SI8810711A - Process for preparing new substituted alcandiphosphonic acids - Google Patents

Abstract

Alkandiphosphonic acids, in particular heteroarylalkandiphosphonic acids acids of formula O3H2 R1-CH2-C-R2 substituted phenyl lower alkyl, and Ffe means hydrogen, hydroxy, amino, lower alkylthio or halogen, and salts thereof have regulatory properties for calcium metabolism and they can be used as medicines for healing disorders that can be linked to disorders calcium metabolism. Let's prepare them, for example. such that v to compounds of formula O3H2 X in which R 1 represents a 5-membered heteroaryl residue, having as heteroatom (e) 2 to 4 atoms N or 1 or 2 atoms N as well as 1 atom O or S, which is unsubstituted or C-substituted with lower alkyl, unsubstituted or with lower alkyl, lower alkoxy and / or halogen substituted phenif, lower alkoxy, hydroxy, din alkylamino, lower alkylthio and / or halogen, and / or N-substituted with lower alkyl or unsubstituted or with lower alkyl, lower alkoxy and / or halogen R ^ alk-C - R. in which pomeni1 is functionally modified and Χ2 a free or functionally modified phosphone group, translate Χ1 and into a given diameter Χ2 into free phosphono group.

Description

Process for the preparation of novel substituted alkandiphosphonic acids

Field of the Invention (MPK C 07F 9/65; A 61K 31/675)

The invention is within the scope of the pharmaceutical industry and relates to a process for the preparation of novel substituted alkandiphosphonic acids, which are useful in the pharmaceutical industry as active ingredients for the preparation of medicaments for the treatment of disorders related to disorders of calcium metabolism.

A technical problem

There is an ongoing need to develop technologically advantageous processes for the preparation of novel substituted alkandiphosphonic acids which, by their advantageous pharmacological properties, will outperform compounds known in the art.

The state of the art

Substituted alkaniphosphonic acids prepared by the process of the invention are novel and have not been described so far either by themselves or by methods for their preparation.

Description of solution to a technical problem

The invention relates to a process for the preparation of novel substituted alkandiphosphonic acids, in particular heteroarylalkandiphosphonic acids of the formula

POsHz

R-CH2-C-R POjHz 'in which R represents a ₁ 5-membered heteroaryl group which has as a hetero atom (s), 2 to 4 N atoms, or 1 or 2 N atoms as well as 1 atom is 0 or S, and which is unsubstituted or C-substituted with lower alkyl, unsubstituted or lower alkyl-lower alkoxy and / or halogen substituted phenyl, lower alkoxy, hydroxy, lower alkylamino, lower alkylthio and / or halogen, and / or N-substituted with lower alkyl or unsubstituted or with lower alkyl, lower alkoxy and / or halogen substituted phenylalkyl, and R is hydrogen, hydroxy, amino, lower alkylthio or halogen, and salts thereof.

5-membered heteroaryl residues having, as heteroatom (s), 2 to 4 N atoms or 1 or 2 N atoms as well as 1 atom 0 or S, e.g. imidazolyl, e.g. imidazol-1-yl, -2-yl or -4-yl, pyrazolyl, e.g. pyrazol-1-yl or -3-yl, thiazolyl, e.g. thiazol-2yl or -4-yl or otherwise oxazolyl, e.g. oxazol-2-yl or -4-yl, isoxazolyl, e.g. isoxazol-3-yl or -4-yl, triazolyl, e.g. 1H-1,2,4-triazol-1-yl, 4H-1,2,4-triazol-3-yl or -4-yl or 2H-1,2,3-triazol-4-yl, tetrazolyl, e.g. . · Tetrazol-5-yl, thiadiazolyl, e.g. 1,2,5-thiadiazol-3-yl, and oxadiazolyl, e.g. 1,3,4oxadiazol-2-yl. Said residues may have one or more identical or different, in particular one or two, identical or different substituents listed above. The residues R ^ which are optionally substituted as indicated are e.g. imidazole-2- or -4-yl residues which are unsubstituted or C-substituted on the phenyl moiety unsubstituted or as substituted phenyl as above; C- or N-substituted with C 1 -C 4 -alkyl, such as methyl, e.g. imidazol-2-yl, 1-C 1 -C 4 -alkyl-, such as 1-methylimidazol-2-yl or 2- or 5-C 1 -C 4 -alkyl 1-, such as 2- or 5-methylimidazol-4- il, unsubstituted thiazolyl residues, e.g. thiazol-2-yl, or unsubstituted or with C ₁ -C 1 -alkyl, such as methyl, substituted 1 H-1,2,4-triazolyl residues, e.g. 1-C 1 -C 4 -alkyl-, such as 1-methyl-1H-1,2,4-triazol5-yl, or unsubstituted or unsubstituted or unsubstituted or phenyl substituted or unsubstituted moieties. with C 1 -C 4 -alkyl, such as methyl, C-substituted imidazol-1-yl, pyrazol-1-yl,

1H-1,2,4-triazol-1-yl, 4H-1,2,4-triazol-4-yl or tetrazol1-yl residues, e.g. imidazol-1-yl, 2-, 4- or 5-C ₁ -C 4 -alkyl-, such as 2-, 4- or 5-methylimidazol-1-yl, pyrazol-1-yl, 3- or 4C 4 - C1-4-alkyl- such as 3- or 4-methylpyrazol-1-yl, 1H-1,2,4-tetrazol-1-yl, 3-C1-C4-alkyl-, such as 3-methyl-1H -1,2,4-triazol-1-yl,

4H-1,2,4-triazol-1-yl, 3-C 1 -C 4 -alkyl-, such as 3-methyl-4H-1,2,4-triazol-4-yl or 1H-1,2,4-tetrazole -1-il.

The following are meant by lower residues and compounds e.g. those having up to and including 7, especially up to and including 4 carbon atoms. Further, they have general notions e.g. the following mentions:

Lower alkyl is e.g. C 1 -C 4 -alkyl, such as methyl, ethyl, propyl or butyl, is further iso-, secondary or tertiary butyl, and may also be C 1 -C 4 -alkyl, such as a pentyl, hexyl or heptyl group.

The phenylalkyl is e.g. phenyl-, in particular 1-phenylC1-6-alkyl, such as benzyl.

The lower alkoxy is e.g. C 1 -C 4 -alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, secondary butyloxy or tertiary butyloxy.

