KR840001925B1 - Mono (2-ammonium-2-hydroxy methyl-1,3-propanediol)(2r-cis)-(3-methyloxiranyl) phosphonate - Google Patents

Abstract

The title compd. of formula (I) is prepd. by reacting Bis(2-Ammonium- Hydroxymethyl-1,3-propanediol) (2R-cis)-(3-methyloxiranyl) with a sulfonic acid selected from alkyl sulfonic acid, aryl sulfonic acid, or aralkyl sulfonic acid. The prod. is a kind of phophomycin, which is useful for stopping the growth of bacteria, which generate gram positive or negative disease in the human body or in animals.

Description

Method for preparing mono (2-ammonium-2-hydroxymethyl-1,3-propanediol) (2R-cis)-(3-methyloxyranyl) phosphate

The present invention relates to soluble salts of new (2R-cis)-(3-methyloxyranyl) phosphoric acid, to their preparation and to pharmaceutical compositions containing them.

The new salt according to the present invention is mono (2-ammonium-2-hydroxymethyl-1,3-propanediol) (2R-cis)-(3-methyloxyranyl) phosphate having the structure Known as

Salts of phosphomicin with its non-toxic bases are widely used in humans and various domestic animals to inhibit the growth of bacteria that cause Gram-negative disease.

Italian patent application 25 853 A / 78 (filed July 19, 1978) contains bis (2-ammonium-2-hydroxymethyl-1, 3-propanediol) (2R-cis)-(3-methyloxyranyl) phosphate is found.

However, bis (2-ammonium-2-hydroxymethyl 1,3-propanediol) (2R-cis)-(3-methyloxyranyl) phosphate is a very viscous solution and difficult to formulate as an injectable salt.

In the present invention, (2-ammonium-2-hydroxymethyl-1,3-propanediol) (2R-cis)-(3-methyloxyranyl) phosphate is bis (2-ammonium-2-hydroxymethyl-1, While maintaining the advantages of 3-propanediol) (2R-cis)-(3-methyloxyranyl) phosphate unchanged, bis (2-ammonium-2-hydroxymethyl1,3-propanediol) (2R- It has been found that the use of cis)-(3-methyloxyranyl) phosphate has the advantage of obtaining a less viscous solution than can be obtained with conventional phosphomicin content.

In particular, 688 mg and 1377 mg of bis (2-ammonium-2-hydroxymethyl-1,3-propanediol) (2R-cis)-(3-methyloxyranyl) phosphate in 2.5 ml of water, respectively, Corresponding to 250 mg and 500 mg of phosphomicin), their viscosity at 25 ° C. is 4.8 and 7.2 CPS, respectively. However, 470 mg and 940 mg of mono (2-ammonium-2-hydroxymethyl-1,3-propanediol) (2R-cis)-(3-methyloxyranyl) phosphate of the present invention were contained in 2.5 ml of water, respectively. The prepared solution has a viscosity of 3.9 and 5.0 CPS at 25 ° C., respectively.

Representative pharmaceutical preparations are as follows.

(a) Oral administration (flavour)

Compositions for oral administration according to conventional phosphomicin 250 mg, 500 mg, and 2000 mg contain the following (unit: milligrams).

Mono (2-ammonium-2-hydroxymethyl-1,3-propanediol) (2R-cis)

-(3-methyloxyranyl) phosphate 470 940 3760

Carboxymethyl Cellulose Sodium 80 100 120

Lactose 50 100 300

Titanium Dioxide 50 70 100

Orange 50 50 80

Sucrose (Sakarose) 2300 2740 5640

(b) parenteral administration

For parenteral administration, one vial and one ampoule of water are used as a solvent for injection. Each bottle contains 470,940 or 1880 mg of the salt of the present invention in powder form, respectively. At the time of injection, the powder is dissolved in a solvent. The amount of solvent is 2.5 ml for containing 470 mg and 940 mg of the salt of the present invention, and 5.0 ml for containing 1880 mg.

Mono (2-ammonium-2-hydroxymethyl-1,3-propanediol) (2R-cis)-(3-methyloxyranyl) phosphate according to the invention is prepared according to Italian patent application 25 853 A / 78 Obtained by reacting bis (2-ammonium-2-hydroxymethyl-1,3-propanediol (2R-cis)-(3-methyloxyranyl) phosphate with sulfonic acids such as alkylsulfonic acids, arylsulfonic acids. Preparation of the salt and the physicochemical properties of the obtained product are exemplified in the following examples.

EXAMPLE

A solution containing 262.5 g (1.38 moles) of 4-toluenesulfonic acid monohydrate in 1300 ml of anhydrous ethyl alcohol was first heated at 75 ° C. and then bis (2-ammonium-2-hydroxymethyl in 3300 ml of anhydrous ethyl alcohol. -1,3-propanediol) (2R-cis)-(3-methyloxyranyl) phosphate is added to a suspension containing 500 mg (1.315 moles) and heated with stirring at 70-75 ° C.

Initially the reactants enter the solution almost completely, from which the colorless crystalline solid begins to precipitate slowly. The suspension is slowly cooled to + 3 ° C with ice water bath with stirring.

The precipitate is collected by electrofiltration and washed on a filter with 700 ml of anhydrous ethyl alcohol cooled to + 10 ° C.

Drying in vacuo at 40 [deg.] C. for 16 hours yielded 291.3 g of acid salt in the form of colorless microcrystalline powder at 116 [deg.] C.

Samples for analysis are recrystallized by adding 4 volumes of anhydrous ethyl alcohol to the resulting solution dissolved in warm methanol (ratio 1: 2 P / V) and cooled to + 3 ° C. under stirring.

1 H-NMR (D ₂ O) :( ppm) = 1.53 (d, 3H, CH ₃ )

3.50-2.75 (m, 2H, CH)

3.75 (S, 6H, CH ₂ )

(5% 물-12.5℃[

(5% water-12.5 ℃

IR (in KBr): 800 ^e 900㎝ ^-1

Claims (1)

Reaction of bis (2-ammonium-hydroxymethyl-1,3-propanediol) (2R-cis)-(3-methyloxytanyl) phosphate with a sulfonic acid selected from the group consisting of alkylsulfonic acids, arylsulfonic acids, and aralkylsulfonic acids A process for the preparation of mono (2-ammonium-2-hydroxymethyl-1,3-propanediol) (2R-cis)-(3-methyloxyranyl) phosphate, characterized in that