DE2644911C3 - Derivatives of kanamycin A or B, processes for their preparation and medicaments containing them - Google Patents

Description

where mean:

R ^{1 represents} a hydrogen atom or a methyl group;
R ^{2 is} an amino or hydroxyl group and
R ^{3 is} an S-amino-S-deoxy-aD-glucopyranosyl group

as well as their pharmaceutically acceptable acid

CH, NHR ¹ NH,

HO
HO

addition salts, characterized in that π = 4

2. l-N - [(S) -2-Hydroxy-6-aminohexyl] -kanamycin-A.

3. Process for the preparation of the compounds according to claim 1, characterized in that one compound of the general formula:

R- HO

O OH

Ii i

- NHC-CH (CH,) "NH,
OR- '

in which R ¹ to R ³ and π have the meanings given in claim 1, reduced in a manner known per se, the compound of the general formula (I) isolated and optionally converted into a pharmaceutically acceptable acid addition salt.
4. The method according to claim 3, characterized in that the reduction is carried out with diborane.

5. Medicament, characterized in that it contains a compound according to one of claims 1 or 2, optionally together with a pharmaceutically acceptable carrier.

The invention relates to new antibacterially active derivatives of Kanamycin A or B, a method for Manufacture of these compounds and medicaments containing these compounds.

In DE-PS 25 47 738 new compounds of the following general formula are described:

CH ₂ NHR ¹
JO

NH,

HO-s

HO

V «

R- HO

OH

> - Nl ICI I ₂ CH (CH,) "NI -I ₂
OR- ¹

where mean:

R ^{1 represents} a hydrogen atom or a methyl group;

R ^{2 is} an amino or hydroxyl group;

R ^{3 is} a 3-amino-3-deoxy - «- D-glucopyranosyl group

and
η = I, 2or3,

and their pharmaceutically acceptable acid addition salts.

According to the present invention, which is an embodiment of the previously described Invention, there are provided new compounds of formula (I), wherein n is 4.

Pharmaceutically acceptable acid addition salts of the compounds of the invention are those which form with acids which form non-toxic acid addition salts with pharmaceutically acceptable anions, such as B. the hydrochloride, hydrobromide, sulfate or bisulfate, the phosphate or acid phosphate, the acetate, Maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, p-toluenesulfonate and the carbonate.

The crfinduri ^ s ^ emiiBen Verbiriduri ^ e! -! can n ^ni% h

the process described in the DE-PS mentioned at the outset can be produced by a compound the general formula

CH, NHR ¹ NH,

O OH

Il I

NHC-CH (CH ₂ I ₁₁ NH ₂

wherein R ¹ to R ^{3 are} as defined above and η 4 is reacted with a reducing agent in a suitable solvent for the purpose of reducing the amide bond on the NI.

Some compounds of the general formula (II) are known; z. B. is l-N- (6-amino-2-hydroxy-hexanoyl) -kanamycin A in J. Antibiotics, 1974,27,851. Further connections can be made through to disclosed herein Process analogous. Process are produced.

Generally, the rings are each in the chair shape and each of the substituent groups is arranged equatorial to the ring. Furthermore, there is the glycosidic bond between the hexopyranosyl ring and the 2-deoxystreptamine ring mostly a «bond, based on the former, especially if the compounds of formula (II) of naturally occurring 2-deoxystreptamine aminoglycosides are derived. In addition, the / J-hydroxy-w-aminoalkyl group N-I is in the S or R configuration, or it can be a mixture of act with both optical isomers.

The in vitro investigation of the compounds according to the invention as antibacterial agents was carried out in such a way that the minimum inhibitory concentration (MIC) of the test compound was determined in a suitable medium in which the growth of the microorganism in question no longer occurred. In practice, agar plates, each of which contained the test compound in a particular concentration, were inoculated with a standard number of cells of the microorganism under investigation, and each plate was then incubated ^{at 37 ° C. for 24 hours.} The plates were then examined for the presence or absence of bacterial growth and the appropriate MIC value was determined. The microorganisms used in these studies included strains of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus faecalis.

The in vivo study was carried out using the compounds in mice which were a strain of Escherichia coli were administered subcutaneously. Each compound was given in the form of a range of dose levels applied to groups of mice, and their activity was found to be the value at which they were 50% Protection against the lethal influence of Escherichia coli organisms over a period of 72 hours.

For the use in quantities, the antibacterial compounds according to the invention can be used for can be applied alone, but they are generally mixed with a conventional pharmaceutical Applied carrier, which with regard to the intended route of application according to the usual, pharmaceutical practice is selected. For example, the compounds can be administered orally in the form of Tablets containing such diluents as starch or lactose, or in capsules, either alone or in a mixture with carriers or thinners

H) substances, or in the form of elixirs or Suspensions containing flavoring or coloring agents are applied. You can also do it parenterally be injected, e.g. B. intravenous, intramuscular or subcutaneous. They are used for parenteral administration

i> ideally in the form of sterile, aqueous solutions used that may contain other dissolved substances,

z. B. sufficient salts or glucose to make the solution isotonic.

