FI87653B - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC VERIFICATIONS OF SUBSTITUTES WITH AMINOMETHETIC PHOSPHONES - Google Patents

Abstract

Heteroarylaminomethanediphosphonic acids of the formula <IMAGE> in which R1 represents an optionally benzo- or cyclohexeno-fused 5-membered heteroaryl radical having 2 to 4 N atoms or 1 or 2 N atoms and 1 O or S atom as hetero atom(s) and which is unsubstituted or substituted by lower alkyl, phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy and/or halogen, lower alkoxy, hydroxyl, di-lower alkylamino, lower alkylthio and/or halogen and R2 denotes hydrogen or lower alkyl, and their salts have an action regulating the metabolism of calcium and can be used as pharmaceutical active compounds for the treatment of diseases which can be traced back to disorders thereof. They are prepared, for example, by converting the group(s) X into free phosphono in a compound of the formula <IMAGE> in which X1 denotes a functionally modified phosphono group X and X2 denotes phosphono or likewise a functionally modified phosphono group X.

Description

87653

Process for the preparation of new therapeutically active substituted aminomethanediphosphonic acids - For the preparation of newly substituted aminomethanediphosphonic acids

The invention relates to a process for the preparation of new substituted aminomethanediphosphonic acids, in particular of the formula PO, H * R1-Y-VH (I)

Rt for the preparation of heteroarylaminomethane diphosphonic acids and their salts according to the formula wherein unsubstituted or lower alkyl, unsubstituted or lower alkyl, lower alkoxy and / or unsubstituted by halogen-substituted or halogen-substituted alkyl, lower alkoxy or dialkyl, lower alkoxy, dialkyl, hydroxy or lower alkyl, lower alkoxy and / or halogen-substituted phenyl-lower alkyl, N-substituted, optionally benzo- or cyclohexenocondensed 5-membered, with 2 to 4 N atoms or 1 or 2 N atoms as heteroatoms and 1 O or S atom -:. ·. heteroaryl residue and R2 represents hydrogen or lower. pialkyl, provided that R 2 is other than hydrogen, when R 1 represents a pyrazol-3-yl or isoxazol-3-yl radical optionally substituted by alkyl and / or halogen.

EP patent application 186,405 describes pharmaceutical compositions containing geminal diphosphonic acids for the treatment of abnormal calcium and phosphate metabolism. DE patent application 34 28 524 discloses certain heteroaryl-propane-1,1-diphosphonic acids for disorders of calcium metabolism. FI patent 75830, on the other hand, describes certain methylenediphosphonic acid derivatives which have an anti-inflammatory effect. From JP-A-80/89 293 [cf. Chemical Abstracts 93, 181 017z (1980)] are known as herbicides are compounds of the formula I in which a pyrazol-3-yl or isoxazole residue which is optionally substituted by lower alkyl and R 2 is hydrogen.

Optionally benzo or cyclohexenocondensed 5-membered heteroatoms with 2 to 4 N atoms or 1 or 2 N atoms and heteroaryl radicals having 10 or O atoms are, for example, imidazolyl, e.g. imidazol-2-yl or -4-yl , thiazolyl, e.g. thiazol-2-yl, further thiazol-5-yl or -4-yl, oxazolyl, e.g. oxazol-2-yl, further oxazol-4-yl, triazolyl, e.g. 4H- 1.2,4-triazol-3-yl or 2H-1,2,3-triazol-4-yl, tetrazolyl, e.g. tetrazol-5-yl, thiadiazolyl, e.g.

1,2,5-thiadiazol-3-yl, oxadiazolyl, e.g. 1,3,4-oxadiazol-2-yl, benzimidazolyl, e.g. benzimidazol-2-yl, benzoxazolyl, e.g. benzoxazol-2-yl, or benzthiazolyl, e.g. benzthiazol-2-yl. Said residues may have one or more identical or different substituents, in particular one of the two identical or different substituents mentioned at the beginning. Residues R1f having substitutable N atoms are N-substituted, especially as described above. Residues R 1 are, for example, 1-C 1 -C 4 -alkylimidazol-2-yl radicals, such as 1-methylimidazol-2-yl, 1-phenyl-C 1 -C 4 -alkylimidazol-2-yl radicals, such as 1-Benzylimidazol-2-yl, oxazol-2-yl, thiazol-2-yl, 4- and 5-C1-C4-alkylthiazol-2-yl residues such as 4- or 5-methylthiazol-2-yl -yl, 5-phenylthiazol-2-yl, 1,2,4-thiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazole 2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, benzoxazol-2-yl and benzthiazol-2-yl.

In the following, lower radicals and compounds are meant, for example, those having up to 7, up to 4 87653 or up to 4 carbon atoms. Further, the general terms have the following meanings, for example:

Lower alkyl is, for example, C 1 -C 4 alkyl, such as methyl, ethyl, propyl or butyl, further iso-, sec- or tert-butyl, but it can also be C 5 -C 7 -alkyl, such as pentyl, hexyl or heptyl.

Phenyl-lower alkyl is, for example, phenyl, in particular 1-phenyl-C1-C4-alkyl, such as benzyl.

Lower alkoxy is, for example, C 1 -C 4 alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy or tert-butyloxy.

The dialkylalkylamino is, for example, di-C1-C4-alkylamino, such as dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, N-methyl-N-propylamino or di-butylamino.

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

Halogen is, for example, halogen having an order number of up to 35 "·, such as fluorine, chlorine or bromine.

