Process for preparing new derivatives of diphosphonic acid

(57) The present invention proposes a process for the preparation of novel diphosphonic acid derivatives of general formula I wherein imidazolyl, thiazolyl, benzimidazolyl, imidazolinyl or thiazolinyl radical, which are predominantly hydrogenated or substituted by C 1- 4 alkyl or amino group and R denotes hydrogen atom or C 1-4 alkyl group. These compounds are prepared by reacting a carboxylic het-CH 2 -COOH with a mixture of phosphorous or phosphoric acid and a phosphorus halide.

O

M, p / or₂the CH_O-C-OH ² AND

PORE /₀d ² (AND)

CS 266 345 B2

The invention proposes a process for preparation of novel diphosphonic acid derivatives of general formula I

II p / or₂ the CH₂-C-OH (I)

P / OR /, ·

II ² O

wherein imidazolyl, thiazolyl, benzimidazolyl, imidazolinyl or thiazolinyl, which are either partially hydrogenated or substituted by C 1 -C 4 alkyl or amino, and is hydrogen or C 1 -C 4 alkyl, such as and their physiologically acceptable salts.

DE-OS DE-OS No. 3,205,307 3,203,308 disclose aryl ethane diphosphonates, such as thienyl ethane diphosphonate or pyrazole ethane diphosphonate, with significant anti-inflammatory effects.

In DE-PS δ. No. 1,813,659 discloses diphosphonic acid derivatives of which acid. 1-Hydroxy-ethane-1,1-diphosphonic acid is important as an agent in the treatment of morbus pellets. European Published Application 186,405 describes heteroaromatic alkyl diphosphonates in which the alkylene chain contains at least two carbon atoms.

It has now been found that analogous derivatives of these compounds, in which there is only one carbon atom between the diphosphonate residue and the heterocyclic residue and where the heterocycle is not pyrazole, also exhibit this effect and are also suitable for good calcium binding complex Wide use in disorders of calcium metabolism. In particular, they can be applied very well where bone building and bone breakdown has been compromised, ie, they are suitable for application in diseases of the skeletal system such as osteoporosis, Bechterev's disease and the like.

Because of these properties, these compounds also find use in the treatment of bone metaethases, urinary calculi and to prevent heterotrophic ossification. By influencing the metabolism of calcium, it also forms the basis for application in rheumatoid arthritis, osteoarthritis and degenerative arthrose.

The compounds of formula I according to the invention are prepared by reacting a carboxylic acid of formula II with het-CH₂-COOH (II), in which the het is as defined above, with a mixture of phosphoric acid or phosphoric acid and a phosphorus halide, wherein the molar ratio between phosphoric acid or phosphoric acid and phosphorus halide is 1: 2 to 2: 1 and then saponified to free diphosphonic acid.

The carboxylic acids of formula II are reacted with 1 to 2 moles, preferably 1.5 moles, of phosphoric acid or phosphoric acid at a temperature of 80 to 130 ° C, preferably 100 to 110 ° C. carried out in the presence of diluents such as halohydrocarbons, in particular chlorobenzene and carbon tetrachloride, or also in the presence of dioxane. The subsequent hydrolysis is carried out by boiling with water, but preferably with semi-concentrated hydrochloric acid or hydrobromic acid.

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CS 266 345 B2

The free diphosphonic acids of formula I can be isolated as free acids or in the form of monoalkali, dialkali or ammonium salts. The alkali salts can generally be well purified by precipitation from a mixture of water and methanol or water and acetone. The compounds of formula I can be converted into one other in such a way that, for example, the corresponding unsubstituted compounds of formula I can be obtained from the substituted compounds.

The pharmacologically acceptable salts used are, in particular, alkali or ammonium salts, which are prepared in a conventional manner, for example by neutralizing the compounds with inorganic or organic bases, such as sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, aqueous ammonia or amines such as trimethylamine; triethylamine.

The novel compounds of formula I according to the invention and their salts can be administered in liquid or solid form enterally and parenterally. All conventional administration forms are suitable, for example tablets, capsules, dragees, syrups, solutions, suspensions and the like. Preferably, water is used as the injection medium, which in the case of injection solutions contains conventional additives such as stabilizing agents, solubilizers and buffers.

