DD265900A5 - METHOD FOR PRODUCING NEW SUBSTITUTED AMINOMETHANE PHOSPHONIC ACIDS - Google Patents

Abstract

According to the invention, heteroarylaminomethanediphosphonic acids of the formula (I) are prepared in which R 1 is an unsubstituted or lower-alkyl, unsubstituted or lower alkyl, lower alkoxy and / or halogen-substituted phenyl, lower alkoxy, hydroxy, di-lower alkylamino, lower alkylthio and / or halogen-substituted, optionally benzo or cyclohexeno-fused 5-membered in that heteroatoms represent 2 to 4 N atoms or 1 or 2 N atoms and 1 heteroaryl radical having O or S atom, and R 2 denotes hydrogen or lower alkyl, and their salts have a regulating action on the calcium metabolism and can act as a medicament active ingredient for the treatment be used for disorders of the same cause. They are z. Example, prepared by reacting in a compound of formula (II), wherein X1 is a functionally modified phosphono X and X2 phosphono or also a functionally modified phosphono group X, the group (s) X in free phosphono. Formulas (I) and (II)

Description

Field of application of the invention

The invention relates to a process for the preparation of heteroarylaminomethanediphosphonic acids having valuable pharmacological properties, in particular having a regulatory effect on the calcium metabolism. The compounds according to the invention are used as medicaments, in particular for the treatment of diseases that werdon be associated with disorders of the calcium metabolism.

Characteristic of the known state of the art

There is no information available which compounds have hitherto been used for the treatment of diseases which are based on disorders of the calcium metabolism.

There are also no known data on processes for the preparation of Heteroarylaminomethandiphosphonsäuren.

Object of the invention

The aim of the invention is the provision of novel compounds with valuable pharmacological properties, in particular with a regulatory effect on the calcium metabolism.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention, new substituted amino methane diphosphonic acids, in particular heteroaryl amino methylene diphosphonic acids of the formula

R ₁ -N-CII,

POI 3 H ₂ -N- CII I I R ₂ PO 3 H ₂

Ri is an unsubstituted or lower alkyl, unsubstituted or lower alkyl, lower alkoxy and / or halogen-substituted phenyl, lower alkoxy, hydroxy, Dinideralkylamino, Niederalkylthio and / or halogen C-substituted and / or; by lower alkyl or unsubstituted or by lower alkyl, lower alkoxy and / or halogen

substituted phenyl-lower alkyl N-substituted optionally benzo- or cyclohexeno-fused 5-membered heteroaryl group having as Hete'oatom (e) 2 to 4-N atoms or 1 or 2-N atoms and 10 or S-atom and R _{2 is} hydrogen or Lower alkyl means, with the proviso that R ₂ is other than hydrogen, when R _{1 represents} a pyrazol-3-yl or isoxazol-3-yl radical which is optionally substituted by alkyl and / or halogen, and their salts and processes for the preparation of Division of the compounds of the invention containing pharmaceutical preparations.

Optionally, benzo or cyclohexenocondenbed 5gliedrlgp, as heteroatom (s) 2 to 4N atoms or 1 or 2 N atoms and 10- or S-atom heteroaryl radicals are, for example, imidazolyl, z. Imidazol-2-yl or 4-yl, thiazolyl, e.g. 8th.

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. B. Totrazol-5-yl, thiediazolyl, z. For example, 1,2,5-thiadiazol-3-yl, oxadiazolyl, z. B. 1,3,4-oxadiazol-2-yl, benzimidazolyl, for example benzimidazole-2-γΙ, benzoxazolyl, for example benzoxazol-2-yl, or benzothiazolyl, for example benzothiazol-2-yl. The radicals mentioned may have one or more identical or different, in particular one of the two identical or different substituents mentioned above. Radicals R _t with substitutable N atoms are preferably N-substituted as indicated. Radicals R ₁ are, for example, C 1 -C ₄ -alkylimidazo-2-yl radicals, such as 1-methylimidazol-2-yl, 1-phenyl-C 1 -C ₄ -alkylimidazol-2-yl radicals, such as 1-benzylimidazole radicals. 2-yl, oxazol-2-yl, thiazol-2-yl, 4- and 5-C _t -C ₄ alkylthiazof-2-yl radicals such as 4- or 5-methylthiazol-2-yl, 5-phenylthiazole-2 -yl, 1,2,4-thiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiezol-2-yl, 5-methyl-1,3 , 4-thiadiazol-2-yl, benzoxazol-2-yl and benzothiazol-2-yl.

Hereinafter, lower radicals and compounds are, for example, those which have up to and including 7, in particular up to and including 4, carbon atoms. Furthermore, the general terms have, for example, the following meanings:

Niederalkyi is for example C ₁ -CvAlkYl, such as methyl, ethyl, propyl or butyl, furthermore iso-, secondary- or tertiarybutyl, but can also be a C ₆ -C ₇ alkyl, such as pentyl, hexyl or Heptylgruppo.

Phenyl-lower alkyl is, for example, phenyl, especially 1-phenyl-C, -C ₄ -alkyl, such as benzyl.

Lower alkoxy is, for example, Ct-C ₄ -alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, secondary butoxy or tertiary-butyloxy.

Diniederalkylamino is, for example, di-C ^ alkylamino, such as dimothylamino, diethylamino, N-ethyl-N-methyl-amino, dipropylamino, N-methyl-N-propyl-amino or dibutylamino.

Lower alkylthio is, for example, C ₁ -C ₄ -alkyl, such as methylthio, ethylthio, propylthio or butylthio, and also iso, eic-butyl or tert-butylthio.

Halogen is, for example, halogen of the atomic atoms up to and including 35, such as fluorine, chlorine or bromine.

Salts of compounds of the formula I are in particular their salts with pharmaceutically usable bases, such as non-toxic, of metals of groups I a, I b, II a and II b derived metal salts, eg. As alkali metal, especially sodium or potassium salts, alkaline earth metal, in particular calcium or magnesium salts, copper, aluminum or zinc salt, as ammonium salts with ammonia or organic amines or quaternary ammonium bases, such as optionally C-hydroxylated aliphatic amines, in particular mono- , Oi or Triniederalkylaminen, z. For example, methyl, ethyl, dimethyl or diethylamine, mono-, di- or tri- (hydroxyniedera! Yl) -amines, such as ethanol, diethanolamine or triethanolamine, tris (hydroxymethyl) -amino-methane or 2-hydroxytertiärbutylamin , or N- (hydroxy lower alkyl) -N, N-lower alkylmin; N- (polyhydroxy-lower alkyl) -N-lower alkylamines, such as 2- (dimethylamino) ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, e.g. B. with tetrabutylammonium hydroxide.