Salts of the compounds of the formula I are in particular those formed with pharmaceutically acceptable bases, such as non-toxic metal salts derived from the metals of groups Ia, Ib, Ha and Hb, e.g. alkali metal, especially sodium or potassium salts, alkali metal salts, in particular calcium or magnesium salts, copper, aluminum or zinc salts, as well as ammonium salts formed from ammonia or organic amines or 4 87653 quaternary ammonium bases, such as optionally C-hydroxylated aliphatic amines, in particular tris (hydroxymethyl) of mono-, di- or trialempalkylamines, e.g. methyl, ethyl, dimethyl or diethylamine, mono-, di- or tri- (hydroxy-lower alkyl) amines, such as ethanol, diethanolamine or triethanolamine -amino-methane or 2-hydroxy-tert-butylamine, or N- (hydroxy-lower alkyl) -N, N-dialkylalkylamines or the like.

With N- (polyhydroxy lower alkyl) -N-lower alkylamines, such as 2- (dimethylamino) ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, e.g. tetrabutylammonium hydroxide.

It should also be mentioned in this connection that the compounds of the formula I can exist in the form of their internal salts, for example of the formula po3h2. Thus, said compounds can also be converted • by treatment with a strong protic acid such as hydrohalic acid, sulfuric acid, sulfonic acid, e.g. p-methane or p-toluenesulfonic acid, or sulfamic acid, e.g. N-cyclohexylsulfamic acid, to give the formula ». * A® <I ") K> 2 POjHz to acid addition salts, wherein A" denotes the anion of the protic acid.

The compounds of formula I and their salts have valuable pharmacological properties. In particular, they have a clear regulating effect on the calcium metabolism of warm-blooded animals. In particular, they provide a clear inhibition of intelligence sorption in the rat, which can be demonstrated by both the publication Acta Endocrinol. 7 * 3, 613-24 (1975) by PTH-induced increase in serum calcium after subcutaneous administration of about 0.01 to about 1.0 mg / kg in a TPTX (Thyroparathyroidectomised) rat model with vitamin D3-triggered experimental hypercalcemia. 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 Newbould, Brit. J. Pharmacology 2, 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 excellent as active ingredients in 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 and prosthetic vascular and prosthetic implants. Also advantageously affected are diseases in which abnormal accumulation of sparingly soluble calcium salts is observed, such as arthritis, e.g. Morbus Bechterew, neuritis, bursitis, periodontitis and tendinitis, fibrodysplasia, osteoarthritis or artereosclerosis, as well as diseases in which etus abnormal dissolution such as congenital hypophosphatasia, degenerative processes in articular cartilage, various osteoporoses, Morbus Paget and Osteodystrophy fibrosa as well as tumor-triggered osteolytic processes.

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The test report

Bone antiresorptive test comparing the following compounds: 1- (5-methylimidazol-2-ylamino) methane-1,1-diphosphonic acid (I), a compound of this invention, and 1- (pyrimid 2-ylamino) methane-1,1-diphosphonic acid (II), which is a compound according to EP Patent Application No. 186,405.

The test method used is a rat model in which the thyroid and parathyroid glands (Thyropa-rathyroidectomised, TPTX, rat) have been removed from the rat.

A. Test Method: 1.25 dihydroxyvitamin D3-induced hypercalcaemia in vivo in a thyroid-depleted and parathyroid rat.

The TPTX rat assay was performed in principle according to the published method of Trechsel et al (1987) J. Clin. Invest. 80, 1679-1686, without minor changes. Thyroid and parathyroid removal (TPTX) was performed under anesthesia (Evipane® sodium, Bay-er, Leverkusen, Germany, 80 mg / kg i.p.) in male rats weighing 130-150 g, the strain used was Tif: RAlf (SPF).

After a recovery period of 4 days, the animals were fasted for 24 hours and the serum calcium concentration was determined from an 800 blood sample taken under oxygen / carbon dioxide (1: 1) anesthesia from a retro-orbital venous plexus. Serum was diluted 1:30 with LaCl 3 (0.1 molar in 0.6 molar HCl) and the calcium concentration was determined by atomic absorption spectrophotometry. The elimination of thyroid and parathyroid glands was considered complete if this control calcium value was less than 1.88 mmol / l; animals with a higher value were discarded. The remaining animals were divided into groups of 5 animals.

5 to 8. On the day after surgery, each group of rats was given a daily injection of 1.25 dihydroxyvitamin D3 (125 pmol / kg, s.c. obtained from Hoffman-LaRoche, Basel, Switzerland), together with various doses of the test compound, administered either subcutaneously or orally. After 24 hours of fasting, an orbital blood sample was taken under anesthesia on day 9 and the serum calcium concentration was determined as described above.

In each experiment, the upper and lower limits of hypercalcemia were established in groups of control animals receiving only 1.25 dihydroxyvitamin D3 or saline (100% and 0% hypercalcemia, respectively). The dose required to induce 50% hypercalcemia (ED50) was determined graphically.

Sodium saline solutions of bisphosphonates were prepared in water, followed by dilution to the required concentration with a solution of 0.1% bovine serum albumin in phosphate buffered saline (BSA / PBS). When only free bisphosphonic acid was available, it was first dissolved in an equimolar amount of NaOH and then diluted in BSA / PBS.

e 87653 Β. Score

The results obtained are summarized in the following table:

Test compound Inhibition of bone resorption in TPTX-Vit D3 model (rat) ED50 [mg / kg s.c.] I 0.001 II 0.01 C. Conclusions

The above results clearly show that the compound of this invention is 10 times more active than the compound of EP Application No. 186,405.

