FI92704B - Process for the preparation of therapeutically useful aromatic substituted alkylaminoalkanediphosphonic acids - Google Patents

Abstract

Araliphatylaminoalkanediphosphonic acids of the formula <IMAGE> in which R1 represents an aromatically substituted aliphatic radical, R2 represents hydrogen or a monovalent aliphatic radical and alk denotes a divalent aliphatic radical, and their salts have a marked regulating action on calcium metabolism and can be used as medicaments for the treatment of diseases which can be traced back to disorders thereof. They are prepared, for example, by reacting a compound of the formula <IMAGE> in which X3 denotes carboxyl and R0 denotes a radical R2, with phosphorous acid and phosphorus trichloride and hydrolysing the primary product.

Description

92704

The invention relates to a process for the preparation of aromatically substituted alkylaminoalkanediphosphonic acids.

R, CU, alkI · N - alk - C - OH

I I

R2 for the preparation of therapeutically useful aromatically substituted alkylaminoalkanediphosphonic acids and their salts according to R2, h2 10 3 2, in which R represents phenyl which is unsubstituted or substituted by C1-C4-alkyl, C1-C4-alkoxy and / or with halogen, or imidazolyl or pyridyl, R 2 represents hydrogen or C 1 -C 4 alkyl, alk 'represents C 1 -C 3 alkylene and alk represents C 2 -C 3 alkylene.

The most broadly defined formulas of EP Patent Application 186,405 include compounds that are structurally adjacent to the compounds disclosed in this application. This formula has a very large number of variable substituents and contains e.g. selenium compounds.

In the reference to the compounds actually prepared, no single N-pyridylalkylaminoalkane compound is disclosed, but only some N-pyridylaminoalkanes.

C 1 -C 4 alkyl is, for example, methyl, ethyl, propyl, isopropyl or butyl, further iso-, sec- or tert-but-; · C 1 -C 4 alkoxy is, for example, methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, further iso-, sec- or tert-butyloxy.

292704 C 1 -C 4 alkylthio is, for example, methylthio, ethylthio, propylthio or butylthio, further iso-, sec- or tert-butylthio.

Halogen is, for example, of the order of 35 or less, such as chlorine or fluorine, further bromine.

C 1 -C 3 alkylene alk is, for example, ethylene or 1,3-propylene.

C 2 -C 3 alkylene alk 'is, for example, ethylene or 1,3-propylene, but may also be 1,2-propylene.

Salts of the compounds of the formula I are in particular their internal salts or salts formed with pharmaceutically acceptable bases, such as non-toxic metal salts derived from metals of groups Ia, Ib, Ha and Hb, e.g. alkali metal salts, in particular sodium or potassium salts, alkaline earth metal salts, in particular calcium or magnesium salts, copper, aluminum or zinc salts, as well as ammonium salts formed with ammonia or organic amines or quaternary ammonium bases, such as optionally C-hydroxylated aliphatic amines, in particular mono-, di- or trialem Tris (hydroxymethyl) of -25 dialkylamines, e.g. methyl, ethyl, dimethyl * or diethylamine, mono-, di- or tri- (hydroxy-lower alkyl) amines, such as ethanol, diethanol or triethanolamine -aminomethane or 2-hydroxy-tert-butylamine, or N- (hydroxy-lower-alkyl) -N, N-dialkylalkylamines or the like. N- (polyhydroxy lower alkyl) -N-lower alkylamines, such as 2- (dimethylamino) ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, e.g. tetrabutylammonium hydroxide, as well as both complete and partial salts, i.e. salts having 1, 2, 3 or 4, in particular 2 equivalents of base per mole of acid of the formula I.

