HU184813B - Process for preparing diphosphonate derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of diphosphonate derivatives with valuable pharmacological properties for the treatment of cardiovascular diseases. The aim of the invention is to provide novel compounds with rapid and effective activity for lowering the cholesterol content in the blood and in the tissues. According to the invention, hydrodiphosphonate derivatives of formula Ia are prepared in which R and R 'are the same or different and H, CH is deep 3, C is deep 2 H deep 5 or C deep 4 H deep 9 and A is selected from one of the groups wherein n is one is integer from 1 to 6 and Y, H, CH is deep 3, OCH is deep 3 or a halogen atom, especially CL or F.

Description

The present invention relates to novel diphosphonates of formula (I). The compounds of formula I wherein R and R ', which may be the same or different, represent a methyl, ethyl, propyl or butyl group; A is tert-butyl, YC ₆ H ₄ -, YC ₆ H ₄ -O-C (CH ₃ ) ₂ -, YC ₆ H, C (CH ₃ ) ₂

YC ₆ H ₄ -OC ₆ H ₄ -, YC ₆ H ₄ - (CH ₂ ) - or

Y is -C ₆ H ₄ -O- (CH ₂ ) _n - where n is an integer from 1 to 5 and Y is hydrogen, methyl, methoxy or halogen.

Compounds of formula I wherein X is hydroxy and m is 0

R /

case we make a general picture of A-CO-POj \

The dialkyl aryl phosphonate R is reacted with a dialkyl phosphite of the formula HP (OXOR ') _{2 in} the presence of a catalytic amount of base. When the amount of the base reaches 80-100% of the amount of the reagents, the compounds of formula (I) wherein X is hydrogen and m is 1 can be obtained live.

The gerainal diphosphonates of formula (I) wherein X is hydrogen and m is 0 are prepared by

Aralkyl halide of formula --Z - Z is halogen - in the presence of an alkaline condensing agent

R R '\ / a o ₃ p-ch ₂ -po ^

Tetraalkyl methylene diphosphonate of formula R R '! with.

General procedure (I) produced by the process of the invention

h-diphosphonate derivatives can be used in pharmaceutical compositions as antiatherogenic agents.

POo | ^J R (0) _m

I tf ^p ° 3 _R <

184,813

The present invention relates to novel diphosphonate derivatives, more particularly to dihydrogen diphosphonates, phosphonophosphates and geminal diphosphonates. The compounds are useful in the treatment of human cardiovascular diseases in antiatberogenic compositions.

In the last few years, experiments have been conducted with common hypolipidemic agents, such as clofibrate, for the prevention of coronary heart disease. Recently, the results of these experiments have called into question the therapeutic efficacy of these compounds (see, for example, New Engl. J. Med., 296, 185-190 (1970); Atheiosclerosis Rev., 2, 113-153 (1977); The Chain 8100). 1131-1132 (1978) and Brit. Med. J. 6152, 1585 (1978)).

The desirability of the compounds is to reduce cholesterol not only rapidly in the blood, as most common hypolipidemic agents, but also directly in the tissues.

Therefore, the inventors have carried out studies on diphosphono compounds and have found that diphosphonates of the formula I have remarkable effects as antiatherogenic agents, can modify lipoprotein profiles in favor of high density lipoproteins and can directly extract cholesterol from various types.

In the formula (I), X is hydrogen or hydroxy; R and R ', which may be the same or different, represent a methyl, ethyl, propyl or butyl group; m is 0 or 1; And its meaning is (Vili). A group of formula (IX), Q <), (XI), (XU)), (XUI) or (XIV) wherein n is an integer from 1 to 5 and Y is hydrogen, methyl or methoxy or halogen. , especially chlorine or fluorine, with the proviso that when R and R 'are methyl, m is 0 and X is hydrogen, or if R and R' are ethyl, m is 0 and X is hydrogen or hydroxy, then is other than fenilcsoporítól and that when R and ^R is ethyl, m is 0 and X is hydrogen, then A is other than benzyl or alkylphenyl group, and where R and R 'is alkyl, m is O and X are hydroxy, then A may be other than formula VIII.

The process for the preparation of tetramethyl and tetraethylphenylmethane diphosphonates and phenylmethane diphosphonic acid is described in U.S. Patent No. 3,463,835. U.S. Pat. The preparation of tetraethylbenzylmethylene diphosphonate is described in U.S. Patent No. 1,394,386. French Patent No. 3,982,676, which discloses the preparation of triethylphenylhydroxyphosphonate. U.S. Pat.

The ability to remove cholesterol from tissues makes them useful in the treatment of diseases caused or induced by abnormal cholesterol synthesis, metabolism and deposition. For example, cardiovascular disease is generally associated with cholesterol deposition on arterial walls (Atheromas), hereditary hypercholesterolemia, cholesterol deposition in subcutaneous tissues (Xanthomatosis), cholesterol cholesterol (precipitated cholesterol), tissue and cholesterol-rich hypersensitive platelets-induced thrombosis (Shatti), SJ et al., The Journal of Clinical Investigation, 55, 636-643 (1975)).

Because cholesterol is a precursor of the steroid hormones (male and female sex hormones and corticosteroids), abnormal synthesis of these hormones can be controlled by the use of such compounds. Attempts are currently being made to use phosphonates in the field described above. Some of these compounds of formula I are also effective as hypoglycemic agents.

The diphosphonate derivatives of formula (I) are classified into three types of compounds: hydroxyphosphonates (Ic). In the formulas (Ia), (Ib) and (Ic), A, R and R 'are as defined above.

According to the invention, the compounds of formula (Ia) and (Ib) are readily prepared from the same starting material by reacting a dialkyl acyl phosphonate of formula (II) with a diacyl phosphonate of formula (III) in the presence of a base, preferably an amine. with. The course of the reaction can be controlled by varying the amount of base used. Thus, using a base such as di-n-butylamine in a catalytic amount (about 5 mol%) yields hydroxydiphosphonate compounds (Ia), while using the same base in about 80 to 100 mol% yields phosphonophosphates (Ib). . The two cases are illustrated in Reaction 1. The dialkyl acyl phosphonates of the formula (II) used as starting materials are known compounds and can be synthesized in a known manner by reaction of an acid halide and a trialkyl phosphonate.

The advantage of the process is that while the starting materials (acyl phosphorousates, dialkyl phosphonates, base) are soluble in cold ether, the resulting compounds of formula (Ia) or (Ib) are not soluble, so that they can conveniently be removed from the reaction mixture by filtration. . This will function partly to obtain purified by recrystallization of the obtained compounds were analytical grade ^one product in one step. Therefore, an ether at about 0 ° C is preferably used as a solvent in the process of the invention. In some cases, a small amount of methylene chloride may be added to the ether.