In this connection, it is also to be mentioned that the compounds of the formula I are in the form of internal salts, for example of the formula

Ri -H-OH (I '),

PO ₃ H ₂

may be present. Accordingly, said compounds may also be treated by treatment with a strong protic acid such as with a hydrohalic acid, sulfuric acid, sulfonic acid, e.g. For example, methane or p-toluenesulfonic acid, or sulfamic acid, z. As N-cyclohexylsulfamic acid, in the corresponding acid addition salts of the formula

where A ° is the anion of proton acid.

The compounds of the formula I and their salts have valuable pharmacological properties. In particular, they have a pronounced regulatory effect on the calcium metabolism! of warm-blooded animals. In particular, they cause a pronounced inhibition of bone resorption in the rat, which is evident both in the test arrangement according to A: ta Endocrinol. 78, 613-24 (1975) based on the increase in serum calcium by PTH-induztorten after subcutaneous administration in doses of about 0.01 to about 1.0 mg / kg, and in the TPTX (thyroparathyroidectomised) rat model based on the Vitamin D ₃ triggered show experimental hypercalcaemia after administration of doses of about 0.001 to 1.0 mg sc. Similarly, tumor hypercalcaemia induced by Walker 256 tumors is inhibited after oral administration of about 1.0 to about 100 mg / kg. Further, they show in rat adjuvant arthritis in Newbould, Brit. J. Pharmacology 21, 127 (1963) as well as Kalibara et al., J. Exp. Mod. 159, 13888-96 (1984) at doses of about 0.01 to 1.0 mg / kg sc a marked inhibition on the progression of chronic arthritic processes. They are therefore excellently suitable as active pharmaceutical ingredients for the treatment of disorders which may be associated with disorders of calcium metabolism, for example inflammatory processes in joints, degenerative processes in articular cartilage, osteoporosis, periodontitis, hyperparathyroidism and calcium deposits in blood vessels or prosthetic ones implants. Favorably affected are both diseases in which an abnormal deposition of poorly soluble calcium salts is observed, such as those from the art forms of arthritis, eg. B. ankylosing spondylitis, neuritis, bursitis,

Periodontitis and tendinitis, fibro-Iysplasio, osteoarthrosis or atherosclerosis, as well as those in which an abnormal dissolution of hard tissues is in the foreground, such as hereditary hypophosphatasia, degenerative processes in articular cartilage Osteoporosis of various genesis, Paget's disease and osteodystrophia fibrosa, as well as tumor-induced osteolytic processes.

The invention relates primarily to the preparation of compounds of the formula I in which R 1 is phenyl, hydroxy, lower alkyl, lower alkylthio and / or unsubstituted or lower alkyl, lower alkoxy, unsubstituted or lower alkyl, lower alkoxy and / or halogen, or or halogen C-monorodor C disubstituted, phenyl unsubstituted or optionally substituted by niaderalkyl or unsubstituted or by lower alkyl, lower alkoxy and / or halogen mono- or disubstituted phenyl-lower alkyl, N-monosubstituted imidezolyl, penzimidazolyl, 2H-unsubstituted 1,2,3- or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzthiazolyl or thiadiazolyl and R _{2 is} hydrogen or lower alkyl, and their salts , in particular their internal salts and pharmaceutically acceptable salts with bases.

The invention relates primarily to, for example, the preparation of compounds of formula I wherein R _{1 is} an unsubstituted or lower alkyl, lower alkoxy, unsubstituted or lower alkyl, lower alkoxy and / or halogen mono- or disubstituted phenyl, hydroxy, di-lower alkylamino, Niodernlkylthio and / or Halogen mono- or di-substituted imidazolyl, benzimidazolyl, 2H-1,2,3- or 4H-1,2,4-triazolyl, tetrazoiyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzthiazolyl or thiadiazolyl and R _{2 is} hydrogen or lower alkyl, and their salts, especially their internal salts and pharmaceutically acceptable broom salts.

The invention particularly relates to the preparation of compounds of formula I wherein R _{1 is} a unsubstituiorten or by Ci-C ₄ -alkyl, such as methyl, or an unsubstituted or by Ci-C ₄ -alkyl, such as methyl, C _t -C ₄ - Alkoxy, such as methoxy, and / or halogen, such as chlorine, mono- or disubstituted phenyl, C-substituted thiazolyl, such as thiazol-2-yl radical, benzothiazol-2-yl radical, thiadiazolyl, such as 1,2,4-thiadiazole-5 -yl or 1,3,4-Tiiiadiazol-2-yl radical, oxazolyl such as oxazol-2-yl radical, or benzoxezol-2-yl radical and / or by C, -C ₄ alkyl, such as methyl, or an unsubstituted or by C 1 -C ₄ -alkyl, such as methyl, C 1 -C ₄ -alkoxy, such as methoxy, and / or halogen, such as chlorine, mono- or disubstituted phenyl-C 1 -C ₄ -alkyl, such as benzyl radical N-substituted imidazole, such as imidazol-2-yl radical or imidazol-4-yl radical, or benzimidazol-2-yl radical, and R _{2 is} hydrogen, and their salts, in particular their internal salts and pharmaceutically acceptable salts with bases.

Above all, the invention is superior to the preparation of compounds of the formula I in which Ri is an unsubstituted or C 1 -C ₄ -alkyl, such as methyl, C 1 -C ₄ -alkoxy, such as methoxy, phenyl, hydroxy, di-C 1 -C 4 -alkylamino such as dimethylamino or di-ethylamino, C 1 -C 4 -alkylthio, such as methylthio, or halogen of the atomic number up to and including 35, such as chlorine, substituted thiazolyl, such as thinzol-2-yl or -4-yl radical, and R ₂ for Is hydrogen, and their salts, in particular their internal salts and pharmaceutically acceptable salts and bases.

In particular, the invention relates to the preparation of compounds of the formula I in which R 1 is an unsubstituted or by C 1 -C ₄ -alkyl, such as methyl, C 1 -C ₄ -alkoxy, such as methoxy, phenyl, hydroxy, di-J 1 -C ₄ - Alkylamino, such as dimethylamine or diethylamino, C, -C ₄ alkylthio, such as methylthio, or halogen of the atomic number to and with 35, such as chlorine, C-substituted thiazolyl, such as thiazole 2-ylrost or 1-Ci-C ₄ alkyl such as methylimidazol-2-yl or -4-yl radical, or phenyl-Ci-C ^ alkyl, such as benzylimidazol-2-yl or -4-yl radical and R _{2 is} hydrogen, and their salts, in particular their internal Salts and pharmaceutically acceptable salts with bases.