3 92704

The compounds of formula I and their salts have valuable pharmacological properties. In particular, they have a clear regulatory effect on the calcium metabolism of warm-blooded animals. In particular, they induce a clear inhibition of bone resorption in the rat, which can be demonstrated by both Acta Endocrinol. 78, 613-24 (1975) by PTH-induced increase in serum calcium after subcutaneous administration of about 0.01 to about 1.0 mg / kg in the TPTX (Thyroparathyroidectomised) rat model of Vita-10 administered by D3-triggered experimental hypercalcemia. about 0.001 to 1.0 mg subcutaneously. Similarly, Walker-256-Tumore-induced tumor hypercalcemia is inhibited when administered from about 1.0 to about 100 mg / kg orally. Furthermore, they clearly inhibit the progression of the chronic arthritic process in rat adjuvant arthritis according to New-bould, Brit. J. Pharmacology 21, 127 (1963) and Kaibara et al., J. Exp. Med. 159, 1388-96 (1984) when administered from about 0.01 to 1.0 mg / kg subcutaneously. Therefore, they are excellently suitable as active ingredients for the treatment of diseases that can be associated with disorders of calcium metabolism, for example inflammatory processes in the joints, degenerative processes in articular cartilage, osteoporosis, periodontitis, hyperparathyroidism and vascular implantation and protatants. Likewise, diseases in which abnormal accumulation of sparingly soluble calcium salts is observed, such as arthritis, e.g. Bech-terew's disease, neuritis, bursitis, periodontitis and tendinitis, fibrodysplasia, osteoarthritis or arteriosclerosis, as well as priority is given to abnormal dissolution of hard tissues such as congenital hypophosphatasia, degenerative processes of articular cartilage, various osteoporoses, Paget's disease 35 and Osteodystrophy fibrosa as well as tumor-triggered osteolytic processes.

4 92704

The invention relates in particular to the compounds of the formula I mentioned in the examples and their salts, in particular the inner salts and the pharmaceutically acceptable salts formed with bases.

5

The invention further relates to a process for the preparation of the compounds of the formula I and their salts, based on methods known per se. This is characterized in that 10 R, -N-alk-X3 (V)

A compound of formula Ro wherein R 1 represents R 2 or an amino protecting group and X 3 represents carboxy, carbamyl or cyano is reacted with phosphoric acid and phosphorus trichloride, the primary product is hydrolysed and the compound of formula V wherein X 3 is cyano or carbamyl is reacted with 0 PO 3 H 2 R, -Na lk-C-NH 2 (VI)

In the intermediate or salt of Ro PO 3 H 2, the amino group is replaced by hydroxy treatment with nitric acid, the amino protecting group, if present, is cleaved in each case and, if desired, the compound obtained is converted into another compound of formula I and / or the resulting free compound is a salt or salt. free compound or another salt.

Suitable amino protecting groups Ro are, for example, α-aryl-lower alkyl, such as benzyl or p-methoxybenzyl, α, α, α-triaryl-lower alkyl, such as trityl, or tri-35 lower alkyl, such as trimethylsilyl. α-aryl and α, α, α-tri-aryl lower alkyl can be easily removed again by hydrogenation, trialemp alkyl alkyl silyl and α, α, α-.

> 1 5 92704 triaryl-lower alkyl hydrolytically. The cleavage of α-aryl or vast, α, α, α-tricosyl lower alkyl Ro by hydrogenation takes place in particular by reacting with hydrogen in the presence of a hydrogenation catalyst such as nickel or noble-thallium catalyst, e.g. palladium carbon, especially in lower alkanol at normal pressure and pressure. , e.g. at about 20-30 ° C and at about 0.95 to about 1.3 bar.

The reaction of the compounds of formula V with phosphoric acid and phosphorus trichloride takes place in a conventional manner, the phosphoric acid component being preferably formed in situ by reacting the excess phosphorus trichloride with an aqueous phosphoric acid, e.g. about 75% to about 95%, especially with about 85% phosphoric acid. The reaction is preferably carried out under heating, e.g. to about 70 to about 120 ° C in a suitable solvent such as tetrachloroethane, trichloroethane, chlorobenzene, chlorotoluene or paraffin oil and hydrolytically carrying out the final steps.

