CS202067B2 - Method of preparing alpha-amino-phosphine acids - Google Patents

Abstract

The invention relates to a process for the preparation of alpha-aminophosphinic acid derivatives which are suitable for pharmaceutical purposes. The process according to the invention produces the alpha-aminophosphinic acids of the formula I H Ί — C — NH2 H wherein R 1 is phenyl or naphthyl optionally substituted with at least one C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, methylenedioxy, amino, monoalkylamino, or C 1 -C 4 dialkylamino group or an acetamido moiety, and pharmaceutically acceptable salts and optical isomers thereof. The compounds of formula I may also be in the form of the corresponding zwitterion. Examples of the radical R @ 1 are phenyl, tolyl, xylyl, ethylphenyl, propylphenyl, isopropylphenyl, butylphenyl, isobutylphenyl, sec-butylphenyl, tert. butylphenyl or also naphthyl. Preferably, however, R 1 is substituted phenyl.

Description

The invention relates to a process for the preparation of alpha-aminophosphinic acid derivatives which are suitable for pharmaceutical purposes.

The process according to the invention produces the alpha-aminophosphinic acids of the formula I

H « _{ΊΊCCNH 2}

H wherein R ₁ is phenyl or naphthyl optionally substituted with at least one C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, methylenedioxy, amino, monoalkylamino, or C 1 -C 4 dialkylamino group in an alkyl moiety or acetamido group, and pharmaceutically acceptable salts and optical isomers thereof. The compounds of formula I may also be in the form of the corresponding zwitterion.

Examples of the radical R @ ₁ include phenyl, tolyl, xylyl, ethylphenyl, propylphenyl, isopropylphenyl, butylphenyl, isobutylphenyl, sec-butylphenyl, tert. butylphenyl or also naphthyl. Preferably, however, R ₁ is substituted phenyl.

Suitable substituents for R < ₁ & gt _; are one to three halogen atoms of the formula

-COORg or

-or ₂ where is

R ( ₂₎ is hydrogen or lower alkyl having 1 to 3 carbon atoms, methylenedioxy, a group of the formula

-NR ₃ R ₄ where R ₄ and R 4 are the same or different and represent a hydrogen atom and a lower alkyl group or R 4 and R 4 together form a polymethylene chain of up to 6 carbon atoms, optionally interrupted by an oxygen or nitrogen atom, or modified (C až-Cryry) aryloxy optionally substituted with hydroxy or iodo.

Salts of the compounds of formula I are preferably addition salts with therapeutically acceptable inorganic and organic acids.

Examples of acids include hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, acetic, tri-chloroacetic, oxalic, succinic, maleic, fumaric, almond, lactic, tartaric and citric.

The compounds prepared by the process according to the invention have valuable pharmacological properties, for example they are antimicrobial agents which are effective at low concentrations (0.8 to 50 µg / ml) in inhibiting the growth of in vitro pathogenic bacteria such as Esoherichia coli, Enterobacter cloacae and other Enterobacteria, Pseudomonas aeruginosa and yeasts such as candida albicans and tropicalis. They inhibit the growth of both gram-negative bacteria and yeast in a demonstrable manner.

The novel compounds are also active in vivo. For example, at a dose of 15 to 100 mg / kg administered subcutaneously or orally to mice, 50% of the animals (ΕΙ ^ θ) protect against death caused by a lethal dose of pathogenic bacteria such as Klebsiella pneumoniae or Pseudomonas aeruginosa.

The novel compounds may be administered chemotherapeutically either alone or in combination with other antimicrobial agents. Another valuable property of the compounds of the present invention is their synergistic antibacterial activity with other antimicrobial agents such as rifampioin, trimethoprim, D-oycloserin, fluoro-D-alanine and amphotericin B.

The novel compounds prepared by the process of the invention have low toxicity to mammals and can be used to treat animal diseases, especially mammals, as antiseptics and to protect hydrophobic and other organic substances from degradation by bacteria and other microbes. Particularly suitable are the compounds of formula I, the preparation of which is described in the examples.