For human application it is estimated that

j (i that the daily dose of the antibacterial, compounds of the invention with that of currently used aminoglycoside antibacterial agents is comparable, e.g. B. from 0.1 to 50 mg / kg (in divided doses) on application

r> parenteral route, or from 10 to 100 mg / kg (in divided doses) when administered orally Path. So tablets or capsules of the compounds should contain 0.1 to 1 g of the active compound for oral use Application up to four times a day, while dose units for parenteral application of 10 contain up to 500 mg of active compound. In any case, the doctor can determine the daily dose, which is most suitable for an individual patient, with age, weight and

)> The patient's response may vary. The dose levels given above are examples for average patients. It goes without saying that there are individual cases possible, for which higher or lower dose ranges are appropriate and on which the

• to invention also relates.

The preparation of the new compounds according to the invention is explained in more detail using the following example. Temperatures are given in ^G C.

■ ^{| r>} example

1.0 g (1.36 mmoles) of 1- N - [(S) -2-hydroxy-6-amino-hexanoyl] -kanamycin A-dicarbonate was dissolved in 10 ml of anhydrous trifluoroacetic acid and the solution became

evaporated to dryness under vacuum to form a viscous, rubber-like resin. Of the Residue was with a l-m-diborane solution in 75 ml Tetrahydrofuran under a dry nitrogen atmosphere and the resulting solution was treated for 5 hours

T) heated to 50 to 55 °. Evaporation of the organic Solvent under reduced pressure gave a gummy mass dissolved in 10 ml of 2N hydrochloric acid has been recorded. After 10 minutes the solution became basic to pH 10 with 5N sodium hydroxide solution

M) and finally brought to a pH of 6 with 2η hydrochloric acid. The solution was then filled with a crosslinked dextran containing carboxymethyl groups column in the NH ₄ + form (3.5 χ 90 cm) chromatographed, with water and

μ increasing ammonium hydroxide concentration gradient was eluted from 0- to 0.6-n. The fractions containing the product, as determined by thin layer chromatography, were united and under

Concentrated vacuum to give 0.64 g (63%) of 1-N - [(S) -2-hydroxy-6-aminohexyl] -kanamycin-A to surrender.

Thin layer electrophoresis: R- = 0.85

The electrolyte was a mixture of equal parts Acetic acid and formic acid with a pH of 2, and a potential difference of 900 V was 45 min on the ends of a 20 cm plate coated with silicon dioxide were placed. Detection was carried out by Dryer, the plate, sprayed with a cyclohexane solution of tert-butyl hypochlorite and then Dry, cool and develop the plate with potassium iodide starch solution. Under these conditions the starting material gave an Rf value of 1.0.

Tabel

Mass spectrometry

A sample was converted into the volatile penta-N-acetylocta-O-trimethylsilyl derivative by treatment with acetic anhydride in methanol at room temperature for 24 hours and subsequent reaction with a 2: 1 mixture of hexamethyldisilazane and trimethylchlorosilane at room temperature for 24 hours. e found: 1385; C ₅₈ HiZ ₅ N ₅ Oi ₇ Si ₈ calculated: m / e J 385.

The test results of the compound of the example for antibacterial activity in vitro according to the The procedures previously described are shown in the table below.

organism Escherichia coü Rer. MIC in μ% / τη \ Comparison:
l-N-t (S) -2-hydroxy-
6-aminohexanoyl]
kanamycin-A the same Example of the DE-OS
2644 911 25th 1 the same E 104 6.2 25th 2 the same 110 6.2 25th 3 Escherichia coü 116 6.2 25th 4th the same E172 6.2 so 5 the same 10 6.2 25th 6th the same 36 6.2 50 7th Proteus mirabilis 51 6.2 12.5 8th the same E 173 3.1 25th 9 Proteus vulgaris P133 6.2 6.2 10 the same 8th 3.1 12.5 11th Pseudomonas aeruginosa P136 3, 3.1 12th the same 124 3, 6.2 13th the same Ps 56 3, 6.2 14th the same Ps 52 3, 6.2 15th Klebsieila / Aerobacter Ps 48 3, 25th 16 the same Ps 169 12.5 17th the same K 37 3.1 18th the same K 38 12.5 19th the same K 33 25th 20th Staphylococcus aureus A 39 12.5 21 the same A 40 6.2 6.2 22nd the same S 223 3.1 3.1 23 the same P 222 1.6 25th 24 Pseudomonas aeruginosa (G. AcT) P 202 3.1 6.2 25th Pseudomonas aeruginosa (G. AcT, KPT) P 228 6.2 12.5 26th Escherichia coli (KPT) Ps 53 3.1 12.5 27 Escherichia coli (K AdT, KPT) Ps 54 1.6 50 28 Escherichia coli (K AcT) E174 1.6 100 29 E175 6.2 > 100 30th E 176 1.6 6.2 6.2 12.5 12.5 > 100

G AcT = gentamicin acetyl transferase.

K PT = kanamycin phospho-translcrase.
K AdT = kanamycin ader.yl transferase.
K AcT ~ kanamycin acelyl translerase.

Claims (1)

Claims: Further development of derivatives of kanamycin A or B of the general formula CH ₁ NHR ¹ NH, " _u I I vJrt HO— \)> - O - ^) ^ NHCH, CH (CH ->) ,, NH, > \ X HO R ² HO OR *