DE2632136A1 - ASYMMETRIC CIS-1,2-EPOXY-PROPYLPHOSPHONIC ACID DERIVATIVES, THE METHOD OF MANUFACTURING THEM AND THE MEDICINAL PRODUCTS CONTAINING THEY - Google Patents

Description

PATENT LAWYERS A. C3RÜ.NE.CKER

DiPL-ING.

H. KtNKEUDEV

.. DR - ^) G.

.'W. STOCKMAIR

K.SCHUMANN

- DRf ^ ERNAT-OPU-PHYS.

P, H. JAKO.B

DlPl-- INQ

G. BEZOLD

8 MUNICH 22

MAXlMlUtANSTRASSE 43

.-. ■ · - .. .16. July 1976

P 10 654

AGEKCE NATIONALE DE VALORIZATION DE LA SECHERCHE 13 rue Madeleine Michelis, F-92200 ITEUILLY S / SEIHE, France

SOCIETED'ETUDESETD'APPLICATIONSBIOLOC-IQUES (S.A.B.) 38 rue du General Foy, F-75008 Paris, France

Asymmetrical cis-l ^ -epoxy-propylphosphonic acid derivatives, Process for their preparation and medicaments containing them

The invention relates to new asymmetric cis-1,2-epoxy-propyL · phosphonic acid derivatives, a process ^; for the production of these derivatives as well as drugs containing them _v in particular the use of certain dextrorotatory cis-l ^ -epoxy-propylphosphonic acid derivatives as or in drugs.

The cis-l ^ -epoxy-propylphosphonic acid and a number of its Derivatives are known per se (see, for example, the French Patents 69 15 920 and 69 30 750 and French patent applications Nos. 70 02 084 and 70 02 085, the German Patent 1,046,047 and U.S. Patent 2 770 610). '; ■ -. '

TELEPHONE (089) 00 (28 62 TELEX 06-29 38Ο TELEGRAMS MONAPAT TELECOPER

709808/1 197

The new compounds forming an object of the invention, d. H. the new asymmetric cis-1,2-epoxy ~ propylphosphonic acid derivatives, are characterized by the general formula

- CH - CH O O Il Il CH_ - P - - P - O -

where mean:

M and M, which are the same as or different from each other

can, radicals that are selected from the hydrogen ion and organic-inorganic or organic and / or inorganic cations and

A is a residue that is selected from the group

- The linear (unbranched) or branched alkyl and alkoxy radicals with 1 to Carbon atoms that may have at least one substituent in which

it is an epoxy bridge, or which is selected from the group of alkoxy radicals with 1 to 5 carbon atoms, Alkoxycarbony 1, whose'ALkylrest Has 1 to 5 carbon atoms, amino, alkylamino, nitrile and

- the substituted or unsubstituted aryl, aralkyl and aryloxy radicals.

(\ (\
It should be noted that M and M together, also a divalent cation, such as. B. an alkaline earth metal cation, and that in addition, if A has an amino substituent, this be an ammonium group

709808/1197

A ^? :: - ~ 263213a - ;.

can, and that in this case this group also has the role of the cation (M or "M *) can play *

The compounds according to the invention of the formula given above I exist in two optically isomeric forms; the present invention therefore encompasses both the pure left-handed and dextrorotatory derivatives of the formula I given above as well the racemic derivatives of formula I.

The compounds of Formula I become one after another The process forming the subject of the invention is produced is carried out as follows:

one loads a salt of the general formula

"- ν" ■ ■. II

A 0

wherein A has the meanings given above, E. and R 'hydrogen, material atoms or alkyl radicals with 1 to 4 carbon atoms and M' / ^ an ammonium ion, e.g. If (CH). _{,, H 2} ^ (CHw) ₂ , or a metal cation such as. B. Well, mean

react with cis-1,2-propenyl-phosphonic acid derFormel

₃ ^

the compound of the formula thus obtained is then epoxidized

Ό O

-CH - CH - P - O - P-A

III

-Ii '

709808/1197

below, use an appropriate procedure.

The compounds of formula III obtained as intermediates also represent new connections.

The starting compounds of formula II are prepared by reacting a tertiary amine _r such as. B. trimethylamine, or by reacting a metal cyanide or a metal iodide, such as NaGN or NaI, with a methyl ester of the general formula

IV

P -OCH.
3

in an organic solvent such as acetone, acetonitrile, nitroinethane, dimethylformamide or dimethyl sulfoxide. The compound of the formula II, which is sparingly soluble in the solvent used, is isolated by simple filtration. The quaternary ammonium salts of the formula II, ie the starting compounds, are not available in the pure state. The compounds in which R and R 'are methyl radicals are preferably prepared. The compounds of the formula II obtained as intermediates can also be prepared by reacting a primary or secondary amine with the anhydride (RPO ₉ ) (V). The condensation reaction between the compound of formula II and propenylphosphonic acid can be carried out at a temperature of 20 to 100 ° C. in an organic solvent such as acetone, acetonitrile, branched alcohols, nitromethane, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamine. The preparation of the metal salts of the compounds of the formula III from mixed quaternary ammonium salts and amine salts. can be done, for example, by ion exchange

709808/1197

"": ■■ "■ ..- 5 -: 2832136

on Amberlite resin IR 120 (M), by double reaction with Sodium salicylate in an alcoholic environment or with potassium chloride in an alcoholic environment. . - -; .

The epoxidation of the compound of the formula III can be carried out using any suitable method, for example by reacting hydrogen peroxide in the presence of catalysts such as the oxodiperoxoaquohexamethylphosphoramidowoIfram [W (O ₂ ), ⁰ ] 'HMPT-H ₂ O or the Wolf ramate. of benzyltriraethylammo-

sodium hydroxyl (Triton) and disodium ethylenediamine-tetraacetic acid . (Titriplex III).

When the radical A has an amine substituent in which it is an ammonium residue (A then has the form

wherein B is an -alkylene or alkylenoxy radical and R, R ¹ and R "denote alkyl radicals or hydrogen atoms), then the production process is carried out according to the following scheme:

70980 8/1197

^ B. Me_N

(V)

© ^ -R -N- R ¹

(VI)

CH-O-

Me N

R (VII)

(VIII)

h / B-CH _o -N R '.

D Cn.

(VI) P-CH = CH-CH

CH, CH = CH

B -CH ₂ N-R »- R ⁿ

(ix)

Me ₄ N 0

^X CH _O

"

R (VIII) + (HO) P-CH = CH-CH

c ii O

• 7 09808/1197

The epoxidation of the compound of the formula IX leads to the compound of the formula I ^:

CH ₃ ~ ^CH ■ "CH

The invention is illustrated in more detail by the following examples, but without being limited to it. With those in it The compounds obtained were the racemates. The parts given therein are based on weight.

example 1
Sodium-p, - (SAB 74 202)

Sodium p- -me'thyl-py- (A) -eis-1,2-epoxy-propy Ipyrophosphonat

GH - ^ CH -CH ₃ .

a) - O-methylmethylphosphonic acid chloride

To a solution., Of 208.5 parts of PCl ₅ in 1600 parts of CGI. 183 parts of methyl and tetramethylammonium methylphosphonate (melting point 195 ° C., "BuI, Soc. ChIm.", 1965, page 1925) are added at 70 ° C. in small portions with stirring. After the addition, stirring is continued for 3 hours at the same temperature. ^ The tetramethyl sodium hydrochloride is filtered off, - the solvent is driven off and the product is purified by distillation,

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Bp ₁₀ = 62 ° C, N ^ ⁰ = 1.4360, yield 85

b) Methyl dimethylamidomethylphosphonate To a solution of 101 parts of triethylamine and 48 parts of dimethylamine in 250 parts of benzene, a solution of 128.5 parts of O-methylmethylphosphonic acid chloride and 50 parts of benzene is added at 0 ° C. with stirring. After completion of the addition, the stirring is still .3 hours at ambient temperature continued, the mixture is filtered, the solvent is driven out and then the product is purified by distillation, bp. "= 51 C, N _B = 1.436, yield 90% ^.

c) Tetramethylammonium dimethylamidomethylphosphonate

It is left for a few days at 80 to 90 C in a sealed Reactor that can withstand pressure, a solution of 68.5 parts of methyl dimethylamidomethylphosphonate and 59 parts of trimethylamine react in 180 parts of acetonitrile. The tetramethylammonium salt formed is isolated by filtration after it has been cooled to about 0 ° C. This gives 78.4 parts of a white solid which is very good in water and alcohol is soluble and soluble in nitromebhan in the heat, mp 232 to 233 ° C, yield 80%.

d) Tetramethylammonium and dimethylaimnonium-p, -methyl-p-- cis propen- l-yl-pyrophosphonate

A mixture of 19.6 parts of tetramethylammonium dimethylamidomethylphosphonate, 12.12 parts of cis-propenylphosphonic acid and 100 parts of acetonitrile is stirred for one night at 60.degree. The insoluble material is filtered off, the solvent is driven off under vacuum and 25 parts of a white solid are obtained, the NMR spectrum (H) of which shows the following formula (yield 73.5 %) :

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C-)

e) Sodium p- -methylr-p -cis-propen-l-yl-pyrophosphonate Dissolve the 25 parts of the compound prepared as described above in a little water and pass the aqueous solution through an Amberlite resin IR 120 (Na ) Column. The water is expelled under vacuum, the resulting solid is taken up in warm isopropanol, filtered, dried and you get a white solid which is very good in water, little in alcohol and insoluble in organic solvents, m.p.> 250 C,

rs%.
Elemental analysis for GH ₀ O _n -P ₀ Na ₀

H- O J Z. L

calc .: C 19.4 H 3.26 P 25.4
Found: 19.29 3.57 25.18% NMR (H) iD _o 0

. ^d cba - *

a (m) O = 1.85 ppm ⁵

b, c ". (in) ο '* -' 5 - 7 ppm
d (d) β = 1.3 ppm J = 16.7 Hz
CCM - silica gel G - (type 60)

Eluent CHoOH = 80, Et ₀ N = 5, H ₉ O = 10

Rf = 66

f) Sodium-p .. -methyl · -p ₀ - (-) - cis-l, 2-epoxy-propylpyrophosρh.onat A mixture of 12, 2 parts of sodium _{p_-methyl-p 2} -cis- is stirred for a long time. propen-l-yl-pyrophosphonate, 22 parts of water

