Diphosphonic acid derivatives, process for their preparation and medicines containing those compounds.

The present invention relates to new diphosphonic acid derivatives, processes for their preparation and medicaments which contain these substances.

DE-OS 32 03 307 and DE-OS 32 02 208 aryl ethane diphosphonates, for example the thienyl ethane diphosphonate or a pyrazole ethane diphosphonate with a pronounced anti-inflammatory effect are described.

DE-PS 18 13 659 describes diphosphonic acid derivatives, of which 1-hydroxy-ethane-1,1-diphosphonic acid has become important as a means of treating Paget's disease. EP-OS 186 405 describes, inter alia, pyridylalkyldiphosphonates and DE-OS 34 28 524 describes heteroaromatic alkyldiphosphonates in which the alkylene chain comprises at least 2 carbon atoms. It has now been found that analog derivatives of these compounds, in which there is only 1 carbon atom between the diphosphonate radical and the heterocyclic radical and the heterocycle does not mean pyrazole, also have this effect and are also suitable as good calcium complexing agents for the broader treatment of calcium metabolic disorders. Above all, they can be used very well where the bone build-up and breakdown is disturbed, ie they are suitable for the treatment of diseases of the skeletal system such as B. osteoporosis, ankylosing spondylitis and others

Because of these properties, they are also used in the therapy of bone metastases, urolithiasis and to prevent heterotopic ossifications. By influencing calcium metabolism, they continue to form a basis for the treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis.

The present application accordingly relates to diphosphonates of the general formula I.<chemistry id="chem0001" num="0001"><img file="EP0258618A2_D0001.tif" /></chemistry>in the<ul id="ul0001" list-style="none"><li>Het a heteroaromatic five-membered ring with 2-3 heteroatoms, partially hydrogenated and possibly one</li><li>or can be substituted several times by alkyl, alkoxy, phenyl, cyclohexyl, cyclohexylmethyl, halogen or the amino group, where two adjacent alkyl substituents can also form a ring together,</li><li>Y is hydrogen or lower alkyl,</li><li>X is hydrogen, hydroxy or amino optionally substituted by lower alkyl and</li><li>R is hydrogen or lower alkyl, with the proviso that Het must not represent the pyrazole ring, and their pharmacologically acceptable salts.</li></ul>

Of the 2-3 heteroatoms of the heteroaromatic five-membered ring, one heteroatom generally means nitrogen. The imidazole, imidazoline, isoxazole, oxazole, oxazoline, thiazole, thiazoline, triazole, oxadiazole or thiadiazole radical are preferred.

Alkyl alone or in the case of the alkoxy radical means a hydrocarbon radical with 1-4 C atoms, e preferably the methyl, ethyl and isobutyl radical. Two adjacent alkyl substituents on the heteroaromatic five-membered ring can also form a ring together, preferably a six-membered ring.

Halogen means fluorine, chlorine, bromine and iodine, preferably chlorine.

Compounds in which two alkyl radicals together form a ring can as stereoisomer mixtures or as pure cis or. Submit trans isomers.

Asymmetric carbon atoms can have the R, S or R, S configuration.

Compounds of the general formula I are prepared by processes known per se.

