DK149186B - METHOD OF ANOLOGY FOR THE PREPARATION OF N1- (L - (-) - 2-HYDROXY-4-AMINOBUTYRYL) -4-0- (2 ', 6'-DIAMINO-2', 6'-DIDES-OXY-ALFA, D- GLUCOPYRANOSYL) -6-0- (3 '' - METHYLAMINO-3 '', 4 '', 6 '' - TRIDESOXY-ALFA, D-XYLOHEXOPYRANOSYL) -2-DESOXYTREPTAMIN OR ADDITIONAL SALTS THEREOF - Google Patents

Description

149186

The invention relates to an analogous process for the preparation of the novel N1- (L - (-) - 2-hydroxy-4-aminobutyryl) -4-0- {2 ', 6'-diamino-2', 6'-didesoxy-cC D-glucopyranosyl) -6-O- (3 "-methylamino-3", 4 ", 6" -tridesoxy-o6, D-xylohexopyranosyl) -2-desoXystreptamine, with the general formula I or therapeutically acceptable in the preamble of claim addition salts thereof with mineral or organic acids.

The salts can be obtained by completely or partially neutralizing the five amine groups of the compound of formula I.

Such salts may e.g. be a hydrochloride, a hydrobromide, a nitrate, a sulfate, a phosphate, an acetate, a formate, a benzoate, a maleate, a fumarate, a succinate, a tartrate, a citrate, an oxalate, a benzylate, a glyoxylate, a asparaginate, an alkane or arylsulfonate.

The method according to the invention is characterized by the part of the claim.

In a preferred embodiment of the process, the compound of formula II 'is reacted with the compound of formula II in a solvent which is a mixture of dimethylformamide and water. Dimethylacetamide, dioxane, tetrahydrofuran, pyridine, water, acetone, ethanol, methanol and 1,2-dimethoxyethane alone or in admixture may also be used.

The compound of formula III 'is reacted with the product of formula III, preferably using a solvent which is a mixture of water and 1,2-dimethoxyethane, but also alone or in admixture with dioxane, dimethylacetamide, dimethylformamide, tetrahydrofuran, propylene glycol dimethyl ether or water.

The transition from the compound of formula IV to the compound of formula I occurs in the presence of hydrogen and a metal catalyst. This catalyst is preferably palladium, but platinum, Raney nickel, rhodium, nickel or ruthenium can also be used. Preferably, $ 2 14918 is used a solvent which is a mixture of water and a water miscible solvent such as dioxane. Tetrahydrofuran, 1,2-dimethoxyethane or propylene glycol dimethyl ether may also be used.

The conversion to salt of the compound of formula I can be carried out by conventional methods. It can be obtained by acting on this compound of acids such as e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, benzylic, glyoxylic, aspartic, alkanoic and arylsulfonic acids.

This conversion to salt is preferably carried out in a solvent or a mixture of solvents such as water, ethyl ether, methanol or acetone.

The compound of formula II used as the starting product in the process and the sulfate of the product of formula II are described in Belgian Patent Specification 814,724.

The compound of formula I and its addition salts with acids have an interesting antibiotic effect, partly on gram-positive bacteria such as staphylococci and especially penicillin-resistant staphylococci and streptococci, and partly on gram-negative bacteria, especially coliform bacteria.

These properties make the compound of formula I and its therapeutically acceptable salts suitable for use as medicaments, in particular in the treatment of staphylococci such as staphylococcal septicemia, malignant facial staphylococci, cutaneous staphylococci, pyodermitis, septic and suppurant wounds, anthrax, phlegmone, or after influenza occurring acute staphylococci, bronchopneumonia, pulmonary suppurations and colibacillosis. The product of formula I as well as its therapeutically acceptable salts can also be used in the treatment of Klebsiella, Pseudomonas and Enterobacterin infections.

3 149186

The compound of formula I and its therapeutically acceptable salts can be used to prepare pharmaceutical products containing as active ingredient the said compound or at least a salt thereof.

These pharmaceutical products may be administered by oral, rectal or parenteral route or topically by topical application to the skin and mucous membranes.

The known compound (U.S. Pat.

3,781,268) which come closest to the compounds prepared by the process of the present invention are the compound: N1- (L - (-) - 2-hydroxy-4-aminobutyryl) -4-0- (61-amino-6 'deoxy) -ct, D-glucopyranosyl) -6-O- (3 "-amino-3" -desoxy-α, D-xylohexopyranosyl) -2-deoxystreptamine of the formula

ch2nh2 nh2 M

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U9I86 4

This compound is commercially available in the form of the sulphate under the international designation "Amikacin". In the biological documentation below, favorable comparison experiments are made between the compound of formula I in the form of base or sulphate and "Amikacin".