The dicycloalkylamino is e.g. di-C 1 -C 4 -alkylamino, such as dimethyl amino, diethylamino, N-ethyl-N-methyl-amino, dipropylamino, N-methylN-propylamino or dibutylamino.

Lower alkylthio is e.g. C 1 -C 4 -alkylthio, such as methylthio, ethylthio, propylthio or butylthio, further iso-, secondary or tertiary butylthio.

Halogen is e.g. halogen having an atomic number up to and with 35, such as fluorine, chlorine or bromine.

The salts of the compounds of formula I are, in particular, their salts with pharmaceutically useful bases, such as non-toxic metals of groups Ia, Ib, Ha and Ilb, derived metal salts, e.g. alkali metal salts, in particular sodium or potassium salts, alkaline earth metals, in particular calcium or magnesium salts, copper, aluminum or zinc salts, as well as ammonium salts with ammonia or organic amines or quaternary ammonium bases, as in the present case C-hydroxylated aliphatic amines, in particular mono-, di- or tri-alkylamines, e.g. methyl-, ethyl-, dimethyl- or diethylamine, mono-, di- or tri- (hydroxybenzyl) -amines, such as ethanol-, diethanol- or triethanolamine, tris (hydroxymethyl) amino-methane or 2-hydroxyterb.butylaminor, or N -N, N-nitroalkylamines, resp. N- (polyhydroxynitalkyl) -Nylalkylamines, such as 2- (dimethylamino) -ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, e.g.

with tetrabutylammonium hydroxide.

In this connection, it should also be noted that the compounds of formula I may occur in the form of internal salts, provided that the R ₁ group is sufficiently basic. These compounds can then be converted to the corresponding addition salts also by treatment with a strong protic acid, such as hydrochloric acid, sulfuric acid, sulfonic acid, e.g. methane or p-toluenesulfonic acid, or sulfamic acid, e.g. N-cyclohexylsulfaric acid.

The compounds of formula I and their salts have valuable pharmacological properties. In particular, they have a pronounced regulatory effect on calcium metabolism in warm-blooded creatures. In particular, the rat results in marked inhibition of bone resorption, which can be demonstrated both in the experimental distribution of Acta Endocrinol. 7_8, 613-24 (1975 'with PTH induced increase in serum calcium after subcutaneous administration at doses from about 0.01 to about 1.0 mg / kg, as well as in the Th (Thyroparathyroidectomised) rat model with experimental hypercalculus, Vitamin induced after administration of doses of about 0.0003 to 1.0 mg sc Also inhibited after oral administration of about 1.0 to about 100 mg / kg tumor hypercalcemia induced by Walker's 256 tumors. distribution according to Nevbould, Brit. J. Pharmacology 21, 127 (1963) as well as after Kaibara et al., J. Exp. Med.

159, 1388-96 (1984) at doses of about 0.001 to 1.0 mg / kg sc distinct inhibition of the progression of chronically arthritic processes. Therefore, they are ideally suited as active ingredients for treating diseases that can be linked to disorders of calcium metabolism, e.g. inflammatory processes in the joints, degenerative processes in the articular cartilage, osteoporosis, periodontitis, hyperparathyroidism, and calcium deposits in the veins or on prosthetic implants. They have a beneficial effect on diseases in which we detect anomalous accumulation of difficultly soluble calcium salts, as well as those from the forms of arthritis, e.g. Morbus Bechterew, neuritis, bursitis, periodontitis and tendinitis fibrodisplazij _a, osteoarthroses _a or artereo6 sclerosis, as well as to those, P ^ri which is at the heart of anomal decomposition of hard body tissue, such as hereditary hipofosfatazija, regenerative processes in articular cartilage, osteoporosis of different origin, , Paget raorbus, and <feteod fibroid istrophy, also tumor-triggered osteolytic processes.

The invention 'relates primarily to the preparation of compounds of formula I. in which R1 is imidazolyl, pyrazolyl, 2H-1,2,3-, 1H-1,2,4 or 4H-1,2,4-triazolyl, tetrazolyl , an oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl radical which is unsubstituted or C-mono- or substituted with lower alkyl, lower alkoxy, unsubstituted or lower alkyl, lower alkoxy and / or halogen mono- or disubstituted hydroxy alkylamino, lower alkylthio and / or halogen, and / or Nsubstituted at the N atom which can be substituted, with lower alkyl or phenyl lower alkyl, which is unsubstituted or mono- or disubstituted with lower alkyl, lower alkoxy and / or halogen, and R ₂ represents hydrogen, hydroxy, amino, lower alkylthio or halogen, and their salts, especially their internal salts and pharmaceutically useful salts with bases.

The invention relates primarily to the preparation of e.g. a compound of formula I wherein R _{1 is an} imidazolyl, pyrazolyl, 2H-1,2,3- or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl moiety which is unsubstituted or C-mono or substituted with lower alkyl, lower alkoxy, unsubstituted or lower alkyl, lower alkoxy and / or halogen mono- or disubstituted phenyl, hydroxy, lower alkylamino, lower alkylthio and / or halogen, and / or

N-substituted at the substituent N atom with lower alkyl or phenyl alkyl, which is unsubstituted or mono- or disubstituted by lower alkyl, lower alkoxy and / or

J is halogen, and R ₂ is hydrogen, hydroxy, amino, lower alkylthio or halogen, and salts thereof, especially their internal salts and pharmaceutically useful salts with bases.

The invention relates in particular to the preparation of compounds of formula I, in which R1 is imidazolyl, such as imidazol-1-yl, -2-yl or villous residue, 4H-1,2,4-triazolyl, such as 4H-1,2, A 4-triazol-4-yl residue or thiazolyl, such as a thiazol-2-yl residue, which is unsubstituted or C-mono or substituted with C 1 -C ₄ -alkyl _? such as methyl, C 1 -C 1 -alkoxy, such as methoxy, phenyl, hydroxy, di-C 1 -C 4 -alkylamino, such as dimethylamino or diethylamino, C 1 -C 4 -alkylthio, such as methylthio, and / or halogen with atomic numbers up to and including 35, such as chlorine, and / or N-substituted at the substituent N atom, with C1-C4-alkyl, such as methyl, or phenyl-C1-C4-alkyl, such as benzyl, and R ₂ means, in particular, hydroxy and, in the second instance, hydrogen or amino, and salts thereof, in particular their internal salts and pharmaceutically useful salts and bases.