709808/1197

stoffperoxidklt 110 parts by volume of oxygen, Ο, ΟΈ "files Titriplex III, 0.24 parts sodium tungstate. The epoxidized compound is precipitated with acetone and filtered. The solid obtained is dissolved with a water / alcohol (60/40) mixture Run over a neutral aluminum oxide column (eluent = water / alcohol (60/40)), drive away the solvent and obtain 7.4 parts of a white solid which is very soluble in water (pH about 7), mp> 250 ° C., yield 57 %. Elemental analysis for CH _o 0, P _o Na _o

H- OO J. Z

Calcd .: C 18.45 H 3.08 P 23.85 Na 17.7

found: 18.06 3.12 23.42 16.9 ^c / o

NMR spectrum (H)? D 0

> P 0 0 CH-CH-CH

³ V. ··

d c-> b a.

a (d) O- 1.45 ppm J = Hz
b, c (m) O «^ 2.90 and 3.32 ppm
d (d) £ = 1.4 ppm J = 16.7 Hz
CCM - silica gel G (type 60)

Eluent CH ₃ OH: 80, Et ₃ N: 5, H ₂ O: 10

Rf = 0.654

Example 2

Sodium p ^ -pheny l-p «- (-) -eis-1,2-epoxy-propylpyrophosphonate

(SAB 74 200) ___ ^

a) Metlryl-phenylphosphonite

To a solution of 64 parts of anhydrous methanol and 250 parts of benzene are slowly added at 0 to 5 C with stirring and under a nitrogen atmosphere and under a slight negative pressure 179 parts of the dichloride of the phenylphosphonic acid. According to Be When the addition is complete, the stirring is continued for a further 3 hours

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P ß "3 71 Ί

continues at ambient temperature, drives off the solvent and purifies the product by distillation, b.p. = 104 G, yield 65%. ; ^:

b) methyl dimethylamidophenyl phosphonate . To a solution of 78 parts of methyl phenylphosphonite in 200 parts of CGI, 48 parts of dimethylamine are slowly added at 0 ° to 5 ° C. with stirring. After the addition is complete, stirring is continued for a few hours and the reaction mixture is allowed to stand overnight at ambient temperature. It is filtered, the filtrate is washed with a dicarbonate solution, the solvent is eliminated and the product is then isolated by distillation, _{boiling point} = 105 ° C., yield => 70%.

c- ) Tetramethylammonium ^ -dimethyl · amidoρhenylphosphonate . The procedure is as in Example 1 c, but this time using 99.5 parts of methyl dimethylamidophenylphosphonate; thereby one obtains
loot 86%.

one receives 111 parts of a white solid, mp 245 C, Aus

c ^ ) Natr ium-d ime thylamidopheny lpho sphonat In a reactor equipped with a distillation column. tet is a mixture of 19.5 parts of phenylphosphonic acid dichloride and 10.2 parts of acetic anhydride. Man. The reaction mixture is heated to 110 ° C. while stirring and the acetyl chloride formed is distilled off. After 1 1/2 hours of reaction, the volatile compounds are eliminated in vacuo and the residue is then taken up in acetonitrile.

About 30 parts of a 40% solution of dimethylamine in acetonitrile are slowly added to this solution at about 0 C. The hermetically sealed reactor is one night at 60 ^C: heated. The solvent is driven off and the residue is taken

7Q9808 / 1197

with a little water, then the aqueous solution is allowed to run over an Araberiite resin IR 120 (Na) column. In this way, 17 parts of sodium dimethylamineG-phenylphosphonate are obtained as a white solid, yield 85%.

d) Sodium p-, -phenyl-p ^ -eis-propen-l-yl-pyrophosphonate A mixture of 27 parts of tetraine thy lammonium dimethyl amidophenylphosphonate, 12.2 parts of cis-propenylphosphonic acid and is stirred for one night at 55 C 200 parts of acetonitrile. Filter, evaporate the solvent and leave a solid white residue.

The solid is taken up in a little water, the aqueous solution through an Amberlite resin IR 120 (Na ') column run and carry out the other operations as in example 1 e. In this way, 29.16 parts of one in water are obtained very good, little in alcohol and insoluble in organic solvents, white solid, mp> 250 ° C., yield 90%.

Analysis for C ₉ H ₁₀ P ₂ O ₅₃₂

calc .: C 33.4 H 3.70-- P 19.15 found: 33.77 3.51 - 19.24% NMR spectrum (H), D “0

CH = GH-CH ₃

d. c b a

a (m) ö = 1.85 ppm
b, C (m) S ~ 5-7 ppm
d (m) 6 = 7.6 ppm
GCM - silica gel G - (type 60)

Eluent CH ₃ OH: 80, Et ₃ N: 5, H ₃ O: .15

Rf = 0.698

70 9 808/1197

ORIGINAL INSPECTED

e) Sodium-p .. -phenyl-p ^ - (-) - cis-1 _y 2-epoxy-propylpyrophosphpnat A mixture of 3 parts of sodium-p .. -phenyl-p ^ - is stirred for one night at ambient temperature prapen-l-yl-pyrophosphonävljö parts of hydrogen peroxide with 110 parts by volume of 0 ", Ο, ΌΙ parts of Titriplex III and 0.03 parts of sodium wolframate. Further processing is carried out as in Example 1 (f) using a water / alcohol (60/40) solution. This gives 1.76 parts of a white solid (yield 56%., F.> 250 C), which is very good in water (pH about 6.5), little in alcohol and in

is insoluble in organic solvents.

Analysis for C ₉ H ₁₀ O ₆ P ₂ Na ₂ .H ₂ O ·.

ber .: C. 31, 76 H 3, 53 P. 18 23 N / A 13th , 52 found: 31, 52 3, 55 18 13th 12th ,8th %

NMR spectrum (H) DO

a (d) ei = 1.32 ppm J = 6 Hz
b, c (m) ^ -2.70-3.12 ppm
d (m) Q = 7.60 ppm

CCM silica gel, type 60 ' ^ä ■

- eluent CH ₂ OH: 80, Et ₃ N: 5, H ₂ O: 15, Rf »0.683

Example 3

Sodium p -2,3-epoxy-propyl-p ^ - (-) - cis-1,2-epoxy-propyl pyrophosphonate (SAB 74 024)

a) 0-methallylphosphonic acid chloride ■ To a solution of 208.5 parts of PCl ₅ in 1600 parts of CCl ^

one at 70 ° C in small portions with stirring 220 parts of methyl

709808/1197

and tetramethylammonium allyl phosphonate (m.p. 174 ° C, "Bull. Soc. Chim.", 1965, p. 1925). After the addition, the mixture is stirred continuously for one hour at 70 ° C., filtered, the solvent is expelled and the product is purified by distillation, boiling point ₁₅ = 90 to 91 ° C., N ^ ⁰ = 1.459, yield 78%.

b) - methyl dimethylamidoallylphosphonate

The procedure is as in Example 1 (b) using 154.5 parts of O-methylallylphosphonic acid chloride, the product being obtained a quantitative yield obtained, b.p. = 56 C, N "= 1.4554.

c) Tetramethylammonium dimethylamidoal.lyIphosphonat

The procedure is as in Example 1 (c) using 81.5 Parts of methyl dimethylamidoallylphosphonate, 89.5 parts of a white solid which is very readily soluble in water and alcohol obtained, mp 180 ° G, yield 81%.

d) Tetramethylammoniuni- and dimethylammonium-pj-allyl-p ^ -cis propen-l-yl-pyrophosphonate

A mixture of 22.2 parts of tetramethylanmoniumdimethylamidoallylphosphonate, 12.2 parts of cis-propenylphosphonic acid and 100 parts of acetonitrile is stirred for one night at 60.degree. It is filtered, the solvent is evaporated and 30.96 parts (yield 90%) of a white solid are obtained _? whose NMR spectrum (H) shows the formula given below:

o O

CH = CH-CH ₃

CH = CH-CH ₃ .

e) Sodium allyl-p ^ -cis-propen-l-yl-pyrophosphonate The procedure is as in Example 1 (e), except that the sodium salt is used

7098.08 / 1197

- 15 - \ _. - -; - ■■. ": -. ■ =; '; = .- -; v-vr '' 2632131

in the form of a white solid which is very readily soluble in water (pH Ca 15 _{),, (yield 84%).}

Analysis JfU ';

ber .. ': ".-- · C 25 ν ■ ..; η A, found .: 25.06: 3,

NMR Spectrum (H) D ₀ O

98 ö P. 21
.21 , 9.5 N / A 15th
15th , 9
, 84%. ONa »> ·: . ■ "■" - Il
0 ^ CH = CH-CH ₀

fed

d (dd ·) £ = ^, 2.48 and 2.60 ppm Vv / ■. _; ,: V

e, f (m) ow4,9 and 6 ppm ... "". ■ ".- ■" -. .ν

CGM silica gel type _60:; '

Eluent CH ^ OH t 80j. Et-Ή -X- 5, H "0 r 10- ν λ ^"

f) Sodium p ..- 2.3 ^w propylTp _epoxy-2 - (-) - 1,2-epoxy-propylpyro -> _-: v.

phosp'hönaty »y · ■ · '"^;'^v;. - · V ■ , ^v : - - ■ '"- ^; A mixture is stirred overnight at ambient temperature; from 2.88: parts' natrium-p, ^

phonate, 7 parts of hydrogen peroxide with .110 parts by volume of 0 ~ j 0> 03 ^ parts of Titriplex III and 0.08 parts of sodium tungstate. Otherwise the procedure is as in Example 1 (f). This gives 2 _y 17 parts; a white solid which is very readily soluble in water (pH about 7), yield 66%, -.- '■. . _; . -----

Analysis for C ₆ H ₁₀ F ₂ O ₇ Na ₂ O ₂ .1,5H ^{-:!: ".--} V,

Calcd .: C 21.8: '- H 3 _V 9' P 18.8 ^; Nä.l3: 98 - λ: - / ::: Found .: 22.9 4.2 ^ 18.9 to 14.14% ν: _v:

"709808/1197 _; ν _v ν

"ORIGINAL INSPECTED ^V

NMR Spectrum (H) D ~ 0

₂ ΣHCB,

f. ed _u

c b a

a (d) <f- 1.76 ppm J = 5.7 Hz

b, c, d, e, f (m) σ between 1.8 and 3.5 ppm GCM silica gel, type 60

Eluent CH ₃ OH: 80, Et N: H ₂ O ": 10, Rf = 0.571.