Dio invention relates first and foremost to the preparation of compounds of formula I, wherein Ri is an unsubstituted or, in particular in the 4 and / or 5-position, by C ₍ -C ₄ alkyl, such as methyl, or phenyl mono- or disubstituted thiazole -2-y.Vost, an unsubstituted or 1-position by C, -C ₄ alkyl, such as methyl, or phenyl-Ci-C ^ alkyl, such as benzyl, monosubstituted imidazol-2-yl or 8enzimidazol-2 -ylreiit or an unsubstituted benzthiazol-2-yl or benzoxazol-2-yl radical and R, is hydrogen, and their salt>, in particular their internal salts and pharmaceutically acceptable salts with bases.

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

The inventive method is based on methods known per se and is characterized in that

a) in one at a substitutable N- / uon; the radical Ri optionally intermediately protected compound dor Formoi

N - Γ- Η Ra X ₂

wherein Xi is a functionally modified phosphono group X and X ₂ phosphono or also a functionally modified phosphono group X, the group (s) X converted into free »8 phosphono or

b) one on a substitutable N atom of the radical '; Ri optionally intermediately protected Vorbindung the formol

R ₁ -JJ-CH-O ","

first reacted with phosphorus trioxide and then with water and, if desired, each converted a compound obtained in another compound o'er formula I and / or a resulting free compound in a salt or a raised salt in the free compound or in another salt.

In accordance with the process variant .functional phosphono groups X to be converted into phosphono, they are, for example, in an ester form, in particular a diester form of the formula

-P (= O) (OR), (Ha)

wherein OR is, for example, Niedei iilkoxy or optionally substituted by lower alkyl, lower alkoxy, Hi 'oge ^ ^ trifluoromethyl and / or hydroxy Pheiiyloxygruppe means.

The transfer diner functionally modified in the free phosphono takes place in a conventional manner by hydrolysis, for example in the presence of a mineral acid such as hydrochloric or hydrobromic acid or sulfuric acid, or by reaction with a Triniedeialkyl-halosilane, z. B. with trimethylchlorosilane or especially trimethyliodosilane or Trimethylhromsilan, preferably under cooling, for example in the temperature range of about ⁰ ° C to about 25 ° C.

The starting materials of the formula II can be prepared, for example, by reacting a compound of the formula

Ri-N (R ₂ HH (lib; R ₂ = H)

with at least equimolar amount of an orthoformic acid triester of the formula

HC (OR) ₃ (lic),

wherein OR is, for example, lower alkoxy or an optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and / or hydroxy substituted phenyloxy group, condensed, which is primarily likely a corresponding compound of the formulas

R _{1 is} -NH-CH (OR); (HDD

R ₁ -N = CH-OR (Hd 2)

is formed, and the condensation product with the at least double molar amount of a phosphorous diester, z. B. the formula

and, if desired, the resulting compound (II, R ₂ = H) is lower alkylated to the corresponding compound (II; R ₂ = lower alkyl).

In intermediates II wherein R ₁ is N-substituted by N-alkylene or phenyl-lower alkyl which is unsubstituted or substituted by lower alkyl, lower alkoxy and / or N-halo, the N-substituent can be eliminated, lower alkyl for example by treatment with a haloformate, such as bromo or triethyl Chlorameisensäureniederalkylester, and subsequent hydrolysis of the carbamate formed and a-Phenylniederalkylreste for example by hydrogenolysis, for. B. treating with hydrogen in the presence of a hydrogenation catalyst, for. B. of palladium on carbon and / or platinum oxide, or by metallic reduction, for. B. Treatment with an alkali metal in ammonia.

However, the starting material Hb can also be reacted in a manner known per se with the phosphorous diester He in the presence of ortho-formic acid etheric acid Hc, without isolating the intermediate. Thus, according to a particularly preferred embodiment, in the boiling heat, the corresponding compound Hb in the presence of at least equimolecular amount «ines Orthoameisensäuretriesters Hc with the at least double molar amount of Phosphorigsäurediesters He, excluding the intermediate, z. B. the formula HdI or Ild2, to isolate, and hydrolyzes the primary product II by treatment with aqueous hydrochloric acid in the boiling heat.

The reaction of compounds Hl with phosphorus trioxide according to process variant b) is preferably carried out with in situ formation of the latter, for example by reaction of phosphorus trichloride and phosphorous acid of elevated temperature, e.g. at about 50 to 65 "C, adding the reaction component IH, further heating and hydrolytic work-up of the primary product, a 1: 1 adduct of the aldehyde of the formula

Ri-N-CH-O (IM)

with phosphorus trioxide bit of long unknown structure, preferably by treatment with water.

In a modification of this preferred embodiment of process variant b) is set at about 5O ⁰ C to 7O ⁰ C.

Orthophosphoric acid with about 1.1 - to about 2 times, preferably about 1, Sfachen excess of phosphorus trichloride, adds the P.eektionskomponente IH, heated extended period of time at about 50 ⁰ C to 70 ° C, diluted with 80% phosphoric acid and works hydrolytically.

Starting materials III can be prepared in a customary manner, for example by reacting an amine of the formula

R, -N (R;) - H (Hb; R = H)

with formic acid or a functional carboxy derivative thereof, e.g. With a formic acid ester of the formula H-COOR die),

wherein OR is, for example, an optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and / orpr hydroxy substituted Phenyioxygruppo, or with formamide.

For the intermediate protection of a substitutable N atom of the radical Ri, the usual N-protecting groups and Introductory and Abspaltungsverfahren the same, for example, 2,2,2-Trihalcgen-, such as 2,2,2-triiodo, 2,2,2-tribromo-or

2,2,2-Trichloräthoxycarbor.ylreste z. B. can be removed by treatment with zinc in acetic acid, a-Phenylniederalkoxyerbonyireste, such as carbobenzoxy, the z. B. can be removed by catalytic hydrogenation, and Niederaikansuifonylgruppen such as methane & ulfonyl, dia ζ. B. by treatment with bis (2-methoxyethoxy'inatriumaluminiumhydrid can be cleaved, but also α-phenylalkyl or alkyl groups, the cleavage treated hereafter «wi · *.