In the event that X in the general formula I is OH, the substances are preferably prepared by a) a carboxylic acid of the general formula II<chemistry id="chem0002" num="0002"><img file="EP0258618A2_D0002.tif" /></chemistry>in which Het and Y have the meanings given above, reacted with a mixture of phosphorous acid or phosphoric acid and a phosphorus halide and then saponified to free diphosphonic acid, or<ul id="ul0002" list-style="none"><li>b) a carboxylic acid chloride of the general formula III<chemistry id="chem0003" num="0003"><img file="EP0258618A2_D0003.tif" /></chemistry>in which Het and Y have the meanings given above, with a trialkyl phosphite of the general formula IV P (OR ')₃ (IV), in which R 'is lower alkyl, to an acylphosphonate of the general formula V<chemistry id="chem0004" num="0004"><img file="EP0258618A2_D0004.tif" /></chemistry>in which Het, Y and R 'have the meanings given above, then reacted with a dialkyl phosphite of the general formula VI<chemistry id="chem0005" num="0005"><img file="EP0258618A2_D0005.tif" /></chemistry>in which R 'has the meaning given above, to a diphosphonate of the general formula VII<chemistry id="chem0006" num="0006"><img file="EP0258618A2_D0006.tif" /></chemistry>in which Het, Y and R 'have the meanings given above, react and optionally saponify the resulting tetraesters to diesters or acids of the general formula, or in the event that X in the general formula I is amino which is optionally substituted by alkyl groups,</li><li>c) a carboxylic acid derivative of the general formula VIII<chemistry id="chem0007" num="0007"><img file="EP0258618A2_D0007.tif" /></chemistry>in which Het and Y have the meanings given above and Z represents a nitrile, imino ether or an N, N-dialkylcarboxamido group, with a phosphorus compound of the general formula IX<chemistry id="chem0008" num="0008"><img file="EP0258618A2_D0008.tif" /></chemistry>in which T = halogen, OH or OR ', where R' has the meaning given above, is reacted and, if appropriate, subsequently saponified, or in the case where X in the general formula I is hydrogen.</li><li>d) a compound of the general formula X<chemistry id="chem0009" num="0009"><img file="EP0258618A2_D0009.tif" /></chemistry>in which Het and Y have the meanings given above and A is a reactive radical such as. B. represents halogen or a sulfonate, with a compound of general formula XI<chemistry id="chem0010" num="0010"><img file="EP0258618A2_D0010.tif" /></chemistry>in which R 'has the meaning given above, to a diphosphonate of the general formula XII<chemistry id="chem0011" num="0011"><img file="EP0258618A2_D0011.tif" /></chemistry>in which Het, Y and R 'have the meanings given above, and optionally saponifying the tetraesters formed to form diesters or acids of the general formula I.</li></ul>

The carboxylic acids of general formula 11 used in process a) are reacted with 1-2, preferably 1.5 moles of phosphorous acid or phosphoric acid and 1-2, preferably 1.5 moles of phosphorus trihalide at temperatures of 80-130 ° C., preferably 100-110 ° C. The reaction can also be carried out in the presence of diluents, such as halogenated hydrocarbons, in particular chlorobenzene, tetrachloroethane or else dioxane. The subsequent hydrolysis is carried out by boiling with water, but advantageously with half-concentrated hydrochloric or hydrobromic acid.

In process b), the acid chloride of the general formula 111 is allowed to react with the trialkylphosphite of the general formula IV at temperatures between 0 and 60 ° C., preferably at 20-40 ° C. You can without solvent or in the presence of inert solvents such as diethyl ether, tetrahydrofuran, dioxane or halogenated hydrocarbons, such as. B. methylene chloride work. The acylphosphonate of the general formula V formed as an intermediate can be isolated or directly reacted further.

The subsequent reaction is carried out in the presence of a weak base, preferably a sec. Amine such as. B. dibutylamine at a temperature of 0 to 60 ° C, preferably at 10 - 30 ° C by.

In process c), the nitriles of the general formula VIII are reacted with phosphorous acid at temperatures of 110-180 ° C. The reaction can be carried out without or in the presence of aprotic solvents such as e.g. B. diglycol dimethyl ether or diglycol diethyl ether. However, the nitriles can also be treated with a phosphorus trihalide, e.g. B. phosphorus tribromide or phosphorus trichloride in an inert solvent such as. B. Bring dioxane or tetrahydrofuran to the reaction, optionally with the addition of water, at temperatures of 20 ° -80 ° C. Iminoethers of the general formula VIII are allowed to react with dialkyl phosphites, preferably in the presence of equimolar amounts of sodium in inert solvents such as diethyl ether, dioxane or also benzene, the Reactions usually take place at the reflux temperature of the corresponding solvent. Acid amides of the general formula VIII can be used in inert solvents such as. B. halogenated hydrocarbons or ethers such. B. implement diethyl ether with a mixture of phosphorus pentahalide / phosphorous acid or oxalyl chloride / trialkyl phosphite.