Example 4

Sodium p, -benzyl-p ..- (-) - 1,2-epoxy-propyl-pyrophosphonate

(SAB 74 210) ^ _

a) Tetramethylammonium dimethylamidobenzylphosphonate

^C 6 ^H 5 ^CH 2

A mixture of 100 parts of methylbenzylphophonate and 104 parts of PCl ₅ in 120 parts of CCl is stirred for 5 hours at 50.degree. The solvent and the POCl are eliminated in vacuo, then the residue obtained is slowly added at about

0 C and with stirring to a solution of 25 parts of dimethylamine and 51 parts of triethylamine in 100 parts of benzene. You eliminate filter the solid and drive off the solvent under vacuum. The oily residue obtained is then with 60 parts of trimethylamine in acetonitrile according to example

1 (c) treated, 90 parts of a hygroscopic white solid being obtained, mp 190 ° C, yield 66% "

709808/1197

b) Sodium-p .. -'benzyl · -p ^ -cis- ■ ρroρeΏ-l · - ^ yl-pyrophosphona.t A mixture of 27.2 parts of tetramethylamniOnium-dimethylamidobenzylphosphonate, 12, is stirred for one night at 65 C. 2 parts of cis-propenylphosphonic acid and 100 parts of acetonitrile. It is filtered, the solvent is driven off and the residue is then taken up in a little water. The aqueous solution is run over an Amberlite IR 120 (Na ⁺ ) resin column, the water is then driven off under vacuum, the residue is taken up in acetone and a white precipitate is obtained, which is separated off by filtration, yield 75%. Elemental analysis for CH ₁₀ O _{1 -Na 0} P ₀ ^ H ₀ O

Calcd .: C 35.5 H 4.15 P 18.4
Found: 35.43 4.14 18.43% NMR Spectrum (H) D ₀ O

C ₆ H ₅ -CH ^ '"^ θ /« ^X CH = CH-CH ₃ j e 4-d ·. C 4-b ä

a (m) ü ^ w, l, 9 ppm

b, c (m) α between 5.3 and 7 ppm

d (2d) i = 3.1 and 3.15 ppm J = 2OVHz e (s) <T = 7.3 ppm

CCM silica gel type 60

Eluent CH ₃ OH: 80, Et ₃ N: 5, H ₃ O: 10, Rf = 0.78.

Cj ) Sodium ρ -j -benzyl-p ^ - (-) - cis-1,2-epoxy-propylpyrophosphonate A mixture of 3.2 parts of sodium-p, -benzyl-pj-cis is stirred for one night at ambient temperature -propen-l-yl-pyrophosphonate, 7 parts of hydrogen peroxide with 110 parts by volume of 0 _2? 0.05

709808/1197

Parts of sodium tungstate and 0.02 part of Titriplex III. One falls the product formed is removed by acetone and separated by filtration away. The compound is then passed through a column with activated aluminum oxide (eluent Water / methanol = 4/1). The solvent is used up under vacuum and dries the resulting white residue

over P ₂ < C 32.25 %. 12 ° 6 ^W. ' ^a 2 ^P 2 * ² H ₂ O P 16 , 66 ), -, yield 48 32.31 10 ^H. , 3 Well 12 , 37 16 .32% Elemental analysis for C H 4 , 27 12th , 74 ber .: 4th found:

NMR spectrum (H)

a (d) S = 1.45 ppm J = 5.3 Hz

b, c, d (m) ύ between 2.8 and 3.4 ppm e (s) α = 7.4 ppm

CCM silica gel G

Eluent CH ₃ OH: 80, Br ₃ N: 5, H ₂ O: 10

Rf: 0.79,

Cg ) Sodium-p .. -benzyl-p g - (-) -cis-1,2-epoxypropylpyrpphosphonate A mixture of 2 parts of sodium p ^ -benzyl-p ^ - is stirred for 24 hours at ambient temperature cis-propen-1-yl-pyrophosphonate, 0.25 part of 85% hydrogen peroxide, 0.06 part of W (O ₂ ) ₂ O.HMPT. H _? ö and 9 parts of methanol. Then 30 parts of acetone are added to the reaction medium, the precipitate formed is filtered off and 1.6 parts of a white solid with the same properties as the compound produced in Example 4 (c,) are obtained.

709808/1197

Example 5
Natrxtim-p ₁
propylpyrppho sphonate (SAB 74 212)

a) Tetramethylainmonium-dlmethylamidomethoxyca phosphonat,. . "." ■ -. "- ^:.

A mixture of 104.25 parts of phosphorus pentachloride and 120.5 parts of methyl- is stirred for one day at ambient temperature. and tetramethylamraonium methoxycarbonylmetiylphosphonate in 160

Share CCl ,. The solid is eliminated by filtration, 4th

drives off the solvent and 'the POCl, under vacuum, then the procedure is as in Example 4 (a), 55.6 parts of a white solid is obtained, mp 123 ° C., yield 57%.

b) Sodium-p.-methoxycarbonylmethyl-p ^ -cis-propen-1-yl-pyro =

phosphonate, - , - ,. ,, -. · ..

MatV works as in Example 4 (b), using 5.08 parts of tetrams thy lammonium-dimethy lamidome thoxycarbonylmethylphosphonate j 2.44 parts of cis-propenylphosphonic acid and 20 parts of acetonitrile allowed to react with one another, and receives 4.95 parts (yield 82%) of a white solid. ■

FMR spectrum (H) D "0

ONa OB, '

CH -O-C-CH-P 5-CH-CH-CH

3 "2 ,," ^ _n S "·

0 0 0 0. ;

a (m) <f = 1.88 ppm
b, c (m) £ between 5.2 and 7 ppm d (m), C between 2.74 and 3.10 ppm e (s) = 3.68 ppm

c) Sodium-p «-methoxycarbonylmethyl-p _? - (-) - cis-l, 2-epo3cy-propyl-

pyrophosphonate, "'-" - ·.'', ^ _- , ';

70 9808/1197.

A mixture of 4 parts of the compound prepared in section 5 (b) above, 6 parts of hydrogen peroxide with parts by volume of 0, 0.06 part of NaW0, and 0.02 part of Titriplex is left at ambient temperature for 1 hour with stirring III respond. The product formed is precipitated with acetone and separated off by filtration. This gives 4 parts of a white solid which is purified by chromatography on activated aluminum oxide. ,
Analysis for ^c ₆ ^H ₁₀ ⁰ 8 ^Na 2 ^P 2

calc .: C 22.62 H 3.14 P 19.5. Na 14.45 found: 22.14 3.32 18.72 14.62% NMR Spectrum (H) D ₃ O

0 Well ONa

d I · I c b a

H ₉ -P. .P-CH-CH-CH

"^ 11

0.0

PCHCH "V /

a (d) £ = 1.52 ppm

b, c, d (m) ö, - 3.1 ppm

e (s) o = 3.78 ppm

CCM silica gel type 60

Eluants: MeOH: 80, Et ₃ N: 5, H ₂ O: 5

Rf: 0.65

Example 6

Calcium salt of p ₁ -methylphosphoric acid-p ₉ - (-) - cis-1,2-epoxy

propylphosphonic anhydride (SAB 73 196)

Ca ⁽⁴⁺⁾

-CH-CH-CH.

ν ³

709808/1197

a) Calcium salt of p, -methylphosphoric acid-p2 ~ ^c i ^s ~ l> 2-propenyl-

phosphonic anhydride __ ^ ^ ^ - _

21.2 parts by weight of methyl and tetramethylammonium dimethylamidophosphate (JC.R. Acad. Sci. ", 1959, 249, 1240), 12.2 parts by weight of cis-propenylphosphonic acid (" J. Org. Ghem. ", 1970, 35, 3510) and 80 parts by weight of acetonitrile. The reaction mixture becomes homogeneous after it has been stirred for several hours at 55 ° C. and in the absence of moisture Continuing overnight at the same temperature, the small amount of precipitate formed is eliminated by filtration and the acetonitrile is driven off under vacuum at ambient temperature and with stirring, a concentrated solution of calcium chloride in the same alcohol / water mixture to. the mixture is filtered and the precipitate formed from, takes it in warm methanol again, then dried under vacuum over P ₀ O _n .. This gives 22 , 6 parts (from Prey 79%) of a soluble in water (pH about 5), in organic. Niche solvents insoluble white solid, F. ^ 30 ° C. The elemental analysis data show that the product crystallizes with 1 molecule of water.
Analysis for C ₇ H ₀ O ₁ -P ₀ Ca-H ₀ O

ber .: C 17.64 H 3 , 67 P 22 , 79 Ca 14.7 found: 17.56 3 , 54 22nd , 95 14 % NMR spectrum (H) D ₂ O CH ₃ 0-P ^.
Il
0 Ca (-H-)
'» ^M ·
- ^ "P-CH = CH-CH-
VI! J
0

709808/1197

a (m) ü = 1.90 ppm

b, e (m) δ -5-7 ppm

d (d) £ = 3.6 ppm J = 10.6 Hz

CCM silica gel G - type 60

Eluant CH ₃ OH: 80, Et N: 5, HO: 20 Rf * 0.73.

b) Calcium salt of pj-methylphosphoric acid-p ^ - ^^ cis-l ^ -epoxy propylphosphonic anhydride

A mixture of 14>, 4 parts of the calcium salt of p ^ -methylphosphoric acid-p «-1,2-cis-propenylphosphonic anhydride, 20 parts of hydrogen peroxide with 110 parts by volume of ₀ , 0.28 parts is stirred overnight at ambient temperature Sodium tungstate and 0.08 part of Titriplex III. The epoxidized compound is precipitated with acetone, separated by filtration and then purified as follows: the solid obtained is dissolved in a minimum amount of water and the pH of the solution is adjusted to about 8.5 with a calcium hydroxide solution The precipitate is separated off by filtration, the filtrate is concentrated in vacuo and ethanol is then added to this solution with stirring until a weak precipitate forms, which is separated off by filtration. The product is then precipitated with acetone, filtered off and dried under vacuum over P9O5. In this way, 8.35 parts of a white solid which is soluble in water (pH about 5) and insoluble in organic solvents are obtained,?. 300 ° C, yield 58 %. Analysis for C HgO ^ .Ca.LO

calc .: C 16.65 H 3.47 P 21.7 Ca 13.88 found: 17.47 3.86 20.91. 13.85%

NMR spectrum (H) D _o 0 ₍₄ , \

^Δ . Ca ^v '

⁰ "- ° cba

CHÖ-P _V ^ P-CH-CH-CH ₃ "

0 0 0

70-9808 / 11-9 7

a (d) o "- 1.5 ppm J = 6 Hz

b, c (m) δ ^ 2.9-3.4 ppm

d (d) £ = 3.65 ppm J = 10.6 Hz.