The structure of the compounds of formula (Ia) and (Ib) can be convincingly confirmed by IR or NMR spectra. For each hydroxydiphosphonate compound (Ia), an absorption was observed at 3260-3300 cm ^-1 (typical for the hydroxyl group), whereas this peak was absent from the spectrum of each of the phosphonophosphonates (Ib). Each group of compounds (Ia and Ib) exhibited strong phosphonate absorption at values of 1260 cnr ^- (typical for P = C) and 1060 cm ^-1 (typical for POC).

According to the invention geminiális-diphosphonate compounds of formula (Ic) is prepared by reacting an aralkyl halide of formula ⁷ a A at elevated temperature (about 120 ° C) and an alkaline condensing agent in the presence of a tetraalkilmetilén diphosphonate of formula V. In formula A-Z, A is as defined above and Z is halogen, preferably bromine or chlorine, while in formula V, R and R 'are as defined above. The reaction is illustrated in Reaction 3. A variety of bases can be used in the reaction, such as metal sodium, metal potassium, sodium amide and sodium hydride, with sodium hydride being most preferred.

The tetraalkylmethylene diphosphonates of the general formula (V) used as starting materials were obtained from Monatshefte.

-2134,813

Chemie, 81, 202 (1950) may be prepared according to reaction equation (4).

The tetraalkylmethylene diphosphonate sodium salts of formula (V '), which are highly soluble in the solvents used (e.g., toluene and tetrahydrofuran), can also be used as starting materials in the process of this invention, especially those wherein R and R 'represents an alkyl group larger than the methyl group, i.e., ethyl group, isopropyl group, etc.

Tetramethylgeminal diphosphonates, i.e. compounds of formula Ic wherein R = R'-methyl, may be advantageously synthesized by reacting trimethyl orthoformate of formula VIi with a geminal diphosphonic acid of formula VI. The latter compound is prepared as an alkyl group by hydrolysis of tetraalkylgeminal diphosphonates having alkyl groups other than methyl. The process is illustrated in Reaction Equation ₅ (R '= GH ₃ and R' VCH _{3 in} the starting compound of the reaction sequence and R = R '= CH _{3 in} the product of the reaction sequence).

The structure of the geminal diphosphonates of formula (Ic) obtained by the process of the invention can be clearly determined by IR, mass, NMR spectra. The purity of the geminal diphosphonate esters was tested by gas chromatography (3% SE 30 column, 150X3 mm). SE 30: Dimethylsilicone Resin, SUPELCŐ, INC., USA.

The invention is illustrated by the following examples. 1-8. Examples are the preparation of some diphosphonate derivatives of formula (I).

Example 1

Preparation of Tetramethyl 1- (- chlorophenyl) methane-1-hydroxy-1,1-diphosphonate (Compound 4)

The compound was prepared by adapting the method of D. A. Nicholson and H. Vaughn (Journal of Organic Chemistry, 36, 3843 (1971)).

Dimethylphosphonate (4.40 g, 40 mmol) and di-n-butylamine (0.24 g, 2 mmol) were dissolved in ether (90 mL) and the resulting solution was cooled to 0 ° C. Under fast stirring, 9.96 g (40 mmol) of dimethyl p-4-borobenzoylphosphonate was added dropwise according to the method described in the Journal of the American Chemical Society, 86, 3862 (1964). produced. A white solid almost immediately precipitated. The mixture was stirred for 1 hour at 0 ° C and then filtered to give 13.0 g (36 mmol) of the title product.

The crude product was dissolved in acetone at room temperature for purification and then ether (acetone: ether = 3: 1) was added. 7.9 g (22 mmol) of white crystals were obtained, corresponding to 55% yield (pure compound).

Yield: 90%.

119-123 ° C.

IR spectrum (KBR):

3260 cm ^-1 : OH;

2880 cm ^-1 : aliphatic C-H;

1500 cm ^-1 : aromatic CC;

1280 cnf ^! : P = O;

1060 cm -1: P-0-C.

Mass spectrum: m / e ~

360 (M + 2V: 17%;

358 (M) ⁺ : 52%;

251 (M + 2-PO ₃ Me ₃ ) ⁺ : 33%;

249 (M ~ F0 ₃ Me _I ) *: 100%.

NMR _(CDCl3):

7.90-7.20 (mullet, 4H): phenyl;

4.59-4.20 (triplet, 1H, J = 7Hz): hydrogen of the hydroxy group; removed by exchange with deuterium Qxid;

3.90 - 3.50 (multiplet, 12H): hydrogen atoms of the methyl groups.

Analysis for C ₍ , H _{) 7} C ₁₀ tP ₂ : C [%] H [%] P [%] date: 36.84 4.78 17.27 Liláit: 36.81 4.78 17.26 As proof of its structure converting 4 compounds

was converted to the hydonodisphonic acid inononate salt (compound 10).

A mixture of 3.59 g (10 mmol) of 4 and 15 g of 37% hydrochloric acid was refluxed for 3 hours. Evaporation of the hydrochloric acid and water gave 3.2 g (10 mmol) of a white solid.

Melting point: 192-194 ° C (crude product).

Yield: 100% (crude product):

For purification, hydroxy (p-chlorophenyl) methylene diphosphonic acid was converted to its monosodium salt according to the following procedure (P. F. Pflaumer and J. F. Filcik, Chemical Abstracts, 72, 55656k (1970)):

The solid obtained as described above was dissolved at S5 ° C in a mixture of 4.8 g (80 mmol) of acetic acid and 0.7 g (39 mmol) of water. Sodium acetate trihydrate (1.36 g, 10 mmol) was then added gradually. Almost immediately a large precipitate formed which was filtered and washed thoroughly with ether until the acetic acid was filtered off. The washed precipitate was recrystallized from ethanol / water (20:80) to give 1.94 g (6 mmol) of 1-hydroxyl- (p-chlorophenyl) methane diphosphonic acid monosodium salt (Compound 10) as a white powder.

Yield: 60%.

Example 2

Preparation of tetramethyl-2,2-dimethyl-2- (p-chlorophenoxy) ethane-1-hydroxy-1,1-diphosphonate (compound 7)

The compound was prepared by adapting the method described by K, D. Berlin et al. (Journal of Organic Chemistry, 30, 1265 (1965)) and DA Nicholson and H. Vauhn (Journal of Organic Chemistry, 36, 3843 (1971)). .

By alkaline hydrolysis of ethyl p-chlorophenoxyisobutyrate, p-chlorophenoxyisobutyryl chloride was first prepared and the resulting acid was refluxed in standard thionyl chloride.

Trimethylphosphonate (10.6 g, 86 mmol) was added dropwise to p-chlorophenoxyisobutyryl chloride (20.0 g, 86 mmol) cooled to 0 ° C. Evidence of the completion of the reaction showed the development of methyl chloride. Distillation under reduced pressure gave 19.0 g (62 mmol) of dimethyl p-chlorophenoxyisobutyryl phosphonate as an almost colorless oil.

Boiling point 5 - 10 ~ ² Torr: 115-118 ° C. mining; 72%.

IR spectrum (phoenix) '

3000 cm ^-1 : aliphatic CH;

1740 cm @ -1: C = O;

1500 cm ^-1 : aromatic CC;

1250 cm ^-1 : PO;

1050 cm ^-1 : P-O-C;

830 cm ^-1 : 1,4-disubstituted phenyl.