The invention preferably relates, on the one hand, to the preparation of compounds of formula I in which R1 is unsubstituted or phenyl Csubstituted or. with a C1-C4-alkyl, such as methyl, a C- or N-substituted imidazol-2- or-4-yl residue, e.g. imidazol-2-yl, 1-C 1 -C 4 -alkyl-1 such as 1-methylimidazo-1-yl or 2- or 5-C 1 -C 4 -alkyl-; as 2 or 5-methylimidazol-4-yl, an unsubstituted thiazolyl residue, e.g. thiazol-2-yl, or unsubstituted or with C 1 -C 4 -alkyl, such as methyl, an unsubstituted 1 H-1,2,4-triazolyl residue, e.g. 1-C 1 -C 4 -alkyl, such as 1-methyl-1 H-1,2,4-triazol-5-yl, and R ₂ P 0 is ^{considered to be} hydroxy or other hydrogen, and their salts, in particular pharmaceutically usable salts.

The invention preferably relates, on the other hand, to the preparation of compounds of formula I in which R1 is unsubstituted or phenyl or. with C 1 -C 4 -alkyl, such as methyl, C-substituted imidazol-1-yl, pyrazol-1-yl, 1H-1,2,4-triazol-1-yl, 4H-1,2,4-triazole -4-yl or tetrazol-1-yl residue, e.g. imidazol-1-yl, 2-, 4- or 5-C 1 -C 4 -alkyl-, such as 2-, 4- or 5-methylimidazol-1-yl, pyrazol-1yl, 3- or 4-C 1 -C 4 -alkyl -, such as 3- or 4-methylpyrazol-1-yl ',

1H-1,2,4-tetrazol-1-yl, 3-C 1 -C 4 -alkyl, such as 3-methyl-1H-1,2,4-triazol-1-yl, 4H-1,2,4 -triazole _T 1-yl, 3-C 1 -C 6 -alkyl-, such as 3-methyl-4H1,2,4-triazol-4-yl or 1H-tetrazol-1-yl, and R ₂ is hydroxy or in another the type of hydrogen, and salts thereof, in particular pharmaceutically acceptable salts.

The invention relates primarily to the preparation of compounds of formula I in which R1 is unsubstituted or C1-C4-alkyl, such as methyl, substituted imidazolyl residue, such as imidazol-1-yl, imidazol-2-yl, 1 -raethylimidazol-2-yl, imidazol-4-yl or 2- or

5-methylimidazol-4-yl and R ₂ denotes hydroxy or otherwise hydrogen and their salts, in particular pharmaceutically useful salts.

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

The process of the invention for the preparation of compounds of formula I and their salts is characterized in that

in a compound of formula (II) in which a functionally modified and X1 is a free or functionally modified phosphone group, X1 is converted, and optionally Xg, into a free phosphone group, and optionally the resulting compound is converted to another compound of formula I and / or the resulting free compound is converted into a salt or the resulting salt into a free compound or another salt.

Functionally modified phosphono groups to be converted to phosphono are located e.g. in the form of an ester, especially in the form of a diester of the formula

-P (= O) (OR) 2 (IV), in which OR is e.g. lower alkoxy or optionally lower alkyl, lower alkoxy, halogen, trifluoromethyl and / or hydroxy substituted phenyloxy.

The conversion of a functionally converted to a free phosphonic group is carried out in the usual way by hydrolysis, e.g. in the presence of a mineral acid such as hydrobromic, hydrochloric or sulfuric f

acid, or by metabolising with trinylalkyl halogenosilane, e.g. with trimethylchlorosilane, in the presence of sodium iodide or in particular trimethylodosilane or trimethylbromosilane, preferably under refrigeration, e.g. in the temperature range from about 0 ° to about 25 ° C.

The starting materials of the formula II in which it is hydroxy or amino can be prepared e.g. so that the compound of formula

R ₁ - CH ₂ - COOH (Ha) or preferably its nitrile or acid chloride is reacted with the corresponding phosphoric acid triester of formula P (OR) g (11b) in which R is e.g. lower alkyl, in the presence of trinylalkylamine, e.g. triethylamine, into an intermediate, supposedly into a compound of formula

SR

- OR (Ilc; Rye oxo, imino) and this is further digested with the phosphoric acid diester. With the formula HP (= 0) (OR) ₂ (Ud) or. P (OH) (OR) ₂ (Ile) in which R is e.g. lower alkyl, in the presence of dinylalkylamine, e.g. diethylamine or lower alkali metal alkanoate, e.g. of sodium methanolate, to the corresponding compound of formula

Ri

(ilf; r ' ₂ ' - hydroxy, amino)

The compounds of Il are obtained e.g. so that the corresponding compound of formula

Rl - CH ₃ (lilac), translated with a strong base, e.g. with one of the metal bases mentioned in Embodiment a) of the process, into the carbenate salt and reacted with carbon dioxide, or by converting a compound of formula wherein Y is reactive ester hydroxy, in particular halogen, such as bromine, with an alkali metal cyanide , e.g. with sodium or potassium cyanide, to the corresponding nitrile (lig; Y = CN) and hydrolyzed to the acid, especially under basic conditions.

Starting materials II, in which R _{2 is} hydrogen, are obtained e.g. so that the compound of formula

Rj-CHj-Υ (Ug> in which Y is a reactive ester hydroxy, in particular halogen such as bromine, in the presence of a metal base such as a hydride, amide or hydrocarbon compound of an alkali metal, eg sodium hydride, sodium amide, ditrimethylsilyl sodium amide or butyllithium, · is reacted with a methandiphosphonic acid ester, e.g.

OR

O = P-OR t ^H 2 (Uh)

O = P-OR

OR in which R is e.g. lower alkyl.

A starting material of formula II in which the residue R 1 is attached via an N atom and R ₂ stands for hydrogen or hydroxy can also be prepared by the corresponding compound of formula

Ri-H. (or) in the presence of a strong metal base, such as an alkali metal hydride or a zera-alkali metal, e.g. sodium hydride is reacted with a compound of formula

in which, and X _{2 is,} in particular, the groups of formula IV.

Compounds II in which R _{2 is} lower alkylthio or halogen can be prepared e.g. from the corresponding compounds II in which R ₂ represents hydrogen, such that with a strong base, e.g. one of the metal bases listed above _? is converted to the carbeneate salt and further metabolized by a lower alkylthio carrier, e.g. with dinylalkyl disulfide or lower alkanesulfenyl chloride, or by halogen carriers, e.g. by halogen, e.g. chlorine or bromine, perchloric acid fluoride (FCIO ^) or the like.