CCM - silica gel G - type 60

Eluent CH ₃ OH: 80, Et ₃ N: 5, H ₀ O: 20.

Rf = 0.85

Example 7

Disodium salt of p ^ -methylphosphoric acid-p ^ -iy-cis-l ^ -epoxy propylphosphonic anhydride (SAB 74 207)

a) Disodium salt of the anhydride of pi-methylphosphoric acid-po = 1,2-cis-propenylphosphpnic acid

A mixture of 21.2 parts of methylammonium and tetramethylammonium dimethylamidophosphate, 12.2 parts of cis-propenylphosphonic acid and 80 parts of acetonitrile is allowed to react with stirring overnight at 55.degree. The insoluble material is removed by filtration, the solvent is driven off, the residue is taken up in a little water, the aqueous solution is then run over an Amberlite IR 120 (Na) resin column. The water is driven off under vacuum, the residue is taken up in warm isopropanol, filtered and dried, and 20 parts of a white solid are obtained. . NMR spectrum (H) D ₀ O ^! . . .

a (m) ο => 1.85 ppm

b, c (m) ir - 5.5 - 7 ppm

d (d ') £ = 3.57 ppm J = 11.3 Hz

CCM - silica gel G - type. 60

Eluant CH ₃ OH: 80, Et ₃ N: 5, H ₂ O: 5 Rf: O, 671

709808/119 7

a,) disodium salt of ρ, -methylphosphoric acid-ρ ,, - Ι, 2-ice-pro-

penylphosphonic anhydride

Methyl and sodium dimethyl amidophosphate A mixture of 153 parts of dimethyldimethylamido phosphate, 50 parts of sodium cyanide and 400 parts of dimethyl sulfoxide is allowed to react at 60 to 70 ° C. with stirring for several hours. The preparation is left to stand for one night at ambient temperature, the product is separated off by filtration, washed with DMSO, then with acetone and dried under vacuum. This gives 140 parts of a white solid which is very readily soluble in water.

a ₂ ) Disodium salt of p.-methylphosphoric acid-p ^ l ^ -cis-pro penylphosphonic anhydride

A mixture is left out with stirring overnight at 70.degree 16.1 parts of methyl and sodium dimethyl amidophosphate, 12.2 Parts of cis-propenylphosphonic acid and 60 parts of acetonitrile react. The solvent is driven off under vacuum and the residue is dissolved in a minimal amount of ethanol. This alcohol solution a solution of 4.1 parts of sodium hydroxide in methanol is added, with stirring and at ambient temperature, then stirring is continued for one hour at ambient temperature. The mixture is then brought to reflux and then filtered hot, the solid is washed with alcohol and dried under vacuum. This gives 23.4 parts of a white solid having the same physical constants as that produced in the above section (a,) Product has.

b) disodium salt of p.-methylphosphoric acid-prj-CO-cis-l ^ - epoxypropylphosphonic anhydride

A mixture is stirred for 1 hour at ambient temperature

70 9808/1 19 7

5 parts of the compound obtained in the above section (a), 0.10 part of sodium tungstate, 0.03 part of Titriplex III and 11 parts of hydrogen peroxide with 110 parts by volume of O ₃ . The epoxidized compound is precipitated with acetone, then filtered and the product obtained is purified on a column with activated aluminum oxide (eluent water / methanol = 5/1). This gives 4.1 parts of a white solid, the physical constants of which are as follows:

NMR spectrum

V - 1

P-CH-CH-CH ₃

a (d) (T = 1.5 ppm J = 5.3 Hz

b, c (m) ö ^^ 3.3 ppm

d '(d) £ = 3.65 ppm J = 11.3 Hz

CCM - silica gel G - type 60 ³ eluent CH ₃ OH: 80 Et ₃ N: 5, H ₃ O 10 Rf = 0.525

709808/119 7

Example 8

Sodium salt of p ^ - (2-trimethrlaimoniumthyl phosphoric acid-

CH-CH-CH ₃ .

(a) Sodium salt of gy .- (2-trimethylammonium "umät; tiyl2pnQsgIior ~

A mixture of 5.0 parts of MorpholinophospnoiylctLolin produced according to French patent specification 72 43 780, 2.03 parts of cis-propenylphosphonic acid and 20 parts of acetonitrile is allowed to react overnight at 65 ° C. The viscous residue formed is separated by decantation, then dissolved in an isopropanol / methyl cellosolve mixture.A solution of 0.5 part of alcoholic sodium hydroxide solution is added to this solution, the solvent is expelled, and the residue is then taken up in acetone a hygroscopic white precipitate which is purified by running it over activated aluminum oxide (eluent H ₂ O-CH ₅ OH = 4/1), yield 88 %. RMN spectrum (H): D ₃ O

1 1

P P

709808 / 11-9 7

a (m) S = 1.9 ppm

b, c (m) <$ between 5.3

d (m) ί / ^ 4.3 ppm

e. (m) i / ~ 3.6 ppm

f Cs-) <* =? 3, ^ 5 ppm

(b) sodium salt of

A mixture of 2.5 parts of the compound prepared in paragraph (a) above, 4 parts of hydrogen peroxide with 110 parts by volume of O ₂ , 0.08 part of sodium tungstate and 0.03 part of Titriplex III is stirred overnight at ambient temperature. The epoxidized compound is dropped with. Acetone, then they are separated off by filtration. In this way, 2.2 parts of a white solid are obtained which are purified by chromatography on an activated aluminum oxide column (eluent HpO / methanol: 4/1).

Analysis for CoHvjgM) _Pp] 3a:

Calc .: C 29.6 N 4.32 ITa 7.07
found: 29.75 4.33 7.04%

EMDT spectrum (H): D ₂ O

^W 0 ^ ONa

^(CH 3 ^} 3 "GH CH -O ^ 0 ^ cK 0. ^ CH-CH-CH ₀ f ed 0 I.

a (d) 4 = 1.42 ppm J = 5.3 Hz b, c (m) & between 2.6 and 3.2 ppm
d (m) & = 4.3 ppm
e (m) <^ = 3.6 ppm
f (s) & = 3.15 ppm

709808/1 1.9 7

Example 9

Hatriums al ζ of O ^ - (V-N-Isopropylammoniopropyl ^ hosphor-

^ BA a ^ &. ■■>. ■■! ^ BBl BBBl ^^^ ^ BA ^ ΒΜ.ΒΒΒΙ * ΗΒ1 ^ BB) ^^ M 3bBT I ^ BBt ^ BBI ^ BBi ^^ H ^ Bn ^ BBI ^ BBl ^ BM ^^ Bi ^^ M ^^ ^^ M .BBt ^ HBi ^^ «BB ^ B ^ BB ^ Bl BBBl oBBh BBB) ^- ^ BK BBBt BbWl ^^^ ^ VB ^ MV ^ Bh.

acid-pp-C-) -cis-Ί «2-epoxy-propyl-phosphonic anhydride CSAB 74 217)

Ca) 2- £ ^ CH,) 4 N ⁺ 0 ^] _- 2-oxo-3-isopropyl-1 _Z-3j.2 oxazaphosgiL0rinan

16 parts of dry bromine ^{are slowly added at about 0} ° C. to a solution of 13 »95 parts of 2-chloro-1,3i2-dioxaphosphorinane. After diluting the reaction medium with ethyl ether, a mixture of 3 »2 parts of methanol and 10.1 parts of triethylamine is slowly added at -20 ° C., then a mixture of 5» 9 parts of isopropylamine and 10.1 parts of triethylamine is added at ambient temperature . The reaction medium is washed with water, dried and then concentrated. The residue obtained is dissolved in tetrahydrofuran and treated with 2.7 parts of sodium hydride at ambient temperature. After the hydrogen evolution has ceased, stirring is continued at 50 ° C. for 2 hours. After cooling, the excess sodium hydride is destroyed by adding water, the reaction medium is neutralized with dilute HCl, the 2-methoxy-2-oxo-3-isopropyl-1,3,2-oxazaphosphorinane is extracted with chloroform, and the product is then thoroughly purified Distillation, b.p. _{Q Q5} = 85 ⁰ C The 2-methoxy-2-oxo-3-isopropyl-1,3 _T 2-oxazaphosphorinane is then in a sealed reactor with 12 parts of triethylamine and 30 parts of acetonitrile for a few days at 80 to 90 ⁰ C treated. Man. the tetramethylammonium salt thus formed is separated off by filtration and 12.4 parts of a hygroscopic white solid are obtained, P. 214 to 215 ° C., yield 51%. . ·

709808 / 11-97

("b) _H atriums al ζ of p ^ - (T -Ν — IsopropylammoniopropyiyOhosgiar-

The mixture is left for one night "at 6O ⁰ C a mixture of 2.9! Parts of the compound prepared in the above (a) and 1.4 parts of ice prop enylphosphonsäure in 15 parts of acetonitrile respond. One separates the precipitate formed by decanting It is then dissolved in a little water. The aqueous solution is run over an Amberlite IE 120 (Na ⁺ ) resin column. The water is expelled under vacuum, then the residue obtained is purified by chromatography on an activated alumina column ( Eluting agent H ₂ OZMeOH = 2/1) and receives 1.5 parts of a hygroscopic white solid, yield 40%.

KMR spectrum (H): D ₂ O

α 0

■ 2 ■ · ■ - ■■■ · -. ■ '

(CH-) JCH N - CH ₀ -GH ₉ -CH-OF / P _v

⁰ - (-f) ^lll £ ^ - (K (J XH = CH-CH ₃

g * fed. · C 'b a

a (m) & = 1.85 ppm
b, c (m) ^ between 5 and 7 ppm
d (m) [λ / 3.95 ppm

e (m) S ~ 2 ppm \

f (t) I = 3.1 ppm ■■ ".-.-" ■

g (d) i = 1.12 ppm J = 6.66 Hz

Analysis for Cn

Calc .: C 33.4- H 6.2 N 4.33 Na 7.12 Set ..: 33.22 6.6 4.43 7. ^%

CCM silica gel G (type 60): eluent MeOH / Et ^ N / HgO ^ 80/5/10, E. = 0.63-

7098.08 / 1 197

(c) ^ atrii ^ salt ^ vonjXj- ^ -] i-IsoOrop2; lamiiionio2ropyl) ghospb, or--

Han stirs one part of the compound obtained in paragraph (b) above, 2 parts of hydrogen peroxide with 110 parts by volume of O ₂ , 0.02 part of sodium tungstate and 0.07 part of Titriplex III at ambient temperature for one fold. Furthermore

the reaction is carried out as in Example 8 (b). Included one obtains 0.58 parts of a very good in water and in the organic Solvents little soluble white solid, yield 55%.