Process according to ο Jer according to another method known per se erhaltene obtained compounds of formula I can in in itself

known manner be converted into other compounds of formula I.

Thus, compounds of formula I wherein R _{2 is} hydrogen may be prepared by reaction with a reactive ester such as Hydrogen halide or organic sulfonic acid ester, a lower alkanol lower alkyl R ₂ introduce. One can

abet also by reaction with an aliphatic aldehyde, e.g. with formaldehyde and formic acid, an aliphatic

Remainder, e.g. Methyl, introduce. Further, one can in compounds of formula I, wherein the radical Ri by lower alkyl or unsubstituted or by

if the alkyl, lower alkoxy and / or halogen-substituted phenyl-lower alkyl are N-substituted, the N-substituent split off,

Lower alkyl, for example, by treatment with a haloformate, such as a bromine or Chloroformate lower alkyl, and subsequent hydrolysis of the resulting carbamate and a-phenyl-Nioderalkylreste

for example by hydrogenolysis, e.g. B. treating with hydrogen in the presence of a hydrogenation catalyst, for. B. from

Palladium on carbon and / or platinum diux or by metallic reduction, e.g. B. Treatment with an alkali metal in

Ammonia.

Obtained free compounds of the formula I, including their internal salts of the formula I can be replaced by partial or

complete neutralization with one of the genannton bases initially converted into base salts. In an analogous manner, it is also possible to convert acid addition salts of the formula II into the corresponding free compounds of the formula I or inner salts of the formula I '.

Conversely, the pure compounds of the formula I obtained can be obtained by treatment with one of the abovementioned compounds Transfer protonic acids into acid addition salts of formula Γ. Salts obtained can be converted into the free compounds in known catfish, for. B. by treating with

an acidic reagent, such as a mineral acid, or a base, e.g. B. alkali lye.

The compounds, including their salts, can also be obtained in the form of their hydrates or for crystallization

include solvents used.

owing to the close relationship between the free compounds in the form of their salts and in the form of their salts, the corresponding salts or free compounds are to be understood as meaningful and suitable in the preceding and following among the free compounds or their salts.

The invention also relates to those embodiments of the method according to which one of 6iner at any stage the Run as intermediate compounds available and performs the missing steps or a Starting material in the form e'nes salt and / or racemates or antipodes used or in particular among the Reaction conditions forms. In the process of the present invention, preference is given to using those starting materials which are identical to those mentioned at the outset

lead as particularly valuable described connections; , New starting materials and processes for their preparation also form an object of the invention.

In the case of the pharmaceutical preparations which contain compounds of the formula I or pharmaceutically acceptable salts thereof.

are those for ontral, such as oral or rectal, and parenteral administration containing the pharmacological agent alone or together with a pharmaceutically acceptable carrier. The

Dosing of the active substance depends on the species of warm-blooded animals, the age and the individual condition, as well as on the Application method from. Normally, approx. 75 kg of warm-blooded animals are approx Daily dose of about 20 bits) 1000 mg, preferably about 30 to 300 mg, or with intravenous administration about 1 to 25 mg,

preferably about 1 to 10 mM, advantageously distributed in several different partial doses: to be estimated.

The pharmaceutical preparations contain from about 10% to about 80%, preferably from about 2% to about 60%, of the Active ingredient pharmaceutical preparations according to the invention for entjralen or parerteralan administration are z. B. such in Ooeieeinheitsformen such as dragees, tablets, capsules or suppository, also ampoules. These are known per se Way, e.g. produced by conventional mixing, granulation, coating, solution or lyophilization process. So can

one obtains pharmaceutical preparations for oral use by combining the active ingredient with solid carriers, optionally granulated in the resulting mixture, and the mixture or granules, if desired or necessary, after

Add precursors, tablets or dragee seeds. Suitable excipients are in particular fillers, such as sugars, for. Lactose, sucrose, mannitol or sorbitol, Cellulase propolisates and / or calcium phosphates, e.g. B. Tricalciumphnsphat or Calciumhyu »-genphosphat, further binder,

like strength tenants using z. Corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as the above-mentioned starches

Carboxymothyl starch, cross-linked polyvinylpyrrolidone, agar, alginate, or a salt thereof, such as sodium alginate. Aid are primarily flow regulators and lubricants, for. For example, silica, talc, stearic acid or salts thereof, such as Magnesium or calcium stearate, and / or polyethylene glycol. Dregon kernels are suitable with gc, if necessary Provided with megan-juice coatings, where rnai; Among other things, concentrated ferricyanide, which may be Arabic Gum, talc, polyvinylpyrrolidone, polyethylene glycol! and / or titanium dioxide, lacquers in suitable organic Solvents or solvent mixtures od'jr, for the production of Magansaft-resistunten coatings, solutions of

suitable culluioce preparations, such as acetylcellulose octthalai or hydroxypropylphenylmethylephthalate; The

Tablets or dragee coatings may contain dyes or pigments, e.g. for identification or identification

different doses of active substance, to be attached.

Other oral pharmaceuticals include Ge'atine capsules and soft, closed capsules Gelatin and a plasticizer, such as glycerol or sorbitol. Dia Steckkapselrt can the active ingredient in the form of granules,

z. B. in admixture with fillers, such as Lnctoae, binders, such as starches, and / or or lubricants, such as talc or magnesium stearate, and optionally of stabilizers. In soft capsules, the active ingredient is preferably in suitable liquids,

such as fatty oils, paraffin oil or liquid polyethylene glycols, dissolved or suspended, wherein stabilizers may also be added.

As rectally applicable pharmaceutical preparations are e.g. Suppositories, which consist of a combination of the active ingredient with a suppository baseline. As suppository base are z. As natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkenols. Furthermore, gelatin rectal capsules containing a combination of the active ingredient with a matrix may also be used; as basic materials come z. As liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.

For parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, eg. As a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, wherein suitable lipophilic solvent or vehicle such as fatty oils, eg. As sesame oil, or synthetic fatty acid esters, eg. As ethyl oleate or triglycerides, used, or aq! each injection suspensions, which viscosity-increasing substances, eg. B. sodium coxoxymethylcellulose. Sorbitol and / or dextran and optionally also stabilizers.

The present invention also relates to the use of the compounds of formulas I and their salts, preferably for the treatment of disorders attributable to calcium metabolism disorders, e.g. As the rheumatic type, and especially of osteoporosis.