In process d), the methylene diphosphonic acid ester of the general formula XI is used in the form of its sodium or potassium salt. For this he is with sodium, potassium or the corresponding hydride in an inert solvent such as. B. benzene, toluene or dimethylformamide at a temperature of 0 to 40 ° C, preferably at 25 ° C. The alkali salt is reacted with the corresponding halide or sulfonate without isolation. The temperature is 20 - 110 ° C.

The tetraalkyl esters optionally obtained in processes b), c) and d) can be saponified to diesters or the free tetra acids. The saponification to diesters usually takes place in that the tetraalkyl ester with an alkali halide, preferably sodium iodide in a suitable solvent such as. B. Acetone treated at room temperature.

This creates the symmetrical diester / disodium salt, which can optionally be converted into the diester / diacid by an acidic ion exchanger. The saponification to free diphosphonic acids is usually done by boiling with hydrochloric or hydrobromic acid. However, cleavage with trimethylsilyl halide, preferably bromide or iodide, can also be carried out. Conversely, the free diphosphonic acids can be converted back into the tetraalkyl esters by boiling them with alkyl orthoformates. The free diphosphonic acids of the general formula I can be used as free acids or in the form of their mono- or dialkali or. Ammonium salts are isolated. The alkali salts can generally be cleaned well by reprecipitation from water / methanol or water / acetone.

The compounds of the general formula I can, if appropriate, be subsequently converted into one another. You can e.g. B. be alkylated or, if X in the general formula I is an unsubstituted amino group, can be converted by diazotization into the compounds of the general formula I with X = OH. By hydrogenolytic elimination of an N-benzyl group z. B. represent the corresponding unsubstituted compounds of general formula I.

As pharmacologically acceptable salts, especially alkali or ammonium salts are used, which are used in a conventional manner, for. B. by neutralizing the compounds with inorganic or organic bases such. B. sodium or potassium hydrogen carbonate, sodium hydroxide solution, potassium hydroxide solution, aqueous ammonia or amines such as. B. trimethyl or triethylamine.

The new substances of the formula I according to the invention and their salts can be administered enterally and parenterally in liquid or solid form. All the usual forms of application are possible here, for example tablets, capsules, dragees, syrups, solutions, suspensions, etc. Water is preferably used as the injection medium, which contains the additives, such as stabilizers, solubilizers and buffers, which are more common in injection solutions.

Such additives are e.g. B. tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control. Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules. Solid carriers are e.g. B. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular polymers (such as polyethylene glycols); Preparations suitable for oral administration can, if desired, contain flavoring and sweetening agents.

The dosage can depend on various factors, such as the mode of administration, species, age and / or individual condition. The doses to be administered daily are approximately 1 to 1000 mg / person, preferably 10 to 200 mg / person and can be taken in one go or several times.

For the purposes of the present invention, preference is given, in addition to the compounds mentioned in the examples and by combining all the meanings of the substituents mentioned in the claims, to the following diphosphonic acid and its sodium salts, methyl and ethyl esters.

