GB1566252A - Therapeutically useful phosphonic acid derivatives - Google Patents

Description

(54) THERAPEUTICALLY USEFUL PHOSPHONIC ACID DERIVATIVES (71) We, AGENCE NATIONALE DE VALORISATION DE LA RECHERCHE, a French public establishment under the National Minister of Education of 13 rue Madeleine Michelis, Neuilly/Seine, France, and Societe D'Etudes et D'Applications BioloRiques (S.A.B.), a French Company of limited responsibility of 38 rue du Général Foy, 75008 Paris, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to phosphonic acid derivatives and their preparation and to pharmaceutical compositions.

According to the present invention, there are provided asymmetric cis- 1,2- epoxypropylphosphonic acid derivatives of the formula I

wherein A represents a straight chain or branched alkyl or alkoxy group having up to 8 carbon atoms which is unsubstituted or substituted by an epoxy group and/or by one or more substituents chosen from alkoxy groups having I to 5 carbon atoms, alkoxycarbonyl groups having I to 5 carbon atoms ih the alkyl moiety, amino groups, alkyl amino groups ammonium groups, alkylammonium groups, and nitrile groups provided that A does not represent a cis-l,2-epoxypropyl group, or A represents an unsubstituted or substituted aryl, arallryl, aryloxy or ara aralkoxy group, and each of Me and and M'#, which may be the same or different, represents a hydrogen ion or a monovalent inorganic or organic cation, or mute and M' together form a divalent inorganic or organic cation.

Thus the cations Me and M' M'@ may be individual monovalent cations. In which case when A represents an alkyl or alkoxy group substituted by an ammonium or alkylammonium group, M'o may be formed by the ammonium or alkylammonium substituent.

Further Me and M' may together form a divalent inorganic or organic cation e.g. an alkaline earth metal cation e.g. Cae.

The above compounds of the invention are asymmetric and thus it will be understood A is not a cis- 1 ,2-epoxypropyl group.

Examples of asymmetric cis-l ,2-epoxypropylphosphonic acid derivatives of formula I are those wherein A represents a straight chain or branched alkoxy group having up to 6 carbon atoms which is unsubstituted or substituted by an alkoxy group having 1 to 5 carbon atoms, an alkoxycarbonyl group having 1 to 5 carbon atoms in the alkyl moiety, an ammonium group or an alkylammonium group, and each of Me and M'@, which may be the same or different, represents a hydrogen ion or a monovalent inorganic or organic cation, provided that, when A represents an alkoxy group substituted by an ammonium or alkylammonium group, M'@ is formed by the ammonium or alkylammonium substituent of A, or Ms and M' together form a divalent metal or organic cation.

Especially those wherein A represents a methoxy, ethoxy, propoxy, 3-methoxybutoxy, 2-methoxyethoxy or methoxycarbonylmethoxy group, and M@ and M's are the same and both represent alkali metal cations or monovalent organic cations, or Me and M' together form an alkaline earth metal cation, or a divalent organic cation, or wherein A and M'@ together represent a 2-trimethylammonioethoxy, 3-isopropylammoniopropoxy or 3-trimethylammoniopropoxy group, and Ms represents an alkali metal cation or a monovalent organic cation.

Another group of asymmetric cis- I ,2-epoxypropylphosphonic acid derivatives of formula I are those wherein A represents a straight chain or branched alkyl group having up to 6 carbon atoms which is unsubstituted or substituted by an alkoxycarbonyl group having I to 5 carbon atoms in the alkyl moiety or an epoxy group, provided that A does not represent a cis-l,2-epoxypropyl group, or A represents a phenyl or benzyl group, and each of Ms and M'@, which may be the same or different, represents a hydrogen ion or a monovalent metal or organic cation, or Ms and M' together form a divalent metal or organic cation.

Especially those wherein A represents a methyl, phenyl, 2,3-epoxypropyl, benzyl or methoxycarbonylmethyl group, and Me and M's are the same and both represent alkali metal cations or monovalent organic cations, or Me and M'@ together form an alkaline earth metal cation or a divalent organic cation.

The above compounds of the invention exist in isomer form. The present invention includes the individual optical isomers and racemic mixtures of the compounds of formula I. In particular the invention provides such compounds in laevorotatory or dextrorotatory form as well as in racemic form.

The compounds of formula I may be prepared by epoxidizing a cis-l-propenyl compound of the formula II

wherein A' is as defined for A above and, in addition, if in the desired product of formula I A represents an alkyl group substituted by an epoxy group, A' may represent a corresponding alkenyl group, and M and M'@ are as defined above.

The epoxidation of the compound of formula II can be carried out by any appropriate method, for example by the action of hydrogen peroxide in the presence of a catalyst such as oxodiperoxoaquohexamethylphosphoramido tungsten, [W(O2)O1. HMPT. H2O, or the tungstate of benzyltrimethylammonium hydroxide (Triton B), or sodium tungstate and disodium EDTA (titriplex III) for example.

When A' in the compound of formula II represents an alkenyl group, this is epoxidized with the propenyl group attached to the other phosphorus atom.

The starting compounds of formula II may themselves be prepared by reaction of a compound of the formula III:

(wherein A' is as defined above, each of R and R', which may be the same or different, represents a hydrogen atom or an alkyl group having I to 4 carbon atoms. and Me resents an ammonium, or organo-ammonium for example N(CH3)4,* or H2N(C3)2, group or a metal, for example Na, cation) with cis-lpropenylphosphonic acid which is of the formula:

Further, if desired the cations M"#; in the product obtained may be replaced by other cations within the above definitions for M and/or M'.

The reaction between the compound of formula III and the propenylphosphonic acid may be carried out at a temperature of 20--1000C in an organic solvent for example, acetone, acetonitrile, an alcohol, nitromethane, dimethylformamide, dimethylsulhoxide or hexamethylphosphorotriamide.

The compounds of formula III may be prepared by reaction of a tertiary amine, for example trimethylamine, or a metal cyanide or iodide, for example sodium cyanide or iodide, with a methyl ester of the formula IV:

(wherein A', R and R' are as defined above). The reaction may be carried out in an organic solvent e.g. acetone, acetonitrile, nitromethane, dimethylformamide or dimethylsulphoxide. Compounds of formula III, which are only slightly soluble in the solvent used, may be isolated by simple filtration.

Quaternary ammonium salts of formula III may readily be obtained in the pure state. Preferably compounds wherein both R and R' represent methyl groups are prepared.

Compounds of formula III may also be prepared by reaction of a primary or secondary amine with an anhydride of the formula V: (AlPO2)n (V) wherein A' is as defined above and n is 1, 2 or 3.

Metal salts of compounds of formula II may, if desired, be prepared from mixed quaternary ammonium and amine salts for example either by exchange on an Amberlite resin IR 1 2O(M), by double decomposition with sodium salicylate in alcoholic medium or with calcium chloride in alcoholic medium.

Further, when the radical A' represents an ammonium substituted radical of the form

wherein X is an alkylene or alkyleneoxy radical and R, R' and R" are alkyl (preferably methyl) radicals or hydrogen atoms, the process of preparation for a compound of formula II may be carried out according to the following schemes:

In the above schemes Me represents a methyl group. In the compound of formula IIa M'VQ represents # RR'NH2 when prepared by route 3a) and Me4N when prepared by route 3b).

The epoxidation of the compound of formula lla then leads to a compound of the formula Ia:

The asymmetric cis-1,2-epoxypropylphosphonic acid derivatives of formula I have been found to have antibiotic and antibilharziasis properties. In particular it has been found that the laevorotatory and racemic forms of these derivatives have antibiotic properties and the dextrorotatory and racemic forms have antibilharziasis properties.

Accordingly the invention further provides a pharmaceutical composition which comprises, as active ingredient, an asymmetric cis- I ,2-epoxypropyl- phosphonic acid derivative of formula I together with a pharmaceutically acceptable carrier or diluent. In particular the pharmaceutical composition may be an antibiotic containing, as active ingredient, the said derivative in laevorotatory or racemic form, or may be an antibilharziasis containing, as active ingredient, the derivative in dextrorotatory or racemic form.

Bilharziasis or schistosomosis is the second most widespread, serious disease in the world. It Is caused by certain trematodes, the schistosomes. There is a distinction between intestinal bilharziasis, caused by Schistosoma mansoni, arteriovenous bilharziasis, caused by S. japonicum, and urogenital bilharziasis, caused by S. haematobium.

A halt in the process of the disease can be achieved by curative treatment of the sufferers by use of drugs or by interrupting the epidemiological cycle at the stage of penetration by the cercariae analogously to the protection against malaria obtained by use of chloroquine.

In the treatment of bilharziasis dehydromethine, organo-antimony derivatives, thioxanthone derivatives and, above all, niridazole (Ambilhar R), derived from nitrothiazole, have been used. Using these agents, it has been essentially a case of a therapeutic curative therapy, the drugs only acting on the adult forms and not on the infecting larval forms, the schistosomules. On the other hand, these known agents and, in particular, the nitrothiazole derivatives frequently cause digestive disturbances and sometimes lead to neurological problems accompanied by, for example, acute psychiatric symptoms or epileptic fits. These side-effects have necessitated medical surveillance throughout the course of the treatment and have been lead to the therapy having to be ceased.

It has thus been of great importance to provide an active drug for oral administration which has the two advantages of: a) acting on the schistosomule stage with the object of interrupting the parasitic development cycle in man and as a consequence obtaining the eradication of the disease (mass suppressive prophylaxis); b) also having as low a toxicity as possible to permit prophylactic campaigns which do not require constant medical surveillance.

The compounds of formula I above have been found to fulfill these two conditions, and also have a curative action.

The invention is further illustrated in the following Example. In the Examples the products were obtained as racemic mixtures unless otherwise indicated and parts are by weight unless otherwise indicated.

EXAMPLE 1.

Sodium P'-methyl, P2-(+)cis- I ,2-epoxypropylpyrophosphonate

a) O-Methyl-methylphosphonic acid chloride.