A solution of dimethylphosphonate (2.86 g, 26 mmol) and di-n-butylamine (0.18 g, 1.4 mmol) in ether (65 mL) was cooled to 0 ° C and added slowly with stirring. 79 g (26 mmol) of dimethylchlorophenoxyisobutyryl phosphonate. Almost immediately a white solid formed. The reaction was allowed to proceed for 1 hour with stirring and then the solid was collected by filtration. The crude product was recrystallized from a 60:40 mixture of benzene and hexane to give 7.18 g (17.2 mmol) of the title product, i.e., tetramethyl-2,2-dimethyl-2- (p-chlorophenoxy) ethane-1-hydroxy- 1,1-diphosphonate is obtained in the form of white toluene crystals.

137-139 ° C.

mining; 66%.

IR spectrum (KBr):

3360 cm ^-1 · OH;

3000 cm ^-1 : aliphatic CH;

1500 cm ^-1 : aromatic C-C;

1250 + 1220 cm ~ ⁵ : P = O;

1070 cm ^-1 : P-O-C;

86.0 cm ^-1 : 1,4-disubstituted phenyl.

NMR Spectrum (CDC1 _3):

δ = 7.4-7.0 (multiplet, 4H): phenyl

4.0 - 3.70 (multiplet, 12H): hydrogen atoms of methyl groups bound to phosphate side chains;

3.5-3.4 (sharp peak, 1H): the hydroxyl group

1.58 the hydrogen; Removed by replacement with D ₂ O; (singlet, 6H): hydrogen atoms of branched methyl groups. Analysis a C _I4 H ₂₃ C10 ₈ P ₂ öss; for the compound of formula: C [%] H [%] P [%] date: 40.45 5.58 14.90 found: 40.29 5.94 14.93 Example 3

Preparation of Teirarnethyl 1- [4- (4-chlorobenzoyl) phenyl] methane-1-hydroxy-1,1-diphosphonate (Compound 8)

The compound was prepared by adapting the method described by D. A. Nicholson and H. Vaughn (Journal of Organic Chemistry, 36, 3843 (1971)).

The starting material of 4- (4'-k] -carbobenzoyl) benzoyl chloride is provided by GE Robinson and JM Vernon (Journal of Chemical Society (C), 2586 (1970) and E. Wertheim (Journal of American Chemical Society, 55, 2540 (1933)).

Trimethyl phosphonate (10.9 g, 88 mmol) was added dropwise to acid chloride (22.4 g, 80 mmol) heated to just below its melting point (about 100 ° C). The reaction was exothermic and the white crystals of the acid chloride were converted to a brown oil under strong foaming. The reaction mixture was stirred for 30 minutes

184,813 needles at 100 ° C. During standing and rolling, the oily substance turned to an orange solid. Recrystallization from a 60:40 mixture of chloroform / petroleum ether gave pure dirylethyl 4- (4'-chlorobenzoyl) -benzoyl-5-phosphenate (20 g, 56.7 mmol).

Melting point: 95-97 ° C (yellow powder).

Yield: 71%.

IR spectrum (KBr):

2960 cm ^-1 ; aliphatic CH;

3665 + 1650 cm- ': C = O (belongs to the benzoyl phosphonate and benzophenone side chains);

1590 cm ^-1 ; aromatic CC;

1250 + 1260 cm ^_1: P = 0;

1050 + 1030 em ^-1 : P ~ 0 -C.

A solution of dimethyl phosphonate (2.20 g, 20 mmol) and di-n-butylamine (0.144 g, 1.10 mmol) in ether (40 mL) was cooled to 0 ° C and 7.04 g (20 mL) was added dropwise. mmol) dimethyl 4- (4'-chlorobenzoyl) -benzoylphosphonate with 40 N dichloromethane

2q made with filtered solution. A yellow precipitate soon formed from the yellow material. The reaction mixture being stirred for 1 hour at 0 ^DEG C., the precipitate was filtered and washed with ether. Recrystallization from acetone afforded 2.4 g (5.2 mmol) of tetramethyl 1- [4- (4'-chlorobenzoyl) phenyl] methane -1-hydroxy-1,1-diphosphonate as white crystals.

Melting point; 150-153 ° C.

Yield: 26%.

IR spectrum (KBr):

3280 cní ^! : OH;

³⁰ 1670 cm⁻¹: C = O;

1600 cm ^- ': aromatic C-C;

1260 + 1240 cm ^-1 : P = O;

1050 + 1030 cm ' ¹ : PO-C.

Mass spectrum m / e:

464 (M + 2) ⁺ : 14%;

462 (M) ⁺ ; 42%;

355 (M + 2-PO ₃ Me ₂ ) ⁺ : 32%;

353 (M-PO ₃ Me ₂ ) ⁺ : 100%,

NMR (CDCl3):

Δ = 8.10-7.30 (multiplet, 8H): hydrogen atoms of the two phenyl groups;

4.5-4.3 (triplet, 1H, 3 = 7 Hz): hydrogen of the hydroxy group; Removed by replacement with D ₂ O;

3.95 - 3.60 (multiplet, 12H): hydrogen atoms of the methyl groups.

5q Example 4

Preparation of dimethyl 1- (dimethoxyphosphonyl) p-chlorobenzyl phosphate (Compound 12) gg Equimolar amounts of dimethyl phosphonate (4.40 g, 40 mmol) and di-n-butylamine (5.17 g). (40 mmol) of dinethyl p-chlorobenzoylphosphonate (9.96 g, 40 mmol) was added dropwise. Almost immediately a white solid formed. Azelegyet stirred for 1 hour at 0 ° C, the solid ⁰⁰ was collected by filtration. Recrystallization from 1: 3 dichloromethane / ether at room temperature gave 12.0 g (33 mmol) of white crystals.

Melting point: 81-82 ° C.

Yield: 82%.

184,813 l

IR spectrum (KBr):

2980 cnf ^! : aliphatic CH;

1500 cm ^-1 : aromatic CC;

1290 + 1260 cm &lt; -1 &gt;P-O;

1050 cm ^-1 : P -O- C.

NMR (CDCl3):

δ = 7.5-7.3 (multiplet, 4H): phenyl;

5.58 - 5.40 (doublet, J 11 and 13 Hz, 1H): hydrogen atom of methyl ε (not remotely displaced by deuterium oxide exchange);

3.95 - 3.50 (multiplet, 12H): hydrogen atoms of the methyl groups.

Analysis for C _; , For HjiC10 ₇ Pj:

C {%} H [%} P [% j Calculated: 36.84 4.78 17.27 Found 36.71 4.86 17.33

Example 5

Preparation of dimethyl-1- (dimethoxyphosphonyl) -2,2-dimethyl-2- (p-chlorophenyl)] ethyl phosphate (Compound 16)

Dimethylchlorophenylacetonitrile was prepared by dimethylation of p-chlorophenylaceteneryl in ether with sodium amide and methyl iodide. Hydrolysis of the nitrile followed by refluxing the resulting acid in thionyl chloride gave p-chlorophenylisobutyryl chloride.