1-Hydroxy-2- (3-methyl-1.2.4-thiadiazol-5-yl) ethane-1.1-diphosphonic acid<ul id="ul0003" list-style="none"><li>1-Hydroxy-2- (3-phenyl-1.2.4-thiadiazol-5-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (3-cyclohexylmethyl-1.2.4-thiazidazol-5-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (3-methyl-isoxazol-5-yl) ethane-1,1-diphosphonic acid</li><li>1-Hydroxy-2- (3-phenyl-isoxazol-5-yl) ethane-1,1-diphosphonic acid</li><li>1-Hydroxy-2- (3-methyl-1.2.5-oxadiazol-4-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (2-methyl-1.3.4-oxadiazol-5-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (3-phenyl-1.2.4-oxadiaxol-5-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (1.2.3-thiadiazol-4-yl) ethane-1.1-diphosphonic acid</li><li>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</li><li>1 -Hydroxy-2- (5-methoxy-oxazol-4-yl) ethane-1.1 -diphosphonic acid</li><li>1-Hydroxy-2- (5-ethoxy-oxazol-4-yl) ethane-1,1-diphosphonic acid</li><li>1-Hydroxy-2- (2-amino-oxazol-4-yl) ethan-1-diphosphonic acid</li><li>1-Hydroxy-2- (2,5-dimethyl-oxazol-4-yl) ethane-1,1-diphosphonic acid</li><li>1-Hydroxy-2- (5-ethoxy-2-methyl-oxazol-4-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (2-methyl-1.3.4-oxadiazol-5-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (3-phenyl-1.2.4-oxadiazol-5-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (1.2.3-thiadiazol-5-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (4-methyl-1.2.3-thiadiazol-5-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (5-methylimidazol-4-yl) ethane-1.1-diphosphonic acid 2- (2-methylthiazol-4-yl) ethane-1.1-diphosphonic acid</li><li>2- (2-methylthiazol-4-yl) propane-1,1-diphosphonic acid</li><li>1-hydroxy-2- (2-methylthiazol-5-yl) ethane-1,1-diphosphonic acid</li><li>2- (2-methylthiazol-5-yl) propane-1,1-diphosphonic acid</li><li>1-Hydroxy-2- (1.2.3-triazol-4-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (1.2.4-triazol-3-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (2-amino-imidazol-4-yl) ethane-1,1-diphosphonic acid</li><li>2- (2-methylthiazol-5-yl) ethane-1,1-diphosphonic acid</li><li>1-hydroxy-2- (imidazol-4-yl) propane-1,1-diphosphonic acid</li><li>1-Hydroxy-2- (3a, 4,5,6,7,7a-hexahydrobenzoxazol-2-yl) ethane-1,1-diphosphonic acid</li><li>1-Hydroxy-2- (3a, 4,5,6,7,7a-hexahydrobenthiazol-2-yl) ethane-1,1-diphosphonic acid 2- (imidazol-4-yl) ethane-1,1-diphosphonic acid</li><li>1-Amino-2- (imidazol-4-yl) ethane-1,1-diphosphonic acid</li><li>1-dimethylamino-2- (imidazol-4-yl) ethane-1,1-diphosphonic acid</li><li>1-Hydroxy-2- (2-cyclohexylmethyl-1.3.4-oxadiazol-5-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2 - (- 2-cyclohexyl-1.3.4-oxadiazol-5-yl) ethane-1.1-diphosphonic acid</li><li>1-Hydroxy-2- (2-aminothiazol-5-yl) ethane-1,1-diphosphonic acid</li><li>1-Hydroxy-2- (2-chlorothiazol-5-yl) ethane-1,1-diphosphonic acid</li><li>1-Hydroxy-2- (2-chloro-oxazol-4-yl) ethane-1.1-diphosphonic acid</li><li>1-hydroxy-2- (imidazol-2-yl) ethane-1,1-diphosphonic acid</li><li>1-Hydroxy-2- (1.2.4-triazol-1-yl) ethane-1.1-diphosphonic acid</li></ul>

The following example shows one of the process variants that can be used for the synthesis of the compounds according to the invention. However, they are not intended to be a limitation of the subject matter of the invention. The compounds are generally obtained as high-melting (mp 300 ° C.) solid products (mono- or disodium salt), the structure of which is characterized by H, P and, if appropriate, by¹³C NMR spectroscopy was secured. The purity of the substances was determined by means of C, H, N, P, S, Na analysis and by thin-layer electrophoresis (cellulose, oxalate buffer from P_H = 4.0). To characterize the individual compounds, the M_rel-Values ​​(= relative mobility) related to pyrophosphate (M_rel = 1) specified.

example 1

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

3 g of phosphorous acid are added to 3.5 g of imidazol-4-yl-acetic acid hydrochloride (mp: 198-200 ° C.) in 40 ml of chlorobenzene, and the mixture is stirred for 10 min. at 110 ° C, cools and slowly drops 9 g of phosphorus trichloride. The mixture is heated at 110 ° C. for 16 h, cooled, the chlorobenzene decanted from an orange syrup and 50 ml of 6N hydrochloric acid are added to the residue. The suspension is heated under reflux for 5 h, after cooling with carbon and suction filtered.

The filtrate is concentrated, dried and boiled for 2 hours with acetone. The residue (4.3 g) is dissolved in 40 ml of water, the solution is brought to pH = 5 with 2N sodium hydroxide solution, 50 ml of methanol are added and the precipitate which has separated out is filtered off with suction.