The compounds of formula I are prepared by reacting an aromatic aldehyde of formula II

Η

AND

R, - C = Ο (II), wherein R 1 is as defined above, with ammonium phosphite in an inert solvent such as toluene or xylene, and optionally the racemate mixture obtained is separated into pure racemates and / or the obtained pacemates are separated into optical antipodes and / or the obtained salts are converted into the free compounds or converted to other salts or the obtained free compounds are converted to their salts.

The compounds obtained are in free form when using methods common to amino acids, such as ion exchange or propylene oxide methods.

Thus, as already mentioned, the compounds of the formula I are obtained in free form or optionally in the form of salts with acids or bases. Thus, for example, basic, neutral or mixed salts, and optionally also their hemihydrates, monohydrates, sesquihydrates or polyhydrates, can be obtained. The acid addition salts ε of the novel compounds of the formula I can be converted into the free compounds by known methods, for example by treatment with basic agents such as alkali or ion exchangers. On the other hand, the obtained free bases with organic or inorganic acids can form salts. For the preparation of acid addition salts, especially acids are used for the preparation of which pharmaceutically usable salts are prepared. Such acids include, for example, hydrohalic, sulfuric, phosphoric, nitric, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric acids. new, ascorbic, maleic, hydroxymalein or pyruvic; phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic, embonic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acids; halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic or sulfanilic acid; methionine, tryptophan, lysine or arginine. Particularly suitable optically active salts are the D-form and L-form of tartaric-di-o-toluyltartaric, lactic, mandelic or camphor-10-sulfonic acids.

The obtained free compounds of formula I can also form salts with bases such as hydroxides, carbonates, bicarbonates, alkali metals such as lithium, sodium, potassium, lithium, sodium, potassium or lithium, sodium, potassium or bicarbonate hydroxides , alkaline earth metal carbonates and bicarbonates, such as calcium, magnesium, carbonate or bicarbonate, or alternatively optionally substituted ammonium or heterocyclic bases. Particularly used optically active bases are the D-form and L-form of alpha-methylbenzylamine, brucine, ephedrine and cinchonine.

The aforementioned and other salts of the compounds of formula I, such as picrates, can also be used to purify the free bases obtained, converting the free bases into a salt, which is separated, and the free base is then isolated from the salt.

Due to the close relationship of the compounds of the formula I in the free form and in the form of their salts, when referring to the free compound, the meaning of the corresponding salt is also meant.

According to the preparation process, the novel compounds of the formula I are obtained in the form of racemic mixtures, in the form of racemates or in the form of optical antipodes.

The racemate mixtures can be separated into the pure racemates in a manner known per se, for example by chromatography and / or fractional crystallization, by virtue of their physicochemical differences of their components.

Pure racemates can be separated into diastereomers by methods known per se, for example by recrystallization from an optically active solvent, by microorganisms or by reaction with an optically active acid or base which forms salts with the racemic compound and separating salts prepared in this way, for example and from the diastereomers the antipodes can be released by treatment with suitable agents. Particularly common optically active acids are, for example, the D-form and L-form of tartaric, di-o-toluyltartaric, butyric, mandelic, camphor-10-sulfonic or quinic acids. Preferably, the more effective is isolated from both antipodes.

However, it is also possible to prepare the final products in the form of pure racemates or optical antipodes by using the starting material containing one or more asymmetric carbon atoms in the form of pure racemates or pure optical antipodes. The novel active compounds or their pharmaceutically acceptable salts can be used enterally, such as orally or rectally, as well as parenterally.

Therapeutic compositions containing an antimicrobial active amount of a compound of Formula I or an acid addition salt thereof and a pharmaceutically acceptable solid carrier or liquid diluent may also be prepared by the method of the invention.

The pharmaceutical preparations contain at least one compound of the formula I as active ingredient together with conventional pharmaceutically acceptable carriers. The type of carrier used depends largely on the method of use; for external use, for example in the disinfection of healthy skin, wound disinfection and in the treatment of dermatoses and bacterial mucosal diseases, in particular ointments, powders and elixirs are used. The butter base may be anhydrous, for example consisting of a mixture of wool fat and soft paraffin, or it may consist of aqueous emulsions in which the active ingredient is suspended. Suitable carriers for powders are, for example, rice starch, and other starches; the bulk density of the carrier may optionally be reduced, for example, by the addition of highly disperse silica, or may be increased by the addition of talc.