IMR spectrum (H): D ₂ O

ι-CH N-CH ₀ -CH ₀ -CH ₀ -OE., ¹ ν ^ll "

2 0

/! ν ^ba

0 0 CH-CH-CH,

a (d) j = 1.4 ppm

b, c (m) <f rJ 3.15 ppm

d (m) ί ν 4 ppm

e (m) &

f (t) ί

4 ppm

v 1.95 ppm

~ 3.15 ppm

= 1.2 ppm

J = 5.33 Hz

J = 6.66 Hz ₅

Example 10

Sodium s al ζ of

Phosphorus trichloride, diluted with its own, is 68.8% by weight

709808 / 11-9 7

Own volume of methyl or s chi id, are added dropwise tint he ■ stirring and under maintenance of a temperature of 52.5 parts of conservation of the reaction mixture from -20 to about -30 ⁰ G 3-methoxybutanol, diluted with its own volume of methylene chloride to. After the addition has ended, stirring is continued for 1 hour at ambient temperature. 64 parts of methyl alcohol, diluted with its own volume of methylene chloride, asu, are then added dropwise, keeping the temperature between 0 and 5 ° G Solvent and the gaseous products formed under vacuum and the product is purified by distillation, Bp-Q qc = 93 ° C.

11 parts of dimethylamine are slowly added at 0 to 3 ° C. to a solution of 18.2 parts of methyl and 3-methoxybutyl phosphite in 75 parts of CCl ^. When the addition is complete, stirring is continued for 4 hours at ambient temperature, the precipitate formed is separated off by filtration, the solvent is driven off in vacuo and the residue is then purified by distillation, yield 72 %.

(c) 3-Metho ^ bu ^ l2_3md_Tetramethylammonium-d ghosghat

11.25 parts of the ester obtained in section (b) are allowed to react with 6 parts of trimethylamine in 18 parts of acetonitrile for a few days at 80 to 90 ° C. in a sealed reactor. After cooling to about ^{0 0} G, the tetramethylammonium salt formed is separated off by filtration. This gives 9.9 parts of a hygroscopic white solid, mp 210 ^° C., yield 70%.

70980871 1.97

(d) sodium salt

The mixture is allowed a spurred on long "at 6O ⁰ C a mixture of 8 parts of the tetramethylammonium salt obtained in the above (c), 3.4 parts of cis lropenylphosphonsäure in 20 parts of acetonitrile respond. One separates the precipitate formed by filtration from that sells Solvent and then take up the residue in water, the aqueous solution obtained is passed through an Amberlite IR 120 (ITa) resin column, the water is evaporated in vacuo, then the residue is taken up in acetone and a white color is obtained Solid which is separated by filtration, 72 % yield.

Analysis for CgH ₁₆ Or ₇ P ₂ ITa ₂ :

calc .: G 28.9 H 4.81 P 18.67 Na 13.85 found: 28.64 4.81 19.17 12.23%

CCM silica gel G (type 60): eluent CH ^ OH / Et ^ F / E ^ O = 80/5/10, R _f = 0.831.

(e) Sodium salt_y "on E ^

A mixture of 3.8 parts of the compound obtained in paragraph (d) above, 8.5 parts of hydrogen peroxide with 110 parts by volume of O ₂ , 0.06 part of Ia ₂ WO ^ and 0.02 part of Titriplex is left for 3 hours at ambient temperature III respond. The product formed is precipitated with acetone and separated off by filtration. The product is purified by running it over an activated alumina column using a water / methanol (5/1) mixture as the eluent. This gives 2.2 parts of a white solid which is very readily soluble in water, yield 56%.

709808/1197

MMR spectrum (H):

CH.O-CH-C-H, -O-P P.. .

J ι 2 4 "^ *. s' "\. aba

CH 0 0 0 CH-CH-CH.

ed ³ \ / -

a (d) S = 1.5 ppm J = 5.3

d (d) <i = 1.18 ppm J = 6.7 Hz

e (s) X = 3.33 ppm

OCM silica gel G (type 60): eluent x 80/5/5, E _f = 0.721.

Example 11
Disodium alz

^ 0

A mixture of 21.2 parts of methyl and tetramethylammonium dimethylamidophosphate, 13 parts of n-propyl bromide and 0.5 Parts of tribenzylamine are left for several days at ambient temperature and react with stirring. The tetramethylammonium bromide formed is separated off by filtration and driven off the solvent under vacuum, the residue takes in Ether again, filtered, then the ether is evaporated and receives 10.5 parts of methyl- and n-propyl-dimethylamido-

709 8 0871197

phosphate. The 10.5 parts of methyl and n-propyl dimethyl amidophosphate it is reacted with 6 parts of trimethylamine according to Example 10 (c), 11.2 parts of n-propyl and tetramethylammonium dimethylaminophosphate being added obtained in the form of a hygroscopic white solid.

(t>) Disodium salt of p ^ -n-propylphosphoric acid-Po-cisgrogenyl-ijj ^ S-phosghonic anhydride

When using 4.8 parts of n-propyl and tetraniethylammonium dimethylamidophosphate, 2.44 parts of cis-eropenylphosphonic acid and 20 parts of acetonitrile and when working like Example 7 (a) gave 4.05 parts (70% yield) of a water-soluble white solid.

(c) 5iS: 5ii! iü5§ & i5_y £?: _ Ei -n-Propy ^ phosphoric acid-p2 ~ (+) - cis-

A mixture of 3-7 parts of the compound prepared in the preceding paragraph (b), 6 parts of hydrogen peroxide with 110 parts by volume of O ₂ , 0.06 part of Na ₂ WO ^ and 0.02 part of Titriplex is left at ambient temperature for 1 hour with stirring III respond. The product formed is precipitated with acetone and separated off by filtration. This gives 3 ^ 8 parts of a white solid, which is purified by chromatography on an activated aluminum oxide column (eluent water / methanol = 5/1).

Analysis for C ₆ H ₁₂ O ₇ Fa ₂ P ₂ 1/2 H ₂ O:

Calc .: C 23 H 4.16 P 19.82 Ua 14.7 found: 22.93 4/20 19.84 14.35%

MMR spectrum (H): D ₂ O

709808/1197

a (a) £ = 1.53 ppm, J =
b, c (m) ί ~ 3.25 ppm
d (m) i ^ 3.98 ppm
e (m) α rJ 1.68 ppm
f (t) J = 0.92 ppm

Example 12
Disodium salt of

If the procedure of Example 11 (a) is repeated, but the 13 parts of n-propyrbromide are replaced by 12 parts of ithyTbromid, the ethyl and tetramethylammonium dimethylamidophosphate is obtained in the form of a hygroscopic white pesticide, Έ. 198 ° C.

(b) disodium salt of ^

4.52 parts of ethyl and tetramethylammonium dimethyl amidophosphate are allowed to react with 2.4-4 parts of propenylphosphonic acid according to Example 11 (b), 3.7 parts (yield 68 %) of a white pesticide being obtained.

Analysis: her .: C 21.9 H 3.65 P 22.6 Ha 16.8 found: 21.33 3.62 22.44 1?, 07 %

709808/1197

CCM silica gel (type 60): eluent: MeOH = 80, F = 5, H ₂ O = 10

₃
E _f = 0.79.

(c) Diiatrium Salt_yoii

Han leaves 4.2 parts of that obtained in section (b) above Compound with 10 parts of hydrogen peroxide with 110 parts by volume of Op according to Example 11 (c) react, whereby one 3.66 Parts of a white solid are obtained.

KMR spectrum (H): D ₂ O

"ONa ONa

ed ι ι c b a

CH ₀ -GH ₀ -O-Pv ^ P-CH-CH-CH

0 0 0

a (d) <f = 1.5 ppm, J = 5.3 Hz b, c (m) i λ / 3.3 ppm d (m) i ~ 4.02 ppm e (t) 4 = 1.27 ppm

CCM silica gel (type 60): eluent: MeOH = 80, EtJT = 5, H ₂ O = 10; R _f = 0.707.

Example I3

(a) Metbyl-_and_2-Methoxyä.thylphosghit

One works as in Example 10 (a) using

709808/1197

38 parts of 2-methoxyethanol, Ep. _{N ηΛ} = 68 to 7O ⁰ C, on VJ, u ι

The procedure is as in Example 10 (b), Ep. _{Q Q1} = 68 to 70 ^° C., yield 70%.

(c) 2-Methoxyethyl- ^ d ^ etrameth ^ lammonium-dimethjlamidoghosphat

Using the procedure of Example 10 (c), P. 218 to 22O ⁰ C, yield 84.%.

(d) sodium al ζ

^ i ^ -gb-o sphonic acid e anhydride

12.8 parts of those obtained in paragraph (c) above are left Compound with 6.1 parts of propenyl phosphoric acid in Parts of acetonitrile react according to Example 10 (d), giving 11.5 parts of a white solid, yield 76%.

HMR spectrum (H): '. DgO

ONa ONa

CH ₂ CH ₂ Oi J-CH = CH-CH ₃

f e d 0 0 c b a

a (m) S = 1.92 ppm

b, c (m) S between 5 »2 and 7 ppro d (m) S = 4.05 ppm

e (m) k = 3.7 ppm

f (s) Λ = 3, ^ ppm

CCM silica gel (type 60): eluent: MeOH = 80,

709808/119 7

Et N = 5, H ₂ O = 10; R _f = 0.59

e) § J

^c i ^s . ~ li 2-eg

When using 6.08 parts of the compound obtained in section (d) above, 10 parts of hydrogen peroxide with 110 parts by volume of O ₂ , 0.03 part of Fa ₂ WO ₄ and 0.01 part of Titriplex III and when working as in Example 10 ( e) 5.4 parts of a white solid are obtained, yield 84%.

HMR spectrum (H): D _P 0

_Λ ONa W ^ f ed,, cba CH O-CH -CH, 0-B ^ ^ .P-CH-CH-CH

ti Q

0 0

a Cd) ei = 1.5 ppm, J = 5.3 Hz b, c (m) <5 3.32 ppm
d (m) k = 4.15 ppm
e (m) ά = 3.76 ppm
f (s) J = 3.5 ppm

CCM silica gel (type 60): eluent MeOH / Et, U / H ₂ O 80/5/10, R _f = 0.694.