The invention relates in particular to the compounds of the formula I, their salts, in particular their internal salts; - * · Pharmaceutically formed with animals and bases. ··. preparation of useful salts in which the compounds in which C is unsubstituted or lower alkyl, lower alkoxy, unsubstituted or lower alkyl, lower alkoxy and / or halogen mono- or disubstituted phenyl, hydroxy, dialkylalkylamino or lower alkyl or lower alkyl, lower alkyl C-disubstituted, optionally unsubstituted in the substituent N atom present or, in particular, lower alkyl or unsubstituted or lower alkyl, lower alkoxy and / or halogenated mono- or disubstituted phenyl-lower alkyl, N-monosubstituted-2,3-imidazolyl, or 9 87653 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzthiazolyl or thiadiazolyl and R2 represents hydrogen or lower alkyl.

The invention relates in particular to the preparation of pharmaceutically acceptable salts of the compounds of the formula I, their salts, in particular their internal salts and bases, in which Rx represents unsubstituted or lower alkyl, lower alkoxy, unsubstituted or lower alkyl, lower or lower alkoxy and / or lower alkoxy and -substituted phenyl, hydroxy, dialkylalkylamino, lower alkylthio and / or halogen mono- or di-substituted imidazolyl, benzimidazolyl, 2H-1,2,3- or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzthiazolyl or thiadiazolyl and R 2 represents hydrogen or lower alkyl.

The invention relates in particular to the preparation of pharmaceutically acceptable salts with the compounds of the formula I, their salts, in particular their inner salts and bases, in which the compounds are unsubstituted or C1-C4-alkyl, such as methyl or unsubstituted or C1-C4-alkyl, such as methyl, (C 1 -C 6 -alkoxy, such as nitro and / or halogen, such as chlorine mono- or disubstituted phenyl, C-substituted thiazolyl, such as thiazol-2-yl, benzthiazol-2-yl, thiadiazolyl, such as 1 , 2,4-thiadiazol-5-yl or 1,3,4-thiaziazol-2-yl, oxazolyl, such as oxazol-2-yl, or benzoxazol-2-yl and / or C1-C4-alkyl , such as methyl or unsubstituted or C 1 -C 4 alkyl, such as methyl, C 1 -C 4 alkoxy, such as nitro and / or halogen mono- or disubstituted phenyl-C 1 -C 4 alkyl, such as benzyl starch an N-substituted imidazole such as an imidazol-2-yl residue or an imidazol-4-yl residue, or a benzimidazol-2-yl residue, and R 2 represents hydrogen.

The invention relates in particular to the preparation of the compounds of the formula I, their salts, in particular their pharmaceutically acceptable salts and their bases, with unsubstituted or C1-C4-alkyl, such as methyl, C1-C4-alkoxy, such as nitroxy, phenyl. hydroxy, di-C1-C4-alkylamino, such as dimethylamino or diethylamino, C1-C4-alkylthio, such as methylthio, or a thiazolyl, such as thiazol-2-yl, substituted with a halogen of up to 35, such as chlorine. or a -4-yl residue and R 2 represents hydrogen.

The invention relates in particular to the preparation of pharmaceutically acceptable salts with the compounds of the formula I, their salts, in particular their internal salts and bases, in which the compounds are unsubstituted or C1-C4-alkyl, such as methyl, C1-C4-alkoxy, such as nitro, phenyl, hydroxy, di-C1-C4-alkylamino, such as dimethylamino or diethylamino, C1-C4-alkylthio, such as methylthio, or a halogen having an order of at most 35, such as chlorine, a C-substituted thiazolyl residue, such as thiazol-2-yl; or a 1-C 1 -C 4 -alkyl residue, such as methylimidazol-2-yl or -4-yl, or phenyl-C 1 -C 4 -alkyl, such as benzylimidazol-2-yl or -4- a yl residue and R2 represents hydrogen.

The invention relates in particular to the preparation of pharmaceutically acceptable salts of the compounds of the formula I, their salts, in particular their internal salts of I 87653 and their bases, in which the compounds are unsubstituted or in particular in the 4- and / or 5-position C 1 -C 4 alkyl-, such as methyl or phenyl, mono- or disubstituted thiazol-2-yl, unsubstituted or in the 1-position by C 1 -C 4 -alkyl, such as phenyl or phenyl-C 1 -C 4 -alkyl such as benzyl monosubstituted imidazol-2-yl or benzimidazol-2-yl residue or unsubstituted benzthiazol-2-yl or benzoxazol-2-yl residue and R 2 denotes hydrogen.

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

The process according to the invention is based on methods known per se and is characterized in that a) in the substitutable N atom of the residue Rx, optionally indirectly protected

In a compound according to R 1 - N - C - H (II), * 2 A 1 in which Xx represents a functionally modified phosphono group X and X 2 represents a phosphono or likewise a functionally modified phosphono group x, the group (s) X is converted into a free phosphono, or b) a residue The compound of formula R1-N-CH = O (III) "/ * 2 i2 87653, optionally indirectly protected on the N atom to be substituted, is first reacted with phosphorus trioxide and then with water and, if desired, converted into another compound of formula I and / or the free compound obtained as a salt or the salt obtained as a free compound or another salt.

According to process variant a), the phosphono-converted functionally modified phosphono groups X exist, for example, in ester form, in particular in the diester form of the formula -P (= O) - (OR) 2 (Ha), where OR represents, for example, lower alkoxy or optionally lower alkyl, lower alkoxy, halogen and trifluoromethyl a hydroxy-substituted phenyloxy group.

The conversion of a functionally modified phosphono group to a free phosphono group is carried out in a conventional manner by hydrolysis, for example in the presence of a mineral acid such as hydrochloric acid or hydrobromic acid or sulfuric acid, or by reaction with a trialkylalkyl-halosilane at about 0 to about 25 ° C.