The tincture may contain at least one active ingredient of the formula I in aqueous ethanol, in particular 45-75% ethanol, to which optionally 10-20% glycerin may be added. Solutions prepared from polyethylene glycol and other conventional dissolution agents as well as optionally from emulsifiers can be used with particular advantage in the disinfection of healthy skin. The active substance content of the pharmaceutical preparations for external use is preferably 0.1 to 5%.

Gargles or concentrates for their preparation and slow dissolution tablets in the mouth are suitable for disinfecting the mouth and larynx. The gargles are preferably prepared from alcoholic solutions containing 1 to 5% of the active ingredient to which glycerin or flavoring agents may be added. The solid dosage units preferably have a relatively high content of sugar or the like and a relatively low content of active substances, for example 0.2 to 20% by weight, as well as conventional additives such as binders and flavorings.

Intestinal disinfectants and oral treatment of urinary tract infections are particularly suitable solid dosage units, such as tablets, dragees and capsules, which preferably contain from 10 to 90% by weight of the active compound of the formula I, permitting a daily dose of 0.1 to 2, 5 g for adults and a suitable reduced dose for children. Tablets and dragee cores are prepared by combining the compounds of formula X with solid, powdered carriers such as lactose, sucrose, sorbitol, corn starch, potato starch or amylopectin, cellulose derivatives or gelatin, preferably with the addition of glidants such as magnesium stearate or calcium or polyethylene glycol of suitable molecular weight. The dragee cores may then be coated, for example with a concentrated sugar solution, which may also contain gum arabic, talc and / or titanium dioxide, or they may be coated with varnishes dissolved in volatile solvents or solvent mixtures.

Dyestuffs can be added to these coatings, for example to distinguish doses. Soft gelatin capsules and other sealed capsules consist, for example, of a mixture of gelatin and glycerin and may contain, for example, mixtures of compounds of formula I with polyethylene glycol. Hard gelatin capsules contain, for example, granules of the active ingredient with a solid powdered powder, such as lactose, sucrose, sorbitol, mannitol, starches (e.g. potato, corn or amylopectin), cellulose derivatives, gelatin, magnesium stearate or stearic acid.

In all forms of administration, the compounds of formula (I) may be included as the sole active ingredient or may be combined with other pharmacologically known active and in particular antibacterial and / or antifungal or other antimicrobial active agents, for example to broaden the field of use. For example, they may be combined with 5,7-dichloro-2-methyl-8-quinoline or other 8-quinoline derivatives, sulfamerazine or sulfafurazole or other sulfanilamide derivatives, chloramphenicol or tetracycline or other antibiotics, 4 ', 5-tribromsalieylanilide or other halogenated salicylanilides, halogenated carbanilides, halogenated benzoxazoles or benzoxazolones, co-chlorohydroxydiphenylmethanes, halogenated dihydroxydiphenyl sulfides, 4,4'-dichloro-2-hydroxydiphenyl ether or 2,4,4-trichloro-2,4-trichloro hydroxydiphenyl ether or other polyhalohydroxydiphenyl ethers, or with bactericidal quaternary compounds or certain dithio carbamic acid derivatives such as tetramethylthiuram disulfide. It is also possible to use carriers which themselves have a favorable pharmacological action, for example sulfur as a powder base or zinc stearate as a component of a butter base.

The compounds of formula (I) may also be used to protect organic materials susceptible to bacterial or other microbial attack. The organic material may be natural or synthetic polymeric material, protein or carbohydrate substances, or natural or synthetic fibers or textile materials made therefrom.

The following examples illustrate the process of preparation of the compounds of formula (I) according to the invention, but do not limit it. Temperatures are reported in ° C.

He did

A mixture of 13.6 g of anisaldehyde and 8.3 g of ammonium hypophosphite in 100.0 g of xylene is maintained at reflux temperature with water separation. The xylene is cooled, decanted and the residue is heated to boiling with ethanol to give a white solid. Filtration gave DL-1-amino-p-methoxyphenylmethanephosphoric acid, mp 239-241 ° C (dec.).