Dimethyl p-chlorophenylisobutyrylphosphonate was prepared in 90% yield by addition of equimolar amounts of trimethylphosphonate to the acid chloride cooled to 0 ° C.

Boiling point 5 · 10 ^{3 at} Torr: 108-110 ° C.

IR spectrum (film):

1690 cm ^-1 : C = 0;

1270 cm ^-1 : P-O;

1070 + 1040 cm ^J : P-0-C.

Subsequently, a solution of 3.30 g (30 mmol) of dimethyl phosphonate and 3.1 g (24 mmol) of di-n-butylamine was cooled to 0 ^° C. and dimethyl p-chlorophenylisobutyryl phosphonate (8.72 g, 30 mmol) was added with rapid stirring. A white solid soon formed. The mixture was stirred for 1 hour at 0 ° C and the solid was collected by filtration. Recrystallization from ether gave 9.0 g (75%) of the title product, i.e. dimethyl- [1- (dimethoxyphosphonyl) -2,2-dimethyl-2- (p-chlorophenyl)] - ethyl phosphate. in the form of white crystals.

Mp 62-63 ° C.

IR spectrum (KBr):

2980 cm ^-1: aliphatic CH

1500 cm ^-1 : aromatic C-C;

1280 + 1260 cm ^-1 : P = O;

1080 + 1030 cm -1 ^ P-O-C.

Mass spectrum m / e:

402 (M + 2) ⁺ : 05%;

400 (M) ⁺ : 1.5%;

248 (M-Cl-Ph-C (CH 3) ₂ + H) ⁺ : 100%.

NMR (CDCl3):

δ = 7.5-7.25 (multiplet, 4H): phenyl;

5.05 to 4.80 (dd, J = 9 and 12 Hz.) Of methyl hydrogens _(O-3 D exchange is not removed by acid);

3.85-3.50 (multiplet, 12H): hydrogen atoms of four methyl groups attached to the phosphate and phosphonate side chains;

1.58 and 1.54 (singlet partially overlapping, 6H): hydrogen atoms of the two branched methyl groups.

Example 6

Preparation of tetraethyl 4-phenylbutylidene-1,1-diphosphate (Compound 21)

The preparation of the compound is described by H. R. Hays and T. J. Logan (Journal of Organic Chemistry, 31, 3391 (1966)) and Ο. T. Quimby et al., Journal of Organometallic Chemestry, 13, 199 (1968).

23.066 g (80 mmol) of Utralylmethylene diphosphonate prepared as described in Mpnatshefte Chemie, 81, 202 (1950) was added dropwise to a dispersion of 1.92 g (80 mmol) of sodium hydride in 30 mL of truluyl. When the evolution of hydrogen ceased, 19.9 g (100 mmol) of 3-phenyl-aropyl bromide were added and the mixture was heated at 0 ° C for 14 hours and then at 110 ° C for 2 hours. The residue was dissolved in chloroform, washed several times with a saturated sodium chloride solution, and then dried by filtration through a silicone-treated filter. Distillation under reduced pressure gave a colorless oil having a boiling point of 135-145 [deg.] C. under a pressure of 5 to ¹⁰ Torr. Careful refraction afforded 0.4 g (26 mmol) of tetraethyl 4-phenylbutylidene-1,1-diphosphonate.

Boiling point 5 · 10 ³ Torr pressure: 141-143 ° C. Yield: 32%.

IR spectrum (film): see III. spreadsheet.

Mass spectrum m / e:

406 (M) *: 61%;

301: 100%;

269 (M-POjEtj): 23%.

NMR (CDCl3):

δ = 7.35-7.2 (multiplet, 5H): phenyl;

4.45-3.90 (quintet, 8H, J = 8Hz): hydrogen atoms of four methylene groups attached to phosphonate aliphatic chains;

2.80 - 1.70 (multiplet, 7H): hydrogen atoms of the side chain methylene groups and odd hydrogen atoms;

1.50-1.20 (triplet, 12H, J = 7Hz): H of the four methyl groups.

Example 7

Preparation of 4-phenylbutylidene-1,1-diphosphonic acid (Compound 24)

A mixture of 8.15 g (20 mmol) of tetraethyl 4-phenylbutylidene-1,1-diphosphonate and 40 g of 37% hydrochloric acid was heated at reflux for 15 hours. Drying of the pure acid solution to dryness gave a white sticky material. The compound was triturated several times with ether to remove stickiness. Recrystallization from ether / acetone / hexane (30:40:30) yielded 3.8 g (13 mmol) of a white powder.

Melting point: 190-192 ° C.

Yield: 65%.

IR spectrum (KBr): see Table III.

-5184 813

Example 8

Preparation of tetramethyl 4-phenylbutylidene-1,1-diphosphonate (Compound 27)

The compound was prepared by adapting the method described by D. A. Nicholson et al., Journal of Organic Chemistry, 35, 3149 (1970).

A suspension of 4.5 g (15 mmol) of 4-phenylbutylidene-1,1-diphosphonic acid and 9.8 g (92 mmol) of trimethyl crtoformate was heated at reflux for 90 minutes. To ensure intimate contact between the two phases, rapid mixing? had to be applied. Then an excess of trumpet! orthoform (9.8 g, 92 mmol) was added and the mixture was refluxed for an additional 30 minutes. The methanol and methyl formate formed were removed by distillation to allow the reaction temperature to rise. Heating continued until only one phase remained and trimethyl orthoform distillation began. After removal of this reagent, the brown residue was vacuum distilled! needles to give 3.3 g (9.3 mmol) of a colorless oil. Boiling point 5-10 x ² mmHg: 135-138 ° C.

Yield: 62%.

IR spectrum (film): see III. spreadsheet.

NMR Spectrum (CDC1 _3):

δ = 7.35-7.20 (multiplet, 5H): phenyl;

3.95-3.60 (doublet, 12H, J = 11Hz): hydrogen atoms of methyl groups attached to the phosphonate side chains;

2.80 - 1.60 (multiplet, 7H): hydrogen atoms of the side chain methylene groups and unparalleled hydrogen atoms.

In a similar manner to the methods described above, other compounds of formula (I) were prepared which had the physical characteristics of compounds of formulas I, 11 and III. are summarized in Table.

The NMR spectra of each of the hydroxy diphosphonate esters of formula (Ia) (compounds 1-8) showed the characteristic absorption of a hydroxy group: a sharp peak (for compounds az) and 7, or a triple (for 2, 3, 4, 5). 6 and 8), all of which were removed by exchange with deuterium oxide.

The absorption of the methine hydrogen atoms was a double doublet of 5 (J at 10 and 12 Hz), which is characteristic of a proton attached to two different phosphorus atoms P ₁ and P ₂ :

O-P

The structure of the hydroxy diphosphonate esters of formula (Ia) was further strengthened by acid hydrolysis of compounds 2 and 4 to give the corresponding hydroxyphosphonate acids which were isolated as their monosodium salts for ease of purification.

