraformaldehyde and 855 mg (0.0045 moles) of sodium disulfite.

Yield: 1.75 g white powder.

Example 3 Sisomicin-di-N-methanesulfonic acid, sodium salt analogous to example 1 1.34 g (0.003 mol) sisomi- cin with 180 mg (0.006 Moles) paraformaldehyde and 570 mg (0.003 moles) sodium disulfite.

Yield: 1.6 g of white powder.

Example 4 Sisomicin-mono-N-methanesulfonic acid, sodium salt analogous to Example 1 1.34 g (0.003 mol) sisomicin with 90 mg (0.003 mol) paraformaldehyde and 285 mg (0.0015 mole) sodium disulfite.

Yield: 0.6 g.

Example 5 Sisomicin-penta-N-methanesulfonic acid, sodium salt analogous to example 1 447 mg (0.001 mol) sisomicin in 1 ml water with 150 mg (0.005 Mol) paraformaldehyde and 475 mg (0.0025 mol) sodium disulfite and stirred with 10 ml of methanol.

Yield: 590 mg of white powder.

Example 6 Sisomicin tetra-N-methanesulfonic acid, sodium salt A solution 1.34 g (0.003 mol) of sisomicin in 2.5 ml of water is mixed with 1.66 g (0.012 mol) of hydroxymethanesulfone acid, Sodium salt (97 egg) shaken for 15 h at room temperature and according to the example 1 worked up.

Yield: 2.1 g of white powder.

Example 7 Sisomicin tetra-N-methanesulfonic acid, sodium salt A solution of 134 mg (3 x 10 4 mol) sisomicin in 0.25 ml of water becomes 166 mg (1.2 x 10-3) Hydroxymethanesulfonic acid, sodium salt (97%) shaken at room temperature for 0.5 minutes and the reaction product isolated by stirring with 2 ml of ethanol, which with the obtained according to Example 1 is identical.

Yield: 205 mg of white powder.

Example 8 Sisomicin-tetra-N-methanesulfonic acid, sodium salt The procedure is followed as in Example 1, where paraformaldehyde is replaced by 1,3,5-trioxane.

Yield: 2.1 g.

Example 9 Sisomicin-tetra-N-methanesulfonic acid, sodium salt The procedure is followed as in Example 1, using sodium di- sulfite by a fresh Replaced prepared sodium hydrogen sulfite solution.

Yield: 2.1 g.

Example 10 Sisomicin-tetra-N-methanesulfonic acid, potassium salt analogous to Example 1 1.34 g (0.003 mol) with -360 mg (0.012 mol) of paraformaldehyde and 1.33 g (0.006 mole) potassium disulfite.

Yield: 2.2 g.

Example 11 3 "-N-Ethyl-3" -N-desmethylsisomicin-tetra-N-methanesulfonic acid, Sodium salt As in Example 1, 1.38 g (0.003 mol) of 3 "-N-ethyl-3" -N-desmethylsisomicin are used (German Offenlegungsschrift 2,737,264) with 360 mg (0.012 mol) paraformaldehyde and 1.14 g (0.006 moles) of sodium disulfite.

Yield: 2.2 g of white powder.

Example 12 1-N- (2-Aminoethyloxycarbonyl) -sisomicin-penta-N-methanesulfonic acid, Sodium salt To a solution of 534 mg (0.001 mol) 1-N- (2-aminoethyloxycarbonyl ) -sisomicin (German Offenlegungsschrift 2 753 769) in 0.4 ml of water is added Ice cooling 150 mg (0.005 mole) paraformaldehyde and 475 mg (0.0025 mole) sodium disulfite in 0.4 ml of water and shake for 5 hours at room temperature. The reaction mixture is clarified by filtration and stirred with a total of 20 ml of ethanol, with a white solid product precipitates.

Yield: 0.83 g.

Example 13 1 -N- (2-Aminoethyloxycarbonyl) -s isomicin-tetra-N-methanesulfonic acid, Sodium salt The procedure is analogous to Example 12, but with 120 mg (0.004 mol) of parnformaldehyde and 380 mg (0.002 mole) sodium disulfite.

Yield: 0.8 g.

Example 14 1-N- (2-Aminoethyloxycarbonyl) -sisomicin-tris-N-methanesulfonic acid, Sodium salt The procedure is analogous to Example 12, but with 90 mg (0.003 mol) of paraformaldehyde and 285 mg (0.0015 mole) sodium disulfite.

Yield: 0.68 g.

Example 15 1-N- / 7R, R, S) -2,3,4,5-tetrahydroxypentyl7-sisomicintetra-N-methanesulfonic acid, Sodium salt As in Example 12, 577 mg (0.001 mol) 1-N- / 7R, R, S) -2,3,4,5-tetrahydroxypentyl-7-sisomicin are used (German Offenlegungsschrift 2,832,268) with 120 mg (0.004 mol) paraformaldehyde and 380 mg (0.002 moles) of sodium disulfite.