The following examples illustrate the method of the invention.

Example 1.

18β- (1- (-) - 2-hydroxy-4-aminobutyryl) -4-0- (21,6 t-diamino-2 * -6 ♦ - -didesoxy-gD-gluoopyranosyl) -6-0- (311-methylamino-31 * "4 * 1" 6 "1, -tridesoxy-tE, D-xylohexopyranosyl) -2-deoxystreptamine,

Step A: 4-O- (2'-amino-yl-benzyloxycarbonylamino) -gydesoxy-gD-gl-Pcopyranosyl) -6-O- (3 * t-methylamino-3t 1.4 *.

6 '' - Tridesoxy-α.D-xylohexopyranoylsyl ^ -deoxyoxy streptamine. "... _

To 5.5 g of 4-O- (2,6,6-diamino-2,6,6-didesoxy-α, D-gluco-pyranosyl) -6-0- (3 '' -methylamino-3 ') f, 4 '*' 6 '' -tridesoxy-α, D-xylohexopyranosyl) -2-deoxystreptamine dissolved in 58 ml of distilled water is added at 20-25 ° C 60 ml of dimethylformamide.

Cool to -5 ° C and slowly add 3.01 g of E '- (benzyloxycarbonyloxy) succinimide dissolved in 60 ml of dimethylformamide. Stir for 20 hours at -5 ° C and then 24 hours at 20-25 ° C. Evaporate to dryness and take up in water saturated with n-butanol. Wash with butanol saturated with water. The phases are evaporated to dryness, aqueous phase: 6.21 g, butanol phase: 2.82 g,

Ted chromatography on a layer of silica gel with an eluent of chloroform, methanol and ammonia in a ratio of 4: 4: 1 indicates that the aqueous phase is rich in the expected product. This phase is purified on carboxylic-type ion exchange resin in NH4 form. The product is fixed in aqueous solution and then eluted with 0.1 ΪΓ diluted ammonia water to give 1.72 g of the expected product.

5 149186

Step B: (L - (-) -2-Hydroxy-4-benzyloxycarbonylaminobutryl] -4-O- (2'-amino-α '-benzyloxyoarbonylamino] -1 * 6 * -81-deoxy-g, 1> -glucopyranosyl ) -6-O- (31 ♦ -methylbylamino - 3 '*' 4 * t '6t> -tridesoxy-gD-xylohexopyranosyl) -2-deoxystreptamine.

To a solution of 1.8 g of the product from the previous step in 14 ml of distilled water and 14 ml of 1,2-dimethoxyethane cooled to 5 ° C, 1.1 g of N-hydroxy-succinimide ester of 1 (-) - Y-Benzyloxycarbonylamino-g-hydroxybutyric acid dissolved in 28 ml of dimethoxyethane.

The reaction mixture is kept under stirring for 15 hours between 5 and 10 ° C and evaporated to dryness under vacuum.

Late dry extract is chromatographed on silica gel with an eluent of chloroform, methanol and ammonia water in the ratio 75: 25: 5 »

The expected product is characterized which has an RF value of 0.45 on silica gel and eluted with a mixture of methanol, chloroform and ammonia water in the ratio 2: 2: 1.

Step C: N1 - (. X - (-) - 2-Hydroxy-4-amipobutyl) -4-0- (2,6-diamino-2 * -, 6, -didesoxy-gS-gline; copyranosyl ) -6-O- (5 * - methylamino-5 * 1,4 * '. 61 (tridesoxy-gS-xylohexopyranoyl) -2-deoxystreptamine.

To the solution of 473 mg of the product from the previous step in 6 ml of distilled water, 6 ml of dioxane and 0.15 ml of acetic acid, 90 mg of palladium (105¾) catalyst is added to charcoal. Hydrogen bubbling is carried out. After 5 hours of reaction, 30 mg of catalyst is added. After 1 hour of further bubbling, stirring was stopped and allowed to stand overnight under a hydrogen atmosphere. The catalyst is filtered off and evaporated to dryness under vacuum.

The residue is chromatographed on silica gel with a mixture of methanol, chloroform and ammonia in a 2: 2: 1 ratio and 115 mg of the expected product are obtained.

The product is purified by passage over a carboxylic type ion exchange resin in KH + form (elution with 0.5 H of ammonia water). The yield of the purification is 82.2%.