The starting materials of the formula II can be prepared, for example, by condensing a compound of the formula R1-N (R2) -H (Hb; R2 = H) with at least an equimolar amount of the orthomuric acid triester of the formula HC (OR) 3 (Ile) i: OR denotes, for example, lower alkoxy or optionally phenyloxy substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and / or hydroxy, whereby the corresponding compound of formula R1-NH-CH (OR) 2 (IIId) or R1-N = CH-OR (IId2) is likely to be formed. ) and the condensation product are further reacted with at least twice the molar amount of a phosphoric acid ester, e.g. an ester of formula (OR) 2 (IIe) 0, and the resulting compound (II, R2 = H) is lower alkylated, if desired, to the corresponding compound (II, R2 = lower alkyl). ).

In intermediates II in which the residue R 1 is N-substituted by lower alkyl or unsubstituted or lower alkyl, lower alkoxy and / or halogen-substituted phenyl lower alkyl, the N-substituent can be cleaved with a lower alkyl ester, the carbamate then formed, and α-phenyl-lower alkyl residues, for example by hydrogenation, e.g. by treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on carbon and / or platinum oxide, or by metal reduction, e.g. by treatment with an alkali metal in ammonia.

However, the starting material Hb can be reacted in a manner known per se in the presence of orthomuric acid triester Ile with phosphoric acid diester Ile without isolating l c i4 87653 intermediate. Thus, according to a highly preferred embodiment, at boiling point, the corresponding compound IIb is reacted in the presence of at least an equimolar amount of orthomoformic acid triester Ile with at least twice the molar amount of phosphoric acid diester Ile without isolating an intermediate, e.g. The intermediate according to IId2 and the primary product II are hydrolyzed by treatment with aqueous hydrochloric acid at reflux temperature.

The reaction of the compounds III with phosphorus trioxide according to process variant b) takes place in particular by forming the latter in situ, for example by reacting phosphorus trichloride and phosphoric acid at an elevated temperature, e.g. about 50-65 ° C, by adding reaction component III, heating further and finally hydrolyzing the primary product, an I: 1 adduct of an aldehyde of the formula R1-N-CH = O (III) r2, the structure of which has hitherto been unknown, in particular by treatment with water.

In a variant of this preferred embodiment of variant b), at about 50 to 70 ° C, the orthophosphoric acid is reacted with an approximately 1.1- to 2-fold, in particular approximately 1.5-fold excess, of phosphorus trichloride, then the reaction component III is added, heated for a long time. to about 50-70 ° C, diluted with 80% phosphoric acid and hydrolytically finished.

The starting materials III can be prepared in a conventional manner, for example by reacting an amine of the formula li1 87653 R1-N (R2) -H (lib, R = H) with formic acid or a functional carboxy derivative thereof, e.g. a formic acid ester of the formula H-COOR (Ile), wherein OR represents a phenyloxy group optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and / or hydroxy, or with formamide.

Conventional N-protecting groups suitable for the indirect protection of the N atom to be substituted on the residue R 1 and their coupling and cleavage methods, for example 2,2,2-trihalogen, such as 2,2,2-triiodo, 2,2,2-tribromo - or 2,2,2-trichloroethoxycarbonyl radicals which can be cleaved, for example by treatment with zinc in acetic acid, α-phenyl-lower alkoxycarbonyl radicals, such as carbobenzoxy, which can be cleaved, e.g. by catalytic hydrogenation, and lower alkane sulfonyl groups, such as methanesulfonyl, which can be by treatment with bis- (2-methoxyethoxy) sodium aluminum hydride, as well as. . also α-phenylalkyl or alkyl groups, the cleavage of which is discussed later.

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

Thus, for compounds of formula I wherein R 2 represents hydrogen, lower alkyl R 2 may be attached by reaction with a reactive ester of a lower alkanol such as a hydrohalic acid ester or an organic sulfonic acid ester, i.e. 87653. However, an aliphatic residue, e.g. methyl, can also be added by reaction with an aliphatic aldehyde, e.g. formaldehyde and formic acid.

Furthermore, in compounds of formula I in which the residue is N-substituted by lower alkyl or unsubstituted or lower alkyl, lower alkoxy and / or halogen-substituted phenyl-lower alkyl, the N-substituent, lower alkyl can be cleaved with and α-phenyl-lower alkyl residues, for example by hydrogenation, e.g. by treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on carbon and / or platinum oxide, or by reduction with a metal, e.g. by treatment with an alkali metal in ammonia.

The free compounds of the formula I obtained and their internal salts of the formula I can be converted into base salts by partial or complete neutralization with one of the bases mentioned at the outset. In a corresponding manner, the acid addition salts of the formula I "can also be converted into the corresponding free compounds of the formula I or, respectively, into the internal salts of the formula 1 '.

On the other hand, the free compounds of the formula I obtained can be converted into the acid addition salts of the formula I "by treatment with one of the protic acids mentioned at the outset.

The salts obtained can be converted into the free compounds in a manner known per se, e.g. by treatment with an acidic reagent, such as a mineral acid or, respectively, with a base, e.g. alkali hydroxide.

ii i7 87653

The compounds and 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 their salts, the above and the following free compounds or their salts are to be understood as meaning, if appropriate, also the corresponding salts or the corresponding free compounds.

The invention also relates to those process embodiments which, at some stage in the process, start from the intermediate compound and carry out the missing steps or use the starting material in the form of a salt and / or racemate or anti-epodide or form it, in particular 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.

