DE1805686C - ("Hcis-1,2-epoxypropyl) phosphonic acid amides and an antibiotic agent containing these compounds - Google Patents

Description

«5

in which X and Y are either both dimethylamines) or both are diethylamino or X and Y - N

(CH ₂ ) ₂

- N

represent, wherein both R are methyl or ethyl.

2. Antibiotic agent, characterized by: n content of a compound according to claim 1 in addition to the usual inert substances.

Many known antibiotics are only effective against a limited number of pathogens. There is therefore a need for new antibiotic agents that are particularly effective against those Pathogens act that are resistant to the known antibiotics.

The invention relates to (-) - (cis-1,2-epoxypropyl) -phosphonic acid amides the general formula

O OX

/ \ II /

CH ₃ - CH - CH-P

in which X and Y are either both dimethylamines or both diethylamino or X and Y together the rest of the general formula

45

- N

, (CH ₂ J ₂

- N

a suitable solvent in the presence of a carbodiimide, e.g. B. dicyclohexylcarbodiimide, implemented. The mono-amide is obtained in this way. The diamide can be prepared by using the reaction a second equivalent of the amine is repeated.

The (—Hcis-1,2-epoxypropyl > -phosphonic acid and its salts can be prepared by aerobic fermentation of suitable aqueous nutrient media under controlled conditions using certain Streptomyces strains such as Streptomyces fradiae (NRRL-3417), Streptomyces viridochromogenes (NRRL-3413) and Streptomyces wedmorensis (ATCC-21239).

The following experiments explain the superior effect achieved with the inventive Connections is achieved.

Female white mice with an average _{weight: 21 to 24 g were infected intraperitoneally with 3 to 30 LD SO} doses of the test organism and treated orally with the active ingredient at the time of infection and again 6 hours later. The ED ₅₀ was calculated from the survival rate 7 days after infection. The test organism was Salmonella schottmülleri 3010.

connection

represent, in which both R are methyl or ethyl, as well as antibiotic agents, which these compounds in addition to the usual inert substances.

To prepare the compounds according to the invention, (-) - (cis-1,2-epoxypropyl) -phosphonic acid can first be used or their salts are converted into the acid halide with a halogenating agent. The diacid halide formed is then treated with the appropriate amine, e.g. B. Diethylethylenediamine, generally at ice bath temperatures, to phosphonic acid diamide uragur '"··

Another way of production is that (—Mcis-1,2-epoxypropyl) -phosphonic acid or a salt thereof with the corresponding amine in

(1) P - (- Hcis-1,2-epoxypropyl) -N., N '-dimethyl-Ν, Ν -ethylene-

phosphonic acid diamide,

P- (- Hcis-1,2-epoxypropyl) -Ν ,, Ν, Ν ', N' -tetramethylphosphonic acid diamide,

(3) tetracycline

(4) chloramphenicol

ED ₅₀
(Micro-

ΕΓΗΠΙΠί)

62
690

275

The test results show that the compound (1) is 1½ times more effective than tetracycline and 46 times is more effective than chloramphenicol, while the new compound (2) 1 l times more effective than tetracycline and 4.5 times more effective than chloramphenicol.