Conventional N protecting groups and processes for introducing and cleaving them, e.g. tertiary alkoxymethyl groups, such as dimethoxyraeti1 'which can be cleaved by acid treatment,

2.2.2- trihalogen-, such as 2,2,2-triiodo-, 2,2,2-tribromo- or

2.2.2- Trichloroethoxycarbonyl residues which may be e.g. is cleaved by treatment with zinc in acetic acid, «. -phenylalkyloxycarbonyl residues, such as carbobenzoxy or trityl, which may e.g. is cleaved by catalytic hydrogenation as well as lower alkanesulfonyl groups, such as methanesulfonyl, which can be e.g. is cleaved by treatment with bis (2-methoxyethoxy) sodium aluminum hydride and also by -phenylalkyl or alkyl groups, the cleavage of which is treated below.

In the sense of the process, the compounds of formula I obtained in a manner known per se can be converted into other compounds of formula I. '

Thus, e.g. a compound of formula I in which the amino is converted by treatment with a hydrochloric acid to the corresponding compounds I in which R 1 is hydroxy. Treatment with hydrochloric acid is carried out in the usual manner upon its release in an aqueous solution of one of its salts, e.g. from sodium nitrite, by treatment with acid, e.g. hydrochloric acid effect, forming an intermediate correspondingly unstable diazonium salt, e.g. diazonium chloride which cleaves upon introduction of the ος-hydroxy group nitrogen.

Further, in compounds of formula I in which the residue R.j is N-substituted with lower alkyl or unsubstituted or lower alkyl, lower alkoxy and / or halogen substituted phenylalkyl, the N-substituent is cleaved, lower alkyl e.g. by treatment with a halogenic formic ester such as the lower alkyl ester of bromo- or chloroformic acid, followed by hydrolysis of the resulting carbamate and <x-phenyl-lower alkyl residues, e.g. by hydrogenolysis, e.g. treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on charcoal and / or platinum oxide or by metal reduction, e.g. by treatment with alkali metal in ammonia.)

The resulting free compounds of formula I, including their internal salts of formula I, can be partially or completely neutralized with one of the bases mentioned above. In an analogous manner, acid addition salts can also be converted to the corresponding free compounds. their internal salts.

Conversely, the free compounds of formula I can be converted to acid addition salts of formula I * ¹ by treatment with one of the proton acids initially mentioned.

The resulting salts can be converted in their own way into free compounds, e.g. by treatment with an acid reagent, such as mineral * acid, or. base, e.g. alkali alkali.

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

Due to the close connection between the new compounds in the free form and in the form of their salts, the corresponding salts and / or the corresponding salts or the corresponding salts are reasonably and appropriately considered above and below with the free compounds or their salts. free compounds.

The invention also relates to those embodiments of the process whereby we derive from compounds which can be obtained at any stage of the process as an intermediate and carry out the missing steps or use a starting material in the form of a salt and / or racemate or. antipodes or, in particular, formed under reaction conditions.

In the process of the present invention, such starting materials are preferably used which lead to compounds which were initially designated as particularly valuable. New starting materials and processes for their preparation also form the object of the invention.

The pharmaceutical compositions of the invention containing the compounds of formula I or their pharmaceutically usable salts are enteral, oral or rectal, and parenteral administration containing the pharmacological active ingredient alone or together with a pharmaceutically useful carrier material.

New pharmaceutical preparations include e.g. from about 10% to about 80%, preferably from about 20% to about 60% of the active ingredient. The pharmaceutical compositions according to the invention for enteral or parenteral administration are e.g. such as dosage units such as dragees, tablets, capsules or suppositories, further ampoules. These are prepared in a manner known per se, e.g. by conventional blending, granulating, irritating, dissolving or lyophilizing processes. Thus, pharmaceutical preparations for oral administration can be obtained by effectively combining them with solid carriers, granulating the resulting mixture as appropriate, and granulating the mixture, respectively. the granulate, if desired or as required, is converted into tablets or cores for more expensive after addition of suitable excipients.

Suitable carriers are in particular fillers such as sugars, e.g. lactose, sucrose, mannitol or sorbitol, cellulosic preparations and / or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch adhesive, using e.g. maize, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose and / or-polyvinylpyrrolidone, and / or, if desired, disintegrating agents such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, agar, agar, its 30I, as sodium alginate. Auxiliaries are primarily fluid and lubricant regulators, e.g. silica, talc, stearic acid or its salts, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable gastric juice-resistant coatings, optionally using concentrated sugar solutions containing optionally gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable lacquers. solvents or mixtures of solvents or for the preparation of a solution of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, for the treatment of gastric juice. Dyes or coatings for dragees may be added to dyes or pigments, e.g. to identify or label different doses of the active substance.

Further, orally useful pharmaceutical preparations are gelatin capsule capsules as well as soft, closed gelatin and plasticizer capsules, such as glycerin or sorbitol. The capsule plugs may contain a granulate active ingredient, e.g. in admixture with fillers such as lactose, binders, starches, and / or glidants, 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, and stabilizers may also be added.

For rectally useful pharmaceutical compositions, e.g. optionally suppositories consisting of a combination of the active ingredient with a bulk weight for suppositories. As a basic ma3a for suppositories, e.g. natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules containing a combination of the active ingredient with a base weight may also be used; Liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons are considered to be the substances of basic weight.

For parenteral administration, aqueous solutions of the active substance in water soluble form, e.g. water soluble salts, further suspensions of the active ingredient, such as suitable oily injection suspensions, using suitable lipophilic solvents or solvents such as fatty oils, e.g. sesame oil or synthetic fatty acid esters, e.g. ethyl oleate, or triglycerides, or aqueous injectable suspensions containing viscosity enhancers, e.g. sodium carboxymethylcellulose, sorbitol and / or dextran and optionally stabilizers.

The compounds of formula I and their salts are preferably used for the treatment of inflammation, primarily diseases, κί can be attributed to disorders of calcium metabolism, e.g. from the range of rheumatic forms, and in particular osteoporosis.

Doses below 0.001 mg / kg body weight have only a minor effect on the pathological entrapment. decomposition of hard tissues. Long-term toxic side effects may occur at doses above 100 mg / kg body weight. The compounds of formula I and their salts may be administered either orally or as a hypertonic solution subcutaneously, intra * muscularly or intravenously. Preferred daily doses for these uses are in the range of about 0.1 to 5 mg / kg for oral administration, in the subcutaneous and intramuscular administration in the range of about 0.1 to 1 mg / kg, and in the intravenous administration in the range of about 0, 01 to 2 mg / kg.