Example 14

(a) lMethoxycarbonylmeth ^ l2-_and_Tetramethylammonium - dim ^

amido ^ hosghat
A mixture of 21.2 parts of methyl and tetra

709808/1197

Raethylammonium-dimetb ^ lamidophosphat, 15 -> 3 parts of methyl bromo acetate, 3 parts of tribenzylamine and 100 parts of acetonitrile
React "at 65" to 80 ^° C. for a few hours. After removing the solvent, the residue is taken up in chloroform and the chloroform solution is washed with a
aqueous sodium bicarbonate solution. The chloroform solution is then dried and evaporated, then "treated"
the residue obtained with 7 parts of trimethylamine according to
Example 10 (c).

(b) pinatriumsals_TTon_p_ / | iMetho ^ carbonjlmethylphosphoric acid

A mixture of 2.7 parts of the in the section above
14 (a), 1.22 parts of cis-t? Ropenylphosphonic acid and 10 parts of acetonitrile are allowed to react for 2 days at 70 ° C., then the procedure is as in Example 7, 2.6 parts of a white solid is obtained, yield 70%. ·

A mixture of 2.6 parts of the compound prepared in Section 14 (b) above, 5 ml of hydrogen peroxide with 110 parts by volume of O ₂ , 0.03 part of Ua ₂ WO ₄ and 0.01 part of Titriplex III is stirred for hour at ambient temperature , then continue the treatment as in Example 7 (b). In this way, 1.1 parts of a white solid are obtained.

MMR spectrum (H): O ₅ O

0® Na® 0 "Na

c b

8h_0-C-CH ₀ O-Ps ^ Ρ - CH-CH-CH.
^J it * ti Λν S ^ Ii \ / 3
0 0

j. υπ- \ ji

s V

709808/1197

a (d) I = 1.5 ppm J = 5.3 Hz

b, c (m) k nj 3.3 ppm

d (d) k = 4.7 ppm

e (s) i = 3.9 ppm.

Example 15

Sodium salt of p ^ -0-? Rimethylammoniumprop7l2ph-psph.oric acid

(ch ₃ ) ₃ n;

B-O-P-CH-i O 1 O 0 Q

acid-p ^ -ii ^ -cis-propenylphosglionsaureanh ^ drid

A mixture of 5.32 is stirred for one night at 70.degree
(Peilen morpholinophosphoryl homocholine, prepared according to French patent specification 72 43 780, 2.44 parts of dLs-propenylphosphonic acid and 20 parts of acetonitrile. The product formed is separated off by filtration and 6.25 parts of a hygroscopic white solid are obtained, yield 81 %.

(b) ^ §triumsalz_von_p_ ^ - (3-T! "imethylammöniumpropyl ^ ghosghor-

To a solution of 3 parts of the section above
15 (a) compound prepared, 0.1 part of [V (O ₂ ) P ⁰ "J ' HMPT H ₂ O in 6 parts of methanol is slowly added 0.5 part of 85% hydrogen peroxide at ambient temperature

70 98087 1 197

In addition, the reaction mixture is left overnight at ambient temperature then add 0.56 parts alcoholic Sodium hydroxide solution and the product formed falls through Adding acetone off. After purification by chromatography on an activated alumina column (eluent Water / methanol = 4/1) 1.7 parts of a white one are obtained Solid, yield 65%

Example 16 ;

Disodium salt_of_p ^ - (/^.-

N / A

¹ X / ^Θη *

Ö. 0 / ^ Ö ^ CH

(a) 2-Dimethylamino-2-oxo - 1,3 _? 2-dioxa £ hosgholan

To a solution of 5 parts of pimethylamine. and 10.1 parts of triethylamine in 180 parts of benzene are added slowly at ⁰ ° C a solution of 13 ^ 85 parts of 2-chloro-2-oxo-1,3-dioxaphospholane _r 2 in 27 parts of benzene to · After completion of the addition the mixture is stirred one at ambient temperature, the hydrochloride formed is separated off by filtration and the solvent is driven off under vacuum. The residue is taken nrnn in Gyclohexan again, .then separating the solid formed by filtering off, F. about 50 ⁰ C, 80% yield,

(b) (. ^ .- C ^ anoathy !! - "i} iid_Sodium-N ^ N-dimeth ^ lamidog The mixture is stirred for a few days at ambient temperature

7 0 9808/1197

. "42

Mixture of 'W-, 7 parts of 2-dimethylamino-2-oxo-1,3-dioxaphospholane 2 ₅ and 4.9 parts of NaCN in 70 parts. DMF. The product formed is separated by, filtration, then removed the traces UTaGKT in the manner indicated below: the solid is dissolved in anhydrous methanol, then the pH of the solution is adjusted to 8.5 with a weakly acidic resin, filtered, the solvent is driven off and one in isopropanol, DMSO and DMF soluble, white solid slightly soluble _{in GH 5} CR, (CHO _{2 CO.}

(c / i) Mixed_sodium _and_dimethylammonium_salt_of_gq _i -

anhydride

The mixture is stirred for 4 hours at 70 ⁰ G, a mixture of 13.5 parts of (SS -Cyanoäthyl) -, and sodium N, N-dimethylamidophosphat and 8.1 parts of cis-1-propenyl-phosphonic acid in 40 parts of acetonitrile. It is filtered and 10 parts of a white solid are obtained, the NMR spectrum (H) of which indicates that it is a mixture of the disodium salt and the mixed sodium and dimethylammonium salt. After the filtrate has been evaporated, the residue obtained is purified by passing it through a silica gel column (eluent MeOH / Et3NZH ₂ O = 80/5/15). After evaporation of the solvent, 8.2 parts of a mixture of the bisdimethylammonium salt and the mixed sodium-dimethylammonium-S al ζ are obtained.

The disodium salt of p ^ - ($ -cyanoethyl) phosphoric acid Pp-cis-i-propenylphosphonic anhydride is obtained quantitatively when the mixed salt is run through an Amberlite IR 120 (Na ⁺ ) resin column.

709808/1197

To a mixture of 2 parts of the disodium salt of p ^ - ( β ^ 07anäthyl) Phosphorsäu3? E-p2 ~ cis-1 ~ propenyl-phosphonic anhydride, 0.06 part [.W (O ₂ O ₂ O] HMPT · "H ₂ O in 4.5 parts of methanol at Ümgebttiigstemperatur and Rühren.0,25 parts of 85% are slowly "strength hydrogen peroxide. it sets a laughing at ambient temperature for continued stirring, then falls to the ^e vSxydierte compound with acetone from, yield

Analysis for CgE

Calc .: C 22.2 H 3.01 N 4.33 P 19.19 found: 21.7 3r01 4.27 18.93%

Example 1?

Disodium salt of p ^ -Methyiphost> horsäure-Pö ⁱ - (+) -cis-1,2-

BBHt · «■ * BBBI BBbB BBBB BHBB BBBB» ^ · ΒΒίΒΒ "^^ M ^^ PB Μ b ^ 1 aim ^ ^ m ^ ^^ i ^^^ ^^^ (V ^ V ^^» «hpIV ^^ W ^^^ HOtf * «P ^ M ^^^ MM ~ tt * W WBlV .V ^" ^ HB .B ^ BHV j.1 iljl ^^ B ^ BI * ^ BB> * ^ B * ^^ BBVV BHM B ^^ BBK BPBB BBB ^ B> ^ "βΪ * Β" ^^ BB

A mixture of 2.59 parts of (-) - ^/ 1-phenyl-äthylammoniüoi - (+) ^ cis-1,2-epoxy-propylphosphonate, 2.59 parts of methyl and tetramethylammonium dimethylamidophosphate, 2.29 parts of picric acid and 25 Parts of p-dL-dimethylbenzyl alcohol are allowed to react for 3 hours at 70 ° C. with stirring. The precipitate formed is separated off by filtration and the product is extracted with water. The aqueous phase is washed with chloroform and with ether, then passed through an Amberlite IR 120 (Na ⁺ ) resin column. After the water has evaporated under vacuum, the residue is taken up in warm ethanol, the solid formed is separated off by filtration and in this way 2.2 parts of a white solid with the rotation value Γ <ΐ} | ^ π = + 2 are obtained ° (C = 5, H ₂ O).

70 9808/119 7

- 4 * 1 a "" -

Bacterial and parasitological tests have shown 1.) that the new products according to the invention (compounds of Formula I) have interesting properties in the pharmaceutical field that these new products im have substantial antibiotic properties when in the levorotatory form, and that they are essentially Have antibilharzia properties when in the dextrorotatory form; the present invention also relates to medicaments which contain at least one compound of formula I as active ingredient;

2.) that when the above findings are generalized, other dextrorotatory phosphonic acid derivatives are also very interesting have (advantageous) anti-rosinosis properties; with these other connections it is is the dextrorotatory cis-l ^ -epoxy-propylphosphonic acid and its salts and dextrorotatory cis-1,2-epoxypropylisohypophosphoric acid and its salts; the present The invention therefore also relates to medicaments which have at least one of these described above as active ingredient right-turning products included.

Schistosomosis or schistosomosis is the second world disease. It is caused by trematodes, the schistosomes. Man distinguishes the intestinal bilharzia, those on Schistosoma mansoni is due to the venous artery schistosomiasis (S. japaonicum) and urogenital schistosomiasis (S. haematobium).

The progression of the disease can be stopped by treating the patient with medication or by curative treatment Interruption of the epidenado logical cycle in the stage of the Penetration of the tail larvae, analogous to the protection that comes with Chloroquin is made for malarial hematosis. The therapy

709808/1197

Schistosomiasis is based on the use of dehydfoeraetin, organoantimone derivatives, thioxanthone derivatives, but above all on the niridazo derivative of nitrothiazole (Ambilhar®). It is essentially a curative therapy, the medicament only acting on the adult forms and not on the larval forms with which the patient is infected - the schistosomes. On the other hand, call these drugs, particularly the Nitrofchiazo! Frequently derivatives produces digestive intolerances and sometimes lead to neurological disorders that can lead to acute psychiatric manifestations or epileptic seizures, so that medical supervision is necessary during treatment and even after Beendigung'der therapy ₀

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- yr-

It would be of great importance now to have an oral drug that is three times as much Has the advantage:

- To act on the schistosome stage in order to stimulate the parasite development cycle interrupt in humans and thereby eradicate the disease (suppressive mass prophylaxis),

- to have a healing effect on the mature stage of parasitosis and

- also to be as non-toxic as possible in order to justify prophylactic campaigns that are not continually medical Require supervision.