To a solution of 208.5 parts PCI6 in 1600 parts CCI4 there is added at 70"C in small portions and with stirring 183 parts tetramethylammonium methylmethylphosphonate (M.Pt. = 195"C Bull. Soc. Chim. 1965. page 1925). After the addition stirring is continued for 3 hours at the same temperature. The tetramethylammonium hydrochloride is filtered off, the solvent removed and the product purified by distillation.

B.Pt.12 = 620C nD = 1.4360 Yield = 85% b) Methyl dimethylamido-methylphosphonate.

To a solution of 101 parts triethylamine and 48 parts dimethylamine in 250 parts benzene, there is added at OCC and with stirring a solution of 128.5 parts 0methyl-methylphosphonic acid chloride and 50 parts benzene.

The addition ended, stirring is continued for 3 hours at ambient temperature.

The mixture is filtered, the solvent removed and the product then purified by distillation.

Boiling Point2 = 51"C = = 1.436 Yield 90% c) Tetramethylammonium dimethylamido-methylphosphonate.

There is allowed to react for several days at 8O-900C and in a sealed reactor which can support pressure, a solution of 68.5 parts methyl dimethylamidomethylphosphonate and 59 parts trimethylamine in 180 parts acetonitrile. The tetramethylammonium salt formed is separated by filtration after having been cooled to OOC. 78.4 parts of a white solid, very soluble in water and alcohol and soluble in hot nitromethane, are obtained.

M.Pt. = 232--233"C Yield = 80% d) Tetramethylammonium dimethylammonium P'-methyl, P2-cis-l-propenyl- pyrophosphonate.

There is stirred overnight at 60"C a mixture of 19.6 parts tetramethylammonium dimethylamido-methylphosphonate, 12.2 parts cis- I propenylphosphonic acid and 100 parts acetonitrile. The insolubles are filtered off, the solvent evaporated in vacuo and 25 parts of a white solid obtained the NMR spectrum of which indicated the following formula

Yield = 78.5% e) Sodium P'-methyl, P2-cis- l-propenyl-pyrophosphonate.

The 25 parts of the compound prepared as above are dissolved in a little water and the aqueoussolution passed over a column of Amberlite resin IR 120 (Na@).

The water is evaporated off in vacuo and the solid obtained taken up in hot isopropanol, filtered, dried and a white solid, readily soluble in 'Nater, slightly soluble in alcohol and insoluble in organic solvents, obtained.

M.Pt. > 250"C Yield ^ 95% Elementary analysis C4H805P2Na2 C H P Calculated 19.4 3.26 25.4 Found 19.29 3.57 25.18 NMR (H) D2O

a (m) a = 1.85 ppm b, c (m) a ~ 5 to 7 ppm d(d) = 1.3 ppm T = 16.7 Hz TLC Silica gel (type 60) Eluant CH3OH = 80; Et3N = 5; H2O = 10 Rf = 0.66 f) Sodium P1-methyl, P2-(+)cis- 1 ,2-epoxypropylpyrophosphonate.

There is stirred overnight a mixture of 12.2 parts of sodium P'-methyl, P2-cis-lpropenyl-pyrophosphonate, 22 parts of 110 volume hydrogen peroxide, 0.08 parts titriplex III and 0.24 parts sodium tungstate. The epoxidised compound is precipitated with acetone and filtered. The solid obtained is dissolved in a water/alcohol (60:40) mixture and passed over a column of neutral alumina (eluant:water/alcohol 60:40), the solvent evaporated off and 7.4 parts of a white solid, readily soluble in water (pH N 7), are obtained.

M.Pt. > 2500C Yield = 57% Elementary analysis C4H8OP2Na2 C H P Na Calculated 18.45 3.08 23.85 17.7 Found 18.06 3.12 23.42 16.9 NMR (H)D2O

a (d) a = lAS ppm T = 6 Hz b, c (m) a (m)# N ~ 2.90 and 3.32 ppm d (d) a = 1.4 ppm T = 16.7 Hz TLC Silica gel G (type 60) Eluant CH3OH:80, Et3N:5, H2O:10 Rf = 0.654 EXAMPLE 2.

Sodium P1-phenyl, P2-(#)cis-1,2-epoxypropylpyrophosphonate a) Methyl phenyl-phosphonite To a solution of 64 parts anhydrous methanol in 250 parts benzene there is added slowly at 0--50C with stirring under a nitrogen atmosphere and under a slight subatmospheric pressure 79 parts phenylphosphonic acid dichloride.

When the addition is ended, stirring is continued for 3 hours at ambient temperature; the solvent is removed and the product then purified by distillation.

B.Pt. 0,05 = 104 C Yield = 65% b) Methyl dimethylamido-phenylphosphonate To a solution of 78 parts methyl phenyl-phosphonite in 200 parts CCI4 there is added slowly with stirring at 0--50C 48 parts dimethylamine.

After the addition, stirring is continued for several hours and the reaction mixture left at ambient temperature overnight. It is filtered, the filtrate washed with a bicarbonate solution, the solvent eliminated and the product then separated by distillation.

B.Pt. 0,5= = 105 C Yield = 70% ca) Tetramethylammonium dimethylamido-phenylphosphonate.

Operating as in Example lc) but using 99.5 parts methyl dimethylamidophenylphosphonate, 111 parts of a white solid are obtained.

M.Pt. = 245 C Yield = 86% cp) Sodium dimethylamido-phenylphosphonate.

There is introduced, into a reaction vessel provided with a distillation column, a mixture of 19.5 parts phenylphosphonic acid dichloride and 10.2 parts acetic anhydride. The reaction mixture is heated with stirring to 1100C with distillation of the acetylchloride formed. After 1 hour 30 minutes reaction, the volatile compounds are eliminated in vacuo and the residue then taken up in acetonitrile.

To the solution there is added slowly at about 0 C 30 arts of a solution of 40% dimethylamine in acetonitrile. The reactor was then sealed hermetically and heated overnight at 600C.

The solvent is evaporated off, the residue taken up in a little water and then the aqueous solution passed over and Amberlite IR 120 Nt resin column.

17 parts of sodium dimethylamido-phenylphosphonate are obtained in the form of a white solid.

Yield = 85 /n d) Sodium P1- henA, P2-cis-l -propenyl-pyrophosphonate There is stirred overnight at 550C a mixture of 27 parts tetramethylammonium dimethylamido-phenylphosphonate, 12.2 parts cis- l-propenylphosphonic acid and 200 parts acetonitrile. The mixture is filtered, the solvent evaporated and the white solid obtained as residue.

The solid is taken up in a little water, and the aqueous solution passed over a column of Amberlite resin IR 120 (Na) and the operation concluded as in Example le). 29.16 parts of a white solid, which is very soluble in water, slightly soluble in alcohol and insoluble in organic solvents, are obtained.

M.Pt. > 250 C Yield = 90 /O Analysis CsHtop2o5Na2. H2O C H P Calculated 33.4 3.70 19.15 Found 33.77 3.51 19.24

a (m) a = 1.85 ppm b, c (m) # ~ 5 to 7 ppm d (m) a = 7.6 ppm TLC Silica gel G (type 60) Eluant CH3OH:80; Et3N:5; H2O:15 Rf = 0.698 e) Sodium Pt-phenyl, P-(#)cis-1,2-epoxypropylpyrophosphonate There is stirred overnight at ambient temperature a mixture of 3 parts sodium P'-phenyl, P2-cis-l-propenylpyrophosphonate, 1.6 parts of 110 volume hydrogen peroxide, 0.01 parts titriplex III and 0.03 parts sodium tungstate. The operation is concluded as in Example If) using a water/alcohol solution (60:40).

1.76 parts (yield 56%) of a white solid, (M.Pt. > 2500C) which is very soluble in water (pHN6.5), slightly soluble in alcohol and insoluble in organic solvents, are obtained.

Analysis C,H,OOsP2Na2. H2O C H P Na Calculated 31.76 3.53 18.23 13.52 Found 31.52 3.55 18.13 12.8 NMR (H) D2O

a (d) a = 1.32 ppmt =6Hz b, c, (m) a N 2.703.12 ppm d (m) a = 7.60 ppm TLC Silica gel (type 60) Eluant CH3OH:80, E+3N:5, H2O:15 Rf = 0.683 EXAMPLE 3.

Sodium P'-2,3-epoxypropyl, P-(#)cis-1,2-epoxypropylpyrophosphonate a) O-methyl-allylphosphonic acid chloride To a solution of 208.5 parts PCl5 in 1600 parts CCl4, there is added at 700C in small portions and with stirring 220 parts of tetramethylammonium methyl-allylphosphonate (M.Pt. = 174 C, Bull. Soc. Chim., 1965, page 1925).

After the addition, stirring is continued for 1 hour at 700 C, the mixture filtered, the solvent removed and the product purified by distillation.

B.Pt. ,5 = 90-91 C nD20 = 1.459 Yield = 78% b) Methyl dimethylamido-allylphosphonate.

Using 154.5 parts O-methyl-allylphosphonic acid chloride and operating according to Example lb) the product is obtained with quantitative yield.

B.Pt. O.t = 560C nD20 = 1.4554 c) Tetramethylammonium dimethylamido-allylphosphonate.

Operating as in Example Ic) and using 81.5 parts methyl dimethylamido allylphosphonate, there is obtained 89.5 parts of a white solid which is very soluble in water and alcohol.

M.Pt. = 1800C Yield = 81% d) Tetramethylammonium dimethylammonium P'-allyl, P2-cis- 1 -propenyl- pyrophosphonate.

There is stirred overnight at 60 C a mixture of 22.2 parts tetramethylammonium dimethylamido-allylphosphonate, 12.2 parts cis- 1 - propenylphosphonic acid and 100 parts acetonitrile. The mixture is filtered, the solvent evaporated and 30.96 parts of a white solid obtained, the NMR (H) spectrum of which indicated the following formula

Yield = 90 /O e) Sodium P'-allyl, P2-cis- I propenyl-pyrophosphonate.