The dosage of the compounds used is variable, depending on the circumstances, such as the type and severity of the disease, the duration of treatment and the particular compound. Individual doses contain e.g. from 0.01 to 10 mg, dosage unit forms for parenteral administration, such as intravenous administration, e.g. from 0.01 to 0.1 mg, preferably 0.02 to 0.08 mg, oral dosage unit forms e.g. from 0.2 to 2.5 mg, preferably 0.3 to 1.5 mg / kg body weight. The preferred single dose is 10 to 100 mg for oral administration and 0.5 to 5 mg for intravenous administration. However, up to 4 single doses can be given daily. Higher doses for oral administration are required because of limited resorption. With longer treatments, after an initial larger dosage, we can normally switch to smaller dosages to maintain the desired effect.

The following examples illustrate the invention described above, but do not in any way limit its scope. Temperatures are given in degrees Celsius.

- 20 EXAMPLE 1

Methaniphosphonic acid tetraethyl ester of 14.8 g (0.051 mol) was added dropwise to a suspension of 2.4 g of sodium hydride in 35 ml of absolute tetrahydrofuran and stirred at room temperature until gas evolution was complete. Then 11.3 g (0.0465 mol) were added in portions.

1- Benzyl-2-chloromethylimidazole hydrochloride. The reaction mixture was heated for 20 hours between stirring and reflux until boiling. It is then filtered off from the recovered sodium chloride and the filtrate is evaporated under reduced pressure. (1-Benzyl-ylidazol-2-yl-ethyl) methane-diphosphonic acid crude tetraethyl ester is obtained. 3.0 g (0.065 mol) of tetraethyl ester

2- (1-Benzylimidazol-2-yl) ethane-1,1-diphosphonic acid was heated with 12 ml of 36% hydrochloric acid under reflux for 20 hours until boiling. After evaporation and crystallization of the residue from aqueous methanol, 2- (1-benzylimidazol-2-yl) ethane-1,1-diphosphonic acid monohydrate is obtained, m.p. 181 to 183 °.

EXAMPLE 2

Analogous to Example 1 is obtained from 1-methyl-2-chloromethylimidazole hydrochloride,

1- methyl-5-chloromethyl-1H-1,2,4-triazole hydrochloride and

2- Chloromethylthiazole hydrochloride by conversion to the corresponding ethanediphosphonic acid tetraethyl esters followed by cleavage of the esters with trimethylbromosilane as described

2- (1-Rethylimidazol-2-yl) ethane-1,1-diphosphonic acid, m.p.

295 ° (dec.).,

2- (1-Methyl-1H-1,2,4-triazol-5-yl) ethane-1,1-diphosphonic acid, m.p. 274-275 ° C,

2- (Thiazol-2-yl) ethane-1,1-diphosphonic acid, m.p. 259 ° (dec.).

The starting material 1-methyl-5-chloromethyl 1 H-1,2,4-triazole hydrochloride can be prepared as follows:

11.1 g (0.10 mol) of 5-hydroxymethyl-1-methyl-1H-1,2,4triazole were dissolved in 25 ml of dichloromethane. While cooling with ice and stirring, 29.7 g of thionyl chloride are added dropwise. It is then stirred for 1 hour at room temperature and then at reflux for 20 minutes. The resulting precipitate was filtered off with suction, washed with diethyl ether and dried in vacuo. Tal. 136 to 137 ° C.

EXAMPLE 3

2- (1-Benzylimidazol2-yl) ethane-1,1-diphosphonic acid 3.3 g (0.0072 mol) tetraethyl ester was dissolved in 50 ml of liquid ammonia and 1.0 g of sodium in small pieces was gradually added while stirring until blue. the solution does not persist for a long time. 2.35 g of ammonium chloride are then added in portions. Now allow the ammonia to evaporate, the residue is taken up with diethyl ether, filtered and the filtrate evaporated. 2- (imidazol-2-yl) ethane-1,1-diphosphonic acid tetraethyl ester is thus obtained as a colorless oil.

2.3 g (0.0062 mol) of 2- (imidazol-2-yl) ethane-1,1-diphosphonic acid tetraethyl ester were dissolved in 20 ml of methylene chloride, added

4.8 ml of trimethylbromosilane and allowed to stand at room temperature for hours. It is then evaporated under reduced pressure and 10 ml of methanol and 1 ml of water are added to the residue. 2- (imidazol-2-yl) ethane-1,1-diphosphonic acid is obtained, m.p. 279 to 282 ° (dec.).

EXAMPLE 4

By the conversion of 1-methylimidazol-2-ylmethyl bromide, benzylimidazol-2-ylmethyl chloride, (imidazol-1-methyl) -toluenesulfonic acid ester, imidazol-4-ylmethylchloride or ethazolidinosulfonylmethane hydrophosphinamidosulfonamide analogy to example 1 or 3, we can further prepare:

2- (imidazol-1-yl) ethane-1,1-diphosphonic acid, m.p. 255 ° (dec.);

2- (imidazol-4-yl) ethane-1,1-diphosphonic acid and their salts, e.g. disodium salts.

EXAMPLE 5

Analogous to Example 2 is obtained from 2- (pyrazol-1-yl) ethane-1,1-diphosphonic acid tetraethyl ester, respectively. 2- (imidazol-1-yl) ethane-1,1-diphosphonic acid tetraethyl ester by treatment with trimethylbromsilane and treatment with aqueous methanol 2- (pyrazol-1-yl) ethane-1,1-diphosphonic acid, m.p. 227 ° (dec.), And

2- (imidazol-1-yl) ethane-1,1-diphosphonic acid, m.p. 255 ° (dec.)

The starting esters can be prepared e.g. as follows: Suspend 0.10 g of sodium hydride in 4.0 ml of absolute tetrahydrofuran. A solution of 0.27 g of pyrazole (0.04 mol) in 2.0 ml of tetrahydrofuran is slowly added dropwise. To the resulting clear reaction solution was added 1.2 g of vinylidenediphosphonic acid tetraethyl ester and kept at room temperature for 24 hours. 2 ml of 2-n-ethanol hydrochloric acid are then added. The extracted sodium chloride was filtered off and the filtrate was evaporated.

