DE2644911B2 - Derivatives of kanamycin A or B, processes for their preparation and medicaments containing them - Google Patents

Description

R ² HO OR · ¹

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

and their pharmaceutically acceptable acid addition salts, characterized in that that n = 4

2. 1-N - [(S) -2-Hydroxy-6-aminoheT;!] - kanamycin-A.

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

(!!. ONLY 'NH,

O,

IK)

HO

R ² HO O OH

P i

NHC CHlCH ₂ I _n NH ₂

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 pharmaceuticals containing genes.

Derivatives of Kanamycin A or B, a process for In DE-PS 25 47 738 are new compounds of

Preparation of these compounds and these compounds are described in the following general formula:

CH, NIIR ¹ NH,

! ο "J

IK) ⁷ y O - .; ' IK) R-IIO

OH

NIICH ₂ CHiCII, I ₁₁ NII ₂

where mean:

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

and
η = I, 2or3,

and their pharmaceutically acceptable acid addition s> -> salts.

According to the present invention, which is a further aspect of the invention described above, new compounds of the formula (I) are provided, wherein π 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, Hvtlrobromid, sulfate or Bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, Succinate, p-toluenesulfonate and the carbonate.

The compounds according to the invention can according to

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

CHiNIIR ¹ NH, ,, _Garbage

^ u υπ Il I

ΗΟ-Λ / - "- \ VNHC-CHICHi) ₁₁ NH, (II)

HO

R- HO

where R ¹ to R ^{3 are} as previously defined 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; e.g. is l-N- (6-amino-2-hydroxy-hexanoyl) -kanamycin A in J. Antibiotics, 1974,27,851. Further compounds can be prepared by methods analogous to the methods disclosed here.

Generally, the rings are each in the chair shape and each of the substituent groups is arranged equatorial to Sing. Furthermore, there is the glycosylic 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-deoxystrepiamine aminoglycosides are derived. In addition, the / 3-hydroxy-ü) 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 study of the compounds of the invention as antibacterial agents was so performed that the minimum inhibitory concentration (MIC) of the test compound in an appropriate medium was determined at which the growth of the microorganism in question no longer occurred. In In practice, agar plates were made, each with the test compound in a particular concentration inoculated with a standard number of cells of the microorganism under study, and each plate was then incubated at 37 ° C for 24 hours. The panels were then checked for presence or absence the growth of bacteria was examined, and the corresponding MIC value was found. The at 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

OR- '

in nutrients, or in the form of elixirs or , Suspensions that contain 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

π best used in the form of sterile, aqueous solutions that may contain other, dissolved substances,

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

For human application it is estimated that

JH that the daily dose of 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

Ji parenteral route, or from 10 to 100 mg / kg (in divided doses) when administered orally. So should tablets or capsules of the compounds from 0.1 to 1 g of the active compound for oral administration up to four times a day while

in 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

r> 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

■ w invention also relates.

The preparation of the new compounds according to the invention is illustrated by the following example explained in more detail. Temperatures are given in ° C.

⁴ 'example

1.0 g (1.36 mmol) 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

in under vacuum to dryness to form a evaporated viscous, rubber-like resin. The residue was with a 1 m-diborane solution in 75 ml Tetrahydrofuran under a dry nitrogen atmosphere and the resulting solution was treated for 5 hours

> -> heated to 50 to 55 °. Evaporation of the organic solvent in vacuo gave a rubber-like mass that was taken up in 10 ml of 2N hydrochloric acid. After 10 minutes the solution became with 5 N sodium hydroxide solution to pH 10 basic

mi and finally with 2 η-hydrochloric acid on one brought pH of 6. The solution was then passed to a crosslinked one containing carboxymethyl groups Dextran-filled column in the NH ^ + form (3.5 χ 90 cm) chromatographed, with water and

hi 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: Rf = 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 applied to the ends of a silica coated one for 45 minutes 20 cm plate laid. Evidence was provided by drying the plate and spraying it with a cyclohexane solution of tert-butyl hypochlorite and then drying, cooling and developing the plate with Potassium iodide starch solution. Under these conditions the starting material gave an Rr of 1.0.

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 h and subsequent reaction with a 2: 1 mixture of hexamethyldisilazane and trimethylchlorosilane at room temperature for 24 h, m / e found: 1385; C ₅₈ H, 23N ₅ Oi ₇ Si ₈ calculated: m / e 1385.

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.

Tabel

organism Escherichia coli ReC M. I. C. in [xg / ml Comparison:
lN- | (S) -2-llydrox> -
6-aminohexanoyl]
V-anamycin-A the same Example of the DE-OS
26 44 911 25th 1 the same E104 6.2 25th 2 the same 110 6.2 25th 3 Escherichia coli 116 6.2 25th 4th the same E 172 6.2 50 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, 12.5 11th Pseudomonas aeruginosa P 136 3, 1.1 12th the same 124 3, 6.2 13th the same Ps 56 3. 6.2 14th the same Ps S2 3. 6.2 15th Klebsiella / 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 22nd the same S 223 6.2 3.1 23 the same P 222 3.1 25th 24 Pseudomonas aeruginosa (G. AcT) S / 02 1.6 1.2 25th Pseudomonas aeruginosa (G. AcT, KPT) P 228 3.1 12.5 26th Escherichia coli (KPT) Ps 53 6.2 12.5 27 Escheriwhia coli (K AdT, KPT) Ps 54 3.1 50 28 Escherichia coli (K AcT) K 174 1.6 KX) 29 E 175 l.o > K) 0 30th E 176 6.2 1.6 6.2 6.2 12.5 12.5 > 100

(i AcT = Ucntaniicin-acetyl-transferasc.

K PT = kanamycin phospho-transfcrase.
K AdT = kinanycin-adcnyl-translerase.
K AcT ^ ¹ Kanamycin acetyl transfcrase.

Claims (1)

Claims: I. Further \ usuesialuinu of derivatives of Kanam> cin Λ or B of the general formula HOHO CH ₂ NIIR 'Nile, OH I. I. V- NfICH ₂ CH (CH ₂ I ₁₁ NII,