Treatment of intermediates of formula VI with nitric acid takes place in a conventional manner by liberating them in aqueous solution from their salts, e.g. sodium nitrite, by acid treatment, e.g. under the action of hydrochloric acid, to indirectly form the corresponding unstable diazonium salt, e.g. hydroxy group.

The starting materials of the formula V can be prepared if they are not known, for example by the corresponding

A compound of formula R 1 -N 2 -H (Uh) wherein R q represents R 2 or an amino-protecting group is reacted with a compound of formula Y - alk - X 3 (H 1) wherein Y is halogen, such as bromine 6 92704, or For the preparation of compounds of formula V in which alk represents 1,2-lower alkylene, e.g. ethylene, with a compound of formula alk0 to X3 (IIf) 5 in which alk represents a lower alkyl-1-enyl residue, the amino-protecting group which may be present is cleaved and, if desired, the primary product obtained is hydrolyzed. acid.

The compounds of the formula I obtained by the process or by another process known per se can be converted into other compounds of the formula I in a manner known per se.

Thus, in a compound of formula I wherein R 2 represents hydrogen, this may be replaced by a lower alkyl residue R2 by reaction with a lower alkanal under reducing conditions, for example formaldehyde and formic acid, or alternatively with a reactive ester of a lower alkanol in a conventional manner, especially a base.

Further, the non-aromatic double bonds present at the residue R 1 and / or R 2 can be reduced to simple bonds in a conventional manner by hydrogenation, for example by reaction with hydrogen in the presence of a hydrogenation catalyst such as nickel or a noble metal catalyst, e.g. palladium on carbon. under normal pressure and temperature conditions.

·· Further an aromatic substituent of the residue Rj or resp.

aromatic substituents may be substituted, for example, by the addition of halogen by reaction with a conventional nuclear halogenating agent, e.g. chlorine or bromine, in the presence of a Lewis acid such as ferric chloride.

7 92704

The new compounds may exist depending on the choice of starting materials and procedures in the form of a possible isomer or a mixture thereof, e.g. depending on the number of asymmetric carbon atoms as pure optical isomers, such as antipodes or mixtures of isomers, such as racemates, diastereoisomeric mixtures or racemic mixtures.

The resulting diastereomeric mixtures and racemic mixtures can be separated into the pure isomers, diastereomers or racemates on the basis of the physicochemical differences of the constituents in a known manner, for example by chromatography and / or fractional crystallization.

The racemates obtained can be further decomposed into optical antipodes according to known methods, for example by recrystallization from an optically active solvent, by microorganisms or by reacting the acidic end product with a racemic acid with a salt-forming optically active base and separating the salts thus obtained, e.g. on the basis of their different solubilities into diastereomers from which antipodes can be liberated by the action of suitable substances. Preferably, the more effective is isolated from both antipodes.

25

The resulting free compounds of formula I, including their internal salts of formula I, can be converted into base salts by partial or complete neutralization with one of the bases mentioned at the outset. Similarly, acid addition salts can be converted to the corresponding free compounds, including their internal salts.

«

The resulting free compounds of formula I can again be converted to acid addition salts by treatment with proton-35.

8 92704

The salts obtained can be converted in a manner known per se into other salts having a lower proportion of cation (partial salts) or into free compounds, e.g. by treatment with an acidic reagent such as mineral acid. The free compounds obtained can be converted into salts by treatment with a base, e.g. alkali hydroxide, and / or the salts obtained with a lower cation content (partial salts) can be converted in a similar manner into those with a higher cation content, e.g. complete salts.

The compounds, including their salts, may also be obtained in the form of their hydrates or may contain a solvent used for crystallization.

Due to the close relationship between the new compounds in free form and in the form of salts, the above and the following free compounds or their salts are to be understood as meaning, if appropriate, also the corresponding salts or compounds.