2θ The NMR spectrum of phosphonophosphates of formula (Ib) showed the following characteristic pattern:

δ - 7.5-7.3 multiplet, phenyl; δ = 5.8-5.4 (compounds 11.12, 13 and 14); 5- = 5.1-4.8 (compounds 15, 16 and 17), doublet of doublets, J = 10 and 12 Hz, corresponding to absorption of odd hydrogen; cannot be removed by exchange with deuterium oxide;

δ ~ 3.9-3.5 multiplet, methyl ester groups; δ = 1.60-1.55 (compounds 15, 16 and 17 only), two singlet, branched methyl groups [= C (CH ₃ ) ₂ ],

The mass spectra of all diphosphonate esters (la, lb and le) show the following characteristic: a high molecular weight (10-30%) molecular ion (M ⁺ ) and a base peak (100%) corresponding to a phosphonate ester group (M-PO) ₃ R ₂ ) ⁺ .

The only exception is the mass spectrum of compound 7, which showed no molecular ion, only peaks corresponding to the details of the molecule. The structure of the compound was undoubtedly determined by microanalysis.

Physical properties of the hydroxy diphosphonates of formula (Ia)

compounds number Formula (Ia) melting point [° C] IR absorption [cm ^-1 ] THE R, R 1 tert-butyl ch ₃ 110-112 2 phenyl CH 129-131 3250: OH 3 4-methylphenyl ch ₃ 110-113 2980: aliphatic C-H 4 4-chlorophenyl ch ₃ 119-123 1260 + 1240: P = O 5 4-fluorophenyl ch ₃ 118-122 1050: P-O-C 6 3.4: dimethoxyphenyl ch ₃ 120-123 7 2- (4-chlorophenoxy) prop-2-yl ch ₃ 137-138 3340,1500,1260, 1240, 1070 8 4- (4'-chlorobenzoyl) phenyl ch ₃ 150-153 3280.1670 (0 = 0) 1600.1260 + 1240 1050 + 1030 9 fend 3/4 H 1/4 Well 300 3460 3000 (wide) P-O-H 10 4-chlorophenyl 3/4 H 1/4 Well 300 1200-1080 -950

-6154 81 · Table IL

Physical properties of phosphono-fc phosphates of formula Ib

Number of compounds of formula (Ib)

The R.R '

Melting point IR absorption [° C] (cm ' ¹ )

11 phenyl ch ₃ oil* 12 4-chlorophenyl ch ₃ 81-82

13 4-fluorophenyl ch ₃ 48-49 14 2, 5-methyl-phenyl CH oil 15 2-phenyl-prop-2-yl CH ₃ 47-48 16 2- (4-chlorophenyl) prop-2-yl ch ₃ 62-63 17 2- (4-methoxyphenyl) prop-2-yl CH?

2980: aliphatic C-H 1500: aromatic C-C 1290 + 1260: P = 0 1050: P-O-C

2980: aliphatic C-C 1500: aromatic C-C 1280 + 1260: P = O

CH ₃

I

1200 + 1180: —C Group I

CH?

1050: POC * Boiling point: 152-155 ° C (5 · 10 ' ³ Torr)

Table III tt

Physical properties of diphosphonates of formula (1c)

compounds number Formula (lc) boiling point [° C / mm Hg] melting point [° CJ IR absorptions [cm ^- 'I THE R, R 18 phenyl methyl c ₂ h ₅ 135-138 / 5 · 10 ” ¹ 2980: aliphatic C-H 19 4-chloro-phenylmethyl c ₂ h ₅ 153-156 / 5-10 ^-3 ► 1500: aromatic C-C 1260: P = O 20 2-phenylethyl C ₂ H _s 137-140 / 5-IG ^-2 1170: PO — C ₂ H _s 21 3-phenyl-1-propyl c ₂ h ₃ 141-143 / 5-IQ ^-3 1050: P-O-C 22 phenylmethyl Η 210-212 3400-3200 (broad): OH 23 4-chlorophenyl-phenylmethyl H 237-239 - 1500: aromatic C-C 1230: P = O 24 3-phenyl-1-propyl H 190-192 1040: P-O- 25 phenylmethyl ch ₃ 130-132 / 5 · lü ^-3 2980: aliphatic C-H 26 4-chlorophenyl-methyl ch ₃ 141-144 / 5 · 10 ' ³ > 1500: aromatic C-C 1270: P = O 27 3-phenyl-1-propyl ch ₃ 135-138 / 5 · 10 ² 1195: P-O-CH ₃ 1050: POC

-7ΊΕ4 313

Example 9

Tetraethyl 4-phenoxybutyl idene-1,1-diphosphonate g (320 mmol) was added dropwise to a solution of 7.68 g (320 mmol) of sodium hydride in 60 mL of toluene. When hydrogen evolution ceased, 68.0 g (320 mmol) of 3-phenoxypropyl bromide were added and the mixture was heated at 60 ° C for 14 hours. The toluene was removed in vacuo and the residue dissolved in chloroform, washed several times with a saturated ^one, with brine, and dried over magnesium sulfate. Distillation under reduced pressure gave 50.0 g (118 mmol) of the title compound as a white viscous oil.

Mp: 170-175 ° C / 5-10 ' ² torr

Yield: 37%

IR (grass):

2980: aliphatic C-H

1500: aromatic C-C

1260: P = O, C-0

1170: P-O-C ₂ H ₅

1050: P-O-C NMR (CDCl ₃ ):

Δ = 7.35-7.15 and 6.95-6.8: (multiplet, 5H): phenyl,

4.35-4.05: (quintet, 8H, J = 8Hz): Hydrogen of the four methylene groups attached to the phosphonate group,

4.05 to 3.90 (triplet, 2H, J = 7Hz): Hydrogen of the methylene group adjacent to the phenoxy group, z 2.70 to 2.00 (multiplet, 5H): Hydrogen of the other and two other side chains,

1.45-1.25 (triplet, 2H, J = 7Hz): Hydrogen of the four methyl groups

Elemental Analysis: C 18 H ₂₀ O ₇ P ₂ Calculated: C 51.18 H 7.64 P 14.67 Found: C 51.26 H 7.6 P 14.40

Example 11

Tetramethyl-4-phenoxy-butiiidén-l, l-diphosphonate

A suspension of 5.5 g (17.7 mmol) of 4-phenoxybutylidene-1,1-diphosphonic acid and 9.8 g (92 mmol) of trimethyl orthoformate is heated under reflux for 90 minutes with vigorous stirring. An excess of 9.8 g (92 mmol) of trimethyl orthoformate was added and refluxed for another 30 minutes. The methanol and methyl formate formed were distilled off! while the temperature of the reaction mixture is allowed to rise. Heating is continued until only one phase remains and distillation of the trimethyl orthoform is started. After removal of this reagent, the brown residue was distilled in vacuo to give 4.7 g (12.7 mmol) of a colorless oil.