Operating as in Example le), the sodium salt is obtained in the form of a white solid which is very soluble in water (pH N 5) Yield = 84% Analysis CHl0P2OsNa2 H2O C H P Na Calculated 25 4.16 21.5 15.9 Found 25.06 3.98 21.95 15.84 NMR (H) D2O

a (m) a = 1.88 ppm b, c (m) S N 5 to 7 ppm d (dd) a = 2.48 and 2.60 ppm e, f (m) a N 4.9 and 6 ppm TLC Silica gel (type 60) Eluant CH3OH:80; Et3N:5; H2O:10 Rf = 0.676 f) Sodium P'-2,3-epoxypropyl, P2-(+)-cis- 1 ,2-epoxypropylpyrophosphonate.

There is stirred overnight at ambient temperature a mixture of 2.88 parts of sodium P1-allyl, P2-cis-l-propenylpyrophosphonate, 7 parts of 110 volume hydrogen peroxide and 0.03 parts titriplex III, and 0.08 parts sodium tungstate. The operation is concluded as in Example If).

2.17 parts of a white solid, very soluble in water (pH N 7) are obtained.

Yield = 66% Analysis CH,0P207Na2. 1.5 H2O C H P Na Calculated 21.8 3.9 18.8 13.98 Found 22.9 4.2 18.9 14.14 NMR (H) D2O

a (d) a = 1.76 ppm t = 5.7 Hz b, c, d, e, f, (m) a between 1.8 and 3.5 ppm TLC Silica gel (type 60) Eluant CH3OH:80; Et3N:5; H2O:10 Rf = 0.571 EXAMPLE 4.

Sodium P'-benzyl, P2-(+)-cis- 1 ,2-epoxypropylpyrophosphonate a) Tetramethylammonium dimethylamido-benzylphosphonate

There is stirred for 5 hours at 500C a mixture of 100 parts dimethyl benzylphosphonate and 104 parts PCI5 in 120 parts CCl4.

The solvent and POCI3 are removed in vacuo and the residue obtained then slowly added at arcund OOC and with stirring to a solution of 25 parts dimethylamine and 51 parts triethylamine in 100 parts benzene. The solids are removed by filtration and the solvent removed in vacuo.

The oily residue is then treated with 60 parts trimethylamine in acetonitrile according to Example Ic). 90 parts of a white hygroscopic solid are obtained.

M.Pt. = 1900C Yield = 66% b) Sodium P'-benzyl, P2-cis-1-propenyl-pyrophosphonate.

There is stirred overnight at 65 C a mixture of 27.2 parts tetramethylammonium dimethylamido-benzylphosphonate, 12.2 parts cis-lpropenylphosphonic acid and 100 parts acetonitrile. The mixture is filtered, the solvent evaporated and the residue then taken up in a little water.

The aqueous solution is passed over a column of Amberlite IR 120 (Na@) resin, the water evaporated off in vacuo, the residue taken up in acetone; a white precipitate, which is separated by filtration, is obtained.

Yield = 75% Elementary analysis: C,^H,205Na2P2. H2O C H P Calculated 35.5 4.15 18.4 Found 35.43 4.14 18.43 NMR (H) D2O

a (m) b N 1.9 ppm b, c (m) a (m) # between 5.3 and 7 ppm d (2d) a = 3.1 and 3.15 ppm T = 20 Hz e (s) a = 7.3 ppm TLC Silica gel G (type 60) Eluant CH3OH = 80; EtN = 5; H2O = 10 Rf = 0.78 ca) Sodium P'-benzyl, P2-(+)-cis- I ,2-epoxypropylpyrophosphonate.

There is stirred overnight at ambient temperature a mixture of 3.2 parts sodium P1-benzyl, P2-cis-l-propenylpyrophosphonate, 7 parts of 110 volume hydrogen peroxide, 0.05 parts sodium tungstate and 0.02 parts titriplex III: the product formed is precipitated with acetone and separated by filtration. The compound is then purified by passing over a column of activated alumina (eluant:water/methanol = 4:1). The solvent is evaporated off in vacuo and the white solid obtained dried over P2O5.

Yield = 48% Elementary analysis: C10H12O6Na2P2. 2H2O C H Na P Calculated 32.25 4.3 12.37 16.66 Found 32.31 4.27 12.74 16.32 NMR (H) D2O

a(d)a= 1.45 ppm T = 5.3 Hz b, c, d (m) a between 2.8 and 3.4 e (s) a = 7.4 ppm TLC Silica gel G Eluant CH3OH:80; Et3N:5; H2O:10 Rf:0.79 cp) Sodium P'-benzyl, P2-(+)-cis- 1 ,2-epoxypropylpyrophosphonate.

There is stirred for 24 hours at ambient temperature a mixture of 2 parts sodium P1-benzyl, P2-cis-l-propenylpyrophosphonate, 0.25 parts of 85% hydrogen peroxide, 0.6 parts [W(O2)2Ol. HMPT. H2O and 9 parts methanol. 20 parts acetone are then added to the reaction medium, the precipitate filtered off and 1.6 parts of a white solid, having the same characteristics as the compound prepared under 4cα), obtained.

EXAMPLE 5.

Sodium P1-methoxycarbonylmethyl, P2-(:::)-cis- I ,2-epoxypropylpyrophosphonate a) Tetramethylammonium dimethylamido-methoxycarbonylmethylphosphonate.

There is stirred for 1 day at ambient temperature a mixture of 104.25 parts phosphorus pentachloride, and 120.5 parts tetramethylammonium methylmethoxycarbonylmethylphosphonate in 160 parts CCl4.

The solids are separated by filtration, the solvent and POCI3 removed in vacuo and the preparation then concluded as in Example 4a) to give 55.6 parts of a white solid.

M.Pt. = 123"C Yield = 57% b) Sodium P1-methoxycarbonylmethyl, P2-cis-l -propenylpyrophosphonate.

Operating as in Example 4b) and reacting 5.08 parts tetramethylammonium dim a (m) a = 1.88 pm b, c (m) a between 5.2 and 7 ppm d (m) a between 2.74 and 3.10 ppm e (s) a = 3.68 ppm.

c) Sodium P'-methoxycarbonylmethyl, P2-(+)-cis- 1,2-epoxypropylpyrophosphonate.

There is reacted at ambient temperature for 1 hour with stirring a mixture of 4 parts of the compound prepared earlier under 5b), 6 parts of 110 hydrogen peroxide water, 0.06 parts of Na2WO4 and 0.02 parts titriplex III. The product formed is precipitated with acetone and separated by filtration. 4 parts of a white solid, which are purified by chromatography on activated alumina, are obtained.

Analysis: C8H,008Na2P C H P Na Calculated 22.62 3.14 19.5 14.45 Found 22.14 3.32 18.72 14.62

a (d) a = 1.52 ppm T = 5.13 Hz b, c, d, (m) a N 3.1 ppm e (s) a = 3.78 ppm TLC Silica gel (type 60) Eluant:MeOH:80; Et3N:5; H2O:5 Rf:0.65 EXAMPLE 6.

Calcium salt of P1-methyl-phosphoric, P2-(±)-cis-l ,2-epoxy-propylphosphonic acid anhydride.

a) Calcium salt of P'-methyl-phosphoric, P2-cis-l-propenylphosphonic acid anhydride.

There is introduced into a reaction vessel 21.2 parts by weight tetramethylammonium methyl-dimethylamidophosphate (C. R. Acad. Sci. 1959, 249, 1240), 12.2 parts by weight cis-l-propenylphosphonic acid (J. Org. Chem., 1970, 35, 3510) and 80 parts by weight acetonitrile.

The reaction mixture becomes homogeneous after several hours stirring at 55"C and with the exclusion of humidity. Stirring is then continued overnight at the same temperature, the small quantity of precipitate formed is removed by filtration and the acetonitrile is evaporated off in vacuo. To this residue, dissolved in a minimum amount of a mixture of 2 parts by volume ethanol and 1 part by volume water, there is added, at ambient temperature and with stirring, a concentrated solution of calcium chloride in the same alcohol - water mixture. The precipitate formed is filtered off, taken up in hot methanol and then dried in vacuo over P2Os.

22.6 parts (yield 79%) of a white solid, soluble in water (pH N 5) and insoluble in organic solvents, is obtained.

Melting point: > 3000 C.

Elementary analysis shows that the product crystallises with one molecule of water.

Analysis C4H8OP2Ca. H2O C H P Ca Calculated 17.64 3.67 22.79 14.7 Found 17.56 3.54 22.95 14 NMR (H): D2O

a (m) a = 1.90 ppm b, c (m) # ~ 5 to 7 ppm d (d) a = 3.6 ppm t = 10.6 Hz TLC Silica gel G (type 60) Eluant: CH3OH:80, NEt3:5, H2O:20 Rf = 0.73 b) Calcium salt of P' -methylphosphoric, P2-(+)-cis-1,2-epoxypropyl- phosphonic acid anhydride.

A mixture of 14.4 parts of the calcium salt of P1-methylphosphoric, P2-cis-lpropenylphosphonic acid anhydride, 20 parts of 110 volume hydrogen peroxide, 0.28 parts sodium tungstate and 0.08 parts titriplex III is stirred overnight at ambient temperature. The epoxidised compound is precipitated with acetone, isolated by filtration and then purified in the following manner: the solid obtained is dissolved in the minimum of water, the pH of the solution is adjusted to 8.5 with calcium hydroxide solution, the precipitate is removed by filtration, the filtrate is concentrated in vacuo and then ethanol is added with stirring to this solution until a slight precipitate is formed, which precipitate is removed by filtration; the product is then precipitated with acetone, filtered off and dried under vacuum over P205.

8.35 parts of a white solid, soluble in water (pH N 5) and insoluble in organic solvents, are obtained.