The invention also relates to those embodiments of the process according to which at some stage of the process the intermediate is obtained and the missing steps are carried out or the starting material is used in the form of a salt and / or racemate or antipode or is formed especially under reaction conditions.

The process according to the invention preferably uses starting materials which lead to the compounds initially described as very valuable. The novel starting materials and methods for their preparation also form part of the invention.

The pharmaceutical preparations according to the invention containing the compounds of the formula I or their pharmaceutically acceptable salts are intended for enteral, such as oral or rectal, and parenteral use and contain the pharmacologically active substance alone or in combination with a pharmaceutically acceptable carrier.

The new pharmaceutical preparations contain, for example, about 10 -n. 80%, especially about 20 to about 60% of active ingredient. The pharmaceutical preparations according to the invention for enteral or parenteral use are, for example, in unit dosage form, such as granules, tablets, capsules or suppositories, and also in ampoules. These are prepared in a manner known per se, e.g. by means of conventional mixing, granulating, granulating, dissolving or lyophilizing methods. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating the resulting mixture, and processing the mixture or granules, if desired or necessary after the addition of suitable excipients, into tablets or granules.

Suitable carriers are, in particular, fillers, such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations, further binders, such as starch, e.g. corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinyl. lipyrrolidone and / or, if desired, disintegrants such as the above-mentioned starches, further carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. Excipients are primarily flow control and lubricants, e.g.

silicic acid, talc, stearic acid and / or polyethylene glycol. The granulators are coated with suitable coatings, possibly resistant to gastric fluid, in which case e.g. concentrated sugar solutions, optionally containing gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, leachate solutions in suitable organic solvents or solvent mixtures. Tablets or granules may contain colorants or pigments, e.g., to identify or label different doses of active ingredient.

Other pharmaceutical preparations for oral use include gelatin capsules and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules may contain the active ingredient in the form of granules, e.g. mixed with excipients such as lactose, binders such as starches and / or lubricants such as talc and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, in which case stabilizers may also be added.

Pharmaceutical preparations for rectal administration are, for example, suppositories consisting of a combination of the active ingredient and a suppository base. Suitable suppository base masses are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, rectal capsules made of gelatin containing a combination of active ingredient and base mass can also be used. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

,, 92704

Suitable for parenteral use are primarily aqueous solutions of the active ingredient in water-soluble form, e.g. water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, using suitable lipophilic solvents or excipients, such as fatty oils, e.g. sesame oil, or synthetic fatty acids. ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity enhancing agents, e.g. sodium carboxymethylcellulose, sorbitol and / or dextran and optionally also stabilizers.

The present invention also relates to the use of the compounds of the formula I and their salts, in particular for the treatment of diseases caused by disorders of calcium metabolism, e.g. rheumatic diseases and in particular osteoporoses.

Doses of less than 0.01 mg / kg have only a minor effect on the pathological calcification or dissolution of hard tissues. Doses above 100 mg / kg may cause long-term toxic side effects. The compounds of formula I and their salts can be administered both orally and in hypertonic solution subcutaneously, intramuscularly or intravenously. The best daily doses are about 0.1-5 mg / kg for oral use, about 0.1-1 mg / kg for subcutaneous and intramuscular use and about 0.01 to 2 mg / kg for intravenous use, for example about 0.013 to 0 mg / kg. , 67 mg / kg.

However, the dosage of the compounds used may vary and will depend on the particular circumstances involved, such as the type and severity of the disease, the duration of treatment and the compound in question. Single dosage forms contain, for example, 0.01 to 10 mg, unit dosage forms for parenteral, such as intravenous use contain, for example, 0.01 to 0.1 mg, especially 0.02 to 0.08 mg, oral dosage unit forms contain e.g. , 2 to 2.5 mg, especially 0.3 to 1.5 mg / kg. The most preferred single dose is 10 to 100 mg for oral use and 0.5 to 5 mg for intravenous use and can be administered four times a day. Higher dosages for oral use are necessary due to limited resorption. For longer-lasting treatments, it is possible to initially switch from a higher dosage to a lower dosage in order to maintain the desired effect.