example 1
, 2-Epoxypr opyl) -N, N '-dimethyl -Ν, Ν' -äthylenphosphonsäurediamid

20 g of (H ⁺ ) cation exchange resin are washed well in ethanol. The resin is then suspended in methanol and 5 the suspension to 0 ⁰ C cooled, 2 g of Phenäthylaminsalzes the (-) - (cis-i, 2-epoxypropyl) phosphonic acid are dissolved in 15 to 20 ml of methanol, and the resulting solution is cooled to 0 ^{0 C.} The saline solution and the resin suspension are mixed together and shaken vigorously for 60 seconds, and the mixture is filtered into 10 ml of methanol containing 2 equivalents of pyridine. Excess pyridine is added to the filtrate and the solution is evaporated to near dryness. Evaporation * is repeated twice, each time adding additional pyridine. The pyridine solution is then cooled in an ice bath to 0 ⁰ C, and to this solution are added 2 equivalents mater stirring plus a 10% excess of thionyl chloride. When the addition is complete, the ice bath is removed and the solution is stirred for 1 hour at room temperature. The solution of the di-acid chloride is then transferred to a feed funnel and slowly added to 2 equivalents of Ν, Ν'-dimethylethylenediamine in 30 ml of benzene at ice bath temperatures. When the addition is complete, the ice bath is removed and the mixture is stirred at room temperature for 1 hour. The mixture is then filtered and the filtrate is evaporated to dryness. Toluene is added in portions and the mixture is evaporated off several times in order to remove traces of pyridine. The residue obtained is triturated with ether, and after evaporation of the ether 660 mg of a dark oil are obtained. The oil is chromatographed on silica gel (18 g) in chloroform. After the first yellow stripe has been removed from the column, the solvent is exchanged for 1% methanol-chloroform, and 50 ml portions are collected. Four fractions are collected; fraction no.4 (210 mg) yields 200 mg of P- (- Hcis-1,2-epoxypropyl) -N, N'-dimethyl-N, N'-ethylene phosphonic acid diamide in the pipe distillation; Thin layer chromatography: Rf0.5 (10% CH ₃ OHZCHCl ₃ ); Gas-liquid chromatography: 91 mm / 130 °; Mass spectroscopy: 190 (molecular ion); Main peaks 133, 117 and 174.

Example 2
P - (-) - cis-1,2-epoxypropyl> N, N, N ', N'-tetramethylphosphonic acid diamide

10 g of phenethylammonium (-) - (ice-1,2-epoxypropyD-phosphonate are dissolved in 100 ml of methanol, and the solution is cooled to 0 ° C. 100 g of (H * (-cation exchange resin are washed thoroughly with methanol. The resin The suspension of the cation exchange resin and the solution of the salt are mixed together and shaken vigorously for 60 seconds. The mixture is then filtered in 20 ml of methanol containing 2 equivalents of pyridine. After filtering Excess pyridine is added and the filtrate evaporated to dryness. Evaporation is repeated twice, each time additional pyridine being added. The pyridine solution is then ^{cooled to 0} ° C. in an ice bath and washed with thionyl chloride (2 equivalents plus 10% excess) Stirring added.

When the addition is complete, the ice bath is removed and the solution is stirred for 1 hour at room temperature. The solution is then cooled in an ice bath and a large excess of dimethylamine is bubbled into the pyridine solution. After the addition of the dimethylamine is complete, the ice bath is removed and the mixture is stirred for 1 hour at room temperature. The mixture is filtered and evaporated to dryness. Toluene is added in portions and the mixture is evaporated off several times in order to remove traces of pyridine. The residue obtained is triturated with ether and contains 2.5 g of crude, red oil. The oil is chromatographed on 50 g of silica gel in 5% methanol-chloroform. 2 g of the red oil obtained from the chromatogram are distilled in the tube. 1.25 g of P - (-) - (cis-1,2-epoxypropyl) - Ν, Ν, Ν, N'-tetramethylphosphonic acid diamide are obtained as a pale yellow oil; Thin-layer chromatography: Rf 0.5 (10% CH ₃ OHZCHCl ₃ ): gas-liquid chromatography: 153/130 ^r ; KMR (D ₂ O): most important signals 7.24 τ, 7.41 τ (N-CH ₃ ), 8.42 τ, 8.52 τ (C-CH ₃ ) and multiple «6 to 7 τίΟΗ); Mass spectroscopy: main peaks at 192 (molecular ion), 135 (base

peak), 176, 119, 92 and 44.

Claims (1)

Patent claims: 1. (-) - (cis-1,2-epoxypropyl) -phosphonic acid amides the general formula together the rest of the general formula
R. O OX / \ II / CH ₃ - CH CH-P