DE2002415B - Optically active isomers of epoxy äthylphosphonsäuren and their salts and such compounds containing antibiotic agents - Google Patents

Description

OH

wherein R ″ denotes hydrogen or alkyl having 1 to 4 carbon atoms, and their salts, the direction of rotation being (-) when R ₆ denotes hydrogen, and (+) when R ₆ denotes alkyl having 1 to 4 carbon atoms.

2. Sodium and calcium salts of the acids of claim 1.

3. Antibiotic agent, characterized by a content of a compound according to claim 1 or 2 and an inert substance.

25th

Many antibiotics are already known, but in general they are not used against all pathogens are effective.

From the German Auskschrift 1046 047 are Epoxyäthylphosphonsäurcalkylester known as Pesticides, lubricating oil additives, plasticizers, and flame retardants are recommended.

The invention relates to optically active isomers of epoxyethylphosphonic acids of the general types formula

40

R ₆ O OH

- C - P

OH

45

wherein R ₆ denotes hydrogen or alkyl having 1 to 4 carbon atoms, and their salts, the direction of rotation being (). when R _{6 is} hydrogen, and (+) is when R _{6 is} alkyl of 1 to 4 carbon atoms.

The invention also relates to antibiotic agents which contain such compounds in addition to inert substances contain.

The radical R ₆ can, for example, be methyl or ethyl. Mean isopropyl, n-propyl or butyl. Examples are (+) - (1 * Ethylepoxyäthyl) - phosphonic acid, (+) - (1 * Methylepoxyäthyl) - phosphonic acid and (-) -Epoxyäthylphosphonsäure.

The salts of the acids according to the invention are preferred because they are particularly good in antibiotic agents are useful. The salts are more stable than the free phosphonic acids. Examples of such salts are inorganic Metal salts, such as the sodium, aluminum, potassium, ammonium, calcium, magnesium, silver, and Iron salts. Organic salts that can be mentioned as representative include the salts with primary, secondary or tertiary amines, such as monoalkylamines, dialkylamines, trialkylamines and nitrogen-containing heterocyclic amines. Representative examples are salts with amines, such as H-phenethylamine, diethylamine, dicyclohexylamine, ethylenediamine, Quinine, brucine, lysine, proiamine, arginine, procaine, ethanolamine, morphine, benzylamine, Ν, Ν'-dibenzylethylenediamine, diethanolamine, piperazine, dimethylaminoethanol, 2-amino-2-mi: - ethyl 1-propanol. Theophylline, ester of amino acids and N-methylglucamine. The salts can be either mono- or dibasic. Salts that are pharmaceutical are not used as intermediates in the preparation of the free acid and useful for the production of other salts.

The indication of the rotation of the (1 -R ₆ -Epoxyäthyl) phosphonic acid compounds according to the invention relates to the rotation of linearly polarized light, which is caused by a 5% concentration of the dicyclohexylamine salt of the parent acid in methanol, measured at 405 νημ. The indication (-1 means, like the letter I, that the dicyclohexylamine-d-Rft-epoxyäthvll-phosphonate salt of the compound referred to rotates linearly polarized light counterclockwise (to the left, as seen from the observer).

The compounds according to the invention can be prepared as follows.

One starts from vinylphosphonic acid. those using in Journal Org. Chem. 1963. p. 2975 to 2978. procedures described can be produced. (l-methylvinyl) phosphonic acid can in the in Izv. Akad. Nauk. SSSR. Otd. Khim. Nauk .. 1963. pp. 675 to 683 described manner.

The I-Rft-vinylphosphonic acids or their salts can then be epoxidized to (l-R ,, - Epoxyäthyl) -phosphonic acids or their salts, which then with an optically active amine are reacted from the diastereomeric salts formed are obtained the desired enantiomer in a manner known per se.

_{The corresponding 1-hydroxy-1-R 6-2} -halo-ethylphosphonic acid compound can also be prepared by reacting phosphorous acid, its salts or esters with haloacetaldehyde or a halogenated methylene ketone. An ester obtained in this way can be cleaved under acidic conditions. 1-R ₆ -Vinyl) -phosphonic acid with an N-haloacetamide form an I - halogen - I - R ₆ - 2 - hydroxyethyl - phosphonic acid. The 1,2-disubstituicien Äthvlphosphonsäuren thus obtained are separated into their enantiomers, which are then epoxidized with a base. The cleavage of the racemate can also take place after the epoxidation.

The phosphonic acids according to the invention and their salts inhibit the growth of gram-positive and gram-negative pathogenic bacteria, for example from Salmonella schoümuelleri and Bacillus subtilis. The phosphonic acids according to the invention can therefore be used as antiseptic Mittql for pharmaceutical and medical equipments and in industrial paints. Likewise, they can can be used to separate certain microorganisms from mixtures of microorganisms. They are also useful for treating bacterial infections in humans and animals.

The compounds according to the invention can be used orally as antibiotics, for example as capsules, tablets, Solution or suspension can be administered. These oil formulations can be pharmaceutical using compatible carriers such as lactose. Sugar creamer tider cellulose, granulating mills, preservatives, Binders, flavorings and coating materials are produced. Alternatively They can be administered parenterally by injection in a sterile Carriers are administered, this will normally be done uses a salt which is soluble in the liquid carrier.

The compounds of the invention are used as antibiotics intravenously on humans, for. B. in quantities given from about 1 to 8 g / day, depending on the specific v. ..- used-n compound, locally 1 to 16 mg / ml of an ointment applied.

The following tests show the superiority of the compounds according to the invention.