The following examples illustrate the above invention. However, they are not intended to limit the scope of the invention in any way. Temperatures are shown in degrees Celsius.

Example 1; (0.1 mol) of 3- [N- (3-phenylpropyl) -N-methylamino] -propionic acid hydrochloride, 13.4 ml of 85% phosphoric acid and 50 ml of chlorobenzene are heated with stirring and refluxed under cooling. °. 27 ml of phosphorus trichloride are then added dropwise at 100 [deg.] C. to give off gas. The reaction mixture separates within 30 minutes as a thick mass. Heat to 100 ° for a further 3 hours and then decant the chlorobenzene on top. Remaining tough mass and 100 ml of 9-n. hydrochloric acid is heated for 3 hours with stirring and refluxing. Filter hot by the addition of carbon and then dilute the filtrate with acetone to give 3- [N- (3-phenylpropyl) -N-methylamino] -1-hydroxypropane-1,1-diphosphonic acid as crystals, m.p .: 219 ° (dec.).

The starting 3- [N- (3-phenylpropyl) -N-methylamino] propionic acid hydrochloride can be prepared as follows: 92704 13 (0.15 moles) of N- (3-phenylpropyl) -N-methylamine is added 50 any diethyl ether and then 15.1 g of acrylic acid ethyl ester are gradually added with stirring. A clear solution is formed as the temperature rises slightly at the same time. Allow to stand overnight at room temperature and then distill off the ether. The residual oil is crude 3- [N- (3-phenylpropyl) -N-methylamino) propionic acid ethyl ester.

The ester obtained and 600 ml of 4-n. hydrochloric acid is heated at reflux for 24 hours. It is then evaporated under reduced pressure and the crystalline residue is triturated with acetone. The crystals are filtered off with suction, washed and dried to give 3- [N- (3-phenylpropyl) -N-methylamino] propionic acid hydrochloride.

Example 2: As shown in Example 1, starting from 3- (3-phenylpropylamino) -propionic acid hydrochloride (m.p. 219 °, dec.), 3- (3-phenylprop-2-ylamino) -propionic acid hydrochloride ( mp 126-127 °), 3- [N- (3-phenylpropyl) -N-ethylamino] -propionic acid hydrochloride, oil, 3- (4-enylbutylamino) propionic acid hydrochloride, m.p. 135-137 °, and 3- [3- (pyrid-3-yl) propylamino] -propionic acid hydrochloride or the like, to give 3- (3-phenylpropylamino) -1-hydroxypropane-1,1- diphosphonic acid, m.p. 219 ° (dec.), 3- (3-phenylprop-2-ylamino) -1-hydroxypropane-1,1-diphosphonic acid, m.p. 208-210 ° (dec.), 3- [N- (3-phenylpropyl) -N-ethylamino] -1-hydroxypropane-1,1-diphosphonic acid, m.p. 195-197 ° (dec.), 3- (4-phenylbutylamino) -1-hydroxypropane-1,1-diphosphonic acid, m.p. 191-193 ° (dec.) And 3- [3- (pyrid-3-yl) propylamino] -1-hydroxypropane-1,1-diphosphonic acid po.

Example 3t 9.3 g (26.3 mmol) of 3- (3-phenylpropylamino) -1-hydroxypropane-1,1-diphosphonic acid, 6.1 ml of formic acid and 4.2 ml of 38% A solution of formaldehyde in water is heated at reflux for 36 hours until it boils. The reaction solution is evaporated under reduced pressure and the residue is diluted with acetone. 3- [N- (3-phenyl-propyl) -N-methylamino] -1-hydroxy-propane-1,1-diphosphonic acid is obtained as colorless crystals, m.p. 219 ° (dec.).