Melting point: > 3000C Yield = 58% Elementary analysis C4HsO7P2Ca.H2O C H P Ca Calculated 16.65 3.47 21.7 13.88 Found 17.47 3.86 20.91 13.85 NMR (H): D2O

a (d) a = 1.5 ppm, T = 6 Hz b, c (m) # ~ 2.9 to 3.4 ppm d (d) # = 3.65, T = 10.6 Hz TLC Silica gel G (type 60) Eluant CH3OH: 80, Et3N: 5; H2O : 20 Rf = 0.85 EXAMPLE 7.

Disodium salt of P'-methyiphosphoric, P2-(±) cis-l,2-epoxy-propylphosphonic acid anhydride aa) Disodium salt of P1-methylphosphoric, P2-cis- l-propenylphosphonic acid anhydride. There is reacted with stirring overnight at 55 C a mixture of 21.2 parts tetramethylammonium methyl-dimethylamidophosphate, 12.2 parts by weight cis I-propenylphosphonic acid and 80 parts acetonitrile. Theinsoubles are removed by filtration, the solvent evaporated off and the residue taken up in a little water and then the aqueous solution passed over a column of Amberlite resin IR 120 (Na). The water is evaporated off in vacuo, the residue taken up in hot isopropanol, filtered, dried and 20 parts of a white solid are thus obtained.

NMR (H): D2O

a (m) a = 1.85 ppm b, c (m) # ~ 5.5 to 7 ppm d (d) a 3.57 ppm T= 11.3 Hz TLC Silica gel G type 60 Eluant CH3OH:80, NEt,:5, H2O:5 Rf:0.671 a ) Disodium salt of P1-methylphosphoric, P2-cis-l-propenylphosphonic acid anhy ride.

i) Sodium methyl-dimethylamidophosphate.

There-is reacted with stirring for several hours at 60-70 C a mixture of 153 parts dimethyldimethylamidophosphate, 50 parts sodium cyanide and 400 parts dimethylsulphoxide (DMSO). The preparation is left overnight at ambient temperature, the product separated off by filtration, washed with DMSO and then with acetone and dried under vacuum. 140 parts of a white solid, readily soluble in water, are obtained.

ii) Disodium salt of P'-methylphosphoric, P2-cis- l-propenylphosphonic acid anhydride.

There is reacted with stirring overnight at 700C a mixture of 16.1 parts sodium methyl-dimethylamidophosphate, 12.2 parts cis-l-propenylphosphonic acid and 60 parts acetonitrile. The solvent is evaporated off in vacuo and the residue dissolved in a minimum of methanol. To this alcoholic solution there is added with stirring and at ambient temperature a solution of 4.1 parts sodium hydroxide in methanol, and the stirring then continued for 1 hour at ambient temperature. The stirring is then brought to reflux and filtered hot, the solid is washed with alcohol and dried in vacuo. 23.4 parts of a white solid, having the same physical constants as the product prepared under aa), was obtained.

b) Disodium salt of P-methylphosphoric, P2-(+)-cis-1,2- epoxy ropylphosphonic acid anhydride.

There is stirred for 1 hour 30 minutes at ambient temperature at mixture of 5 parts of the compound obtained under a), 0.07 parts [(WO2)OJ. HMPT.H2O and 2.7 parts 50% hydrogen peroxide.

The epoxidised compound so formed is precipitated with acetone, filtered and the product then Purified by chromatography over a column of activated alumina (eluant:water/methanol 5:1). There are obtained 4.1 parts of a white solid, the physical constants of which were as follows: NMR (H) D2O

a (d) a = 1.5 ppm t = 5.3 Hz b, c (m) # ~ 3.3 ppm d (d) a 3.65 ppm T = 11.3 Hz TLC Silica gel G (type 60) Eluant CHJOH: 80, NEt:5, H3O: 10 Rf = 0.525 EXAMPLE 8.

Sodium salt of P'-(2-trimethylammonio-ethyl)-phosphoric , P2-(+) cis-1 ,2-epoxy- propylphosphonic acid anhydride

a) Sodium salt of P1 -(2-trimethylammonio-ethyl)-phosphoric, P2-cis-lpropenylphosphonic acid anhydride.

There is reacted overnight at 650C a mixture of 5.04 parts morpholinophosphorylcholine prepared according to French Patent No. 72 43 780 of 8th December 1972, 2.03 parts cis-l-propenylphosphonic acid and 20 parts acetonitrile.

The viscous residue formed is separated by decantation and then dissolved in a mixture of isopropanol and methyl cellosolve. To this solution there is added a solution of 0.5 parts alcoholic sodium hydroxide solution; the solvent is removed and the residue then taken up in acetone. A white hygroscopic precipitate is obtained which is purified by passage over activated alumina (Eluant: H2O/CH3OH:4: 1).

Yield = 68% NMR (H): D2O

a (m) # = 1.9 ppm b, c (m) # between 5.3 and 7 ppm d (m) a N 4.3 ppm e (m) 8 N 3.6 ppm f(s) 8 = 3.15 ppm b) Sodium salt of P1-(2-trimethylammonioethyl)-phosphoric, P2-(i) cis-1,2epoxypropylphosphonic acid anhydride.

There is stirred overnight at ambient temperature a mixture of 2.5 parts of the compound prepared under a) above, 4 parts of 110 volume hydrogen peroxide, 0.08 parts sodium tungstate and 0.03 parts titriplex III. The epoxidised compound so formed is precipitated with acetone and then separated by filtration. 2.2 parts of a white solid, which is purified by chromatography over a column of activated alumina (eluant, water/methanol 4:1), are obtained.

Analysis: C8H,NO7P2Na C N Na Calculated 29.6 4.32 7.07 Found 29.75 4.33 7.04 NMR (H) D2O

a (d) a = 1.42 ppm t = 5.3 Hz b, c (m) # between 2.6 and 3.2 ppm d (m) # = 4.3 ppm e (m) 8 = 3.6 ppm f(s) 8 = 3.15 ppm EXAMPLE 9.

Sodium salt of P-(γ-N-isopropylammoniopropyl)-phosphoric, P2-(+)-cis-1,2-epoxy- propylphosphonic acid anhydiide a) 2-((CH3)4N#O#]-2-oxo-3-isopropyl-1,3,2-oxazaphosphorinane.

To a solution of 13.95 parts 2-chloro-1,3,2-dioxaphosphorinane in CCI4 there is added slowly at 0 C 16 parts dry bromine. After dilution of the reaction medium with diethyl ether there is added slowly at -200C a mixture of 3.2 parts methanol and 10.1 parts triethylamine and then at ambient temperature at mixture of 5.9 parts isopropylamine and 10.1 parts triethylamine. The reaction medium is washed with water, dried and then evaporated.

The residue dissolved in tetrahydrofuran is treated at ambient temperature with 2.7 parts sodium hydride; after hydrogen evolution has ceased, stirring is continued for 2 hours at 500 C.

After recooling, the excess sodium hydride is destroyed by adding water, the reaction medium neutralised with dilute HCl, and the 2-methoxy-2-oxo-3isopropyl-1,3,2-oxazaphosphorinane extracted with chloroform and.then purified by distillation (B.Pt. 0.05 85"C).

The 2-methoxy-2-oxo-3-isopropyl-1,3,2-oxazaphosphorinane is then treated in a sealed reactor with 12 parts trimethylamine and 30 parts acetonitrile for several days at 8e90"C. The tetramethylammonium salt formed is separated by filtration to give 12.4 parts of a white hygroscopic solid.

M.Pt. = 2l4-2l50C Yield = 51% b) Sodium salt of P(γ-N-isopropylammoniopropyl)phosphoric, P2-cis- 1 propenyl-phosphonic acid anhydride.

There is reacted overnight at 600C a mixture of 2.9 parts of the compound prepared under a) above and 1.4 parts cis-l-propenylphosphonic acid in 15 parts acetonitrile. The precipitate is separated by decantation and then dissolved in a little water.

The aqueous solution is passed over a column of Amberlite resin IR 120 (Na@).

The water is removed in vacuo and then the residue obtained purified by chromatography on a column of activated alumina (eluant H2O/MeOH:2:l); 1.5 parts of a white hygroscopic solid are obtained.

Yield = 40% NMR (H) D2O

a (m) a = 1.85 ppm b, c (m) # between 5 and 7 ppm d (d)6 N 3.95 ppm e (m) a N 2 ppm f (d) a = 3.1 ppm g (d)a = 1.12 ppm, t = 6.66 Hz Analysis: CgH20NO"P2Na C H N Na Calculated 33.4 6.2 4.33 7.12 Found 33.22 6.6 4.43 7. I I TLC Silica gel G (type 60) Eluant MeOH = 80, Et3N = 5, H2O = 10 Rf = 0.63 c) Sodium salt of P-(γ-N-isopropylammonio-propyl)-phosphoric, P2-(+)-cis1,2-epoxypropyl-phosphonic acid anhydride.

There is stirred overnight at ambient temperature 1 part of the compound obtained under b), 2 parts of 110 volume hydrogen peroxide, 0.02 parts sodium tungstate and 0.007 parts titriplex III; the reaction is completed as in Example 8b); there are obtained 0.58 parts of a white solid, readily soluble in water and slightly soluble in organic solvents.

Yield = 55% NMR (H) D2O

ad) 8 = 1.4 ppm # = 5.33 Hz b, c (m) 8 N .15 ppm d (m) 8 N 4 pm e (m) d N l.Sppm f (t) a N 3.15 ppm g (d) a = 1.2 ppm # = 6.66 Hz EXAMPLE 10.

Sodium salt of P1-3-methoxybutyl-phosphoric, P'-(+) cis- 1 ,2-epoxypropyl- phosphonic acid anhydride a) Methyl-3-methoxybutyl-phosphite.

To 68.8 parts by weight of phosphorus trichloride diluted with its own volume of methylene chloride, there is added dropwise with stirring while keeping the temperature of the reaction medium at -20 to -300C, 52.5 parts 3-methoxybutanol diluted in its own volume of methylene chloride. The addition ended, stirring is continued for 1 hour at ambient temperature.