6 149186 N.M.R. spectrum (in 1 ^ 0) = • 'CH2 Ji «2 Jr02 /-0.(8) D H / * - \ BH-0 ^ °.

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Pharmacological studies on the compound of the formula in «Antibacterial activity in vitro,

Bone antibacterial activity is measured in vitro by the dilution method in liquid environment. '

You make a series of glasses in which you have distributed the same quantity of nutritional environment. Growing amounts of the antibiotic tested are distributed and then inoculated each glass with a bacterial strain. After an incubation time of 18, 24, or 48 hours in a heat cabinet at 37 ° 0, the inhibition of bacterial growth is assessed, allowing the minimum inhibitory concentrations (MIC) of the compound, expressed here in μg / ml, to be determined as a base.

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149186

These results show that the compound of formula I has good activity against Gram-positive and Gram-negative germs, and in particular is pronounced against the latter.

This effect is particularly interesting on certain amino-glycoside resistant strains *

The compound of formula II and its sulfate already have a good antibiotic effect ·

The compound of formula I has a very greatly enhanced effect over these two compounds, in particular against certain normally aminoglycoside resistant germs.

The growth of the effect is particularly significant for certain strains of Pseudomonas, Proteus and Klebsiella.

Example 2.

The sulphate of N 2 - (II - (-) - 2-Hydro: ry-4-aminobutryl) .- 4-0- (2> .6t- -άί8ΐη1ηο-2 «.6 t-didesoxy-tt .D-glulopyrano8.71) -6-O- (5β-Methyl) amino-31 '.4 * * .61 t'-tridesoxo (gD-xylohexopyranosyl) -2-desory-streptamine .

1.8 g (1 - (-) - 2-hydroxy-4-aminobutyryl) -4-0- (2,6,6-diamino-2 ', 6'-didesoxy-ajD-glucopyranpsyl) -6-0 - (3'1-methyl-amino-3'f, 4f ', 61'-tridesoxy-α, D-xylohexopyranosyl) -2-deoxy-streptamine is dissolved in 120 ml of distilled water. Using a burette, sew to a pH of 2 by adding 13.5 ml of 1 M sulfuric acid. The solution is evaporated to 20 ml and filtered on sintered glass. Evaporate to 10 ml again and then 200 ml of methanol are added. The white suspension obtained is stored in the refrigerator for 20 hours and filtered on sintered glass. The obtained white crystals are rinsed with methanol and then dried under reduced pressure. 1.87 g of product is obtained. The mother liquor is evaporated to dryness to give another yield of 0.35 g of product, = + 76.5 ° + 2.5 ° (c = 0.6i »water).

E.M.R. spectrum (0): CH3-CH: 1.21 p.p.m., doubled, J * 6 Es 0Η3-ιΦ 2.75 p.p.m.

H ': 5.15 p.p.m.

H1 ^ s 6.03 p.p.m.

U9186 12 ff * - (1 - (-) - 2-hydroxy-4-aminobutyryl 1) -4-O- (2 *, 61-di-amino <~ 2 *, 6 '-didesoxy-α, I) -glucopyranoyl) -6-O- (3 '' -methyl-amino-3 '', 4 '*' 6 * '-tridesoxy-α, 1' -xylohexopyranosyl) -2-deoxy-streptamine used as a starting product in Example 2 is prepared as set forth in Example 1 above.

Pharmacological study of the sulfate of Example 2, Antibacterial effect in vitro.

The antibacterial effect is measured in vitro by the dilution method in a liquid environment.

You make a series of glasses in which you distribute the same amount of nutritional environment. Growing amounts of the tested antibiotic are distributed, and then each glass is seeded with a bacterial strain »After incubation for 18, 24 or 48 hours in a heating cabinet at 37 ° C, the inhibition of bacterial growth is assessed by screening, which allows to determine the minimum inhibitory concentrations (MIC). ) of the product, expressed here in μg / ml base.

149186 13 MIG iu, g / ml 18 h 24 h 48 h (Staphyloc.occus Milieu 0.4 0.6 1 / aureus + human albumin} ATCC 5638 5 # 0.6 1 5 Penicillin Sensitive + Serum from foal 10 # 0, 6 1.5 2 (Staphylococcus Environment 0.6 0.6 1> aureus + human albumin) 5 # 0.6 2 10 (UC 1128. ___) + serum from (Penicillin resistant foal 10 # 12 5

Staphylococcus aureus Exp. No. 54146 0.2 0.4 0.6

Staphylococcus aureus Co 15 # E cephalexin 5 10 40

Streptococcus poyogenes A 561 0.4 0.4 0.6

Streptococcus faecalis 5432 5 5 10

Streptococcus faecalis 99 F 74 2 5 15

Bacillus subtilis ATCC 6633 0.05 0.05 0.1

Escherichia coli, tetracycline sensitive ATCC 9637 2 5 20.