Such additives are, for example, tartrate and citrate buffers, ethyl alcohol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) to control viscosity. Liquid carriers for injectable solutions must be sterile and are preferably ampoules. As solid carriers, for example, starch, lactose, mannitol, methylcellulose, talc, high disperse silicic acid, high molecular weight fatty acids (eg stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, vegetable and animal fats and solid high molecular polymers (such as polyethylene glycols); for oral administration, suitable preparations may contain flavoring agents and sweeteners.

The dosage may depend on a variety of factors such as administration mode, compound administration, age and / or individual condition of the patient. The daily dose is about 1 to 1000 mg per person, preferably 10 to 200 mg per person, and can be administered once or divided into several portions.

The following diphosphonic acids, as well as their sodium salts, methyl esters and ethyl esters, are preferred for the purpose of the present invention, in addition to the examples of compounds and combinations of all the substituents of the derivative compounds mentioned.

Acid Acid Acid Acid Acid Acid Acid Acid Acid Acid Acid 1-hydroxy-2- (3-methyl-1,2,4-thiadiazol-5-yl) ethane-1,1-diphosphonic acid, 1-hydroxy 2- (3-Phenyl-1,2,4-thiadiazol-5-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (3-cyclohexylmethyl-1,2,4-thiadiazol-5) Ethyl-1,1-diphosphonic acid, 1-hydroxy-2- (3-methylisoxazol-5-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (3-phenylisoxazol-5-yl) ) Ethane -1,1-diphosphonic 1-Hydroxy-2- (3-methyl-1,2,5-oxadiazol-4-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (2-methyl-1,3,4-oxadiazole) - 5-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (3-phenyl-1,2,4-oxadiazol-5-yl) ethane-1,1-diphosphonic acid, 1-hydroxy- 2- (1,2,3-thiadiazol-4-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (1,2,5-thiadiazol-4-yl) ethane-1,1-diphosphonic acid 1-hydroxy-2- (4-oxazolin-2-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (5-methoxyoxazol-4-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (5-ethoxyoxazol-4-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (2-aminooxazol-4-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (2,5-dimethyloxazol-4-yl) ethane-1,1-diphosphonic acid, 1-Hydroxy-2- (5-ethoxy-2-methyl-oxazol-4-yl) -ethane-1,1-diphosphonic acid, 1-hydroxy-2- (2-methyl-1,3,4-oxadiazol-5-yl) Ethane-1,1-diphosphonic acid, 1-hydroxy-2- (3-phenyl-1,2,4-oxadiazol-5-yl) ethane-1,1-diphosphonic acid

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1-hydroxy-2- (1,2,3-thiadiazol-5-yl) ethane-11-diphosphonic acid, 1-hydroxy-2- (4-methyl-1,2,3-thiadiazole-5-) yl ethane-1,1-di-phosphonic acid, 1-hydroxy-2- (5-methylimidazol-4-yl) ethane-1,1-diphosphonic acid,

CS. 266 345 B2 2- (2-Methylthiazol-4-yl) ethane-1,1-diphosphonic acid, 2- (2-Methylthiazol-4-yl) propane-1,1-diphosphonic acid, 1-hydroxy-2- (2 methyl-thiazol-5-yl) ethane-1,1-diphosphonic acid, 2- (2-methylthiazol-5-yl) propane-1,1-diphosphonic acid, 1-hydroxy-2- (1,2,3-triazole) 4-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (1,2,4-triazol-3-yl) ethane-1,1-diphosphonic acid -aminoimidazol-4-yl) ethane-1,1-diphosphonic acid 2- (2-methylthiazol-5-yl) ethane-1,1-diphosphonic acid 1-hydroxy-2- (imidazol-4-yl) propane-1,1-diphosphonic acid, 1-hydroxy-2- (3α, 4,5,6,7,7α-hexahydrobenzoxazol-2-yl) ethane-1 1-diphosphonic acid, 1-hydroxy-2- (3α, 4,5,6,7,7α-hexahydrobenzthiazol-2-yl) ethane-1,1-diphosphonic acid, 2- (imidazol-4-yl) ethane -1,1-diphosphonic acid, 1-amino-2- (imidazol-4-yl) ethane-1,1-diphosphonic acid, 1-dimethylamino-2- (imidazol-4-yl) ethane-1,1-diphosphonic acid 1-hydroxy-2- (2-cyclohexylmethyl-1,3,4-oxadiazol-5-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (2-cyclohexyl-1,3,4-oxadiazol-5-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (2-aminothiazol-5-yl) ethane-1 1-hydroxy-2- (2-chloro-thiazol-5-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (2-chloro-oxazol-4-yl) ethane-1,1 diphosphonic acid, 1-hydroxy-2- (imidazol-2-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (1,2,4-triazol-1-yl) ethane-1,1 -diphosphonic.