There is then added dropwise 64 parts methyl alcohol diluted in its own volume of methylene chloride while keeping the temperature between 0 and 5 C.

The reaction ended, the solvent and gaseous products formed are removed in vacuo and the product purified by distillation.

B.Pt. 0.05 = 930C b) Methyl-3-methoxybutyl-dimethylamidophosphate To a solution of 18.2 parts methyl-3-methoxybutyl-phosphite in 75 parts CCI4 there is added slowly at 0-3 C with stirring 11 parts dimethylamine.

The addition ended, stirring is continued for 4 hours at ambient temperature, the precipitate removed by filtration, the solvent removed in vacuo and the residue then purified by distillation.

Yield = 72% c) Tetramethylammonium 3-methoxybutyl-dimethylamidophosphate.

There is reacted for several days at 80--900C in a sealed reactor 11.25 parts of the ester obtained under b) and 6 parts trimethylamine in 18 parts acetonitrile. The tetramethylammonium salt formed is separated by filtration after having been cooled to OOC. 9.9 parts of a white hygroscopic solid are obtained.

M.Pt. = 210"C Yield = 70% d) Sodium salt of P1-3-methoxybutylphosphoric, P2-cis-l-propenyl-phosphonic acid anhydride.

There is reacted overnight at 600C a mixture of 8 parts of the tetramethylammonium salt obtained under c) and 3.4 parts cis-l-propenylphosphoric acid in 20 parts acetonitrile. The precipitate is removed by filtration, the solvent evaporated off and the residue then taken up in water.

The aqueous solution is passed over a column of Amberlite resin IR 120 (Nao).

The water is evaporated off in vacuo and the residue then taken up in acetone; a white solid, which is separated by filtration, is obtained Yield = 72% Analysis: C8H1O7P2Na2 C H P Na Calculated 28.9 4.81 18.67 13.85 Found 28.64 4.81 19.17 12.23 TLC Silica gel G (type 60) Eluant: CH3OH:80, Et3N:5, H2O:10 Rf:0.831 e) Sodium salt of P'-3-methoxybutylphosphoric, P2-(±cis-l,2- epoxypropylphosphonic acid anhydride.

There is reacted for 3 hours at ambient temperature a-mixture of 3.8 parts of the compound obtained under d), 8.5 parts of 110 volume hydrogen peroxide, 0.06 parts Na2Wo4 and 0.02 parts titriplex III. The product formed is precipitated with acetone and separated by filtration. The product is purified by passage over a column of activated alumina using, as eluant, a mixture of water and methanol (5:1). There are obtained 2.2 parts of a white solid which is readily soluble in water.

Yield = 56% NMR (H) D2O

a (d) 8 = 1.5 ppm T = 5.3 Hz d (d) a = 1.18 ppm t = 6.7 Hz e (s) a = 3.33 ppm TLC Silica gel G (type 60) Eluant:CH3OH:80, Et3N:5, H2O:5 Rf = 0.721 EXAMPLE 11.

Disodium salt of P1-n-propylphosphoric, p2~(+) cis-l,2-epoxypropylphosphonic acid anhydride a) Tetramethylammonium n-propyl-dimethylamidophosphate

A mixture of 21.2 parts tetramethylammonium methyldimethylamidophosphate, 13 parts n-propyl bromide and 0.5 parts tribenzylamine are reacted for several days at ambient temperature with stirring. The tetramethylammonium bromide formed is removed by filtration, the solvent evaporated off in vacuo, the residue taken up in diethyl ether, filtered, then the ether is evaporated off and 10.5 parts methyl-n-propyl-dimethylamidophosphate obtained.

The 10.5 parts methyl-n-propyl-dimethylamidophosphate are reacted with 6 parts trimethylamine according to the method of Example 10 c); 11.2 parts tetramethylammonium n-propyl-dimethylamidophosphate are obtained in the form of a white hygroscopic solid.

b) Disodium salt of P'-n-propylphosphoric, P2-cis-1-propenylphosphonic acid anhydride.

Using 4.8 parts tetramethylammonium n-propyldimethylamidophosphate, 2.44 parts of cis-l-propenylphosphonic acid and 20 parts acetonitrile and operating as in Example (7aa), 4.05 parts (yield = 70 NO) of a white solid, soluble in water, are obtained.

c) Disodium salt of P1-n-propyiphosphoric, P2~(+) cis-1,2-epoxypropyl- phosphonic acid anhydride.

There is reacted at ambient temperature for 1 hour with stirring a mixture of 3.7 parts of the compound prepared under b) above, 6 parts of 110 volume hydrogen peroxide, 0.06 parts Na2WO4 and 0.02 parts titriplex III.

The product formed is precipitated with acetone and separated by filtration.

3.8 parts of a white solid, which are purified by chromatography over a column of activated alumina (eluant, water/methanol 5:1), are obtained Analysis: CEHl2O,Na2P2. +H2O C H P Na Calculated 23 4.16. 19.82 14.7 Found 22.93 4.20 19.84 14.35 NMR (H) D2O

a(d) 8= 1.53 ppm, T= 5.3 Hz b, c (m) b N 3.25 ppm d (m) a N 3.98 ppm (in) # N 1.68 ppm f (t) a = 0.92 ppm EXAMPLE 12.

Disodium salt of P'-ethylphosphoric, P2-(+) cis- 1 ,2-epoxypropylphosphonic acid an hydride a) Tetramethylammonium ethyl-dimethylamidophosphate.

By replacing the 13 parts n-propyl bromide by 12 parts of ethyl bromide and operating as in example IIa), tetramethylammonium ethyl-dimethylamido phosphate is obtained in the fotin of a white hygroscopic solid (M.Pt. 198 C) b) Disodium salt of Pi-ethylphosphoric P2-cis- l-propenylphosphonic acid anhydride There are reacted 4.52 parts tetramethylammonium ethyl-dimethylamido phosphate and 2.44 parts cis-l-propenylphosphonic acid according to Example IIb); 3.7 parts (yield 68%) of a white solid are obtained.

Analysis C H P Na Calculated 21.9 3.65 22.6 16.8 Found 21.33 3.62 22.44 17.07 TLC Silica gel (type 60) Eluant: MeOH = 80, Et3N = 5, H2O = 10 Rf = 0.79 c) Disodium salt of P'-ethylphosphoric, P-(#)cis-1 ,2-epoxypropylphosphonic acid anhydride There are reacted 4.2 parts of the compound obtained under b) with 10 parts of 110 volume hydrogen peroxide according to Example llc); 3.66 parts of a white solid are obtained NMR (H) D2O

a (d) a = 1.5 ppm t = 5.3 Hz b, c (m) # ~ N 3.3 ppm d (m) a N 4.02 ppm e (t) a = 1.27 ppm TLC Silica gel (type' 60) Eluant MeOH = 80, Et3N = 5, H2O = 10 Rf = 0.707 EXAMPLE 13.

Disodium salt of P1-(2-methoxyethyl)-phosphoric, P2-(+)-cis- 1,2-epoxypropyl- phosphonic acid anhydride a) Methyl-2-methoxyethyl-phosphite Operating as in Example 10a) but using 38 parts 2-methoxyethanol, methyl-2 methoxyethyl-phosphite was obtained.

B.Pt. 0O, 68-700C n020 1.4215 b) Methyl 2-methoxyethyl dimethylamidophosphate Operating as in Example 10b) but using the product of a) above, methyl-2methoxyethyl-dimethylamidophosphate was obtained B.Pt. OO1 68-700C Yield = 70% c) Tetramethylammonium 2-methoxyethyl-dimethylamidophosphate Operating as in Example 10c) but using the product of b) above, tetramethylammonium 2-methoxyethyl-dimethylamidophosphate was obtained M.Pt. = 218-2200C Yield = 84% d) Sodium salt of P'-(2-methoxyethyl)-phosphoric, P2-cis- 1 -propenyl phosphonic acid anhydride.

There are reacted 12.8 parts of the compound obtained under c) above with 6.1 parts propenylphosphonic acid in 40 parts acetonitrile according to Example 10d); 11.5 parts of a white solid are obtained Yield = 76% NMR (H) D2O

a (m) a = 1.92 ppm b, c, (m) a between 5.2 and 7 ppm d (m) a = 4.05 ppm e (m) = 3.7 ppm f(s) = 3.4 ppm TLC Silica gel (type 60) Eluant: MeOH:80, Et3N:5, H2O:10 Rf = 0.59 e) Sodium salt of P'-(2-methoxyethyl)phosphoric, p2~(+) cis- 1 2-epoxypropyl- phosphonic acid anhydride.

Using 6.08 parts of the compound obtained under d), 10 parts of 110 volume hydrogen peroxide, 0.03 parts Na2 WO4 and 0.01 parts titriplex III and operating as in Example 10e), 5.4 parts of a white solid are obtained.

Yield = 84% NMR (H) D2O

a (d) a = 1.5 ppm T = 5.3 Hz b, c (m) (m) # ~ 3.32 ppm d (m) a = 4.15 ppm e (m) = 3.76 ppm f (s) a = 3.5 ppm TLC Silica gel (type 60) Eluant = MeOH:80, Et3N:5, H2O:10 Rf = 0.694 EXAMPLE 14.

Disodium salt of P'-methoxycarbonylmethylphosphoric, P2-(±cis-1,2-epoxy- propylphosphonic acid an hydride a) Tetramethylammonium (methoxycarbonylmethyl)-dimethylamidophosphate.

There is reacted for several hours at 65--800C a mixture of 21.2 parts tetramethylammonium methyl-dimethylamidophosphate, 15.3 parts methylbromoacetate, 3 parts tribenzylamine and 100 parts acetonitrile.

After having removed the solvent, the residue is taken up in chloroform and the chloroform solution washed with an aqueous solution of sodium bicarbonate.