MP: 155-160 ° C / 5'10 ' ² torr: 72%

IR (film):

2980: aliphatic CH 1500: aromatic C-C 1270: P-O + CO 1195: PO-CH ₃ 1050: POC NMR (CDCl 3):

δ = 7.35-7.15 and 6.95-6.8 (multiplet, 5H): phenyl,

4.0-3.85 (triplet, 2Η, J = 7Hz): hydrogen of the methylene group adjacent to the phenoxy group,

3.85-3.70 (doublet, 12H, J = 11Hz): hydrogen of the methyl group attached to the phosphomate group,

2.80-1.90 (multiplet, 5H): Hydrogen of the side chain methylene. Elemental analysis: Calculated for C, 45.71; H, 6.60; 16.91 Found: C, 45.89; H, 6.76; P, 16.70

12-15. Examples relating to the pharmacological activity of the compounds of formula (I) are illustrated by the following Examples.

Example 10

Phenoxybutylidene-1,1-diphosphonic acid

A mixture of 27.0 g (64 mmol) of tetraethyl 4-phenoxybutylidene-1-diphosphonate and 40 g of 37% hydrochloric acid was heated under reflux for 15 hours. Evaporation of the pure acid solution to dryness gave a white viscous oil which was recrystallized from acetone / ether (10:90) to give 5.95 g (19.2 mmol) of a white powder.

m.p. 189-192 ° C: 30%

IR (KBr):

3400-3200 (broad): OH

1500: aromatic C-C

1230: P = O + C = C

1040: P-O12. example

Investigation of the effect of the compounds of the formula I on the metabolism of fat in healthy rats

Description of the method used:

Groups of 4 or 5 members of normal Wistar rats weighing approximately 200 g were treated with diphosphonate derivatives (200 µg / kg / day p.o.) for 4-21 days. The water-soluble compounds were added in water or dissolved in 24M bicarbonate buffer. The fat soluble compounds were added dissolved in cereal oil. The rats were weighed and the animals were decapitated with mild ether anesthesia overnight. Blood was collected and serum analyzed. Among the parameters of blood that reflect changes in fat metabolism are the following:

- free fatty acids; Measured by W. G. Duncombe (Clin. Acta, 9, 122 [1964]);

-818 «81?

- triglycerides; enzymatic process (Boehringer Mannheim Kit 126 012);

Phospholipids; molybdate / vanadate reaction (Boehring.er Mannheim Kit 124 9 74);

Lipoproteins: cholesterol after heparin-CaCl 3 precipitation according to M, Burstein et al. (La Presse Medicale, 43, 974 (1958)) and D. Watson (Gin. Chin. Acta. J., 637 (1960)).

Results obtained:

Except for Compounds 1 and 3, diphosphonates of Formula 1, when measured in normal and cholesterol-treated rats, reduced serum free fatty acids. The effect appears to be generalized to these diphosphonates having a p-chlorophenyl side chain and to indicate their role in fat metabolism. Similar properties have been described for a number of hypclipidemic agents (Hypolipidemic Agents, ed. David Kritchevsky, 41, Handbook of Experimental Pharmacy, Springer-Verlag, 349-408 (1975)). Significant reductions in serum t'glycerides were observed for compounds 2, 4, 7, 8, 10, and 19, as well as the acid form of compound 4. In many cases, compounds 2, 4, 7, 8, 11, 12, 15, 16,21 and 27 have been found to increase the amount of serum phospholipids. In activity, compound 4 was more than twice as likely as the others. The amount of cholesterol present in the β-lipoprotein fraction (very low density lipoproteins [VLDL = very low density lipoproteins] and low density lipoproteins [LDL = lcw density iipop.roteins]) decreased, while in the α-lipoprotein fraction (high density lipoproteins [HDL] = high density liopoproteins]) increased cholesterol, leading to a favorable increase in the α-cholesterol / β-cholesterol ratio. During prolonged treatment, this effect was accompanied by decreased cholesterol levels in the liver and aorta, compared with clofibrate for comparison, and a 33.6% decrease in phospholipids and a 52.2% decrease in α / β ratio. These results are consistent with those reported by CE Day et al. (Artery, 5, 90-109 (1979)) and KR Müller and GG Cortesi (Artery, 4, 564-577 (1978)), which confirmed that Clofibrate reduced HDL cholesterol levels in rats.

The above-described results show that these diphosphonates have an effect on lipid metabolism, in particular in increasing lipid (mainly cholesterol) content in α-lipoproteins and decreasing lipids (mainly triglycerides) in β-lipoproteins. ). Because it is known that HDL cholesterol levels are inversely correlated with the risk of cardiovascular disease (see N.E. Miller, Lipids, 13, 914-919 (1978)), diphosphonates having HDL-level properties are useful in the treatment of atherosclerosis. It is important to note that the acid or salt form of Compound 4 and the fairly simple diphosphonate Compound I do not possess these properties. It is also important to note that diphosphonates which differ in structure from compounds 2, 4, 7, and 8 do not have an effect on lipid metabolism. In this connection, reference is made to the studies of others: W. Hollander et al., Atherosclerosis, 31, 307325 (1978); and Mellies et al., Artery, 6, 38 (1979).

Example 13

Investigation of the effect of compounds of formula I on cholesterol-treated rats

Description of the method used:

In order to increase cholesterol in tissues, especially the liver, rats were kept on a high fat and cholesterol diet for 10 days to 3 months. The animals received the following composition: 20% casein, 37% butter, 9.1% cellulose, 18.9% dextrose, 4.5 cholesterol, 1.8% sodium cholate, 7.3% mineral, 1% vitamin and 0.4% choline.

The rats were then given normal food and treated with various compounds (200 ng / kg / day) for 10 days to 3 months. The serum parameters listed above were measured. Liver and aortic lipids were extracted by the method of J. Foich et al., J. Biochem., 226, 497 (1957). Total lipids were determined by the sulfophospho vanillin reaction (see N. Zölner and K. Kirsch, Z. Ges. Exp. Med., 135, 545 (1962)) and cholesterol was determined by the Liebermann-Burchard reaction.

Results obtained:

The diet described above increased the total amount of lipids, especially triglycerides and cholesterol by 8 to 10 times. Compounds 2, 4, 7, 8, 11, 12, 16 and 19! treatment, the total amount of lipids in the liver and / or the amount of cholesterol in the liver is significantly reduced. The same result was obtained with examination of aortic tissue. This indicates that the diphosphonates tested have a cholesterol-removing effect in tissues. Because cholesterol deposition is known to play an important role in the formation and / or development of atherosclerosis, preventing the deposition of cholesterol in tissues such as the aorta may be useful in treating or preventing atherosclerotic disease.