The following examples show the process variants that can be used for the synthesis of compounds of the present invention. However, these examples do not limit the subject matter of the application. As a rule, the compounds precipitate as high-melting (melting point greater than or equal to 300 ° C) solid products (mono- or disodium salts), the structure of which is detected by H-, p- and optionally¹³C-NMR spectroscopy. The purity of the substances was determined by elementary urine

C, Η, N, P, S, Na - analyzes as well as thin layer electrophoresis (cellulose, oxalate buffer pH ® 4). The M-value is given for characterization of individual compounds_rel relative mobility related to pyrophosphate (M_rel^with 1).

Example 1

1-Hydroxy-2- (imidazol-4-yl) ethane-1,1-diphosphonic acid

To 3.5 g of imidazol-4-yl-acetic acid hydrochloride (melting point 198-200 ° C) in 40 ml of chlorobenzene was added 3 g of phosphorous acid, the reaction mixture was stirred for 10 minutes at 110 ° C, then Cool 9 g of phosphorus trichloride. The reaction mixture is heated at 110 ° C for 16 hours, then cooled, the chlorobenzene is decanted from an orange-colored syrup, and the residue is treated with 50 ml of 6 N hydrochloric acid. The suspension is refluxed for 5 hours, mixed with charcoal after cooling, and filtered off with suction.

The filtrate was concentrated, dried and boiled with acetone for 2 hours. The residue (4.3 g) was dissolved in 40 ml of water, adjusted to pH 5 with 2N sodium hydroxide solution, treated with 50 ml of methanol and the precipitated formed was filtered off with suction.

1.2 g of product (16.9% of theory) with melting point greater than 290 DEG C. are obtained. The compound was obtained as a monosodium salt with 2 moles of crystalline water (M._rel « 0,37).

Example 2

In an analogous manner to that described in Example 1, it is obtained by reacting phosphorous acid and phosphorus trichloride with

CS 266 345 B2

(a) 2-methyl-thiazol-4-ylacetic acid (mp 119-121 ° C; produced by 2-saponification of the corresponding ethyl ester) boiling point: 127 ° C / 13 Pa, obtained according to

J. Chem. Soc. 1946, 91 from gamma-bromoacetacetate by reaction with thioacetamide) 1-hydroxy-2- (2-methylthiazol-4-yl) ethane-1,1-diphosphonic acid, in the form of the disodium salt as a monohydrate. Yield: 57%. melting point above 300 ° C; M_re^ « = 0,55;

b) (3a, 4,5,6,7,7a-hexahydrobenzimidazol-2-yl) acetic acid (mp 168-170 ° C; produced by saponification of the ethyl ester (mp 141-143 ° C) obtained by reaction 1 ); 2-diaminocyclohexane with imino ether of ethyl cyanoacetate), 1-hydroxy-2- (3α, 4,5,6,7,7α-hexahydrobenzimidazol-2-yl) ethane-1,1-diphosphonic acid, in the form of the Sodium salt as dihydrate. Yield: 12%. melting point above 300 ° C; M_rel =0,45;

c) (4-imidazolin-2-yl) acetic acid (mp 108-110 ° C; produced by saponification of ethyl ester (mp 102-105 ° C), produced by reacting ethylenediamine with iminoether of ethyl cyanoacetate) 1- Hydroxy acid -2- (4-imidazolin-2-yl) ethane-1,1-diphosphonic acid as the free acid monohydrate. Yield: 14%. melting point ca 250 ° C (decomposition); M_rel = 0,45;

d) 2-amino-4-thiazol-4-ylacetic acid (mp 218-221 ° C; produced by saponification of ethyl ester (oily substance), prepared by reaction of thiourea with gamma-bromoacetacetic acid ethyl ester) 2- ( 2-Amino-4-thiazolin-4-yl) ethane-1-hydroxy-1,1-diphosphonic acid as the free acid dihydrate. Yield: 59%. mp 190-195 ° C (decomposition)? M_rel » 0,40. '