. . Pharmaceutical preparations containing compounds of formula I or pharmaceutically acceptable salts thereof 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 dosage of the active substance depends on the species, age and individual condition of the warm-blooded animal and the mode of administration. A warm daily dose of about 20 kg will normally be administered orally in a daily dose of about 20 to 1000 mg, especially about 30 to 300 mg, or intravenously, about 1 to 25 mg, especially about 1 to 10 mg, preferably in multiple doses. as an equal * partial dose.

87653 BC

The pharmaceutical preparations contain, for example, from about 10% to about 80%, in particular from 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, further 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 mixture obtained 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 and / or calcium phosphates, e.g. tri-calcium phosphate or calcium hydrogen carbonate, further binders, such as starch, e.g. corn, wheat or wheat. potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone and / or, if desired, disintegrants such as the above-mentioned starches, further. . carboxymethyl starch, crosslinked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. Excipients are primarily flow control and lubricating agents, e.g. silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearate 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 arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures, propyl esters 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. Capsules 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 or magnesium stearate 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.

Suitable for parenteral use are primarily aqueous solutions of the active ingredient in water-soluble form, e.g. in the form of a 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 acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-improving 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 as a hypertonic solution subcutaneously, intramuscularly or intravenously. The best daily doses are about 0.1 to 5 mg / kg for oral use, about 0.1 to 1 mg / kg for subcutaneous and intramuscular use, and about 0.01 to 2 mg / kg for intravenous use.

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, e.g. 0.01 to 0.1 mg, especially 0.02 to 0.08 mg, oral dosage unit forms contain e.g. 0.2 - 2.5 n 87653 mg, in particular 0.3 - 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 in four single daily doses. 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: 6.57 g (17 mmol) of 1- (thiazol-2-ylamino) -methane-1,1-diphosphonic acid tetraethyl ester are dissolved in 70 ml of n-hydrochloric acid and heated under reflux for 6 hours. During the reaction, the product precipitates in the form of a fine white precipitate. Allow to cool to room temperature and filter and wash with aqueous methanol. 4.33 g (93% of theory) of 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acid, m.p. 275e (dec.).

The starting material can be prepared, for example, as follows: A mixture of 10.0 g (0.1 mol) of 2-aminothiazole: 20.0 ml (0.12 mol) of orthomuric acid triethyl ester and 26.6 ml (0.2 mol) diethyl phosphite, heated at reflux for 1 hour. The ethanol released is distilled off, whereupon the internal temperature gradually rises to about 150e. The residue is taken up in chloroform and filtered through silica gel. The crude product is purified by column chromatography (silica gel / ethyl acetate). 4.37 g (11% of theory) of 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acid tetraethyl ester are obtained, m.p. 103 - 104e.

22 87653

Example 2: 1- (Oxazol-2-ylamino) methane-1,1-diphosphonic acid, m.p. 245 ® (dec.) And 1- (benzoxazol-1-ylamino) -1,1-diphosphonic acid, m.p. 270® (dec.).

Example 3: 4.36 g (10 mmol) of 1- (benzthiazol-2-ylamino) methane-1,1-diphosphonic acid tetraethyl ester are heated in 40 ml of n-hydrochloric acid over 6 hours to 110-120 °. During the reaction, the product precipitates in the form of a white precipitate. Cool to room temperature and filter and wash with aqueous methanol. 3.09 g (95% of theory) of 1- (benzthiazol-2-ylamino) methane-1,1-diphosphonic acid are obtained, m.p. 290® (dec.).

The starting material can be prepared, for example, as follows:

A mixture of 3.0 g (20 mmol) of 2-aminobenzthiazole, 4.0 ml (24 mmol) of orthomuric acid triethyl ester and 5.3 ml (40 mmol) of diethyl phosphite is heated to 120-125® over 5 hours. The yellow precipitate which precipitates at the beginning of the reaction gradually becomes a solution again, the liberated ethanol being distilled off during the reaction. The crude product which solidifies on standing is purified by column chromatography (silica gel / ethyl acetate / methanol). 5.62 g (64% of theory) of 1- (benzthiazol-2-ylamino) methane-1,1-diphosphonic acid tetraethyl ester are obtained, m.p. 165-167®.

Example 4: 1.30 g (3.2 mmol) of 1- (4-methylthiazol-2-ylamino) methane-1,1-diphosphonic acid tetraethyl ester are heated in 20 ml of n-hydrochloric acid to 100 ° over 20 hours. After cooling, 20 ml of methanol are added. After stirring, the product crystallizes in the form of fine white crystals. The filtrate is washed with methanol and petroleum ether. Yield: 615 mg (67% of theory) of 23 87653 1- (4-methylthiazol-2-ylamino) methane-1,1-diphosphonic acid, m.p. 294 ° (dec.).

The starting material can be prepared, for example, as follows:

A mixture of 2.33 g (20 mmol) of 2-amino-4-methylthiazole, 4.0 ml (24 mmol) of orthomuric acid triethyl ester and 5.3 ml (40 mmol) of diethyl phosphite is heated over 4 hours at 120 DEG C. 125E C. The ethanol released is distilled off. The residue is purified by column chromatography (silica gel / ethyl acetate / methanol). 1.32 g (17% of theory) of 1- (4-methylthiazol-2-ylamino) methanethyl, 1-diphosphonic acid tetraethyl ester are obtained in the form of a viscous oil.

Example 5: 1.97 g (4.9 mmol) of 1- (5-methyl-thiazol-2-ylamino) -methane-1,1-diphosphonic acid tetraethyl ester are heated in 20 ml of n-hydrochloric acid for 6 hours under reflux. Allow to cool and stand at room temperature whereupon the product crystallizes. It is filtered and washed with acetone and petroleum ether. Yield: 0.64 g (45% of theory) of 1- (5-methylthiazol-2-ylamino) methane-1,1-diphosphonic acid, m.p. 208 ° (dec.).