Doses of less than 0.01 mg / kg body weight affect the pathological calcification or dissolution of hard tissues only insignificantly. At doses above 100 mg / kg body weight long-term toxic side effects may occur. The compounds of the formula I and their salts can be administered both orally and hypertonic solution subcutaneously, intramuscularly or intravenously. The preferred daily doses for these applications are in the range of about 0.1 to 5 mg / kg by oral application, in the range of about 0.1 to 1 mg / kg by subcutaneous and intramuscular administration and in the range of about 0.01 by intravenous administration to 2mg / kg.

However, the dosage of the compounds used is variable and depends on the particular conditions such as type and severity of the disease, duration of treatment and the particular compound. Single doses contain, for example, from 0.01 to 10 mg, dosage unit forms for prprentet & le, such as intravenous administration z. From 0.01 to 0.1 mg, preferably 0.02 to 0.08 mg, oral dosage unit forms, e.g. B from 0.2 to 2.5 mg, preferably 0.3 to 1.5 mg per kg of body weight. The preferred single dose is 10 to 100 mg in the case of oral administration and 0.5 to 5 mg in the case of intravenous administration and can be administered daily in up to 4 single doses. The higher dosages for oral administration are required due to the limited absorption. For longer-lasting: Treatments can usually be switched to low dosages after initially higher doses to maintain the desired effect.

Ausführungsbeisplel

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. I emperatures are given in Celsiusgradon.

BeispieM

6.57 g (17 mmol) of 1- (thiazol-2-ylamino) -ethan-1,1-diphosphone tetra-tetraethyl ester are dissolved in 70 ml of η-hydrochloric acid and heated to reflux for 6 hours. In the course of the reaction, the product precipitates in the form of a fine white precipitate. After cooling to room temperature, it is filtered and washed with aqueous methanol. This gives 4.33 g (93% of th.) Of 1- (thiazol-2-ylarnino) -methane-1,1-diphosphonic acid of mp 275 ° C (dec.).

 The starting material may e.g. be prepared as follows:

A mixture, boräthend from 10.0 g (0.1 mol) of 2-Aniinothiazol, 2L ₁ OmI (0.12MoI) Orthoameisensäuretriäthylester and 26.6ml (0 2 mol) of diethyl phosphite is heated to reflux for 1 hour. The liberated ethanol is distilled off, whereby the Innsntemperetur gradually increases to about 150 ° C. 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-iThiazol-2-ylamino) methene-1,1-diphosphonic acid tetraethyl ester are obtained from Smp. 103-104 ⁰ C.

Example:

In an analogous manner as described in Example 1 mm and 1- (oxazol-2-ylamino) methane-1,1-diphosphonic acid and mp. 245 ⁰ C (Zers.i and 1-iBenzoxazo! -2-ylamino) methane-1 , 1-diphosphonic acid, m.p. 270 ° C (dec.).

Example 3:

4.36 g (10 μmol) of 1- (3-thiazol-2-ylamino) methane-1,1-diphosphonic acid tetroethyl ester are heated to 110 ° C.-120 ° C. in 40 ml of n-hydrochloric acid for 6 hours. In the course of the reaction, the product precipitates in the form of a white precipitate. After cooling to room temperature, it is filtered and washed with aqueous methanol. This gives 3.09 g (95% of theory) of 1- (8-benzothiazol-2-ylamino) methane-1,1-diphosphinic acid of the mp 290 ° C. (dec.).

The Ausgangsmatei ial can z. R. be prepared as follows:

A mixture consisting of 3.0 g (20 mmol) of 2-aminobenzothiazole, 4.0 ml (24 mmol) of triethyl orthoformate and 5.3 ml (40 mmol) of diethyl phosphite is heated at 120 ° C.-12 ° C. for 5 hours. The precipitate at the beginning of the reaction yellow precipitate

is gradually coming back into solution. The released ethanol is distilled off during the reaction. The solidified on standing crude product is purified by column chromatography (silica gel / ethyl acetate / methanol). 5.62 g (64% of theory) are obtained.

Th.)! - (eanzthiuzol ^ laroinoimethan-i.i-diphosphonsaur · * tetraäthylesfer of mp. 165-167X.

Example·):

1.30 g (3.2 mmol) of 1- (4-methylthiazol-2-yl-amino) -methane-1,1-diphosphonic acid tetraethyl ester are heated in 20 ml of hydrochloric acid for 20 h to 100X. After cooling, 20 ml of methanol were added. During the subsequent stirring, the product precipitates in the form of fine white crystals. The filtrate is washed with methanol and Petroiäther. Yield:

615 mg (67% of theory) of V (4-methylthiazol-2-ylamino) -methane-1,1-diphos. 234 ⁰ C (Zers.).

The output file la! can z. B. be prepared as follows:

A mixture consisting of 2,33g (2OmMoI) 2-amino-4-methylthiazole, 4.0ml (24mMo!) Orthoameisensäuretriäthylester and

5.3 ml (4OmMoI) diethyl phosphite is heated to 120-125 ⁰ C for 4 hours. The released ethanol is distilled off. The residue

is purified by column chromatography (silica gel / ethyl acetate / methanol). N.an receives 1.32 g (IV% of theory) of 1- (4-methylthiazol-2-yl-8-methane-1,1-diphosphonic acid tetraethyl ester in the form of a viscous oil.

Example S:

1.97 g (4.9 mmol) of 1- (5-methylthiazol-2-ylamino) methane-1,1-diphosphonic acid tetraethyl ester are refluxed in 20 ml of n-hydrochloric acid for 6 hours. Upon cooling and standing at room temperature, the product crystallizes. It was 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 (mp 208 ⁰ C dec.).!...

The starting material may, for. U. can be prepared as follows: A mixture consisting of 1,14g (10mMoI) 2-amino-5-methylthiazole, 2.0ml (12mMol) ortho-formic acid triethylester and

2.65 ml (2OmMoI) of ethyl phosphite is heated at 4 ° C for hours to * 0 ° -125 ° C. The released ethanol is distilled off. The

Residue is purified by column chromatography (silica gel / ethyl acetate / methanol). This gives 1.97 g (49% of theory) of 1 - (5 Methylthiazol ^ -ylaminolmethane-i.i-diphosj.honsäure-tetraäthylester in the form of a viscous oil.

4.02 g (8.7 mmol) of 1- (5-phosphonediazyl-2-ylamino) methane-1,1-diphosphite ionization tetrahydrate ester are refluxed in 30 ml of n-hydrochloric acid for 18 hours. After cooling to room temperature v. A little methanol is added and filtered. The filtrate is refluxed in methanol for 1 hour, filtered hot and washed twice with hot methanol. Yield: 2.90 g (95%)

d. Th.) 1 - ('5-Phenylthiazol-2-ylamino) meihan-1,1-diphosphonic acid of mp. 29O ⁰ C (Zors.).