1.2 g = 16.9% of theory are obtained with an mp&gt; 290 ° C. The compound is obtained as a monosodium salt with 2 mol of water of crystallization. (M_rel = 0,37 )

Example 2

In an analogous manner to that described in Example 1, reaction of phosphoric acid and phosphorus trichloride also gives<ul id="ul0004" list-style="none"><li>a) 2-Methyl-thiazol-4-ylacetic acid (mp: 119-121 ° C; prepared by saponification of the corresponding ethyl ester (bp₁₃: 127 ° C), which according to J.Chem.Soc. 1946, 91 from -y-bromoacetoacetic ester was prepared by reaction with thioacetamide) the 1-hydroxy-2- (2-methyl-thiazol-4-yl) ethane-1,1-diphosphonic acid, which as a disodium salt with 1 mol of water of crystallization in one 57% yield was isolated; Mp&gt; 300 ° C, M,_el = 0.55.</li><li>b) (3a, 4,5,6,7,7a-hexahydrobenzimidazol-2-yl) acetic acid (mp: 168-170 ° C; prepared by saponification of the ethyl ester (mp: 141-143 ° C), which is obtained by reacting 1,2-diaminocyclohexane with the imino ether of ethyl cyanoacetate was prepared) the 1-hydroxy-2- (3a, 4,5,6,7,7a-hexahydrobenzimidazol-2-yl) ethane-1,1-diphosphonic acid, which is used as the sodium salt was isolated with 2 mol of water of crystallization in a yield of 12%; Mp&gt; 300 ° C; M_rel: 0.45.</li><li>c) (4-Imidazolin-2-yl) acetic acid (mp: 108-110 ° C; prepared by saponification of the ethyl ester (mp: 102-105 ° C), which was prepared by reacting ethylenediamine with the iminoether of the cyanoacetic acid ethyl ester) 1-Hydroxy-2- (4-imidazolin-2-yl) ethane-1,1-diphosphonic acid, which was isolated as the free acid with 1 mol of water of crystallization in a yield of 14%; Mp: about 250 ° C; M_rel: 0.45.</li><li>d) 2-Amino-4-thiazolin-4-yl-acetic acid (mp: 218-221 ° C; prepared by saponification of the ethyl ester (oily substance), which was prepared by reacting thiourea with γ-bromoacetoacetic acid ethyl ester) the 2- ( 2-Amino4-thiazolin-4-yl) ethan-1-hydroxy-1,1-diphosphonic acid, which was isolated as a free acid with 2 mol of water of crystallization in a yield of 59%; Mp: 190-195 ° C CE; M_rel: 0.40.</li></ul>

Example 3

2- (1,2,5-Thiadiazol-4-yl) ethane-1,1-diphosphonic acid tetraethyl ester

A solution of 1.62 g of tetraethyl methane diphosphonate in 10 ml of absolute toluene is added dropwise to 0.2 g of sodium hydride (69%) in 10 ml of absolute toluene. When the evolution of hydrogen has ended, 1 g of 4-bromomethyl-1,2,5-thiadiazole in 10 ml of absolute toluene is added and the mixture is stirred at room temperature for 12 hours. A little water is added, the organic phase is separated off, dried and concentrated. The residue is purified on a silica gel column (100 g; eluent: methylene chloride / methanol IV 98: 2). This gives 1.18 g = 55% of a colorless oil.

Example 4

2- (1,2,5-thiadiazol-4-yl) ethane-1,1-diphosphonic acid

1.18 g of the 2- (1,2,5-thiadiazol-4-yl) ethane-1,1-diphosphonic acid tetraethyl ester described in Example 3 are mixed with 3.3 ml of trimethylbromosilane under nitrogen. The mixture is left to stand at room temperature for 24 hours, the solution is concentrated, the residue is mixed with water, the solution is adjusted to pH = 5 with NaOH and methanol is added. The precipitate is filtered off. In this way, 0.56 g = 53% of the desired diphosphonic acid is obtained as the disodium salt with 1 mol of crystal water; Mp&gt; 300 ° C; M_rel: 0.9.