The starting material can be prepared, for example, as follows:

A mixture of 1.14 g (10 mmol) of 2-amino-5-methylthiazolo [sol, 2.0 ml (12 mmol) of orthomuric acid triethyl ester and 2.65 ml (20 mmol) of diethyl phosphite is heated 4 1/2 within 120 hours to 120-125e. The residue is purified by column chromatography (silica gel / acetic acid / ether / methanol). 1.97 g (49% of theory) of 1- (5-methyl-thiazol-2-ylamino) -methane-1,1-diphosphonic acid-tetraethyl ester are obtained in the form of a viscous oil.

24 87 653

Example 6: 4.02 g (8.7 mmol) of 1- (5-phenylthiazol-2-ylamino) methane-1,1-diphosphonic acid tetramethyl ester are heated in 30 ml of n-hydrochloric acid for 18 hours under reflux. Allow to cool to room temperature, add a small amount of methanol and filter. The filtrate is heated at reflux in methanol for 1 hour, filtered hot and washed twice with hot methanol. Yield: 2.90 g (95% of theory) of 1- (5-phenyl-thiazol-2-ylamino) -methane] -1-diphosphonic acid, m.p. 290 “(dec.).

The starting material can be prepared, for example, as follows:

A mixture of 2.93 g (16.6 mmol) of 2-amino-5-phenylthiazole, 3.3 ml (19.9 mmol) of orthomuric acid triethyl ester and 4.4 ml (33.5 mmol) of diethyl phosphite, heated first to 120 ° within 2 hours, then to 130® within 2 hours. The ethanol released is distilled off during the reaction. The product which solidifies on cooling is purified by chromatography (silica gel / ethyl acetate / methanol). 4.12 g (54% of theory) of 1- (5-phenylthiazol-2-ylamino) methane-1,1-diphosphonic acid tetraethyl ester are obtained, m.p. 151 - 153®.

Example 7: 2.5 g (5.96 mmol) of 1- (1-benzimidazol-2-ylamino) methane-1,1-diphosphonic acid tetraethyl ester are dissolved in 25 ml of 1N hydrochloric acid and heated to 100-110® over 26 hours. . During the reaction, the product precipitates in the form of a fine white precipitate. It is filtered hot and washed with water and then methanol. 0.23 g (13% of theory) of 1- (1-benzimidazol-2-yl-amino) -methane-1,1-diphosphonic acid is obtained, m.p. 265® (dec.).

The starting material can be prepared, for example, as follows: li 25 87 653 6.66 g (50 mmol) of 2-aminobenzimidazole, 10.0 ml (60 mmol) of orthomuric acid triethyl ester and 13.3 ml (101 mmol) of diethyl phosphite, mixed together and heated for 2 hours 125-130e until the ethanol no longer distills off. The residue is purified by column chromatography (silica gel / ethyl acetate / methanol, 9: 1). 2.89 g (14% of theory) of 1- (1-benzimidazol-2-ylamino) -methane-1,1-diphosphonic acid tetraethyl ester are obtained, m.p. 169 - 170 *.

Example 8: 7 g of phosphorus trichloride and 4.0 g of phosphoric acid are mixed together and heated to 60 ° for 1 hour with stirring. 6.12 g of N- (thiazol-2-yl) -formamide are added and the mixture is further heated to about 60 ° over 6 hours. 30 ml of water are then added, the mixture is filtered off with suction, washed with aqueous methanol and dried under reduced pressure. 2.0 g of 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acid are obtained, m.p. 275 * (dec.).

Example 9: 2.0 g (20.4 mmol) of crystalline orthophosphoric acid and 3.5 g (25.5 mmol) of phosphorus trichloride are stirred for 1 hour at 55-60e. 4.08 g (20.0 mmol) of N- (4-phenylthiazol-2-yl) formamide are then added. The reaction mixture is allowed to stand for about 24 hours at 60 ° C. Dilute with 10 ml of 80% phosphoric acid and allow to stand overnight at room temperature. Then reheat to 60-70 °, stir for 2 hours at 60-70 ° C, add 30 ml of water and 20 ml acetone and stir for 2 hours at 60 [deg.] C. Allow to cool to room temperature, filter off a fine, pale yellow precipitate and wash with a 3: 2 mixture of water and acetone. 180 mg (2.6% of theory) of 1- (4-phenylthiazol-2-ylamino) methane-1,1-diphosphonic acid, mp 298 * (dec.).

26 87653 The starting material can be prepared as follows: 13.22 g (75 mmol) of 2-amino-4-phenylthiazole are heated for 5 hours at 110e and with 40 ml of formic acid. Allow to cool to room temperature and pour over ice. A white precipitate forms which is filtered and washed with ice water. Crystallize from petroleum ether to give 7.01 g (45.8% of theory) of 4- (phenylthiazol-2-amino) formamide, m.p. 161-164 °.

Example 10: In a manner known per se, e.g. as shown in Examples 1-7, the following can be prepared: 1- (imidazol-2-ylamino) methane-1,1-diphosphonic acid, 1- (imidazol-4-ylamino) methane-1,1-diphosphonic acid , 1- (1-methylimidazol-2-ylamino) methane-1,1-diphosphonic acid, 1- (tetrazol-5-ylamino) methane-1,1-diphosphonic acid, 1- (oxazol-2-ylamino) methane 1,1-Diphosphonic acid, 1- (1,3,4-thiadiazol-2-ylamino) methane-1,1-diphosphonic acid, 1- (5-methyl-1,3,4-thiadiazol-2-ylamino) methane- 1,1-diphosphonic acid, m.p. 260e (dec.), 1- (3-phenyl-1,2,4-thiadiazol-5-ylamino) methane-1,1-diphosphonic acid, m.p. * 198.