The compounds according to the invention satisfy these three conditions. In addition, they have a strong antibacterial activity on both gram-positive and gram-negative germs Germs on.

toxicity

The compounds according to the invention are extremely low in toxicity. In the following (Table I) some toxicities (lethal dose 50 or DL 50) are given by way of example, which according to the method von Karber and Behrens ("Arch. Exp. Pathol. Pharm.", 177, 1935, page 579) in a mouse Evic Geba 0 Swiss EOPS KMRI Han with a weight of 24 to 26 g were determined.

Table I.

73196 DL p. O. 50 in g / kg 74200 17th SAB 74202 > 10 SAB 74207 15th SAB 74212 14.5 SAB > io SAB i. v. 0.68 0.55 1.5 M. 2.9

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Antibacterial activity "

The compounds according to the invention have an antibacterial effect Activity in vivo on both gram-positive and gram-negative germs. The following is an example of the activity of SAB 73 196, SAB? 4,200, 74-202 and 74 212 in one infected Mouse specified

Activity against Sa2mon £ lla_tjphimurium __ (strain 05). Groups of 15 "pathogen-free" mice C J H weighing

of 20 g are 2.10 germs in 0.20 ml physiological serum by intraperitoneal route and simultaneously by oral route 0.5 mg of the product to be examined in 0.25 ml of distilled Given water. The duration of treatment is 5 days, i.e. a total of 2.5 mg of product are administered per mouse. The test results obtained after 15 days are as follows Table II given.

Table II

Number of survivors after 15 days Mice

mean survival, lifetime (in days) of the before Mice perished for 15 days

SAB 73196
SAB 74200
SAB 74202
SA3 74212 10
15th
14th
15 · '■ -'. ^8th Comparison mice 0 . 10

The search for germs in the blood and stool of the surviving mice was negative.

709 808/1197

Activity against Staphylococcus aureus Groups of 10 mice are administered intraperitoneally to 10 eggs suspended in 0.20 ml of 5% sterile mucus ₄ . The day before, the group of mice to be treated is administered orally 2 mg of the product to be tested in 0.25 ml of distilled water Mouse receives 10 mg of product in this way. The test results obtained after 15 days are summarized in the following table III.

Table III.

Number of mice surviving after 15 days

Mean survival time (in days) of those who died 15 days ago Mice

SAB 73196 10 6.2 SA3 74200 7th SAB 74202 10 SAS 74212 10 2.5 Comparison mice 2

Activity against Escherichia coli (wild rodents),

_H .M. _ »- · - _ - _- - - ~ - - -. - - - -. - _ _ _ - -. - PT "

Groups of 10 mice are intraperitoneally given 10 eggs, suspended in 0.20 ml of 5% sterile mucilage * administered. The day before, the group of mice to be treated is given 2 mg of the product to be examined orally administered in 0.25 ml of distilled water. Treatment is on the day of microbe inoculation and then for 3 days repeated, i.e. it is carried out on a total of 5 days,

709808/1197

each mouse thus receiving 10 mg of product. The test results obtained after 15 days are summarized in Table IV below _o

Table IV

Number of after 15 days surviving mice

Mean survival time (in days) of those who died 15 days ago Mice

SA3 73196 8th . 5.5 SA3 74200 .10 SAB 74202 ".9 .5. SAB 74212 10 Comparison mice 3 3.2.

In summary _9, this shows that the novel derivatives according to the invention have very good antibiotic activity.

7 0 9 8 0 8/1197

- vr-

Preventive antibilosomiasis activity for the schistosomal stage

The experiment consists in getting mice with tail larvae infected by Schistosoma mansoni and she immediately thereafter by oral route with the product to be examined; treated, the total duration of the treatment being 5 days. The applied Test conditions are consistent with the work of

ES Warren and "PA Peters:" Comparison of penetration and maturation of Schistosoma mansoni in the hamster _s mouse guinea pig and rat "in" Amer. J. Trop. Med. Hyg. ", 1967 ₉ 16, 718-722;

SR Smith and EJ Terry: "The infection of laboratory hosts with cercariae of S. mansoni and the recovery of adult worms" in Parasitology "1965 ^ 695-700;

Μ · Α. Stirewalt, R.E. Kuntz and S.A. Evans: "The relative susceptibilities of commonly used laboratory mammals to infection by S. mansoni "in Amer. J. Trop. Med. Hyg" 1966, 31, 57-82.

The strain S. mansoni was isolated on M _a dagaskar ₅ 1968 imported in France in 1966 and by successive transfers on hamsters (45 days) and on the mollusks supercarrier Biomphalaria pfeifferi (at 23 C _5, emission of. Tail larvae within 45 days) to keep alive. The tail larvae are washed and counted after their emission.

The mice are infected subcutaneously by injecting 100 tail larvae in 0.25 ml of water per mouse in the lateral Skin. A group of 20 mice is infected and 20 mice serve as a comparison group. The one to be examined Product is administered orally to the mice through a nasogastric tube immediately after infection. the administered doses are 1 mg or 2 mg of product per mouse and per day within 5 days or a total of 5 mg or 10 mg per mouse. All mice are sacrificed on 4-5 days

70 9 805/1197.

The peritoneum and liver of the mice are after Smith's procedure is washed and the male and female adult schistosomes are counted. Then it will be the anatomic-pathological examination of the liver, spleen and intestines of the mice was carried out. Under these conditions can be found in the comparison mice when "washing the Liver and peritoneum between 4-0 and 60 adult schistosomes per 100 injected tail larvae *

The following are examples (in Tables V, VI, VII and VIII) the results are given which were obtained in mice which 'mit SAB 73 196, 74-208, 74 213 and 74-220 in their racemic Shape was obtained, as were the results obtained with the levorotatory and dextrorotatory enantiomers of SAB 74-207 were obtained. It was found that the levorotatory isomer at the doses used (1 or 2 mg per mouse per day) is inactive, while the dextrorotatory isomer (SAB 76 227) has been found to have remarkable activity (Table IX),

Table V

Experimental results regarding the activity of SAB 73 196, administered at a dose of 1 mg per day for 5 days a mouse infected with S. mansoni

liver
DaEm Number of worms at
the comparison mice 4th
9 Number of worms at
the treated mice V ■ overall tf 13th 1
2 8th
19th • 0
'7 3 27 7th

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Table VI

Experimental results regarding the activity of SAB 74-208, administered at a dose of 2 mg per day for 5 days to a mouse infected with S. mansoni

liver
colon Number of worms at
the comparison mice 6th
12th Number of worms in the
treated mice 9 all in all <? ' 18th 1
3 15th
22nd 4th
7th 4th 37 11

Hardly any eggs in the liver and intestines.

Table VII

Test results relating to the activity of SAB 74 213, administered at a dose of 2 mg per day for 5 days to a mouse infected with S. mansoni

liver
colon Number of worms at
the comparison mice % Number of worms
in the treated
Μϊιιγγτι 1
2 all in all <? 2
8th d ¹ 3 8th
32 10 2
6th 40 8th

Absence of infJlamatory granulomas, very isolated eggs in the mucous membrane.

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* SV- Table VIII

Experimental results regarding the activity of SAB 74 220, administered at a dose of 2 mg per day for 5 days to a mouse infected with S * mansoni

Number of worms at
the comparison mice 4th
7th Number of worms bea
the treated mice 0
3 o '< 11 d> 3 Liver.
colon 15th
15th 1
7th all in all 30th 8th

Few inflammatory granulomas (more numerous in the intestine) *

Table IX

Experimental results relating to the activity of SAB 76 227 _9, the dextrorotatory enantiomer of SAB 74-207, administered at a dose of 1 mg per day for 5 days to a mouse infected with S. mansoni

Number of worms, at
the comparison mice * - Number of worms:
the treated mouse " O
• V 4th
25th O
O liver
colon 9
5Ö 29 O
5 O all in all 59 5

No oviposition in the liver _c

70 980 8/119 7

- * sr-

5V-

Three additional experiments were carried out with a single dose of SAB 73 196 of 1.25 mg, 2.5 mg or 5 mg administered orally to mice. The results obtained are given in Table X below. If these experiments do not show the relationship between dose and effect, do they show two remarkable facts?

- a very significant decrease in the number of female worms,

- single-dose activity, which is of considerable importance in prophylactic treatment.

Table Σ

Experimental results relating to the activity of SAB 73,196 administered in a single dose to a S. mansoni infected mouse

Number of worms in the
Comparison mice 26th Number of worms in the with
a single dose treated 1
Ma ^- U c * ^ i τι 5
3
11 2
1
3 <$ Dose in mg 14th 1 ₉ 25
2 _s 5O
5

There is a significant decrease in "treated" mice the number of adult schistosomes to be observed. The anatomic-pathological examination of the mice revealed the following results:

- spleen ; Splenomegaly (enlarged spleen) in the reference mice,

no spelnomegaly in the treated mice;

- intestines ; central inflammatory granulomas by ^e ier in the control mice _s

no eggs in the treated mice; · - liver ; inf lammatory G-ranulorae with eggs in the

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- YT--

like mice,

no eggs in the "treated" mice.

It is extremely important that there should be no eggs "in the mice treated with SAB 73,196" was found. Also, there were never any toxicity phenomena "in the" treated Mice "observed.

The preventive anti-rosinosis activity of the racemisehen Derivatives of the invention seem distinctly different from the clockwise Enantiomers to be derived from that contained in these derivatives is. It has also been found that the right-handed cis-1,2-epoxypropylphosphonic acid, its salts and its derivatives have excellent preventive properties against BiI-resiniosis own, while the levorotatory enantiomers does not have this effect at the doses used.

The following are the results obtained in mice obtained with the sodium salt of (+ ^ cis-i, 2-Epö: xy-propylphosphonic acid (Table XI) were obtained, as well as, for comparison, the results obtained with his left-handed Isomers, the sodium salt of (-) - cis-1,2-epoxypropylphosphonic acid (Fosf.omycin) were obtained (! Table XII).

Table XI

Sodium salt of (+) - cis-1,2-epoxy-propylphosphonic acid Experimental results on the activity when administered orally at a dose of 2 mg per day for 5 days on ■ a mouse infected with S. mansoni

liver
colon

Number of? / Ürmer be: the comparison mice

8th
27

2 12

Number of worms in the treated mice

0 5

all in all

35

14th

The anatomic-pathological examination of the organs revealed the following:

.Spleen; Splenomegaly (enlarged spleen) in the comparison mice, no splenomegaly in the treated mice, intestine: central inflammatory granulomas caused by eggs in the comparison mice,

no eggs in the treated mice, liver: inflammatory granulomas with eggs in the comparison mice,

no eggs in the treated mice.

In addition, no toxicity phenomenon has ever been observed in the treated mice observed.

