DE2161527C3 - 3'-Deoxykanamycin, its preparation and medicaments containing it - Google Patents

Description

(HD

\ K NHCOZ.

in which P and Z have the above meanings, the protective group P is split off in a manner known per se, the azido group - N _{3 is} converted into the amino group in the usual way by catalytic hydrogenation, the benzyl group in the usual way by hydrogenative cleavage in the presence of a palladium catalyst and the Amino · protecting group —COZ removed in the usual way by hydrolysis.

3. Medicaments consisting of a compound according to claim 1 and customary carriers and / or diluents and / or auxiliaries.

The invention relates to 3'-deoxykanamycin, its preparation and medicaments containing it. It

CH ₂ NH ₂

HO

O — CH,

has an antibacterial effect, especially against kanamycin-resistant staphylococci (Staphylococcus aureus) and Escherichia coli, which were isolated from sick people. The invention is based on Findings from a series of studies by H. Umezawa et al Inactivation of poor drugs by resistant bacteria educate people who have been isolated from sick people. On the basis of this discovered mechanism Research was carried out into new antibiotic derivatives against bacteria resistant to ar / neemia. Hamao U m e ζ a w a and coworkers have established ("Science", 157, 1559 [1967]) that drug-resistant Gram-negative bacteria from patients who carry the R-factor, drug-resistant staphylococci and resistant Pseudomonas aeroginosa produce an enzyme that inactivates kanamycin by the Phosphate residue from adenosine triphosphate transferred to the 3'-position hydroxyl group of the kanamycin will.

NH,

Kanamycin R '= OH
3-deoxykanamines in R '= H

NH,

21 61 52

On the basis of the above findings it is assumed that the replacement of the 3 'hydroxyl group of kanamycin by hydrogen to inhibit the phosphorylation of kanamycin through resistant bacteria, which causes this

Antibiotic is given the ability to be kanamycin resistant Attack bacteria.

The process for the preparation of 3-deoxykanamycin is characterized in that one 3'-deoxy sugar of the general. in Formula 1

-CH, - O

O — CH,

inderX means a halogen atom, in a manner known per se with a protected in a manner known per se 6-O- (3-Amino-3-deoxy-u-D-giucopyranosyl) -2-deoxystreptamine of the general formula 11

NHCOZ

NHCOZ

(St.

in which P is an alkylidene group and Z is an alkoxy group, condensed from the resulting condensation product of the general formula III

CH ₂ N,

NHCOZ

-CH, - O

NHCOZ

\ | \ NHCOZ O \ | __J / O — CH, -

in which P and Z have the above meanings, the protective group P in a manner known per se splits off the azido group - N, in the usual way by catalytic hydrogenation into the amino group transferred, the benzyl group in the usual way by hydrogenative cleavage in the presence of a palladium catalyst and the amino protective group - COZ is removed in the usual way by hydrolysis. the Condensation is carried out in a suitable solvent or in a suitable solvent mixture.

The synthetically produced 3'-deoxykanamycin inhibits the growth of a wide variety of bacteria on a similar scale as the canal

6 «, mycin, as can be seen from the table. On the contrary / in addition to kanamycin, however, it also inhibits the growth of kanamycin-resistant staphylococci, kanamycin-resistant staphylococci Escherichia coli and kanamycin

21 6i

resistant Pseudomonas aeruginosa. The 3'-deoxykanamycin, continues to inhibit the infections that by staphylococci, Bacillus pneumoniae, Salmonella typhosa and Pseudomonas aeruginosa Mice.

Its antibacterial properties also surpass those of the well-known 6 "deoxykanamycin, such as shows the same table.

The 3'-deoxykanamycin shows a low toxicity (LD ₅₀ > 200 mg / kg in mice, iv) and such a high blood level after intravenous injection. As a result, the derivative of the present invention is a valuable chemotherapeutic agent for treating and curing many types of infections, including those caused by gram-negative and gram-positive resistant bacteria. The table shows comparative data on the known 6 "deoxykanamycin (JA-AS 8 415/65, J. of Antibiotics [Japan], Ser. A, 16, 173 to 174).

Antibacterial spectra of 3'-deoxykanamycin
and 6 "deoxykanamycin

Test organisms *)

Minimum inhibitory concentration (mcg / ml)

3'-des-6 "-deoxykanaoxykanamycin mycin

example

a) Production of 6'-Azido-2 ', 2 ", 4'-tri-O-benzyl-OilidNN' ^^

² 5

30th

35

Staphylococcus aureus 1.56 1.56

FDA 209 P

Escherichia coli

NIHJ 3.12 1.56

K-12 3.12 1.56

K-12 ML 1629 **) 3.12> 100

K-12 ML 1630 **) 3.12> 100

Salmonella typhosa T-63 0.78 0.78

Pseudomonas aeruginosa No. 45 1.56 100

(isolated from sick)

Proteus rettgeri GN 466 6.25 3.12

*) Nutrient agar. 37 C. 18 hours.