Example 11: Tablets containing 50 mg of active ingredient, e.g. 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof, e.g. sodium salt, can be prepared as follows:

Ingredients (1000 tablets): active substance 50.0 g lactose 50.7 g wheat starch 7.5 g polyethylene glycol 6000 5.0 g 27 87653 talc 5.0 g magnesium stearate 1.8 g demineralized water q.s.

Preparation: All 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 together. The rest of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 100 ml of water. The resulting paste is added to the powder mixture and the mixture is granulated, adding water if necessary. The granulate is dried overnight at 35e, sieved through a sieve with a mesh size of 1.2 mm and compressed into concave tablets with a diameter of about 6 mm on both sides.

Example 12: Tablets containing 100 mg of active ingredient, e.g. 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof, e.g. sodium salt, can be prepared as follows:

Ingredients (1000 tablets): active substance 100.0 g lactose 100.0 g wheat starch 47.5 g magnesium stearate 3.0 g: Preparation: All solids are first sieved through a sieve with a mesh size of 0.6 mm. Then the active substance,. lactose, magnesium stearate and half of the starch it is mixed with each other. The rest of the starch is suspended in 40. . to 1 ml of water and this suspension is added to 100 ml of boiling water and the mixture is granulated, if necessary by adding water. The granulate is dried overnight at 35e, sieved with a sieve with a mesh size of 1.2 mm and compressed into concave tablets on both sides with a diameter of about 6 mm.

Example 13: Tablets containing 100 mg or equivalent can also be prepared as described in Examples 11 and 12. 50 mg of any of the other compounds of the formula I mentioned in Examples 1 to 10, this being also possible in the form of salts with bases, e.g. the disodium salt.

Example 14; Chewable tablets containing 75 mg of active ingredient, e.g. 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof, e.g. sodium salt, can be prepared e.g.

Composition (1000 tablets): active substance 75.0 g mannitol 230.0 g lactose 150.0 g talc 21.0 g glycine 12.5 g stearic acid 10.0 g saccharin 1.5 g 5% gelatin solution q.s.

Preparation: All solids are first sieved through a sieve with a mesh size of 0.25 mm. The mannitol and lactose are mixed, granulated by adding a gelatin solution, sieved with a sieve with a mesh size of 2 mm, dried at 50e and sieved once more with a sieve with a mesh size of 1.7 mm. The active ingredient, glycine and saccharin se-. . mix thoroughly, add mannitol, lactose granulate, stearic acid and talc, then mix thoroughly and compress both sides into concave tablets with a diameter of about 10 mm and · * with a fracture groove on the top.

li 29 87653

In a similar manner, tablets containing 75 mg of another compound of the formula I shown in Examples 1 to 10 can also be prepared, which can also take the form of salts with bases, e.g. the disodium salt.

Example 15: Tablets containing 10 mg of active ingredient, e.g. 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof, e.g. sodium salt, can be prepared as follows:

Composition (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: All 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 together. 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 ° C, sieved through a sieve with a mesh size of 1.2 mm and compressed into concave tablets with a diameter of approx.

10 mm and with a breaking groove on the upper side.

In a similar manner, tablets containing 10 mg of another compound of formula I mentioned in Examples 1-10 30 8 7 6 5 3 can also be prepared, which can also take the form of salts with bases, e.g. the disodium salt.

Example 16: Gelatin capsules containing 100 mg of active substance, e.g. 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof, e.g. sodium salt, can be prepared e.g.

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 a magnesium stearate 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 O (elongated).

Similarly, capsules can be prepared containing 100 mg of another compound of formula I according to Examples 1-10, which can also take the form of salts formed with bases, e.g. as the disodium salt.

. . Example 17: 0.2% solution for injection or infusion; can be prepared, e.g., as follows: an active ingredient, e.g. 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof, e.g.

i: 31 87653 sodium 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. For the preparation of 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 (10)