Escherichia coli, tetracycline resistant: ATCC 11303 0.6 1 1

Escherichia coli Exp. T OggBg 112

Escherichia coli, gentamicin resistant E 55 123 D 0.4 0.4 2 149186 14 MIC 1 µg / ml 18 h 24 h 48 h

Klebsiella pneumoniae Exp. 52 145 0.2 0.2 0.4

Klebsiella pneumoniae 2536 gentamicin resistant 0.4 0.4 0.6

Proteus mit. (indole -) A 235 -2 5 5

Proteus vulgaris (indole +) A 232 2 5 10

Salmonella thyphl murium 420 2 5 20

Enterobacter cloacae 681 0.2 0.4 0.4

Providencia Du 48 10 20 40

Pseudomonas 3935 Exp. gentamicin sensitive 2 5 10

Serratia 2532 gentamicin resistant 225

Experimental infection with Escherichia coli.

The effect of the sulfate on an experimental infection with Escherichia coli on mice is investigated. Holds of 10 male mice are infected by intraperitoneal injection of 0.5 ml of a 24 hour culture in nutrient broth of the Escherichia coli bile strain diluted to 1/6 with distilled water.

By subcutaneous injection, a specific amount of the product is administered 1 hour, 5 hours and 24 hours after injection.

Mortality is recorded over 8 days,

The results are as follows: 15 149186 bd

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Comparison test.

Using the liquid dilution method described on page 6 gives the following favorable results: MIC in hg / ml_

Compound of Formula I Amikacin (Sulfate) 18 h 24 h 48 h 18 h 24 h 48 h Escherichia coli Du 308 2 2 2 33 5 • "" You 317 2 2 2 2 3 5 "" "324 0.6 2 3 2 3 5 "" "336 5 10 10 10 20 40" "" 337 1 1 2 2 2 3 "" "352 2 2 3 3 3 5" "" 350 2 2 2 2 3 '5

Klebsiella pneumoniae Du 221 0.4 0.4 0.4 1 1 1 "" "222 0.4 0.4 1 1 1 1" "" 223 0.4 0.6 2 3 3 5 "" "226 0, 4 0.4 1 2 2 2 "" "229 0.4 0.4 0.4 0.6 1 1" "" 230 0.4 0.4 0.4 1 1 1 "" "214 0.4 0 , 6 0.6 0.6 1 1

Compound of Formula I Amikacin (base) 18 hours 24 hours 48 hours 18 hours 24 hours 48 hours

Proteus mirabilis D 234 3 5 10 10 10 10 "" D 235 3 5 10 5 10 10 "" D 266 2 3 5 5 10 10 "" D 267 3 5 5 5 10 10 "" D 268 3 5 5 5 5 10

Streptococcus aureus 586476 0.4 0.6 1 2 5 5

Escherichia coli 54127 1 χ χ 2 2 5

Klebsiella pneumoniae Coc 260 0.4 0.4 0.6 0.6 0.6 1

Proteus morganii You 33 112 125

Claims (1)

U9186 Patent Claims, Analogous Process for Preparation of -2-Hydroxy-4-Aminobutyryl) -4-0- (2 ·, 6, -Diamino ** 2 ·, 6′-Cl -O- (3 '' -methylamino-3 '', 4 '', 6 '' -tri-deoxy-α, D-xylohexopyranosyl) -2-deoxystreptamine of formula I ch2 nh2 nh2 / ~ ° \ | CH2 OH, OI ro «% sh2 <» <HN 'OH' · (I) or therapeutically acceptable addition salts thereof with mineral or organic acids, characterized by reacting a compound of formula II CH NHj, 'ΜΗλ h rr æ / - <, _ jw · hk2 oh3 o J-o H (iKn A - OH 149186 with the compound of formula II * IN-0-C-0-CH2 ~ ^ ^ (TT ·) <ysw % to give the compound of formula III ch2 hh-co-ch2- ^ yo nh2 hoN I • liH2. ch5 0 ho * (ν ^ Ά} W- (III) OH treated with the compound of formula III1 <0 Q f "V ^ noc-ch- (ch2) 2 ΝΚ-ίί-0-0Η2- ^ y (III ') OH o to obtain the compound of formula I?