**) Kanamycin inhibits these strains even in one concentration of 50 mcg / ml not. ^ -

The preparation of 3'-deoxykanamycin is explained in detail in the following examples.

50

ethoxycarbonylkanamycin [in the general formulas, Z = OC ₂ H ₅ , P = CH (CH ₃ ) ₂ ] ^M

0.4 g 6 - azido - 2,4 - di - O - benzyl - 3,6 - dideoxya-D-glucopyranosyl chloride (general formula I with X = Cl) and 0.45 g 6-O- {2-O- Benzyl-3-ethoxycarbonylamido - 3 - deoxy - 4,6 - O - isopropylidene) - N, N '- diethoxycarbonyl-2-deoxystreptamine [general formula II with Z = OC ₂ H ₅ , P = CH (CHj) ₂ ] dissolved in a mixture of 16 ml of dry benzene - dioxane (3: 1). The reading was refluxed after adding 0.6 g of mercury cyanide. After 6 hours of reaction, an additional gram of mercury cyanide was added and the mixture was refluxed for an additional 10 hours. The reaction mixture was then filtered and the residue washed with chloroform. The filtrate and the combined washings were washed with water, dried over sodium sulfate and evaporated. One he-I; IELT 0.95 g of a syrup which then on a column of silica gel unit chloroform-acetone (: ^i;: 1) was chromatographed. The fraction which showed a substance with an Rf value of 0.5 in the thin-layer chromatogram with silicon dioxide with the same solvent mixture was evaporated, and 0.2 μg of a solid substance with a melting point of 263 to 264 ° C. was obtained . [«] S? = 497 ° (c = 0.9; pyridine); IR spectrum: 210C cm " ¹ (N ₃ ).

Analysis for C ₅₁ H ₆₈ N ₆ O ₁₆ :

Calculated ... C 59.98 .. H 6.71. N 8.23%;
found-i .... C 59.79, H 6.76, N 7.91%.

b) 0.82 g of the product prepared according to the method described in Example a) were dissolved in 20 ml of an 80% strength aqueous acetic acid. The solution was ^{heated to 90 °} C. for 5 minutes. The reaction mixture was then poured into water and the resulting precipitate was filtered off and dried. 0.79 g of a solid substance were obtained. The deacetonation product was dissolved in a hot mixture of 120 ml of ethanol and p-dioxane (5: 1) and the solution was shaken for 4 hours at 45 ° C. with hydrogen at atmospheric pressure and in the presence of Raney nickel. The reaction mixture was then filtered and evaporated 0.6 g of a solid substance was obtained. The derivative, which had no azide group, was then dissolved in 90 ml of an ethiinol-water mixture (8:) containing a small amount of acetic acid ^r C under c: hydrogenated with hydrogen under pressure from an atmosphere in the presence of palladium black. The reaction mixture was filtered off and evaporated. 0.3 g of a solid substance was obtained. The debenzylated product, the structure of which was identified by means of IR and NMR spectra, was heated with 10 ml of 1N barium hydroxide solution for 9 hours at 90 ° C. Carbon dioxide was then passed in and, after the precipitate formed was filtered off, the solution was concentrated entrusted. The concentrated solution was applied to a column which was loaded with "Amberlite IRC-50" (MH ^ - form) and was developed with 0.3 N ammonium hydroxide. The fraction which on the chin layer chromatogram with n-butanol — pyridine — water — acetic acid | 6: "4: 3: 1) contained a substance which _{showed an Rf Kanir} , _yon value of 2.2 was collected and The addition of Ac et or gave 90 mg of 3'- De $; oxykanamycin [«]? = + 146 ° (c = 0.2; water).

Analysis for C ₁₈ H ₃₆ N ₁ O ₁₀ :

Calculated .. C 46.14. H 7.75%;
found .... C 46.10. H 7.70%

Claims (2)

Qn 61 527 claims: 1. 3-Deoxykanamycin of the formula CH-, ΝΗ, HO ³ OH 2. Process for the preparation of 3-deoxykanamycin according to claim 1, characterized in that a 3-deoxy sugar of the general formula I in which X denotes a halogen atom, in a manner known per se with a protected in a manner known per se 6-0-13-Amino-3-deoxy - «- D-glucopyranosyl) -2-deoxystreptamine of the general formula II NHCOZ NHCOZ in which P denotes an alkylitlengruppc and Z denotes an alkoxy group, condensed, from the condensation obtained ation prodiict of the general formula 111 CH ₂ N ₃
O NHCOZ j \ NHCOZ * .— CH, - O \