A process for the preparation of therapeutically acting heteroarylaminomethane diphosphonic acids of the formula PO 2 H 2 R 1 -N-in (I) ia tojHa and their salts, in which formula R 1 represents an unsubstituted or lower alkyl, unsubstituted or lower alkyl, and lower alkoxy / substituted phenyl, lower alkoxy, hydroxy, di-lower alkylamino, lower alkylthio and / or halogen C-substituted and / or lower alkyl, with unsubstituted or lower alkyl, lower alkoxy and / or halogen substituted phenyl lower alkyl N-substituted or members containing such as heteroatoms 2 to 4 N atoms or 1 or 2 N atoms and 10 or S atom and R 2 represents hydrogen or lower alkyl, provided that R 2 is different hydrogen when R is one optionally with alkyl and / or halogen substituted pyrazol-3-yl or isoxazol-3-yl residue, characterized in that a) in a compound of formula (II) which is optionally transiently protected in a substitutable N atom in the residue Rx, Ri ~ ϊ ~ I ~ h (ii) <in which formula Xx represents a functionally converted phosphono group X and X2 represents phosphono or also a functionally converted phosphono group X, the group (s) X is converted to free phosphono, or b) a compound of formula (III) which is optionally partially protected in a substitutable N atom in the residue Rx, R, -N-CH = 0 (III) phosphorus trioxide and then with water, and, if desired, a recovered compound is converted to another compound of formula I and / or a free compound into a site or a received salt into a free compound or other site. 2. A process as claimed in claim 1 for the preparation of heteroarylaminomethane diphosphonic acids of the formula POaHj Ri - »- έΗ (I) K * PO1H2 and their salts, in which formula Rx or halogen substituted phenyl, lower alkoxy, hydroxy, di-lower alkylamino, lower alkylthio and / or halogen mono- or disubstituted imidazolyl-, ben-simidazolyl-, 2H-1,2,3- or 4H-1,2,4-triazolyl-, tetra- zolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzthiazolyl or thiadiazolyl residue and R 2 represents hydrogen or lower alkyl, characterized in that a) in a compound of formula (II) R represents a group of the formula -CH (X1) - (X2) Ha in which Xx represents a functionally converted phosphono group X3 and X2 represents phosphono or also a functionally converted phosphono group X3, the group (s) X3 is converted to free phosphono, and , if desired, is converted to: 39 87653 a recovered compound to another compound of formula I and / or a recovered free compound to a site or a received salt to a free compound or other site. Process according to claim 1, characterized in that compounds of formula I or salts thereof are prepared in which Rx represents a C unsubstituted or lower alkyl, lower alkoxy, unsubstituted or lower alkyl, lower alkoxy and / or halogen mono- or disubstituted phenyl, hydroxy, di-lower alkylamino, lower alkylthio and / or halogen C-mono- or C-disubstituted, in the optionally substitutable N-atom unsubstituted or preferably with lower alkyl, lower alkoxy and / or haloalkoxy and / or halo phenyl lower alkyl N-monosubstituted imidazolyl, benzimidazolyl, 2H-1,2,3- or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzthiazolyl or thiadiazolyl residue and R 2 represent hydrogen or lower alkyl. Process according to claim 1, characterized in that compounds of formula I or salts thereof are prepared in which Rx represents an unsubstituted or with C 1 -C 2 alkyl or an unsubstituted or with C 1 -C 2 -. alkyl, Cx-C4 alkoxy and / or halogen mono- or disubstituted phenyl residue C-substituted thiazolyl residue, benzthiazol-2-yl residue, thiadiazolyl residue, oxazolyl residue or benzoxazol-2-yl residue and / or one having C ^-C ^ alkyl or with an unsubstituted or with Cx-C4 alkyl, Cx-C4 alkoxy and / or halogen mono- or disubstituted phenyl-Cx-C4 alkyl residue N-substituted imidazol-2-yl residue or benzimidazol-2-yl residue and R 2 represents hydrogen . Process according to claim 1, characterized in that compounds of formula I or salts thereof are prepared in which Rx represents an unsubstituted or C C-C-alkyl, C,-C C alkoxy, phenyl, hydroxy, di-C 1 -C 4 alkylamino, C 1 -C 4 alkylthio or halogen having the order of not more than 35 C-substituted thiazolyl residue, a 1-C 1 -C 4 alkylimidazol-2-yl or -4 yl residue, or a phenyl-C1-C4 alkyl-imidazol-2-yl or -4-yl residue and R 2 represents hydrogen. 6. A process according to claim 1, characterized in that compounds of formula I or salts thereof are prepared in which R 1 represents an unsubstituted or C 1 -C 4 alkyl or phenyl mono- or di-substituted thiazole. 2-yl residue, an unsubstituted or in the 1-position with C 1 -C 4 alkyl or, respectively. phenyl-C ^-C ^ alkyl monosubstituted imidazol-2-yl or benzimidazol-2-yl residue or an unsubstituted benzoxazol-2-yl or benzthiazol-2-yl residue and R 2 represents hydrogen. Process according to claim 1, characterized in that 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof is prepared. Process according to Claim 1, characterized in that 1- (methyl-1,3,4-thiadiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof is prepared, 1- ( 3-phenyl-1,2,4-thiadiazole-5-ylamino) methane-1,1-diphosphonic acid or a salt thereof, 1- (benzimidazol-2-yl-amino) methane-1,1-diphosphonic acid or a salt thereof , 1- (benzthiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof, 1- (benzoxazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof, 1- (4-methylthiazole) 2-ylamino) methane-1,1-diphosphonic acid or a salt thereof, 1- (5-methyl-thiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof, 1- (5-phenylthiazole) 2-ylamino) methane-1,1-diphosphonic acid or a salt thereof or 1- (4-phenylthiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof. II 4i 87 653 9. A process according to claim 1, characterized in that 1- (1,3,4-thiadiazol-2-yl-amino) methane-1,1-diphosphonic acid or a site thereof is prepared, 1- (1- methylimidazol-2-ylamino) methane-1,1-diphosphonic acid or a site thereof or 1- (oxazol-2-ylamino) methane-1,1-diphosphonic acid or a site thereof. Process according to Claim 1, characterized in that compounds of formula I or salts thereof are prepared in which R 2 represents an unsubstituted or with C 1 -C 2 alkyl, C 1 -C 2 alkoxy, phenyl, hydroxy, di-C ^-C ^ alkylamino, C ^-Cj alkylthio or halogen having the order of highly substituted thiazolyl residue and R 2 represents hydrogen, preferably 1- (thiazol-2-ylamino) -methane-1,1-diphosphonic acid or a site thereof, 1- (oxazol-2-ylamino) methane-1,1-diphosphonic acid or a site thereof, 1- (benzimidazol-2-ylamino) methane-1,1-diphosphonic acid or a site thereof, 1- (benzthiazole) 2-ylamino) methane-1,1-phosphonic acid or a site thereof or 1- (benzoxazol-2-ylamino) -methane-1,1-diphosphonic acid or a site thereof.