The chloroform solution is dried and evaporated and the residue obtained is treated with 7 parts trimethylamine according to Example 10c).

b) Disodium salt of P'-methoxycarbonylmethylphosphoric, P2-cis-l-propenylphosphonic acid anhydride.

There is reacted for two days at 70 C a mixture of 2.7 parts of compound a) prepared above, 1.22 parts cis-l-propenylphosphonic acid and 10 parts acetonitrile and the preparation is completed according to Example 7a) to give 2.6 parts of a white solid.

Yield = 70% c) Disodium salt of P'-methoxycarbonylmethyiphosphoric, P2-(+) cis-1,2 epoxypropylphosphonic acid anhydride.

There is stirred for an hour at ambient temperature a mixture of 2.6 parts of the compound prepared under b), 5 ml of 110 volume hydrogen peroxide, 0.03 parts Na2 WO4 and 0.01 parts titriplex III, and the operation then completed according to Example 7b). 1.1 parts of a white solid are obtained.

NMR (H) D2O

a (d) a = 1.5 ppm J = 5.3 hz b, c (m)6 N 3.3 ppm d (d) a = 4.7 ppm J = 9.3 Hz e (s) oA = 3.9 ppm EXAMPLE 15.

Sodium salt of P'-(3-trimethylammoniopropyl)phosphoric, P2-(+) cis-1,2epoxypropylphosphonic acid anhydride

a) Morpholine salt of P1-(3-trimethylammoniopropyl)phosphoric, P2-cis- 1 - propenylphosphonic acid anhydride.

There is stirred overnight at 700C a mixture of 5.32 parts morpholinophosphorylhomocholine prepared according to French Patent No. 72.43 780 of 8th December 1972, 2.44 parts cis-l-propenylphosphonic acid and 20 parts acetonitrile.

The product is separated by filtration and 6.25 parts of a white hygroscopic solid are obtained.

Yield = 81% b) Sodium salt of P1-(3-trimethylammoniopropyl)phosphoric, P2-(+) cis-1,2- epoxypropylphosphoric acid anhydride.

To a solution of 3 parts of the compound prepared under a) above, 0.1 part of [W(O2)2O]. HMPT. H2O in 6 parts methanol, there are added slowly at ambient temperature 0.5 parts of 85% hydrogen peroxide. After the addition, the reaction mixture is left overnight at ambient temperature and then there is added 0.56 parts alcoholic sodium hydroxide solution and the product precipitated by the addition of acetone. After purification by chromatography on a column of activated alumina (eluant, water/methanol -4:1) 1.7 parts of a white solid are obtained.

Yield 65% EXAMPLE 16.

Disodium salt of P'-(p-cyanoethyl)phosphoric, P2-(+)-cis-1,2-epoxypropyl phosphonic acid anhydride.

a) 2-Dimethylamino-2-oxo- 1,3,2-dioxaphospholane.

To a solution of 5 parts dimethylamine and 10 parts trimethylamine in 180 parts benzene there is added slowly at OOC, a solution of 13.85 parts 2-chloro-2-oxo 1,3,2-dioxaphospholane in 27 parts benzene. When the addition is finished, the mixture is agitated at room temperature and then the hydrochloride is removed by filtration. Then the solvent is evaporated off under vacuum. The product obtained is added to cyclohexane and then the product is isolated by filtration.

M.Pt ^ 500C Yield = 80%.

b) Sodium salt of several days. The product obtained is filtered off and small amounts of NaCN are withdrawn by dissolving the solid in anhydrous methanol. Then the pH of the mixture is adjusted to 8.8 with a weakly acid resin. After filtration a white solid is obtained which is soluble in isopropanol, DMSO and DMF.

c,) Mixture of sodium and dimethylammonium salts of P'(p-cyanoethyl)phosphoric, P2-cis-l-propenylphosphonic acid anhydride.

13.5 Parts sodium (ss-cyanoethyl)-N,N-dimethylamidophosphate and 8.1 parts cis-l-propenylphosphonic acid are mixed for 4 hrs at 700C in 40 parts acetonitrile.

After filtration, 10 parts of white solid, the N.M.R. (H) spectrum of which shows that this compound is a mixture of disodium salt and sodium dimethylammonium salt, are obtained. The product is purified by passing through a silicious column (eluant:MeOH:80, Et3N:S, H2O:15). After evaporation of solvent there is obtained 8.2 parts of a mixture of bis-dimethylammonium salt and sodium dimethylammonium salt.

c) Disodium salt of P'(ss-cyanoethyl)phosphoric, P2-cis-l-propenylphosphonic acid anhydride.

The disodium salt is quantitatively obtained by passing the mixture of salts from step c1) through an Amberlite IR 120 Na@ resin column.

d) Disodium salt of P'-(2-cyanoethyl)phosphoric, P2-(+)-cis- 1 ,2-epoxypropyl- phosphonic acid anhydride.

At room temperature, with stirring, 0.25 parts 85% hydrogen peroxide are slowly added to a mixture of 2 parts disodium salt of P1-(p-cyanoethyl)phosphoric, P2-cis- 1 -propenylphosphonic acid anhydride and 0.06 parts Na2W2O4 in 4.5 parts methanol. The mixture is stirred overnight at room temperature and the product is precipitated by addition of acetone.

Yield 95% Analysis: C"H,NO,P2Na2. 0.5 H20 C H N P Calculated: 22.2 3.01 4.33 19.19 Found: 21.7 3.01 4.27 18.93 The following pharmaceutical tests have been carried out to show the properties of typical compounds according to the invention.

TOXICITY The compounds of formula I according to the invention have an extremely low toxicity. As an example the toxicities (lethal dose 50 or LD 50) determined by the method of Karber and Behrens (Arch. Exp. Pathol. Pharm. 177, 1935, page 379) in Evic Ceba 9 Swiss EOPS NMRI Han mice of 24-26 g, for several compounds are given in Table I below.

TABLE I

LD 50 in g/kg Test Compound Example oral intravenous 6 17 0.68 2 > 10 0.55 1 15 1.5 7 14.5 1.4 5 > 10 2.9 ANTIBACTERIAL ACTIVITY The compounds of formula I according to the invention have an in vivo antibacterial activity both on gram positive and on gram negative bacteria.

As an example we describe activity in infected mice.

Activity on Salmonella typhimurium (strain C5) A. Batches of 15 mice C3H "pathogen free" and weighing 20 g received intraperitoneally 2.104 bacteria in 0.20 ml of physiological serum and simultaneously orally 0.5 mg test compound in 0.25 ml distilled water. The treatment lasted for 5 days i.e. in total 2.5 mg test compound per mouse.

The results of the test were evaluated at 15 days and are given in Table IIA below.

TABLE IIA

Average survival time Test Compound Number of mice surviving (in days) of mice dead Example at 15 days before 15 days 2 15 1 14 8 5 15 Control 0 10 B. Batches of 10 mice C3H "pathogen free" and weighing 20 g received intraperitoneally 104 bacteria in 0.10 ml of physiological serum and simultaneously orally I mg of test compound in 0.25 ml of distilled water. The treatment lasted for 5 days i.e. a total of 5 mg test compound per mouse.

The results of the test were evaluated at 15 days and are given in Table IIB below.

TABLE II B

Average survival time Test Compound Number of mice surviving (in days) of mice dead Example at 15 days before 15 days 6 10 Control 0 6.2 No bacteria were found in blood or cells of the surviving mice in either Test A or B.

Activity of Staphylococcus aureus (strain 124) Batches of 10 mice received intraperitoneally l(r bacteria in suspension in 0.20 ml of sterile 5% mucin.

The previous day the mice to be treated had received orally 2 mg of the test compound in 0.25 ml distilled water.

Treatment was repeated on the day of microbial inoculation and then for 3 days, i.e. 5 days in all, each mouse thus receiving 10 mg of test compound.

The results of the test were evaluated at 15 days and are given in Table III below: TABLE III

Average survival Test Compound Number of mice surviving (in days) of the mice Example at 15 days dead before 15 days 6 10 2 7 6.2 1 10 5 10 Control 2 2.5 Activity on Escherichia coli (strain from wild rodent) Batches of 10 mice received intraperitoneally 108 bacteria in suspension in 0.20 ml sterile 5% mucin.

The previous day the mice to be treated had received orally 2 mg of the test compound in 0.25 ml distilled water.

The treatment was repeated on the day of microbial inocculation and then for 3 days, i.e. in total 5 days, each mouse thus receiving 10 mg of compound.

The results of the test were evaluated at 15 days and are given in Table IV below: TABLE IV

Average survival Test Compound Number of mice surviving (in days) of the mice Example at 15 days dead before 15 days.

6 8 5.5 Control 3 3.2 ANTIBILHARZIASIS ACTIVITY Mice were infested with cercariae of Schistosoma mansoni and then immediately treated orally with test compound, the total length of treatment being 5 days.

The experimental conditions followed were in accord with the works of: - WARREN K. S. and PETERS P. A.: Comparison of penetration and maturation of Schistosoma mansoni in the hamster, mouse, guinea pig and rat.

Amer. J. Trop. Med. Hyg. 1967, 16. 718-722.

- SMITH S. R. AND TERRY R. J.: The infection of laboratory hosts with cercariae of S mansoni and the recovery of adult worms, Parasitology, 1965, 55, 695-700.

- STIREWALT M. A., KUNTZ R. E. and EVANS A. S.: The relative susceptibilities of commonly used laboratory mammals to infection by S. mansoni, Amer. J. Trop. Med. Hyg. 1966, 31, 57-82.

The strain of S. mansoni was isolated in Madagascar in 1966, imported into France in 1968 and refined by successive passage through hamsters (45 days) and the mollusc vector Biomphalaria pfeifferi (at 230C, cercariae emission in 45 days).

The cercariae were washed and counted after their emission.

The mice were infested subcutaneously by injecting under the skin of the flank 100 cercariae in 0.25 ml water per mouse. The mice were infested at a rate of 20 for each test compound as well as 20 mice constituting a control.