Yield: 0.65 g.

Example 16 1-N- / 7R, R, S) -2,3,4,5-tetrahydroxypentyl7-sisomicintris-N-methanesulfonic acid, Sodium salt As in Example 12, 577 mg (0.001 mol) 1-N - / (R, R, S) -2,3,4,5-tetrahydroxypentyl-7-sisomicin are used with 90 mg (0.003 mol) of paraformaldehyde and 285 mg (0.0015 mol) of sodium disulfite.

Yield: 0.55 g.

Example 17 Netilmicin tetra-N-methanesulfonic acid, potassium salt Corresponding to Example 6 are 475 mg (0.001 mol) of netilmicin with 0.6 g of hydroxymethanesulfonic acid, Potassium salt implemented.

Yield: 0.75 g.

Example 18 3 "-N-Ethyl-3" -N-desmethyl-sisomicin-tetra-N-methanesulfonic acid, Sodium salt The procedure is analogous to Example 1, but with 1.38 g (0.003 mol) of 3 "-N-ethyl-3" -N-desmethyl-sisomic in (German Offenlegungsschrift 2 737 264).

Yield: 2.05 g.

Example 19 Gentamicin tetra-N-methanesulfonic acid, sodium salt Man works as in Example 1, but with 1.40 g (0.003 mol) of gentamicin (as a mixture the gentamicins C1 C2 and C1a / 4: 4: 27).

Yield: 1.88 g.

Example 20 Gentamicin-penta-N-methanesulfonic acid, potassium salt analogous to Example 1 1.40 g (0.003 mol) gentamicin with 450 mg (0.015 mol) paraformaldehyde and 1.67 grams (0.0075 moles) of potassium disulfite.

Yield: 2.54 g.

Example 21 Sisomicin tetra-N-methanesulfonic acid, sodium salt Mix equal volumes of solutions A and B together in a syringe and uses the mixture obtained in this way for the therapeutic treatment of bacterial bacteria Infections.

Solution A = 447 mg (0.001 mol) sisomicin in 1 ml phosphate buffered (pH 7) physiological saline solution.

Solution B = 536 mg (0.004 mol) hydroxymethanesulfonic acid, sodium salt in 1 ml of phosphate-buffered (pH 7) physiological saline solution.

Claims (6)

Claims 1) Compounds of the formula (I) where Me stands for sodium, potassium or hydrogen, R1 for methyl or ethyl, R2 for NH-X², N-alkyl, N-hydroxyalkyl, N-hydroxyalkyl X² Hydroxyalkylene-NH-X², where X2 has the meaning given above, R3 and R4 are different from one another and are hydrogen or hydroxy and R5 is a radical of the formulas 2 len-NH, NH-CO-O-alkylene-NH-X, NH-CO-O-hydroxyal- X 2 kylen-NH-X, NH-CO-O-alkylene-N-hydroxyalkyl, NH-CO- '2 X where x1, X2, X3, X4 and X5 are identical or different and are CH2-SO3Me or hydrogen, at least one of the radicals X1 to X5 not being hydrogen. 2) Compounds according to claim 1, characterized in that alkyl in R2 for C1-C4-alkyl, hydroxyalkyl in R2 for C2-C5-hydroxyalkyl with 1 to 4 hydroxyl groups, Hydroxyalkylene in R2 for C3-C6 hydroxyalkylene with 1 to 4 hydroxyl groups and alkylene in R2 stand for C2-C6-alkylene. 3) Compounds according to claim 1, characterized in that R2 represents one of the radicals -NH-CH2-S03Na, -NH-CH2-SO3K, -NH-CH2-SO3H, -NH-CO-O-CH2CH2-NH-CH2-SO3Na, stands. 4) Process for the preparation of the compounds of the formula (I), characterized in that a compound of the formula (II) wherein R1, R3 and R4 have the meaning given in claim 1, R2 F stands for amino, alkylamino, hydroxyalkylamino, aminohydroxyalkylamino, aminoalkylcarbonylamino, aminohydroxyalkyloxycarbonylamino, hydroxyalkylaminoalkyloxycarbonylamino, aminohydroxyalkylcarbonylamino, and R5 stands for a radical of the formulas is, with HO-CH2-SO3Me 'or a mixture of formaldehyde and Me'HSO3 or a mixture of formaldehyde and Me2'S205 or a mixture of formaldehyde and SO2 in aqueous solution, where Me' stands for sodium or potassium. 5) Antibiotic active drug, characterized in that it contains a compound according to claims 1 to 3 as active ingredient. 6) Use of compounds according to Claims 1 to 3 in combating of diseases caused by bacteria.