EXAMPLE 6

By metabolizing the (imidazol-1-yl-methyl) p-toluenesulfonic acid ester with the methaniphosphonic acid tetraethyl ester and hydrolyzing the primary ethanediphosphonic acid ester in analogy to Example 5, 2- (imidazol-1-yl) ethane 1,1-diphosphonic acid can be further prepared. , tal. 255 ° C (dec.) And its salts, e.g. its disodium salt.

EXAMPLE 7

In an analogous manner as described in Examples 1 to 6, it can be further prepared

2- (2-methylidazol-4 (5) -yl) ethane-1,1-diphosphonic acid; 2- (2-Phenylimidazol-4 (5) -yl) ethane-1,1-diphosphonic acid; 2- (2-Methylimidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid, m.p. 245-246 °,

2- (imidazol-4-yl) -1-hydroxy-ethane-1,1-diphosphonic acid, m.p. 238-40 ° (dec.);

1- amino-2- (1-benzylimidazol-2-yl) -ethan-1,1-diphosphonic acid;

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

1- amino-2- (1-methylimidazol-4-yl) -ethan-1,1-diphosphonic acid;

2- (1-Methylimidazol-2-yl) -1-hydroxy-ethane-1,1-diphosphonic acid monohydrate, m.p. 261 ° (dec);

2- [4 (5) -methylimidazol-5 (4) -yl] -1-hydroxy-ethane-1,1-diphosphonic acid, m.p. 217-8 ° (dec.);

2- (1-Benzylimidazol-2-yl) -1-hydroxy-ethane-1,1-diphosphonic acid, m.p. 171 ° (dec);

2- (imidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid, m.p. 239 ° (dec);

2- (1H-1,2,4-triazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid, m.p. 255 ° (dec.);

2- (pyrazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid, m.p. 234 °;

2- (pyrazol-3-yl) -1-hydroxy-ethane-1,1-diphosphonic acid; 2- (4H-1,2,4-triazol-4-yl) -1-hydroxy-ethane-1,1-diphosphonic acid;

2- (2-methylimidazol-4 (5) -yl) -1-hydroxy-ethane-1,1-diphosphonic acid, m.p. 261-2 ° (dec.);

2- (2-Phenylimidazol-4 (5) -yl) -1-hydroxy-ethane-1,1-diphosphonic acid, m.p. 223-4 ° (dec);

2- (4,5-dimethylimidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid, m.p. 233-4 ° (dec.).

EXAMPLE 8

3.4 g (0.0094 mol) of 2- (1-benzylimidazol-2-yl) -1-hydroxy-ethanediphosphonic acid are dissolved in 40 ml of liquid ammonia and gradually added while stirring 1.0 g of sodium in small pieces until blue does not retain the solution for a long time. 2.35 g of ammonium chloride are then added in portions. The ammonia was then allowed to evaporate, the residue was taken up with 20 ml of hot water, filtered and 10 ml of concentrated hydrochloric acid was added to the filtrate. The separated crystals were filtered and recrystallized from aqueous methanol. 2- (imidazol-2-yl) -1-hydroxyethanediphosphonic acid is thus obtained, m.p. 235 ° (dec.).

EXAMPLE 9

3.59 g (0.01 mol) of 1-amino-2- (1-benzylimidazol-2-yl) ethane-1,1-diphosphonic acid are dissolved in 20 ml of 1-n sodium hydroxide, 0.82 g of sodium nitrite is added and cool to 0 °. Then, 18 ml of 2-n hydrochloric acid are added slowly while stirring. The mixture was then stirred for another hour at 0-10 ° and the product was filtered off. Recrystallization from water afforded 2- (1-benzylimidazol-2-yl) -1-hydroxy-ethane-1,1-diphosphonic acid, m.p. 171 ° (dec.).

EXAMPLE 10

11.95 g of 2-phenylimidazol-4-yl-acetic acid hydrochloride is heated while stirring and refluxing with 7.1 ml of 85% phosphoric acid and 25 ml of chlorobenzene at 100 °. Subsequently, 13.9 ml of phosphorus trichloride were added dropwise at 100 °, developing gas. The reaction mixture was eliminated in a dense mass for 30 minutes. Heat for another 3 hours at 100 ° C and decant the supernatant chlorobenzene. The remaining bulk is heated under stirring and reflux to boiling with 40 ml of 9-n hydrochloric acid for 3 hours. It is filtered hot with the addition of charcoal and the filtrate is diluted with acetone, eliminating crude 2- (2-phenylimidazol-4-yl) -1hydroxy-ethane-1,1-diphosphonic acid. This is recrystallized from water, m.p. 238-240 ° (dec.).

EXAMPLE 11

3.36 g of 2- (2-phenylimidazol-4-yl) -1-hydroxy-ethane-1,1-diphosphonic acid sesquihydrate are suspended in 10 ml of water and 10 ral of 2n sodium hydroxide solution is added dropwise while stirring. The resulting solution was evaporated and the syrup residue was mixed with 40 ml of methanol. The crystalline precipitate was filtered off and dried. Disodium 2- (2-phenylimidazol-4-yl) -1-hydroxyethane-1,1-diphosphonate dihydrate is obtained from m.p. 281-283 ° (dec.).

EXAMPLE 12

In the analogous manner as described in Examples 10 and 11, 2-methylimidazol-4-ii acetic saliva and 2- (2-methylimidazol-4-yl) -1-hydroxy-ethane 1,1-diphosphonic hydrochloride can be prepared acid from the soil. 261-262 ° (dec.) Disodium 2 (2-methylimidazol-4-yl) -1-hydroxy-ethane-1,1-diphosphonate monohydrate, m.p. 292-295 ° (dec.).

EXAMPLE 13

In the analogous manner as described in Examples 10 and 11, disodium 2- (2-methylimidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonate dihydrate, m.p. 295-297 ° (dec.);

Disodium 2- (4,5-dimethylimidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonate monohydrate, m.p. 286-290 ° (dec.); disodium 2- (imidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonate dihydrate, m.p. 291-293 ° (dec.);

disodium 2- (pyrazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonate monohydrate, m.p. > 300 ° (dec.).

EXAMPLE 14

0.141 g of 2- (imidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid are dissolved in 1 ml of water and a solution of 0,121 g of tris (hydroxymethyl) methylamine in 2 ml of water is added. Evaporate under reduced pressure to dryness, take in 6 ml of warm methanol and cool to crystallization. The white precipitate was filtered off with suction and dried for 80 hours under reduced pressure. Mono-tris (hydroxymethyl) methylammonium 2- (imidazol-1-yl) -1-hydroxyethane-1,1-diphosphonate was obtained from m.p. 170-175 ° C.