Example 14

Investigation of the effects of the compounds of the formula I on acid and salt forms in hypercalcemic rats

Description of the method used:

In recent years, research has shown that diphosphonic acids are effective in inhibiting the aortic and renal calcification in hypercalcemic animals (see M. Potokar and M. Schmidt-Dunker, Atheroscleosis, 30, 313-320 (1978)). These compounds also have the effect of preventing the increase in plasma calcium by vitamin D. This effect may be useful in the regression of previously established atherosclerosis (see I. Y. Rosenblum et al., Atherosclerosis, 22, 411-424 (1975)). Since the diphosphonates in the acid and non-acid form have these properties, the acid and non-acid forms of Compound 4 were investigated. The assays were performed in a manner similar to the Potokar method (see above). For a group of four male Wistar rats, 4 compounds are acid or

-9184813 salt form was added. A dose of about 5G mg / kg / day was administered as drinking water containing 0.05% active ingredient. The rats were treated with the compounds for 15 days. From day 5 to day 10, hypercalcaemia was induced in control and test animals by the administration of 75000 U-vitamin D ₃ / kg / day. Diphosphonate treatment was continued from day 10 to day 15. The animals were then sacrificed with mild ether anesthesia and serum calcium was determined by the method of BC Ray Sarkar and UPS Chanhan (Anal Biochem., 20, 155 (1967)).

Results obtained:

Calcium deposition plays a role in the late stages of the development of atherosclerotic plaques (see W. Hollander, Exp. Mol. Path., 25, 106 (1976)), and some diphosphonate acids have been shown to have an effect on calcium metabolism, and that this effect alone may be useful in the treatment of late stages of atherosclerosis. The fact that serum calcium is not reduced by any of the esterified forms, except that the acid and salt forms of Compound 4 by 20 and 14%, respectively, indicates that non-esterified diphosphonate causes an effect on calcium metabolism and calcification of pancreatic tumors (Atheroma).

Some of the results of studies of the pharmacological activity of the compounds of formula I, prepared by the process of the present invention, are summarized in Table IV.

//.

Comment:

- The IV. The results in Table 1 are expressed as a percentage of the control values. An exception is the serum calcium value, which is less than 15% different from the control, and is not considered significant (NS = not significant).

- Serum free fatty acids, triglycerides, and phosphonolipids were measured in normal rats (N) and rats (C.F.) fed with cholesterol for 10 days.

- Serum α! Β cholesterol, total lipids, and liver and aortic cholesterol were determined in normal and previously high-cholesterol diet rats.

Serum calcium was measured in hypercalcemic rats

The pharmacological examination of the compounds of formula (I) according to the invention shows that they have specific properties and activity in relation to lipids and lipid metabolism and are useful in the treatment of cardiovascular diseases. This is supported by:

- Lipid metabolism in normal rats is affected by lowering serum free fatty acids, lowering triglycerides, and increasing phospholipids. The latter may be associated with an increase in HDL lipids, especially HDL cholesterol, most

Pharmacological activity of the phosphonates of formula (I)

compounds ; k Serum Serum W: • um S initialize Liver Liver aorta aorta Serum row- free t n- phospho kol erin suspended all kolesz- all kolesz- Kai number fat: acids Glick srid lipids αϊβ Lipton refund lipid refund Clumon N C.F N C.F N C.F N C.F C.F C.F C.F C.F 2 NS -56 -21 -15 + 25 NS +88 -24 -50 -30 NS NS 4 -48 -67 -24 -21 +43 +21 +220 -31 -56 -47 NS NS 7 +28 -40 -33 NS +26 NS +27 NS -25 -27 -19 NS 8 -38 -52 -16 -17 NS +36 +51 -25 NS NS -39 NS 5 _ +27 _ - - 64 3 NS NS NS NS - - - NS 1 NS +24 -43 NS - - - NS 4 weeks -17 -29 NS NS NS NS NS NS NS -20 10 -27 -17 NS NS NS NS NS NS NS -14 clofibrate NS +19 -34 NS - NS - - - - 12 -50 NS +26 + 169 -32 -57 -37 -30 NS 11 -21 +32 +21 + 25 -18 -51 - - - 15 _; +36 + 15 -25 _ 16 __ +28 - +24 -32 -36 -46 -. - 13 NS NS -81 - - - · - - 14 NS NS -15 - - - - - . 26 -44 +36 -18 NG - - - __ - 19 -44 -65 -16 -24 NS NS -35 NS NS -60 NS NS 21 - +46 + 17 +33 - - - - 27 - +42 +33 -49 - - - -

-10184 kills 3

4, 5, and 12 and 13.

The compounds have the important property of significantly reducing the levels of liver and aortic lipids, especially cholesterol, in rats fed a high fat and cholesterol diet. Experiments not reported herein have also shown that compounds such as Compounds 2 and 4 increase cholesterol excretion in bile and faeces, leading to a net reduction in cholesterol in tissues.

Thus, it is agreed that the primary effects of the diphosphonates of formula (Ϊ) are different and novel compared to conventional hypolipidemic compounds. The specificity of these effects (increased HDL, removal of cholesterol from tissues) strongly suggests their use in the treatment of atherosclerosis. Experiments in rabbits, in which atherosclerosis was induced by cholesterol feeding, confirmed previous observations, namely that the 4 compounds containing the β-Cl side chain were most effective.

Furthermore, the fact that the acid and salt forms of Compound 4 have an effect on calcium metabolism suggests that non-esterified forms of the diphosphonates described herein may also be useful in the treatment of late stages of atherosclerosis.

Example 15

Investigation of hypoglycemic effect of diphosphonates of general formula (I)

Male Wistar rats (150-200g) (5-member group) were treated with previously tested phosphonates for 4 days. The animals were fasted overnight and decapitated on day 5 with mild ether anesthesia. Blood samples were collected using EDTA (as an anticoagulant). Results are expressed as [mean ± reach]. The results shown in Table V show that p-chlorophenyl diphosphonate was the most effective, especially when administered by I.P.

Table V.

Hypoglycemic effect

Method of administration, dose and carrier control was lok Plasma glucose [mg / 100 ml] 4 2 21 compounds 27 i.p. .; 50 mg / kg; aqueous buffer 87 * 3 36 * 1 p.o. .; 50 mg / kg; aqueous buffer 132 * 8 100 * 12 p.o. .; 50 mg / kg; corn oil 125 * 10 90 * 5 p.o. .; 100 mg / kg; aqueous buffer 111 * 7 93 * 12 p.o. .; 5C mg / kg; corn oil 125 * 10 110 * 10 p.o. .; 200 mg / kg; aqueous buffers 131 * 4 88 * 5 p.o. .; 200 mg / kg; aqueous buffer 131 * 4 102 * 9

Glucose was determined by the enzymatic method of W. Wermer and H. G. Wielinger (Z. Analyt. Chem., 252, 224 (1970)) (Boehringer Mannheim, Kit No. 124036).

Also included within the scope of the invention are lipoglycemic and antiatherogenic compositions containing one or more compounds of Formula (I) as an active ingredient in a pharmaceutically acceptable amount.