The test compound was administered orally to the mice by means of a stomach tube immediately after their infestation. The administration doses were 1 or 2 mg test compound per mouse per day for 5 days, i.e. a total of 5 mg or 10 mg per mouse. All the mice were killed on the 45th day. The peritonea and the livers were washed according to the technique of Smith and the adult male and female schistosomes counted.

Anatomo-pathological examination of the liver, of the spleen and of the intestine of the mice was carried out. There were found among the control mice, on washing the liver and the peritonea, between 40 and 60 adult schistosomes per 100 cercariae injected.

The results obtained in mice treated are set out in Tables V, VI, VII and VIII below: TABLE V Results of the tests of activity of the compound of Example 6 at a rate of 1 mg per day for 5 days in mice infested with S. mansoni.

Number of worms in | Number of worms in the control mice the treated mice g g g Liver 8 4 0 1 Intestine 19 9 7 2 Intestine ~~~~~~~~. ~~~~~~~~ 19 9 7 2 Total 27 13 7 3 TABLE Vl Results of the tests of activity of the compound of Example 11 at a rate of 2 mg a day for 5 days in mice infested with S. mansoni.

Number of worms in Number of worms in the control mice the treated mice 0 s e Liver 15 6 4 1 Intestine 22 12 7 3 Intestine ~~~~~~~ 22 12 7 3 Total 37 18 11 4 TABLE VII Results of the tests of activity of the compound of Example 4 at a rate of 2 mg per day for 5 days in mice infested with S. mansoni.

Number of worms in Number of worms in the control mice the treated mice dl Liver 15 1 6 13 5 Intestine 22 12 23 -3 Intestine 22 12 23 -3 Total 37 18 36 8 TABLE VIII Results of the tests of activity of the compound of Example 5 at a rate of 2 mg per day for 5 days in mice infested with S. mansoni.

Number of worms in Number of wroms in the control mice the treated mice Liver d b c 15 5 2 Intestine 22 12 12 5 l Total 37 18 17 7 Three other tests have been carried out administering orally to the mice a single dose of 1.25 mg, 2.5 mg or 5 mg of the compound of Example 6.

Even if these tests do not give evidence of a dose-action relationship, they demonstrate two remarkable facts: - a very significant reduction in the number of female worms, - the single dose activity, the important of which is considerable in prophylactic treatment.

TABLE IX Results of the tests of activity of the compound of Example 6 administered as a single dose to mice infested with S. mansoni.

* Numbers of worms in Number of worms in the mice treated the control mice with a single dose Dose in mg dl 14 26 1.25 5 2 14 26 2.50 3 1 14 26 5 11 3 A considerable reduction in the number of adult schistosomes in the treated mice is observed.

An anatomo-pathological examination of the mice gave the following results: - spleen: spleen enlargement in the control mice, absence of spleen enlargement in the treated mice; - intestine: inflammatory granulomae centred on eggs in the control mice, no eggs in the treated mice; - liver: inflammatory granulomae with eggs in the control mice, no eggs in the treated mice.

It is extremely important to note the absence of eggs in the mice treated with -the compound of Example 6.

Finally toxicity phenomena were not observed in the treated mice.

The preventative activity against bilhariziasis of the racemic form of the derivatives clearly appears to come from the dextrorotatory enantiomer contained in this form.

In addition, it has been discovered that the dextrorotatory cis-l,2-epoxypropylphosphonic acid and its derivatives including its salts present excellent antibilharziasis properties, whilst the laevorotatory enantiomer does not have any such properties at the doses employed.

CONCLUSIONS The compounds of formula I according to the invention administered by the oral route in mice infested with cercariae of S. mansoni have the property of reducing the development of the adult schistosomes and, more particularly, the female forms, even at single dose. In addition anatomo-pathological examination shows a total or quasi-total absence of eggs in the treated mice. Moreover, the tolerance to the treatment is good.

In this way, the conditions necessary for a prophylactic approach to bilharziasis and for mass treatment are combined.

Antibiotic activity complementary to the anti-bilharziasis activity of the derivatives in their racemic form is interesting due to the frequent microbial super infections suffered by the people inhabiting infested tropical zones.

CURATIVE ANTIBILHARZIASIS ACTIVITY AT THE ADULT STAGE The tests carried out have enabled the following facts to be demonstrated: - the derivatives of the invention in their racemic form have only low curative activity in the mouse infested with cercariae of S. mansoni, the association of these racemic derivatives with an amine such as benzylamine or methylbenzylamine improves their curative activity, - de?ttrorotatory enantiomers of these derivatives are curatively active without it being necessary to add an amine thereto.

Curative activity of the racemic compound of Example 6 in the presence of benzylamine hydrochloride The experiment consists in infesting mice by the transcutaneous route with 100 cercariae of S. mansoni and in treating them orally for 5 days with the compounds to be tested from the 40th day following the infestation. The daily doses employed were 1 mg of the test compound and 0.5 mg of benzylamine hydrochloride.

Examination of the mice was carried out either immediately after the treatment or after a further period of 10 days.

The results obtained on batches of 25 mice, of which 10 were killed on the 45th day and 15 on the 55th day after the infestation are shown in Table X below: TABLE X Curative effects obtained by administering for 5 days 1 mg of the compound of Example 6 and 0.5 mg of benzylamine hydrochloride. (Infestation by 100 cercariae.

Number of worms in the treated mice Number of worms in control mice at 45 day at 55 days at 45 days at 55 days at 45 days 14 mice 10 mice 15 mice 10 mice (see note) dl 2 dl' 2 dl- 2 dl' e Liver 5 4 5 3 1 0 0 0 Intestine 17 7 20 12 5 3 ~~~~. 0 0 Total 22 11 25 15 6 3 0 0 Note: the 15th mouse had 10 worms dl and 2 worms 2 in the intestine.

Anatomo-pathological examination therefore reveals that, on the 55th day, i.e.

10 days after the stopping of the treatment, all the worms are dead in 14 mice out of 15.

The combination of the compound of Example 6 and benzylamine hydrochloride has a very high curative activity vis-a-vis the infestation by S.

mansoni.

In another experiment, the infestation of the mice was effected by a massive quantity of cercariae (1000 by the transcutaneous route). The treatment for 5 days was started on the 48th day of the infestation and the anatomo-pathological examination was carried out on the 61st day, i.e. 8 days after the end of the treatment.

The results of this treatment are given in Table XI below.

TABLE XI Curative effects obtained by administering for 5 days 1 mg of the compound of Example 6 and 0.5 mg of benzyl amine hydrochloride (infestation by 1000 cercariae).

Number of worms in Number of worms in control mice treated mice (on 48th day) (on 61st day) 6 2 g g , Liver 160 80 49 24 Intestine 44 35 2 1 Total 204 115 51 25 Examination revealed that 95% of the worms counted in the treated mice are dead.

CONCLUSION The derivative of the invention administered orally from the 40th day of the infestation of the mice by the cercariae of S. mansoni have the property of lysing the adult worms. This curative action necessitates the addition of an amine such as the benzylamine in the case of the derivatives in their racemic form. The dextrorotatory enantiomers are active directly. It thus appears that the curative and preventative anti-bilharziasis activities must be related to the dextrorotatory enantiomers of the derivatives of the invention.

The compounds according to the invention may be administered in oral or parenteral pharmaceutical forms. Suitably the compounds can be administered in forms associated with a pharmaceutically acceptable vehicle selected from the group consisting of solid extenders, ingestible containers of capsules and cachets, non-solvent liquid media, solvent liquid media comprising a solvent and at least one additive selected from the group consisting of sweetening, flavouring, colouring, preserving and surface active agents, and sterile liquid media.

For oral administration, the derivatives are preferably used in the form of their calcium salts, but for the parenteral route (intramuscular or intravenous routes), the sodium salts are preferred.

The posology in an adult is from 1 to 3 g per 24 hours for oral administration to be distributed throughout the day (in the form of e.g. tablets, gelatine capsules, suspensions or granules). Long-acting compositions (called "delayed action" forms) enable administration to be reduced to once or twice daily.

The following Example illustrates a composition according to the invention.

EXAMPLE 7.

Tablets are prepared in accordance with the usual technique with the following composition: - calcium salt of P1-methylphosphoric, P2 cis-1 ,2-epoxypropylphosphonic acid anhydride 400 mg - benzylamine hydrochloride 200 mg -- colloidal silica 10 mg - talc 50 mg - starch 40 mg The words TRITON, TITRIPLEX, AMBERL.ITE, AMBILMAR and CELLOSOLVE are registered Trade Marks.