Table XII

I Sodium salt of (-) - cis-1,2-epoxypropylphosphonic acid (Fosfomycin)

Experimental results on the activity when administered orally at a dose of 2 mg per day for 5 days on a mouse infected with S. mansoni

liver
colon Number of worms at
the comparison mice $ Count the worms
the treated mouse egg S '
17th all in all; 2
12th d * 22nd δ
27 14th 11
27 35 38

709808/1 197

During the anatomic-pathological examination of the organs numerous inflammatory granulomas centered around eggs were found in both liver and intestines in those treated Animals observed From these two experiments carried out in parallel, it can be seen that

- the levorotatory isomer of cis-1,2-epoxypropylphosphonic acid (Sodium salt) or that. Fosf omycin completely inactive is and neither is the development cycle of the schistosomes in adult worms still inhibits egg deposition;

- the dextrorotatory isomer of cis-1 _? 2-epoxy ~ propylphosphonic acid (sodium salt) is very active ₉ as it completely prevents (inhibits) the laying of eggs and led to a very considerable reduction in the number of adult worms, both male and female

Conclusions

The derivatives of the invention have ₉ when administered orally to a mouse. infected by tail larvae of the So mansoni strain, the property of reducing the development of the fully grown schistosomes and especially the female forms in a single dose Eggs in the treated animals _o In addition, the tolerance (tolerance) in the treatment is excellent. The dextrorotatory isomer of cis-1 _S 2-epoxy · = propylphosphonic acid has a completely analogous effect o

The derivatives according to the invention thus combine the conditions which are necessary for a prophylactic treatment of the disease and for a mass treatment _o The complementary antibiotic activity to the antibilharziosis activity of the derivatives according to the invention in their racemic form is advantageous because of the frequent microbial transmission infections among which the peoples who suffer in the

709808/1197

Parasite-rich (contaminated) tropical zones live *

__ ^ _i _ £ g £ Stage_ The experiments carried out show the following facts:

- The derivatives according to the invention have in their racial Form only a slight curative activity (effect) in one infected with tail larvae of the So mansoni strain Mouse,

- beiKombination this raceiaischen derivatives with an amine, such as benzylamine or -methylbenzylamine _s occurs a healing activity in appearance,

the dextrorotatory enantiomer of these derivatives are healing active (effective) j without it being necessary ₉ to combine it with an amine, =

Healing effects of racemic SAB 73 196 in the presence of ■

The test consists in the fact that mice subcutaneously with 100 tail larvae from the strain S ₀ mansoni infected and for 5 days orally with the to be tested product _s s starting at 40 _o day after infection _s be treated be _0. The applied daily doses 1 mg SAB 73 196 and 0.5 mg benzylamine hydrochloride «, the mice are examined immediately after the end of treatment or after an additional waiting period of 10 days«

! The results are compiled below (Table XIII) obtained with groups of 25 mice, 10 of which killed on the 45th day and 15 on the 55th day after infection became.

Table XIII

Medicinal effect achieved with administration of 1 mg SAB 73 196 in combination with 0.5 mg benzylamine hydrochloride for 5 days (Infection with 100 tail larvae)

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■ ..'-. ■ Φ after 55
Days
15 mice
' *% 2632136 after 55
Day ^ n
14 mice
(see α. pussnc 5 3
20 12 Number of worms at de
treated mice 0 0
0 0 Number of worms at
the comparison mice 25 15 after 45
Days
10 mice
$ ξ 0 0
Footnote:
the 15th mouse
pointed in the dari
10 females
Worms and liver
colon after 45
Days
10 mice
ö ⁷ 0 1 0
5 -3 'd masculine
Worms on all in all . 5 4
17 7 6 3 22 -Ii-.

The anatomic-pathological examination showed that on 55th days, i.e. 10 days after the end of treatment, every Worms in 14 out of 15 mice were dead.

The combination of SAB 73 196 with benzylamine hydrochloride has a very great healing effect on the infection S. mansoni from.

In another experiment, the mice were infected with of a large amount of tail larvae (1000 by transcutaneous route) * The 5-day treatment was carried out on the 48th day after the infection started and the anatomic pathological examination was started on the 61st day, i.e. 8 days after the end of the treatment. During this treatment were the results given below (Table XIV) are obtained.

Table XIV

Medicinal effect obtained by administering 1 mg of SAB 73 in combination with 0.5 mg benzylamine hydrochloride for 5 days (infection with 1000 tail larvae): ..

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Number of worms at
the comparison mice
(on the 48th day) % Number of worms at
the treated mice
(on the 61st day) 24
1 liver
.Colon <f 80
35 d * 25th all in all ' 160
44 49
2 204 51

The investigation showed that 95% of the worms counted the treated mice were dead.

Healing effects of SAB 76 227, the dextrorotatory enantiomer of the disodium salt of p ^ -Methylphosphoric acid-pp-cis-

IIi2- £ P £ ^ -prop2l £ b £ sph £ n £ acid anhydride (βλΒ_7 ^ _ 207)

The SAB 76 227 was administered at a dose of 1 mg for 5 days, beginning on the 45th day after infection. The anatomic-pathological examination was carried out immediately after End of treatment and 10 days after the end of treatment, i.e. on the 50th and 60th days. The one with it The results obtained are shown below (Table XV).

Table IV

Medicinal effect obtained by administration of 1 mg SAB 76 227 for 5 days (infection with 100 tail larvae)

Number of worms at
the comparison mice
(on the 45th day) 3
15th Number of worms at
the treated mice
(on the 50th day) Z liver
colon * 18th & 1
O all in all 8th
34 119 7 2
O 1 42 2 * - ■ v u a «u b /

(ολ

The examination showed that on the 50th day the counted Worms were still alive, but on the 60th day all worms were dead.

Healing effect of the right-turning cis-1,2-epoxy-propyl-

The dextrorotatory enantiomer of cis-1,2-epoxy-propylphosphonic acid, their salts and their derivatives also have a very strong healing effect on schistosomiasis, which is not the case with the levorotatory isomer. the

The results obtained are given below «

Table XVI

Medicinal effect obtained by administering 1 mg for 5 days of the sodium salt of (+) - cis-1,2-epoxypropylphosphonic acid (Infection with 100 tail larvae)

Number of worms at
the comparison mice
(on the 55th day) . · 3 ■
12th Number of worms at
the treated mice
(on the 55th day) • ■% ■ " Liver ■:
.Colon 15th (f 0
0 all in all 5.
20th 0
1 ο ■ '. . 25th ι - ■

7 0 9808/1197

The anatomic-pathological examination showed that on the 55th day, i.e. 10 days after the end of the treatment, all but one were dead. The liver of the mice was rich in inflammatory G-ranulomas around eggs were centered around, indicating that the female worms laid eggs and disappeared under the influence of the treatment was.

Conclusions

The derivatives according to the invention have when they are on oral Ways administered from the 40th day after infection of a mouse with tail larvae of the S. mansoni strain, the Ability to dissolve adult worms. This healing effect requires the combination with an amine, such as benzylamine when the derivatives are used in their racemic form. The dextrorotatory enantiomers are direct active. It appears that the curative and preventive antibilharziosis activity is due to the dextrorotatory enantiomers of the derivatives according to the invention.

Pharmaceutical preparations £ Medicines_l) __ The novel derivatives phosphorylated according to the invention can be in the form of oral or parenteral pharmaceutical preparations administered. For oral administration The derivatives are preferably used in the form of their calcium salts, for parenteral administration (intramuscular or intravenous route) the sodium salts are suggested.

The dosage in an adult is 1 to 3 S per 24 hours when administered orally, spread over the day. (Tablets, capsules, suspensions, granules and the like). preparations with long-term effects (so-called "sustained release" preparations allow the dose to be reduced to 1 or 2

709808/1197

daily gifts

The following example explains a pharmaceutical according to the invention Preparation (a medicament according to the invention), it should be noted, however, that the invention by no means is limited to it.

At.sp_ie l_fü

According to a common procedure, tablets are made with the after made in the following composition:

Calcium salt of p ^ -Methylphosphoric acid-pp-

cis-1,2-epoxy-propylene phosphonic anhydride

(SAB 73 196) 400 mg

Benzylamine hydrochloride 200 mg

colloidal silicon dioxide 10 mg

Talc 50 mg

Strength 40 mg

Patent claims:

709808/1197

Claims (5)

Claims (I. / Asymmetrical cis-1 ^ -Epoxy-propylphosphonic acid berivate, characterized by the general formula CH ₃ -CH-CH-P - 0 - Ϊ - _A where mean: Ii ^ ⁺ 'and M ¹ ^ ⁺ , which may be the same or different from one another can, Eeste, which are selected from the group hydrogen ion and the organic-inorganic Cations and A is a residue that is selected from the group - the linear (unbranched) or branched alkyl and alkoxy radicals with 1 to 8 carbon atoms, which can have at least one substituent which is an epoxy bridge acts, or is selected from the group of alkoxy radicals with 1 to 5 carbon atoms, Alkoxycarbonyl, the alkyl radical of which has 1 to 5 carbon atoms, amino, Alkylamino, Fitril ^ and - the substituted or unsubstituted aryl, aralkyl and aryloxy radicals. 2. Compounds according to claim 1, characterized in that they are in the left-handed, right-handed or racemic Form. 3. Process for the preparation of the asymmetric cis-1,2-epoxypropylphosphonic acid derivatives according to claim 1 and / or 2, 709808/1197 characterized in that a salt of the general Formula. · "." .- (H) VC - ■■> - <f A 0 wherein A has the meanings given above, E and R ¹ hydrogen atoms or alkyl radicals with T to 4 carbon atoms and M ¹ ^ an ammonium ion, such as U (CHx) _2. , HpU (CH ^ J ^, ο which mean a metal cation, can react with cis-1,2-propenyl-phosphonic acid and that at the same time product obtained then epoxidized. 4. Medicines with antibiotic properties, characterized in that they have at least one asymmetric active ingredient cis-1,2-epoxy-propylphosphonic acid derivative according to a of claims 1 and 2 in the levorotatory or racemic Form, optionally with a customary, pharmaceutically acceptable carrier and / or excipient. 5. Medicines with antibilharziosis properties, thereby characterized in that they contain at least one asymmetric cis-1,2-epoxypropylphosphonic acid derivative according to claim as active ingredient 1 and / or 2 in the right-handed or racemic Form or dextrorotatory ■ cis-1,2-epoxypropylphosphonic acid or one of their salts, optionally in combination with a customary, pharmaceutically acceptable carrier and / or Excipient. 70 9808/1197