The Ausnangsmaterial can z. B. are prepared as follows: A mixture consisting of 2.93g (16.6 mmol) 2-amino-B-phenylthiazole, 3.3 η I (19, OmMoI) triethyl orthoformate

and 4,4ml (i3,5mMol) of diethyl phosphite is first for 2 hours at 120 ⁰ C, then heated to 130 ° C for 2 hours.

Ethanol released is distilled off in the course of the reaction. The ProoJ't solidifying on cooling gets through Chromatography (silica gel / ethyl acetate / methanol). This gives 4.12 g (54% of theory) of 1- (6-phenylthiazole-2-one

ylamino) methane-1,1-diphosphoric acid tetr (ethyl ester of mp 151-153 "C.

Example 7:

2.5 g <5.96 mmol) of 1- (1-benzimidazol-2-ylamino) methane-1,1-diphosphonic acid uretetraethyl ester are dissolved in 25 ml of 1N-fischer acid and heated to 100-11O ⁰ C for 26 hours during the course of the reaction the product falls in the form of a fine, white precipitate

It is filtered hot and washed with water and then with methanol. This gives 0.23 g (13% of theory) of 1'i'i Benzimidazol-2-ylamino) methane-1,1-diphosphonic acid, mp. 265 ⁰ C (dec.). The starting material may, for. B. be prepared as follows.

6.66 g (60 mmol) 2-aminobenzimidazole, 10.0 ml (60 mmol) triethyl cetate and 13.3 ml (101 mmol)

Diethyl phosphite are mixed and stirred for 2 hours at 125-130 ° C until no more ethanol distilled off. The residue will be

purified by column chromatography (silica gel / ethyl acetate / methanol, 9: 1). Mnn receives 2.89 g (14% of theory) of 1- (1-benzimidazol-2-ylamino) methane-1,1-dlphosphonsauretetraäthylester, mp. 169-17O ⁰ C.

Example 8:

7 g of phosphorus trichloride are mixed with 4.0 g of phosphorous acid and heated for one hour with stirring to 60 ⁰ C, rvmn adds 6,12g N- (thiazol-2-yl) formamide and heated for a further 6 hours to about 6O ⁰ C. Then stirred with 30 ml of water, filtered off with suction, washed with aqueous methanol and dried under reduced pressure. This gives 2.0 g of 1 - (thiazol-2-ylamino) methane-1,1-diphosphonic acid, mp. 275 ° C (dec.).

Example 9:

2.0 g (20,4mMol) crystalline orthophosphoric acid are stirred with 3.5 g (25,5mMol) of phosphorus trichloride for 1 hour at 55-60 ⁰ C. Thereafter, 4.08 g (20, OmMoI) of N- (4-phenylthiazol-2-yl) formamide are added. The reaction mixture is allowed to stand for about 24 hours at 60 ° C. For dilution, 10 ml 80% 80% phosphoric acid added and allowed to stand overnight at room temperature. Then we re-heated to 60-7O ⁰ C and are further 1.37 g (1OmMcI) Phoshortrichlorid added, can be 2 hours 60 to 70 ⁰ C. Continue mixing, add 30ml water ur.d 20ml acetone added and the mixture stirring for 2 hours at 60 ⁰ C. , The mixture is allowed to cool to room temperature, filtered from the fine, pale yellow precipitate and washed with water / acetone 3: 2. The residue is purified by boiling 1 time with water / acetone 1: 1 and 2 times with methanol. This gives 180 mg (2.6% of theory) of 1- (4-phenylthiazol-2-ylamino) methane-1-diphosphonic acid, mp 298 ^J C (dec.) The starting material can be prepared as follows:

13.22 g (7 μmol) of 2-amino-4-phenylthiazole are reacted with 40 ml of formic acid at 110 ° C. for 5 hours. Allow to cool to room temperature and pour on ice. It precipitates a white precipitate, which is filtered off and washed with ice water. It is recrystallized from petroleum ether to obtain 7.01 g (45.8% of theory) of 4- (phenylthiazole-2-amino) formamide from St np. 16 VI 64 ⁰ C.

Boit Game 10:

In a conventional manner, for. As described in Examples 1 to 7, it is also possible to produce:

1- (lmldazol-2-ylamino) methane-1,1-dipho8phonsäure,

1- (imidazol-4-ylflmi.> O) methane-1,1-dlpho8phonsäure,

1- (1-methylimidazol-2-ylamino) methane-1,1-diphosphon8äure,

1- (tetrazol-5-ylamino) mqthan-1,1-diphosphonic acid,

1 - (oxazol-2-ylamino) methane-1,1-diphosphonic acid,

i-d ^ ^ AThiadiazol -ylaminoJmethan-I.I-diphosphonic acid,

1- (5-methyl-1,3,4-thiadiazol-2-ylamino) methane-1,1-diphO8phonsäuro, mp 260 ⁰ C (dec.). 1 - (3-phenyl-1,2,4- thiiidiazol-5-ylamino) methane-1,1-diphosphonic acid, m.p. 198 ⁰ C.

Example 11:

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

Bettandteile (for 1000 tablets)

Active ingredient 50.0 g

Lactoeo 50.7 g Wsizen starch 7.5 g

Polyethylene Glycol 1000 5.0 g

Talc 5.0 g

Magnesium stearate 1.8 g

demineralised water q.s.

production:

All solid ingredients are first z'.r by. Sieve with 0,6rr.m mesh size driven. Then the active ingredient, the lactose, the talc, the 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 a boiling solution of the polyethylene glycol in 100 ml of water and the mixture is granulated, if necessary with addition of water. The Granulai is dried by power at 3E ° C, driven through a sieve with 1.2mm Masnhenweito and concave on both sides. Compressed tablets of about 6mm in diameter.

Example 12:

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

Ingredients (for 1000 tablets) 100.0 g active substance 100.0 g lactose 47.0 g Weizonstärke 3.0 g Magnesiumsiearat

production:

All solid ingredients are first passed through a 0.6mm mesh screen. Then the active ingredient, the lactose, the talc, the magnesium stearate and the Hfcifte of the starch is mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water and the mixture is granulated, if necessary adding water. The granules are dried overnight at 35 ° C, driven through a sieve with 1.2mm mesh size and pressed on both sides concave tablets of about 6mm diameter.