Example 4: As shown in Example 1, starting from 3- [4,4- (di (p-fluorophenyl) butylamino] propionic acid ethyl ester via 3- [4,4-di (p-fluorophenyl] butylamino] propionic acid hydrochloride, mp 165-166 °, 3-14,4-di (p-fluorophenyl) butylamino] -1-hydroxypropane-1,1-diphosphonic acid is obtained, mp 220-222 ° (dec.).

The starting material can be prepared, for example, as follows: 26.1 g (0.1 mol) of 4,4-di (p-fluorophenyl) butylamine and 18.1 g of 3-bromopropionic acid ethyl ester are boiled with potassium carbonate (21.0 g) in 200 ml. 2-butanone for 24 hours with stirring and refluxing. The reaction mixture is filtered and the filtrate is evaporated under reduced pressure. Crude 3- [4,4-di (p-fluoro-phenyl) -butylamino] -propionic acid ethyl ester is obtained as an oil.

In a similar manner, starting from N- (2-phenylethyl) -N-methylamine and 4-bromobutyric acid ethyl ester, 4- [N- (2-phenylethyl) -N-methylamino] butyric acid ethyl ester and 4- [N- (2 -phenylethyl) -N-methylamino] butyric acid hydrochloride gives 4- [N- (2-phenylethyl) -N-methylamino] -1-hydroxybutane-1,1-diphosphonic acid.

Example 5: As shown in Example 1 using N- [3- (imidazol-4-yl) propyl] -N-methylamine as starting material 3- (N- [3- (imidazol-4-yl) propyl] -N-methylamine -no} -propionic acid ethyl ester and 3- (N- [3- (imidazol-4- [5,9704] yl) propyl] -N-methylamino} -propionic acid hydrochloride give 3- {N- [3-imidazole 4-yl) propyl] -N-methyl-amino} -l-hydroxypropane-l, 1-diphosphonic acid.

The starting material can be prepared, for example, as follows: 16.8 g (0.12 mol) of 3- [imidazol-4 (5) -yl] propionic acid and 13.1 ml of thionyl chloride are brought to reflux for 2 hours. After distilling off the excess thionyl chloride, 3- [imidazol-4 (5) -yl] propionic acid hydrochloride remains as a semi-solid mass (100% yield).

23.4 g (0.12 mol) of 3-thymidazol-4 (5) -ylpropionic acid hydrochloride are dissolved in 80 N dimethylformamide and cooled to -10 °. Methylamine gas is bubbled into the solution for 2 hours until the weight gain is 15 g. Allow to stand overnight at room temperature, then evaporate the reaction mixture to dryness under reduced pressure. The residue is chromatographed on 220 g of silica gel using a chloroform / methanol / concentrated ammonia mixture (80: 20: 1) as eluent. Fractions containing product give colorless crystals of 3- [imidazol-4 (5) -yl] -propionic acid polo- (N-methyl) amide from tetrahydrofuran, m.p. 168-170 °.

· To a suspension of 2.8 g of lithium aluminum hydride in 200 ml of tetrahydrofuran is added portionwise with stirring 10.9 g (0.0718 moles) of 3- [imidazol-4 (5) -yl] propionic acid (N-methyl) amide and then heated to reflux for 30 hours. The reaction mixture is then cooled to 0 ° and added dropwise. tain 3 ml water, 2.2 ml 10-n. sodium hydroxide solution and 8.2 ml of water. The inorganic precipitate is filtered off and the filtrate is evaporated in vacuo. The remaining oil is crude N- (imidazol-4 (5) -yl-propyl] -N-methylamine.