The antibacterial effectiveness of ( ± ) -Epoxyätrnlphosphonsäure and (±) -l-Methylepoxyäthylphosphonsäure. both compounds in the form of their mono-idicyclohexylamine) salt was determined according to the method described in Science, Vol. 166 (1969), p. 122. As Testorganismu ■> Salmonella lehnttmuelleri 3010 was used was used as test animals mice. The lin / el dose (microgram. Oral) which is necessary was determined from the values obtained. to protect 50% of the infected animals

The compounds were used as mono- (dicyüohexylaminl-Salzgebeti. For therapeutic use, however, one would sometimes use the disodium salt or di-calcium salt. Therefore, the amount of the disodium salt was calculated which _{corresponds to the 1 D MI} dose of the mono-ldicyclohexylamineJ- The amounts by weight thus obtained were divided by 2, since it has been shown that in vitro the total effectiveness of epoxyethylphosphonic acid is with the (-) -enantiomer and all effectiveness of 1-methylepoxyethylphosphonic acid with the (- ■ ι-enantiomer.

The table below shows the effectiveness of the compounds compared to chloramphenicol and tetracycline.

\ t connection KD. ,,

1 () -epoxyethylphosphonic acid;

as disodium salt! 275

2 'l t-H-methylcpoxyethyl-phosph-;

Phonic acid as disodium salt \ ! 35

<Chloramphenicol j 275

4 Tetracycline I 690

The labelle shows that compound I is more effective than tetracycline and compound 2 is more effective from tetracycline and chloramphenicol.

example 1

0.0085 mol of racemic (l-methylepoxyethyl) -phoisphonic acid in 50 ml of methanol are treated with 1 equivalent of quinine in 20 ml of methanol. Diie The solution is concentrated to 10 mf and left to stand at room temperature, the quinine salt crystallizing out The mass is obtained by filtering and in «. Recrystallized methanol, 0.793 g of a quinine salt with a m.p. = 149 to 153 ° C.

The original mother liquor is concentrated and mixed with ethyl acetate to give a second crystallized salt obtained (0.45 g) having a melting point = 191 to 195 ^'1 C.

0.40 g of the crystallized salt with a temperature of 191 to 195 "C are dissolved in 20 ml of water, treated with sodium hydroxide and contacted with methylene chloride. The aqueous solution of the sodium salt of phosphonic acid, cooled to 0" C, is treated with a cation exchanger treated from nucleus sulfonated polystyrene in the acid form to a pH of 1 M. The resin is filtered off and the filtrate is treated with dicyclohexylumine until the pH is about 6. The solvent is removed under reduced pressure, and 0.076 g of the monodicyciohexylamine salt of ί +) -ί 1-methyl-epoxyethyl) phosphonic acid with a m.p. = 189 to 199 C, ["] / \ ma + are obtained from methanol 6.59 (c = 3.8% methanol) crystallized.

Example 2

To a solution, cooled to -5 C, of 0.11 mol of Rhenish epoxyethylphosphonic acid in 300 ml of aqueous! / Ethanol are 13.3 g (0.11 mol) D-I -t-) - <i-phenethylamine given the solvent is removed under reduced pressure. The residue is taken up in 300 ml of methanol to boiling

jo heated and filtered to remove some insoluble material to remove. 100 ml of ethyl acetate are added, and thereby a sticky solid is precipitated which is filtered off.

A further 100 ml of ethylacetate are added to the filtrate and the mixture is heated to the boil and left to cool and crystallize. The crystallized material is abl'riert. and from the Mother liquor, a second crystal fraction is obtained after the concentration. The two crystal fractions are combined and recrystallized from methanol ethyl acetate, with three crystal frictions an F. = 156 to 161 C (0.700 g). F. = 156 to 168 C (1.55g) and F. - 157 to 162 C (l.2gi result.

The second and third fractions are combined and recrystallized from methanol, giving crystals with a F. = 166 to 169 ° C (1.00g). These crystals are washed with acetone, whereupon crystals with a M. 0.300 g of the washed crystals are dissolved in 10 ml of MeOH. cooled to 0 C. dissolved and treated with a cation exchanger made of polystyrene nucleus sulfonated in the acid form up to a pH of I. The resin. ^: 'd removed by filtration, and the filtrate is treated with 0.223 g of dicycloxylamine. The filtrate solvent is concentrated to a volume of 2 ml under reduced pressure, 4 ml of acetone are added, and the mixture is heated to the boil and allowed to cool. Upon cooling, crystallization occurs, and 0.175 g of Dicyclohexylaminsiilzes with an F = 183-191 ⁰ C. [ «] = -15.4 obtained ηΐμ ° (c = 5% MeOH) <'*.
The original mother liquor from the crystallization of D- (+) -a-Phenyläthylaminsalzes is concentrated to give results in a resinous mass, which was dissolved in methanol, cooled to ⁰ -5 C and kernsulfoniertem with a cation exchanger from

Polystyrene in the acid form is treated up to a pll of I. The resin is removed by filtration, and the filtrate is treated with i .- (-) - </ - Phenyhithylamine treated to a pH of 6. The methanol is reduced to a reduced pressure teaches in a small volume, ethyl acetate is added, and the solution is allowed to crystallize at OC, giving crystals which after two Further crystallizations from methanol / ethyl acetate give 0.32 g with a m.p. = 168 to 170 ° C.

Claims (1)

Patent claims: 1. Optically active isomers of Epoxyäthylphosplionäuren the general formula H ₁ C R "O OH I T / c - p