Example 13:

Tablets containing in each case 100 mg or 50 mg of another of the compounds of the formula I mentioned in Examples 1 to 10 can also be prepared in an analogous manner as described in Examples 11 and 12, these also being used in the form of salts and bases, eg. B. as disodium salt may be present.

Example 14:

Chewable tablets containing 75mg of active ingredient, e.g. 8.1 - (Thiazol-2-yl-1nnimoethane-1,1-diphosphonic acid or a salt, eg the sodium salt thereof, can be prepared, for example, as follows:

Composition: (for 1000 tablets)

Active ingredient 76.0 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.

production:

All solid ingredients are first forced through a 0.25 mm mesh screen. The mannitol unci the lactones are mixed, granulated with the addition of gelatin solution, forced through a sieve of 2 mm mesh width, dried at 50 ⁰ C and again forced through a sieve with chenweite 1.7mm * Ma. The active ingredient, the glycine and the saccharin are mixed thoroughly, the mannitol, the lactose added, the stearic acid and the talcum added, the whole thoroughly mixed and pressed to both sides concave tablets of about 10mm diameter with scored groove on the top.

in analogous Weleu and tablets, each containing 75 mg of another of the mentioned in Examples 1 to 10 compounds of formula I can be made hei, which also in the form of salts with bases, for. B. as disodium salt may be present.

Example 16:

Tablets containing 10mg of active ingredient, e.g. B. 1- (thiazole-2-ylamine) -mathan-1,1-diphosphonic acid or a salt, e.g. B. the Netriumealz thereof, can be divided as follows:

Composition (for 1000 tablets)

Active ingredient 10.0 g

Lactose 328.5 g

Corn starch 17.5 g

Polyethylene glycol 6000 5.0 g

Talc 26, Cg

Magnesium Stearate 4.0g

demineralized8Was8er q.s.

production:

The solid ingredients are first passed through a sieve of 0.6mm mesh. Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are intimately mixed. The other half of the starch is suspended in 65 ml of water and this suspension added to a boiling solution of Pofyäthylenglykols in 260 ml of water. The resulting paste is added to the powdery substances, the whole is mixed and granulated, if necessary with the addition of water. The granules are dried overnight at 35X, forced through a sieve of 1.2 mm mesh size and pressed on both sides concave tablets of about 10mm diameter with scored on the top. In an analogous manner, tablets containing 10 mg of another compound of the formula I according to Examples 1 to 10 can be prepared, these also in the form of salts with bases, for. B. as disodium salt may be present.

Example 16:

Gelatin capsules containing 100 mg of active ingredient, e.g. 1- (tniazol-2-ylamino) methane-1,1-diphosphonic acid or a salt, e.g. the sodium salt thereof can be prepared as follows:

Composition (for 1000 capsules) Active substance 350.0 g

microcrystalline cellulose 30.0 g

Sodium lauryl sulfate 2.0 g

Magnitium stearate 8.0 g

Sodium lauryl sulfate is sieved through a 0.2 mm mesh screen to the drug (lyophilized) and intimately mixed for 10 minutes. For dit microcrystalline cellulose is sieved through a sieve with a mesh size of 0.9 mm and again 10 minutes inniy mixed. Finally, the magnesium stearate is filtered through a sieve with a mesh size of 0.8 mm and, after 3 minutes of further mixing, each 390 mg of the mixture is filled into gelatin size 0 capsules (elongated).

In an analogous manner, capsules containing 100 mg of another compound of the formula I can be prepared according to the Seispielen 1 to 10, which also in the form of salts with bases, for. B. as Disatriumsab, may be present.

Example 17:

For example, a 0.2% solution for injection or infusion may be prepared as follows

Active ingredient, e.g. 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acids or a salt, e.g. As the sodium salt thereof 5.0 g

Sodium chloride 22.5 g

PHhr buffer pH = 7.4 300.0 g

Water, bntmin. ad 2500.0 ml

The active ingredient is dissolved in 1000 ml of water and filtered through a microfilter. It is mixed with the Pufferlosuno and filled with water to 2500ml. For the preparation of dosage unit forms are each 1.0 or 2.5 ml in glass ampules (containing 2.0 or 5.0 mg of active ingredient) filled.

Claims (23)