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Example 6: As shown in Example 1, starting from 3- [4- (4-methoxyphenyl) butylamino] propionic acid hydrochloride, m.p. 150-152 °, 3- [3- (4-methoxyphenyl) propyl-N-methylamino] propionic acid hydrochloride, m.p. 108-110 °, 3- [3- (4-chlorophenyl) propyl-N-methylaminolpropionic acid hydrochloride, m.p. 128-130 °, 3- [3- (3-methylphenyl) propyl-N-methylamino] propionic acid hydrochloride, m.p. 97-98 °, 3- [3- (imidazol-4 (5) -yl] -propyl-N-methylamino-propionic acid dihydrochloride as a semi-solid, 3- [3- (pyrid-2-yl) propyl-N-methyl -aminolpropionic acid dihydrochloride, mp 157-160 ° (dec.) 3- [N- (2-phenylethyl-N-methylamino] propionic acid hydrochloride, mp 144-145 ° (dec.) and 3- [N- (2-phenylethyl) amino] propionic acid hydrochloride, mp 150-152 °, or the like, can further prepare 3-14- (4-methoxyphenyl) butylamino] -1-hydroxypropane-1,1-diphosphonic acid , mp 160-164 ° (dec.), 3- [3- (4-methoxyphenyl) propyl-N-methylamino] -1-hydroxy-propane-1,1-diphosphonic acid, mp 154- 156 ° (dec.) 3- [3- (4-chlorophenyl) propyl-N-methylamino] -1-hydroxypropane-1,1-diphosphonic acid, mp 162-166 ° (dec.), 3- [3- (3-methylphenyl) propyl-N-methylamino] -1-hydroxypropane-1,1-diphosphonic acid, mp 193-195 ° (dec.), 3- [3- (imidate) sol-4 (5) -yl) propyl-N-methylamino] -1-hydroxypropane-1,1-diphosphonic acid, mp 130-136 ° (dec.) 3- [3 - (pyrid-2-yl) propyl-N-methylamino] -1-hydroxypropane-1,1-diphosphonic acid, m.p. 142-147 ° (dec.), 3- [N- (2-phenylethyl) -N-methylamino] -1-hydroxypropane-1,1-diphosphonic acid, m.p. 187-188 ° (dec.) And 3- [N- (2-phenylethyl) amino] -1-hydroxypropane-1,1-diphosphonic acid, m.p. 205-206 °.

Example 7; 1.83 g (0.005 mol) of 3- (4-phenylbutylamino) -1-hydroxypropane-1,1-diphosphonic acid are dissolved in 10 ml of n-sodium hydroxide. The resulting solution is evaporated to dryness under reduced pressure and the product is crystallized further.

II

17 92704 with methanol. Disodium 3- (4-phenylbutylamino) -1-hydroxypropane-1,1-diphosphonate is obtained, m.p. 313-316 ° (dec.)

In a similar manner, disodium 3- [N- (3-phenylpropyl) -N-methylamino] -1-hydroxypropane-1,1-diphosphonate is obtained, m.p. 321-325 °.

Example 8: Tablets containing 75 mg of active substance, e.g. 3- [N- (3-phenylpropyl) -N-methylamino] -1-hydroxypropane-1,1-diphosphonic acid or a salt thereof, e.g. disodium salt , can be prepared as follows:

Ingredients (1000 tablets): active substance 75.0 g lactose 268.5 g corn starch 22.5 g polyethylene glycol 6000 5.0 g talc 15.0 g magnesium stearate 4.0 g demineralized water q.s.

Preparation: The solids are first sieved through a sieve with a mesh size of 0.6 mm. The active ingredient, lactose, talc, magnesium stearate and half of the starch are then mixed thoroughly. The rest of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 260 ml of water. The resulting paste is added to the powdered substances, mixed and granulated, if necessary further; water. The granulate is dried overnight at 35 °, sieved with a sieve with a mesh size of 1.2 mm and compressed on both sides into concave tablets with a diameter of about 10 mm and a break groove on the upper side.

18 92704

Example 9: Tablets containing 10 mg of active ingredient, e.g. 3- [N- (3-phenylpropyl) -N-methylamino] -1-hydroxypropane-1,1-diphosphonic acid or a salt thereof, e.g. disodium salt , can be prepared as follows:

Ingredients (1000 tablets): active substance 10.0 g lactose 328.5 g corn starch 17.5 g polyethylene glycol 6000 5.0 g talc 25.0 g magnesium stearate 4.0 g demineralized water q.s.