The amount of phosphonate compounds in the pharmaceutical compositions is selected so that the desired effect is safely achieved while maintaining a reasonable value for money / risk ratio associated with the drug treatments. Within the acceptable and safe range of medical judgment, the dosage of the phosphonate compounds will be varied depending upon the severity of the condition being treated, the duration of treatment, and the particular phosphonate compound used. The phosphonates are prepared as pharmaceutically acceptable products containing and animal tissues without undesirable toxicity, irritation or allergic symptoms, and the product-specific risk / benefit ratio is also within reasonable limits.

The pharmaceutical compositions of the invention may be formulated for oral administration in admixture with a solid carrier such as lactose, sucrose, sorbitol, mammoth, starch, amylopectin, cellulose derivative and / or gelatin. Wetting gels such as magnesium stearate, calcium stearate, carbowsx and / or polyethylene glycol may be used for blending. Sometimes, it may be advantageous to use capsules, in which case the mixture may contain concentrated sugar, acacia, talc and / or titanium dioxide.

In some cases, some phosphonates may be admixed with buffer solutions, cereal oil, olive oil, glycerol, commercial fillers, and such compositions may be administered in the form of sealed solid gelatin capsules, drops or syrups.

In addition, the phosphonates can be formulated with "Imhausen H" to form suitable suppositories.

For example, Compounds 4 and 9 were formulated as compressed tablets containing 10% magnesium stearate and 25% starch, and the final concentration of the active ingredient was 100-300 mg. In addition, the compounds of formula I are also used in the form of solutions in drinking water or cereal oil at concentrations of 2-100 mg / ml.

The aforesaid 'Imhausen H' is a semi-synthetic material which is a mixture of triglycerides of C 10 -C 18 fatty acids derived from cocoa butter and mono- and diglycerides of the same fatty acids.

Claims (15)

Patent claims A process for the preparation of diphosphonate derivatives of formula I wherein X is hydrogen or hydroxy; R and R ', which may be the same or different, are methyl, ethyl, propyl or butyl; A is (VIII), (IX), (X), (Xt), (XII), (XIII) or (XIV) wherein Y is hydrogen, methyl, methoxy or halogen, preferably chloro or fluoro, while n may be an integer from 1 to 5; m is 0 or 1; -111 With the proviso that when R and R 'are methyl, m is 0 and X is hydrogen, or if R and R' are ethyl, m is 0 and X is hydrogen or hydroxy, then A can only be different from phenyl; R and R 'are ethyl, m is 0 and X is hydrogen, then A is different from benzyl or alkylphenyl, and if R and R' are alkyl, m is 0 and X is hydroxy, then A is can only be different from the group of formula (Vili), characterized in that (a) in the presence of a catalytic amount of a dialkyl acyl phosphonate of formula (II) wherein A and R are as defined above, in the preparation of compounds of formula (Ia) wherein R, R ', A and n are as defined above; Reacting a dialkyl phosphonate of formula (III) wherein R 'is as defined above, or b) in the preparation of compounds of formula (IIb) wherein R, R 'and A are as defined above, a dialkyl acylphosphonate of formula (II) wherein A and R are as defined above is a dialkyl of formula (III) -phosphonate - wherein R 'is as defined above - in the presence of 80 to 100 mol% of the total amount of reactants in the presence of a base, or c) in the preparation of compounds of formula Ic where R 'and R are as defined above, an aralkyl halide of formula A-Z wherein A is as defined above and Z is halogen, preferably chlorine or bromine; or a salt thereof with a tetraalkyl methyl diphosphonate of formula (V) wherein R and R 'are as defined above, or d) in the preparation of tetramethylgemnetal diphosphonate of formula (le) wherein both R and R 'are methyl, a tetraalkylgeminal diphosphonate of formula (Ic) wherein A is as defined above and R and R 'is as defined above, with the proviso that they may be other than methyl, then hydrolyzed to give the geminal diphosphonic acid of formula (VI) - wherein A is reacted with the trimethyl orthoformate of formula (VII) above. 2. The process of claim 1, wherein a base is used in an amount of about 5 mol% of the total amount of reagents. 3. A process for carrying out the process of claim 1) a) or b), wherein the base is an amine. A process for carrying out the process according to claim 1, a) or b), or the process according to any of claims 2 or 3, characterized in that the reaction is carried out at a temperature of about 0 ° C and ether is used as solvent. 5. A process according to claim 1, wherein the starting material is a sodium salt of a compound of formula V having the formula: R and R 'is as defined in claim 1. 6. The process of Claim 1 c), wherein the basic condensing agent is Metal Sodium or Potassium, sodium amide or sodium hydride are used. 7. A process according to claim 1 c) or a process according to any one of claims 5 or 6, wherein the reaction is carried out in a solvent at about 1120 ° C. 8. A process for the preparation of process (a) of claim 1 for the preparation of tetramethyl 1- (p-chlorophenyl) thietane-1-hydroxy-1,1-diphosphonate, characterized in that dimethyl p-chlorobenzoyl phosphonate is dimethyl reaction with phosphonate. 9. The process of claim 1 for the preparation of tetranethyl -2,2-dimethyl-2- (p-chlorophenoxy) ethane-1-hydroxy-1,1-diphosphonate, characterized in that chlorophenoxy isobutyryl phosphonate is reacted with dimethyl phosphonate. 10. A process according to claim 1 for the preparation of 1- (4- (4-chlorobenzoyl) phenyl) -methyl-1-hydroxy-1,1-diphosphonate, characterized in that dimethyl-4- (4'- chlorobenzoyl) benzoyl phosphonate is reacted with dimethyl phosphonate. ³⁰ 11. A process for the preparation of dimethyl 1- (dimethoxyphosphonyl) p-chlorobenzyl phosphate according to claim 1, wherein the dimethyl p-chlorobenzoyl phosphonate is reacted with dimethyl phosphonate. 12. The process of claim b) Method 35 for the preparation of [1- (dimethoxyphosphonyl) -2,2-dimethyl-2-phenyl] ethylphosphate comprising reacting dimethylphenylisobutyrylphosphonate with dimethylphosphonate, 13. The method of claim 1, b) Method 40 for the preparation of [1- (dimethoxyphosphonyl) -2,2-dimethyl-2- (p-chlorophenyl)] ethyl phosphate, which comprises reacting dimethyl p-chlorophenylisobutyryl phosphonate with dimethyl phosphonate. . 14. The method of claim 1, c) 45 Methods for the preparation of tetraethyl 4-phenylbutylidene-1,1-diphosphonate comprising reacting tetraethylmethylene diisophonate with 3-phenylpropyl bromide. A process for the preparation of tetramethyl butylidene-1,1-diphosphonic acid according to claim 1 (d), Characterized in that the tetraethyl 4-phenylbutylidene 1,1-diphosphonate is hydrolyzed and the resulting 4-phenylbutylidene 1,1-diphosphonic acid is reacted with trimethyl orthoformate. 4 pieces of figure Published by the National Office of Inventions Published by: Hiir -r Zoltán Head of Department Published by: Technical Publisher COPYLUX Printing and Duplication Small Cooperative