Example 2

In a similar manner to that described in Example 1, it was obtained

(a) starting from benzaldehyde D, L-1-aminophenylmethanephosphoric acid, m.p. 239-240 ° C (dec.);

b) using p-chlorobenzaldehyde as the starting material D, L-1-amino-p-chlorobenzylphosphoric acid, m.p. 228 DEG-23 DEG C.;

c) using 2,4-dichlorobenzaldehyde as the starting material D, L-1-amino-1- (2,4,4-dichlorophenyl) methanephosphoric acid, mp 244 ° C;

d) starting from 2-naphthaldehyde D; L-1-amino (2-naphthyl) methanephosphonic acid, mp 237-239 ° C;

e) starting from piperonal (3,4-methylenedioxybenzaldehyde) D, Ir-1-amino-1- (3,4-methylenedioxyphenyl) methanephosphoric acid, m.p. 235-236 ° C;

f) starting from 4-dimethylaminobenzaldehyde D, L-1-amino-1- (4-dimethylaminophenyl) methanephosphoric acid, mp 223-224 ° C;

g) starting from 2,4-dihydroxybenzaldehyde D, L-1-amino-1- (2,4-dihydroxyphenyl) methanephosphonic acid, m.p. 260 DEG C. (with decomposition);

h) using p-acetamidobenzaldehyde D, L-i-amino-1- (4-acetamidophenyl) methanephosphoric acid as the starting material.

Example 3

250.0 g of the active compound are mixed with 550.0 g of lactose and 292.0 g of potato starch, moistened with an alcohol solution of 8 g of gelatin and granulated with a sieve. After drying, it is mixed with 60.0 grams of potato starch, 60.0 grams of talc, 10 grams of magnesium stearate and 20.0 grams of colloidal silica, compressed into 10,000 tablets each weighing 125 mg and containing 25 mg of active ingredient. which optionally have a dividing line for finer adjustment of the dosage.

Example i

From 100 g of the active ingredient, 379.0 g of lactose and from an alcoholic solution of 6.0 g of gelatin, a granulate is prepared which, after drying, is mixed with 10.0 g of colloidal silica with 40.0 grams of talc, with 60.0 g of potato starch. and 5.0 g of magnesium stearate and pressed into 10,000 dragee cores. These cores were then coated with concentrated syrup 533.5 g of crystalline sucrose, 20.0 g of shellac, 75.0 g of gum arabic, 250.0 g of talc, 20.0 g of colloidal silica and 1.5 g of dye and dried. The dragee obtained contains 10 mg of active ingredient and a weight of 150 mg.

Example 5

25.0 g of the active ingredient and 1975 g of finely ground suppository (e.g. cocoa butter) are mixed thoroughly and then melted. It is mixed until a homogeneous melt is formed, and from this homogeneous melt, 1,000 suppositories of 2.0 g are poured. Each contains 25 mg of active ingredient.

Examples

To prepare the syrup with 0.25% of active substance are dissolved in 3 liters of distilled water, 1.5 ¹ of liters of glycerin, 42 g of methyl ester of p-hydroxybenzoic acid, 18 g of n-propyl p-hydroxybenzoic acid and gentle warming 25.0 g active 4 liters of 70% sorbitol solution, 1000 g of crystalline sucrose, 350 g of glucose and a flavoring agent, for example 250 g of orange peel essence or 5 g of natural lemon flavor and 5 g of a mixture of the two essences; the solution obtained is filtered and the filtrate is made up to 10 liters with distilled water.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of alpha-aminophosphinic acids of the general formula I R 1 —C — NH 3 OH (I). where R 1 represents a phenyl or naphthyl group optionally with at least one substituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, methylene, amino, monoalkylamino or C 1 -C 4 dialkylamino group or an acetamido group, and pharmaceutically acceptable salts and optical isomers thereof, characterized in that the aldehyde of formula XI ', as defined above, is reacted with ammonium phosphite in an inert solvent such as toluene or xylene, and optionally the mixture obtained the racemates are separated into pure racemates and / or the racemates obtained are separated into optical antipodes and / or the obtained salts are converted into free compounds or converted to other salts or the obtained free compounds are converted into their salts. 2. A process according to claim 1 for the preparation of D, L-1-amino-p-methoxyphenylmethanephosphinic acid, characterized in that anisaldehyde is reacted with ammonium phosphite.