Preparation: The solids are first sieved through a sieve with a mesh size of 0.6 mm. The active ingredient, lactose, talc, magnesium stearate and half of the starch are then mixed thoroughly. The rest of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 260 ml of water. The resulting paste is added to the powdered substances, mixed and granulated, if necessary with the addition of water. The granulate is dried overnight at 35 °, sieved with a sieve with a mesh size of 1.2 mm and compressed on both sides into concave tablets with a diameter of about 10 mm and a fracture groove on the top.

Example 10: Gelatin capsules containing 100 mg of active substance, e.g. 3- [N- (3-phenylpropyl) -N-methylamino] -1-hydroxypropane-1,1-diphosphonic acid or its salt, e.g. the disodium salt, can be prepared as follows: 1992704

Composition (1000 capsules): active substance 350.0 g microcrystalline cellulose 30.0 g sodium laurilsulfate 2.0 g magnesium stearate 8.0 g

Sodium lauryl sulphate is sieved through a sieve with a mesh size of 0.2 mm into the active substance (lyophilized) and mixed thoroughly for 10 minutes. The microcrystalline cellulose is then sieved into this mixture with a sieve with a mesh size of 0.9 mm and mixed again for 10 minutes. Finally, the mixture is sieved into magnesium stearate with a sieve with a mesh size of 0.8 mm and mixed for 3 minutes, after which each time 390 mg of the mixture is filled into gelatin capsules, size 0 (elongated).

Example 11: A 0.2% solution for injection or infusion can be prepared, e.g., as follows: an active ingredient, e.g. 3- [N- (3-phenylpropyl) -N-methylamino] -1-hydroxy -propane-1,1-diphosphonic acid or a salt thereof, e.g.

disodium salt 5.0 g sodium chloride 22.5 g. phosphate buffer, pH = 7.4 300.0 g water, demineralized ad 2500.0 ml

The active substance is dissolved in 1000 ml of water and filtered through a microfilter. Add the buffer solution and make up to 2500 ml with water. To prepare unit dosage forms, 1.0 or 2.5 ml glass ampoules (containing 2.0 or 5.0 mg of active ingredient, respectively) are filled.

Claims (3)

A process for the preparation of therapeutically usable aromatically substituted alkylaminoalkanediphosphonic acids of Formula I PO3H2 I (I) R, CU, alk'-N-alk C - OH II R2 po3h2 and their salts is unsubstituted or substituted x C C-C4 alkyl, C,-C4 alkoxy and / or halogen, or imidazolyl or pyridyl, R₂ is hydrogen or C1-C4 alkyl, alk represents C Ci-Cj alkylene and alk represents C 2 -C 3 alkylene, characterized by reacting a compound of formula V R 1 -N-alk-X 2 (V) Ro in which Ro represents a residue R 2 or an amino protecting group; and X3 represents carboxy, carbamyl or cyano, with phosphoric acid and phosphorus trichloride, hydrolyzes the primary product and replaces in a fresh compound of formula V in which X3 is cyano or carbamyl, obtained intermediate of formula VI .. po3h2 R, -N -alk-C-NH2 (VI) Ro PO3H2 or resp. its hydroxy amino group by treating with nitrogen acidity, in each case, optionally cleaves any amino protecting group and, if desired, transfers the obtained compound into another compound of formula I and / or a recovered free compound in a salt or a salt obtained in a free compound or other salt. 2. A process according to claim 1, characterized in that 3- (3-phenylpropylamino) -1-hydroxypropane-1,1-diphosphonic acid or a salt thereof is prepared. 3. A process according to claim 1, characterized in that 3- [N- (3-phenylpropyl) -N-methylamino] -1-hydroxypropane-1,1-diphosphonic acid or a salt thereof is prepared. «·