EXAMPLE 15

In the analogous manner as described in Example 14, di-tris (hydroxymethyl) methylammonium 2- {imidazol-4-yl) -1-hydroxy-ethane-1,1-diphosphonate was obtained from m.p. 116-119 ° (dec.);

di-tris (hydroxymethyl) methylammonium 2- (4,5-dimethylimidazol-1 yl) -1-hydroxy-ethane-1,1-diphosphonate monohydrate m.p. 110-113 ° (dec.) And di-tris (hydroxymethyl) methylammonium 2- (5-methylimidazol-4-yl) -1 hydroxy-ethane-1,1-diphosphonate from m.p. 122-126 ° (dec.).

EXAMPLE 16

In the analogous manner as described in Examples 10 to 15, 2- (1-benzylimidazol-1-yl) ethane 1,1,1-diphosphonic acid disodium 2- (1-benzylimidazol-2-yl) ethane-1,1 can be prepared from the monohydrate - diphosphonate dihydrate from the ground. > 300 °.

EXAMPLE 17

In the analogous manner as described in Examples 10 to 15, disodium 2- (pyrazol-1-yl) ethane-1,1-diphosphonate monohydrate, m.p. > 300 °.

EXAMPLE 18

Tablets containing 100 mg of active substance, e.g. 2 (imidazol-4-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or its salts, e.g. disodium salts can be prepared as follows:

Ingredients (per 1000 tablets) active ingredient 100.0 g lactose 100.0 g wheat starch 47.0 g magnesium stearate 3.0 g

Preparation: First, press all the solids through a sieve with a width of 0.6 mm. Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are mixed. The other half • of the starch is suspended in 40 ml of water and this suspension is added to the boiling solution of polyethylene glycol in 100 ml of water and the mixture is granulated if necessary with the addition of water. Dry the granulate overnight at 35 °, squeeze through a sieve with a mesh width of 1.2 mm and squeeze into concave concave tablets of about 2 mm diameter.

mm.

Tablets may also be prepared in an analogous manner, each containing 100 mg of one of the other compounds of formula I in Examples 1 to 17, which may also be present in the form of salts and bases, e.g. as the sodium salt.

EXAMPLE 19

Chewable tablets containing 75 mg of active substance, e.g. 2- (imidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or its salts, e.g. disodium salts can be prepared e.g. likewise:

Composition: (for 1000 tablets) active ingredient '75, 0 g mannitol 230.0 g lactose 100.0 g talcum 21.0 g glycine 12.5 g stearic acid 10.0 g saccharin 1.5 g% gelatin solution q .s'.

Preparation: All solids are first pressed through a sieve with a loop width of 0.25 mm. Mannitol and lactose are mixed, with the addition of the gelatin solution, granulated, pressed through a sieve with a loop width of 2 mm, dried at 50 ° and again pressed through a sieve with a loop width of 1.7 mm. The active substance, glycine and saccharin are carefully mixed, mannitol, lactose granulate, stearic acid and talc are added, all thoroughly mixed and pressed into both concave tablets of about 10 mm diameter with a split notch.

Chewing tablets can also be prepared in an analogous manner, each containing 75 mg of the other compound of formula I in Examples 1 to 17, which may also be in the form of salts with bases, e.g. as the sodium salt.

EXAMPLE 20

Tablets containing 10 mg of active substance, e.g. 2 (imidazol-1-yl) -hydroxy-ethane-1,1-diphosphonic acid or its salts, e.g. disodium salts can be prepared as follows:

Ingredients: (per 1000 tablets) active ingredient 10.0 g lactose 115.7 g corn starch 17.5 g polyethylene glycol 6000 5.0 g talcum powder 5.0 g magnesium stearate 4.0 g demineralized water q.s.

Preparation: First, press the solid components through a sieve with a width of 0.6 mm. Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are thoroughly mixed.

The other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 260 acres of water. The resulting adhesive is added to the powders, mixed and granulated, if necessary with the addition of water. Dry the granulate overnight at 35 °, squeeze through a sieve with a width of 1.2 mm and squeeze into concave concave tablets of about 10 mm diameter with a split notch on the upper side.

Tablets containing 10 mg of another compound of Formula I according to Examples 1 to 17 may also be prepared in an analogous manner, which may also be in the form of salts with bases, e.g. as the sodium salt.

EXAMPLE 21

Gelatin plug capsules containing 100 mg of active substance, e.g. 2- (imidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof, e.g. disodium salt can be prepared as follows:

Ingredients: (per 1000 capsules) active ingredient 350.0 g microcrystalline cellulose 30.0 g sodium lauryl sulfate 2.0 g magnesium stearate 8.0 g

Sodium lauryl sulfate was sieved through a sieve with a loop width of 0.2 mm to the substance (lyophilized) and the two components were thoroughly stirred for 10 minutes. The microcrystalline cellulose sign 0.9 is then passed through a sieve with a width of 0.9 mm and stirred again for 10 minutes. Finally, a 0.8 mra magnesium stearate sign is obtained through a sieve with a width of 0.8 m and after 39 minutes of further mixing, the mixture is filled with 390 mg of the mixture into gelatin capsules of size 0 (elongated).

Capsules containing 100 mg of other compounds of formula I according to Examples 1 to 17 may also be prepared in an analogous manner, these may also be in the form of salts with bases, e.g. as disodium salt.

EXAMPLE 22

0.2% injection or the infusion solution can be prepared e.g. likewise:

The active substance, e.g. 2- (imidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid, or a salt thereof, e.g. its sodium salt 5.0 g sodium chloride 22.5 g phosphate buffer pH = 7.4 300.0 g water, demin. ad 2500.0 ml

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

Claims (30)