WHAT WE CLAIM IS: 1. An asymmetric cis-l,2-epoxypropylphosphonic acid derivative of the formula I

wherein A represents a straight chain or branched alkyl or alkoxy group having up to 8 carbon atoms which is unsubstituted or substituted by an epoxy group and/or by one or more substituents chosen from alkoxy groups having 1 to 5 carbon atoms, alkoxycarbonyl groups having 1 to 5 carbon atoms in the alkyl moiety, amino groups, alkylamino groups, ammonium groups, alkylammonium groups, and nitrile groups provided that A does not represent a cis-1,2-epoxypropyl group, or A represents an unsubstituted or substituted aryl, aralkyl, aryloxy or aralkoxy group, and

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (43)

**WARNING** start of CLMS field may overlap end of DESC **. CONCLUSION The derivative of the invention administered orally from the 40th day of the infestation of the mice by the cercariae of S. mansoni have the property of lysing the adult worms. This curative action necessitates the addition of an amine such as the benzylamine in the case of the derivatives in their racemic form. The dextrorotatory enantiomers are active directly. It thus appears that the curative and preventative anti-bilharziasis activities must be related to the dextrorotatory enantiomers of the derivatives of the invention. The compounds according to the invention may be administered in oral or parenteral pharmaceutical forms. Suitably the compounds can be administered in forms associated with a pharmaceutically acceptable vehicle selected from the group consisting of solid extenders, ingestible containers of capsules and cachets, non-solvent liquid media, solvent liquid media comprising a solvent and at least one additive selected from the group consisting of sweetening, flavouring, colouring, preserving and surface active agents, and sterile liquid media. For oral administration, the derivatives are preferably used in the form of their calcium salts, but for the parenteral route (intramuscular or intravenous routes), the sodium salts are preferred. The posology in an adult is from 1 to 3 g per 24 hours for oral administration to be distributed throughout the day (in the form of e.g. tablets, gelatine capsules, suspensions or granules). Long-acting compositions (called "delayed action" forms) enable administration to be reduced to once or twice daily. The following Example illustrates a composition according to the invention. EXAMPLE 7. Tablets are prepared in accordance with the usual technique with the following composition: - calcium salt of P1-methylphosphoric, P2 cis-1 ,2-epoxypropylphosphonic acid anhydride 400 mg - benzylamine hydrochloride 200 mg -- colloidal silica 10 mg - talc 50 mg - starch 40 mg The words TRITON, TITRIPLEX, AMBERL.ITE, AMBILMAR and CELLOSOLVE are registered Trade Marks. WHAT WE CLAIM IS:

1. An asymmetric cis-l,2-epoxypropylphosphonic acid derivative of the formula I

wherein A represents a straight chain or branched alkyl or alkoxy group having up to 8 carbon atoms which is unsubstituted or substituted by an epoxy group and/or by one or more substituents chosen from alkoxy groups having 1 to 5 carbon atoms, alkoxycarbonyl groups having 1 to 5 carbon atoms in the alkyl moiety, amino groups, alkylamino groups, ammonium groups, alkylammonium groups, and nitrile groups provided that A does not represent a cis-1,2-epoxypropyl group, or A represents an unsubstituted or substituted aryl, aralkyl, aryloxy or aralkoxy group, and

each of Me and M'u, which may be the same or different, represents a hydrogen ion or a monovalent inorganic or organic cation, or My and and M'@ together form a divalent inorganic or organic cation.

2. A compound according to claim 1 wherein M'u is formed by an ammonium or alkylammonium substituent of A, when A represents an alkyl or alkoxy group substituted by an ammonium or alkylammonium group.

3. An asymmetric cis-l ,2-epoxypropylphosphonic acid derivative of formula I given in claim 1 wherein A represents a straight chain or branched alkoxy group having up to 6 carbon atoms which is unsubstituted or substituted by an alkoxy group having 1 to 5 carbon atoms, an alkoxycarbonyl group having 1 to 5 carbon atoms in the alkyl moiety, an ammonium group or an alkylammonium group, and each of Mu and M'u, which may be the same or different, represents a hydrogen ion or a monovalent inorganic or organic cation, provided that, when A represents an alkoxy group substituted by an ammonium or alkylammonium group, M'u is formed by the ammonium or alkylammonium substituent of A, or M# and and M'# together form a divalent metal or organic cation.

4. A compound according to claim 3 wherein A represents a methoxy, ethoxy, propoxy, 3-methoxybutoxy 2-methoxyethoxy or methoxycarbonylmethoxy group, and My and and M'# are the same and both represent alkali metal cations or monovalent organic cations, or Mu and M'u together form an alkaline earth metal cation, or a divalent organic cation.

5. A compound according to claim 3 wherein A and M'u together represent a 2-trimethylammonioethoxy, 3isopropylammoniopropoxy or 3-trimethylammoniopropoxy group, and Mu represents an alkali metal cation or a monovalent organic cation.

6. An asymmetric cis-l,2-epoxypropylphosphonic acid of formula I given in claim 1 wherein A represents a straight chain or branched alkyl group having up to 6 carbon.

atoms which is unsubstituted or substituted by an alkoxycarbonyl group having 1 to 5 carbon atoms in the alkyl moiety or an epoxy group provided that A does not represent a cis- 1 ,2-epoxypropyl group, or A represents a phenyl or benzyl group, and each of M and M'u, which may be the same or different, represents a hydrogen ion or a monovalent metal or organic cation, or M and and M'# together form a divalent metal or organic cation.

7. A compound according to claim 6 wherein A represents a methyl, phenyl, 2,3-epoxypropyl, benzyl or methoxycarbonylmethyl group, and My and M' M'# are the same and both represent alkali metal cations or monovalent organic cations, or My and and M'# together form an alkaline earth metal cation or a divalent organic cation

8. Sodium P'-methyl, P2-(I)cis-l ,2-epoxypropylpyrophosphonate.

9. Sodium P'-phenyl, P2-(+)cis-l ,2-epoxypropylpyrophosphonate.

10. Sodium P'-2,3-epoxypropyl, P2-(+)cis-l ,2-epoxypropylpyrophosphonate.

11. Sodium Pt-benzyl, P2-(+)cis-1,2-epoxypropylpyrophosphonate.

12. Sodium P1-methoxycarbonylmethyl P2-(+)cis- 1 ,2-epoxypropylpyro phosphonate.

13. The calcium salt of P1-methyl-phosphoric, P2-(+)cis-l 2-epoxypropyl phosphonic acid anhydride.

14. The disodium salt of P'-methylphosphoric, P2-(+)cis-l 2-epoxypropyl- phosphonic acid anhydride.

15. The sodium salt of P-(2-trimethylammonioethyl)phosphoric, P2-(+)cis- 1,2- epoxypropylphosphonic acid anhydride.

16. The sodium salt of P'-(γ-N-isopropylammoniopropyl)-phosphoric, P2-(j)- cis-l ,2-epoxypropylphosphonic acid anhydride.

17. The sodium salt of P'-3-methoxybutylphosphoric, P2-(+)cis-1,2-epoxy- propylphosphonic acid anhydride.

18. The disodium-salt of P'-n-propylphosphoric, P2-(+)cis-l 2-epoxypropyl- phosphonic acid anhydride.

19. I he disodium salt of P'-ethylphosphoric, P2-(l)cis-l,2-epoxypropyl- phosphonic acid anhydride.

20. The disodium salt of P'-(2-methoxyethyl)phosphoric, P2-(+)c is-I 2-epoxy- propylphosphonic acid anhydride.

21. The disodium salt of P'-methoxycarbonylmethylphosphoric, P2-(+)cis-1,2epoxypropylphosphonic acid anhydride.

22. The sodium salt of P1-(3-trimethylammoniopropyl)-phosphoric, P2-(+)cis- 1,2-epoxypropylphosphonic acid anhydride.

23. The disodium salt of P'-(p-cyanoethyl)-phosphoric, P2-(+)cis-l,2-epoxy- propylphosphonic acid anhydride.

24. A compound as claimed in claim I or 2 in laevorotatory or dextrorotatory form.

25. A compound as claimed in claim 3, 4 or 5 in laevorotatory or dextrorotatory form.

26. A compound as claimed in claim 6 or 7 in laevorotatory or dextrorotatory form.

27. A process for preparing a compound of formula I as claimed in claim 1 which process comprises epoxidising a cis-propenyl compound of the formula II

wherem A' is as defined for A in claim 1 and, in addition, if in the desired product of formula I A represents an alkyl group substituted by an epoxy group, A' may represent a corresponding alkenyl group, and M and M' M'@ areas defined in claim 1.

28. A process according to claim 27 wherein the compound of the formula II is obtained by reacting a compound of the formula III

(wherein A' is as defined in claim 28, each of R and R', which may be the same or different, represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and M" represents an ammonium or organo-ammonium group or a metal cation) with cis-l-propenylphosphonic acid and, if desired, replacing the cations M"@ in the product by other cations within the definitions of M@ and/or M'e in claim 1.

29. A process for preparing a compound of formula I as claimed in claim I substantially as described in any one of Examples I to 5.

30. A process for preparing a compound of formula I as claimed in claim 1 substantially as described in any one of Examples 6 to 15.

31. A process for preparing a compound of formula I as claimed in claim 1 substantially as described in Example 16.

32. A compound according to claim 1 prepared by the process claimed in claim 27, 28 or 31.

33. A compound according to claim 1 prepared by the process claimed in claim 29.

34. A compound according to claim 1 prepared by the process claimed in claim 30.

35. A pharmaceutical composition which comprises, as active ingredient, a compound as claimed in claim 1, 2, or 23 together with a pharmaceutically acceptable carrier or diluent.

36. An antibiotic composition which comprises, as active ingredient, a compound as claimed in claim 1, 2 or 23 in racemic or laevorotatory form together with a pharmaceutically acceptable carrier or diluent.

37. An antibilharziasis composition which comprises, as active ingredient, a compound as claimed in claim 1, 2 or 23 in racemic or dextrorotatory form together with a pharmaceutically acceptable carrier or diluent.

38. A pharmaceutical composition which comprises, as active ingredient, a compound as claimed in any one of claims 3 to 5 and 13 to 22 together with a pharmaceutically acceptable carrier or diluent.

39. An antibiotic composition which comprises, as active ingredient, a compound as claimed in any one of claims 3 to 5 and 13 to 22 in racemic or laevorotatory form together with a pharmaceutically acceptable carrier or diluent.

40. An antibilharziasis composition which comprises, as active ingredient, a compound as claimed in any one of claims 3 to 5 and 13 to 22 in racemic or dextrorotatory form together with a pharmaceutically acceptable carrier or diluent.

41. A pharmaceutical composition which comprises, as active ingredient, a compound as claimed in any one of claims 6 to 12 together with a pharmaceutically acceptable carrier or diluent.

42. An antibiotic composition which comprises, as active ingredient, a compound as claimed in any one of claims 6 to 12 in racemic or laevorotatory form together with a pharmaceutically acceptable carrier or diluent.

43. An antibilharziasis composition which comprises, as active ingredient, a compound as claimed in any one of claims 6 to 12 in racemic or dextrorotatory form together with a pharmaceutically acceptable carrier or diluent.