1. Process for the preparation of heteroarylaminomethane diphosphonic acids of the formula POiH? Ri-N-CH (I), R ₂ PO ₃ H ₂ wherein Ri is an unsubstituted or lower alkyl, unsu'ostituiertes or by lower alkyl, lower alkoxy and / or halogen-substituted phenyl, Niedsralkoxy, hydroxy, Diniederalkylamino, lower alkylthio and / or halogen C-substituted and / or lower alkyl, unsubstituted or lower alkyl, lower alkoxy and / or halogen-substituted phenylthioalkyl N-substituted optionally benzo or cyclohexeno-fused 5-membered, as heteroatom (s) 2 to 4N atoms or 1 or 2N-atomo and 1 O- or S-atom having heteroaryl and R _{2 is} hydrogen or lower alkyl, with the proviso that R _{2 is} different from hydrogen, when R _{1 is} a substituted by alkyl and / or halogen-substituted pyrazol-3-yi- or lsoxazol-3-yl radical, and their salts, characterized in that a) in a compound of the formula optionally protected intermediately at a substitutable N atom of the radical R ₁ xl Ri-S-C-H (II), wherein X _{1 is} a functionally modified phosphono group X and X ₂ phosphono or also a functionally modified phosphono group X, the group (s) X is converted into free phosphono b) a compound of the formula which may optionally be intermediately protected on a substitutable N atom of the radical R ₁ -I) -CH-O _{|| m} K ₁ -J-C first reacting with phosphorus trioxide and then with water and, if desired, in each case converting a compound obtained into another compound of the formula I and / or a free compound obtained into a salt or a salt obtained into the free compound or into another salt. 2. The method according to claim 1 for the preparation of Heteroarylaminomethandiphosphonsäuren the formula wherein R 1 is an unsubstituted or lower alkyl, unsubstituted or substituted by lower alkyl, lower alkoxy and / or halogen-substituted phenyl, lower alkoxy, hydroxy, di-lower alkylamino, lower alkylthio and / or halogen mono- or disubstituted imidazolyl, benzimidazolyl, 2H-1,2,3 or 4H Is 1,2,4-triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzthiazolyl or thiadiazolyliest and R _{2 is} hydrogen or lower alkyl, and their salts, characterized in that a) in a compound of the formula wherein X represents a group of the formula -CH (X ₁ ) (X ₂ ) Il a, wherein X _{1 is} a functionally modified phosphono group X ₃ and X ₂ phosphono or also a functionally modified phosphono group X ₃ , the group (n) X ₃ in transferred free phosphono and -2 265 SKH) if desired, converting a compound obtained into another compound of the formula I and / or a free compound obtained in a salt or a salt obtained into the free compound or into another salt. 3. The method according to claim 1, characterized in that compounds of formula I, wherein Ri is a C-unsubstituted or lower alkyl, lower alkoxy, unsubstituted or by lower alkyl, lower alkoxy and / or halogen mono- or disubstituted phenyl, hydroxy, Diniederalkylamino, Niederalkylthio and / or halo C-mono- or C-disubstituted phenyl-lower alkyl, unsubstituted or preferably substituted by lower alkyl or unsubstituted or by lower alkyl, lower alkoxy and / or halogen or di-substituted N-monosubstituted imidazolyl, 3enzimidazolyl- , 2H-1,2,3- or 4h-1,2,4-triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzthiazolyl or thiadiazolyl and R _{2 is} hydrogen or lower alkyl stands, or produces their salts. 4. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} a unsubstitutarten or by lower alkyl, lower alkoxy, unsubstituted or by lower alkyl, lower alkoxy and / or halogen mono- or disubstituted phenyl, hydroxy, di-lower alkylamino, lower alkylthio and or halogen mono- or disubstituted imidazolyl, benzimidazolyl, 2H-1,2,3- or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, • Benzthiazolyl- or Thiadiazolyl and R _{2 is} hydrogen or lower alkyl, or produces their salts. 5. The method according to claim 2, characterized in that compounds of formula I, wherein R _{1 is} an unsubstituted or lower alkyl, lower alkoxy, unsubstituted or by lower alkyl, lower alkoxy and / or halogen roc.io- or disubstituted phenyl, hydroxy, di-lower alkylamino, Lower alkylthio and / or halogeno, n- or disubstituted imidiazolyl, benzimidazolyl, 2H-1,2,3- or 4H-1,2,4-triazolyl, tetoyl, oxazolyl, benzoxazolyl, oxadiazolyl , Thiazolyl, benzthiazolyl or thiadiazolyl and R _{2 is} hydrogen or lower alkyl, or produces their salts. 6. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} an unsubstituted or by C ₁ -C ₄ -AlkVl ° of an unsubstituted or by C ₁ -C ₄ -AIkYl, C ₁ -C ₄ -Alkoxy and / or halogen mono- or di-substituted phenyl radical C-substituted thiazolyl radical, benzothiazol-2-yl radical, thia-diazolyl radical, oxazolyl radical or benzoxazol-2-ylre3t and / or by C ₁ -C ₄ -A ^ yI or an unsubstituted or by C ₁ -C ₄ -A ^ yI, C ₁ -C ₄ alkoxy and / or halogen mono- or di-substituted phenyl-C 1 -C ₄ -alkyl radical N-substituted imidazol-2-yl radical or benzimidazol-2-yl radical ur d R _{2 is} hydrogen, or produces their salts. 7. The method according to claim 2, characterized in that compounds of formula I, wherein R _{1 is} an unsubstituted or by C ₁ -C ₄ -A ^ yI, C ₁ -C ₄ -alkoxy, phenyl, hydroxy, di-dC- Alkylamino, C ₄ -C ₄ -alkylthio or halogen of the atomic number to and with 35 substituted thiazolyl and R _{2 is} hydrogen, or produces their salts. 8. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} an unsubstituted or by C ₁ -C ₄ -AlkVl, C ₁ -C ₄ -AIkOX /, phenyl, hydroxy, di-dC ^ alkylamino , d-dj-alkylthio, or halogen of the atomic number to and with 35 C-substituents thiazolyl radical, 1-C 1 -C ₄ -alkylimidazol-2-yl or 4-yl radical or phenyl-C, C ₄ -alkylimidazole-2-one yl or -4-rest and R _{2 is} hydrogen, or produces their salts. 9. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} an unsubstituted or mono- or disubstituted by C ₁ -C ₄ -AIkYl or phenyl thiazol-2-yl radical, an unsubstituted or in the 1-position by C ₁ -C ₄ -AIM or phenyl-dC ^ alkyl monosubstituted imidazol-2-yl or benzimidazol-2-yl radical or an unsubstituted benzoxazol-2-yl or benzthiazol-2-ylrect and R _{2 is} hydrogen , or their salts. 10. The method according to claim 1, characterized in that one produces 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof. 11. The method according to claim 1, characterized in that one produces 1- (methyl-1,3,4-thiadiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof. 12. The method according to claim 1, characterized in that one produces 1- (1,3,4-thiadiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof. 13. The method according to claim 1, characterized in that one produces 1- (1-methylimidazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof. 14. The method according to claim 1, characterized in that one produces 1- (oxazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof. 15. The method according to claim 1, characterized in that one produces 1- (3-phenyl-1,2,4-thiadiazol-5-ylamino) methane-1,1-diphosphonic acid or a salt thereof. 16. The method according to claim 1, characterized in that one prepares 1- (Benzimidazüf-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof. 17. The method according to claim 1, characterized in that one produces 1- (benzothiazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof. 18. The method according to claim 1, characterized in that one produces 1- (benzoxazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof. 19. The method according to claim 1, characterized in that one produces 1- (4-methylthiazol-2-ylamino) mathan-1,1-diphosphonic acid or a salt thereof. 20. The method according to claim 1, characterized in that one prepares ~ 1- (5-methylthiazol-2-ylamino) methano-1,1-diphosphonic acid or a salt thereof. 21. The method according to claim 1, characterized in that one produces 1- (5-phenylthiazol-2-ylamino) methano-1,1-diphosphonic acid or a salt thereof. 22. The method according to claim 1, characterized in that one produces 1- (4-Phanylthiazol-2-ylamino) methano-1,1-diphosphonic acid or a salt thereof. 23. The method according to claim 2, characterized in that 1- (thiazol-2-ylamino) methane-1,1-diphosphonic acid. 1- (oxazol-2-ylamino) methane-1,1-diphosphonic acid, 1- (benzimidazol-2-ylamino) -methane-1,1-diphosphonic acid, 1- (benzthiazol-2-ylamino) -methane-1,1 diphosphonic acid or 1- (benzoxazol-2-ylamino) methane-1,1-diphosphonic acid or a salt thereof.