A process for the preparation of substituted alkandiphosphonic acids, in particular heteroarylalkandiphosphonic acids of the formula P0 ~ H " I ³ r ₁ -ch ₂ -cr ₂ after ₃ h ₂ in which R ₁ represents a 5-membered heteroaryl residue having, as heteroatom (e), 2 to 4 N atoms or 1 or 2 N atoms as well as 1 atom 0 or S , and which is unsubstituted or C-substituted with lower alkyl, unsubstituted or lower alkyl, lower alkoxy and / or halogen substituted phenyl, lower alkoxy, hydroxy, lower alkylamino, lower alkylthio and / or halogen, and / or N-substituted lower alkyl or unsubstituted or lower alkyl, lower alkoxy and / or halogen substituted phenylalkyl, and R ₂ represents hydrogen, hydroxy, amino, lower alkylthio or halogen, and their salts, characterized in that in a compound of formula X, R, - CH _O - C - R _o I 2 and 2 (II), which is optionally intermediate protected on a substituent N atom, of the residue R 2, in which X 1 is a functionally modified and X _{2 a} free or functionally modified phosphone group, is converted X 4 and optionally X ₂ in free phosphon - 34 group, and optionally the resulting compound is converted to another compound of formula I and / or the resulting free compound is converted into a salt or salt obtained into a free compound or another salt. Process according to claim 1, characterized in that compounds of formula I are prepared in which imidazolyl, pyrazolyl, 2H-1,2,3-, 1H-1,2,4- or 4H-1,2,4 -triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl, which is unsubstituted or C-monoally substituted by lower alkyl, lower alkoxy, unsubstituted or lower alkyl, lower alkoxy and / or halogenated, and / or halogenated, or halogenated, or halogenated , lower alkylamino, lower alkylthio and / or halogen, and / or N-substituted at the substituent N atom, with lower alkyl or phenyl lower, alkyl which is unsubstituted or mono- or disubstituted by lower alkyl, lower alkoxy and / or halogen, and R ₂ represents hydrogen, hydroxy, amino, lower alkylthio or halogen, or salts thereof. Process according to claim 1, characterized in that compounds of formula I are prepared in which R 1 is imidazolyl, pyrazolyl, 2H-1,2,3- or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, an isoxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl residue which is unsubstituted or C-mono or substituted with lower alkyl, lower alkoxy, unsubstituted or lower alkyl, lower alkoxy and / or halogen mono- or disubstituted phenyl, hydroxyalkyl, lower alkyloxyamino, lower alkyl and / or halogen, and / or N-substituted at the substituent N atom, with lower alkyl or phenyl alkyl 35 which is unsubstituted or mono- or disubstituted by lower alkyl, lower alkoxy and / or halogen, and Ρθ ®θηΐ hydrogen, hydroxy, amino, lower alkylthio or halogen, or salts thereof. Process according to claim 1, characterized in that compounds of formula I are prepared in which R1 is imidazolyl, 4H1,2,4-triazolyl or thiazolyl residue, which is unsubstituted or C-mono or substituted with -C ^ - alkyl, C 1 -C 4 -alkoxy, phenyl, hydroxy, di-C 1 -C 4 -alkylamino, -C 1 -alkylthio and / or halogen with an atomic number not exceeding 35, such as chlorine, and / or N-substituted at a substituent N atom with C 1 -C 6 -alkyl or phenyl-C 1 -C 4 -alkyl, and R _p represents hydroxy, hydrogen or amino, and salts thereof. 5. A process according to claim 1, wherein the compounds of formula I are prepared in which R is unsubstituted or phenyl C-substituted or. with C 1 -C 4 -alkyl C- or N-substituted imidazol-2- or -4-yl residue, unsubstituted thiazolyl residue, or unsubstituted or with C 1 -C 4 -alkyl N-substituted 1H-1,2,4- a triazolyl radical, and R ₂ is hydroxy or hydrogen, or salts thereof. Process according to claim 1, characterized in that compounds of formula I are prepared in which R1 is unsubstituted or phenyl or. with -C 1-4 alkyl C-substituted imidazol-1yl, pyrazol-1-yl, 1H-1,2,4-triazol-1-yl, 4H-1,2,4-triazol-4-yl or tetrazol-1 is a radical, and R _p is hydroxy or hydrogen, and salts thereof. A process according to claim 1, characterized in that compounds of formula I are prepared in which R 1 is unsubstituted - 36 or C 1 -C 6 -alkyl substituted imidazolyl moiety and R 1 represents hydroxy or hydrogen, and salts thereof. Process according to claim 1, characterized in that 2- (imidazol-4-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared. A process according to claim 1, characterized in that 2- [4 (5) -methylimidazol-5 (4) -yl] -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared. A process according to claim 1, characterized in that mo 2- (imidazol-2-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof. A process according to claim 1, characterized in that mo 2- (1-methylimidazol-2-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof. Process according to claim 1, characterized in that mo 2- (1-benzylimidazol-2-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof. Process according to claim 1, characterized in that mo 2- (1-methylimidazol-4-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof. Process according to claim 1, characterized in that mo 1-amino-2- (1-methylimidazol-4-yl) ethane-1,1-diphosphonic acid or a salt thereof. A process according to claim 1, characterized in that mo-1-amino-2- (1-benzylimidazol-4-yl) ethane-1,1-diphosphonic acid or a salt thereof is prepared. A process according to claim 1, characterized in that 2- (1-methylimidazol-2-yl) ethane-1,1-diphosphonic acid or a salt thereof is prepared. A process according to claim 1, characterized in that 2- (1-benzylimidazol-2-yl) ethane-1,1-diphosphonic acid or a salt thereof is prepared. Process according to claim 1, characterized in that 2- (imidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared. The process of claim 1, wherein 2- (imidazol-1-yl) ethane-1,1-diphosphonic acid or a salt thereof is prepared. A process according to claim 1, characterized in that 2- (1H-1,2,4-triazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared. Process according to claim 1, characterized in that 2- (pyrazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared. Process according to claim 1, characterized in that 2- (pyrazol-1-yl) ethane-1,1-diphosphonic acid or a salt thereof is prepared. Process according to claim 1, characterized in that 2- (imidazol-4-yl) ethane-1,1-diphosphonic acid or a salt thereof is prepared. A process according to claim 1, characterized in that 2- (thiazol-2-yl) ethane-1,1-diphosphonic acid or a salt thereof is prepared. 25. A process according to claim 1, characterized in that 2- (imidazol-2-yl) ethane-1,1-diphosphonic acid or its - 38 A process according to claim 1, characterized in that 2- (1-methyl-1H-1,2,4-triazol-5-yl) ethane-1,1-diphosphonic acid or a salt thereof is prepared. Process according to claim 1, characterized in that 2- (pyrazol-3-yl) -1-hydroxy-ethane-1, Ιτ-diphosphonic acid or a salt thereof is prepared. A process according to claim 1, characterized in that 2- (4,5-dimethylimidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared. A process according to claim 1, characterized in that 2- (2-methylimidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared. Process according to claim 1, characterized in that 2- (4H-1,2,4-triazol-4-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared.