Certain 1-hydroxyethane, 1,1-di-phosphonic acid derivatives useful in treating calcium metabolism disturbances

The present invention provides diphosphonates of the general formula: ##STR1## wherein Het is an imidazole, oxazole, isoxazole, thiazole, pyridine, 1,2,3-triazole, 1,2,4-triazole or benzimidazole radical, which is optionally substituted by alkyl, alkoxy, halogen, hydroxyl, carboxyl, an amino group optionally substituted by alkyl or alkanoyl radicals or a benzyl radical optionally substituted by alkyl, nitro, amino or aminoalkyl, A is a straight-chained or branched, saturated or unsaturated hydrocarbon chain containing 2 to 8 carbon atoms, X is a hydrogen atom, optionally substituted by alkanoyl, or an amino group optionally substituted by alkyl or alkanoyl radicals and R is a hydrogen atom or an alkyl radical; and the pharmacologically acceptable salts thereof. The present invention also provides processes for the preparation of these diphosphonates and pharmaceutical compositions containing them.

The present invention is concerned with new diphosphonic acid derivatives, 
processes for the preparation thereof and pharmaceutical compositions 
containing them. 
Federal Republic of Germany Patent Specification No. 32 03 308 describes 
arylethane-diphosphonates, for example thienylethane-diphosphonate, which 
have an outstanding anti-inflammatory action. European Patent 
Specification No. 0 084 822 describes, inter alia, 
pyrazolealkyl-diphosphonates which have an antiarthritic action. 
Federal Republic of Germany Patent Specification No. 18 13 659 describes 
diphosphonic acid derivatives of which 1-hydroxyethane-1,1-diphosphonic 
acid has achieved importance for the treatment of Paget's disease. 
We have now found that analogous derivatives of this compound, in which the 
alkyl chain is substituted by an aromatic heterocyclic radical, also 
display this action and, in addition, are well suited as good calcium 
complex formers for the wider treatment of calcium metabolism 
disturbances. In particular, they can very well be used in cases where the 
build up and breakdown of bone is disturbed, i.e. they are suitable for 
the treatment of diseases of the skeletal system, for example 
osteoporosis, Paget's disease, Bechterew's disease and the like. 
On the basis of these properties, however, they can also be used in the 
therapy of bone metastases, urolithiasis and for the prevention of 
heterotopic ossification. Due to their influencing of the calcium 
metabolism, they also form a basis for the treatment of rheumatoid 
arthritis, osteoarthritis and degenerative arthrosis. 
Thus, according to the present invention, there are provided diphosphonates 
of the general formula: 
##STR2## 
wherein Het is an imidazole, oxazole, isoxazole, thiazole, pyridine, 
1,2,3-triazole, 1,2,4-triazole or benzimidazole radical, which can 
optionally be substituted by alkyl, alkoxy, halogen, hydroxyl, carboxyl, 
an amino group optionally substituted by alkyl or alkanoyl radicals or a 
benzyl radical optionally substituted by alkyl, nitro, amino, or 
aminoalkyl, A is a straight-chained or branched, saturated or unsaturated 
hydrocarbon radical containing 2 to 8 carbon atoms, X is a hydrogen atom, 
a hydroxyl group optionally substituted by alkanoyl or an amino group 
optionally substituted by alkyl or alkanoyl radicals and R is a hydrogen 
atom or an alkyl radical; as well as the pharmacologically acceptable 
salts thereof. 
In all cases, alkyl means itself or in an alkoxy radical a hydrocarbon 
radical containing up to 4 carbon atoms, the methyl, ethyl and isopropyl 
radicals being preferred. By alkanoyl radical there is to be understood an 
alkanoyl radical containing up to 6 carbon atoms, especially a formyl, 
acetyl, propionyl, butyryl or valeroyl radical, acetyl and propionyl 
radicals being preferred. 
By halogen, there is to be understood fluorine, chlorine, bromine and 
iodine, chlorine and bromine being preferred. 
The chain A preferably means --(CH.sub.2).sub.n --, wherein n is 2 to 5, 
##STR3## 
wherein m is 2 to 5, --CH.dbd.CH--CH.sub.2 --CH.sub.2 --, 
--CH.dbd.CH--CH.sub.2 --CH.sub.2 --CH.sub.2 --and--CH.dbd.CH--CH.dbd.CH--, 
the saturated radicals being especially preferred. 
The substituent X is preferably hydroxyl or amino, hydroxyl being 
especially preferred. 
The compounds of general formula (I) can be prepared by known processes. 
For the case in which X in general formula (I) is a hydroxyl group, the 
compounds are preferably prepared in that: 
(a) a carboxylic acid of the general formula: 
EQU Het--A--COOH (II), 
in which Het and A have the above-given meanings, is reacted with a mixture 
of phosphorous acid and a phosphorus halide and subsequently saponified to 
the free diphosphonic acid, or 
(b) a carboxylic acid chloride of the general formula: 
EQU Het--A--COCl (III), 
in which Het and A have the above-given meanings, is reacted with a 
trialkyl phosphite of the general formula: 
EQU P(OR').sub.2 (IV) 
in which R' is a lower alkyl radical, to give an acyl phosphonate of the 
general formula: 
##STR4## 
in which Het, A and R' have the above-given meanings, subsequently reacted 
with a dialkyl phosphite of the general formula: 
##STR5## 
in which R' has the above-given meaning, to give a diphosphonate of the 
general formula: 
##STR6## 
in which Het, A and R' have the above-given meanings, and the resultant 
tetraester optionally saponified to diesters or acids of general formula 
(I) or for the case in which X in general formula (I) is an amino group 
optionally substituted by alkyl radicals, 
(c) a carboxylic acid derivative of the general formula: 
EQU Het--A--Z (VIII), 
in which Het and A have the above-given meanings and Z is a nitrile, imino 
ether or an N,N-dialkylcarboxamido radical, is reacted with a phosphorus 
compound of the general formula: 
EQU PT.sub.3 (IX), 
in which T is halogen, hydroxyl or OR', R' having the above-given meaning, 
and optionally subsequently saponified, or for the case in which X in 
general formula (I) is a hydrogen atom 
(d) a compound of the general formula: 
EQU Het--A--Y (X), 
in which Het and A have the above-given meanings and Y is a reactive 
residue, for example halogen or sulphonate, is reacted with a compound of 
the general formula: 
##STR7## 
in which R' has the above-given meaning, to give a diphosphonate of the 
general formula: 
##STR8## 
in which Het, A and R' have the same meanings as above, and the resulting 
tetraester optionally saponified to diesters or acids of general formula 
(I). 
The carboxylic-acids of general formula (II) used in process (a) are 
reacted with 1 to 2 and preferably 1.5 mole of phosphorous acid and 1 to 2 
and preferably 1.5 mole of phosphorus trihalide at a temperature of from 
80.degree. to 130.degree. C. and preferably of from 100.degree. to 
110.degree. C. The reaction can also be carried out in the presence of 
diluents, for example halogenated hydrocarbons, especially chlorobenzene 
or tetrachloroethane, or also dioxan. The subsequent hydrolysis can be 
carried out by boiling with water but preferably with semi-concentrated 
hydrochloric or hydrobromic acid. Phosphorus acid and phosphorus trihalide 
may be substituted in this reaction by phosphorus pentoxide, 
phosphorus-penta-halide respectively phosphorus oxi-halide. (DE-A No. 21 
30 794, DE-A No. 26 58 961, DE-A No. 27 02 631 and DE-A No. 29 43 498) 
In the case of process (b), the acid chloride of general formula (III) is 
reacted with the trialkyl phosphite of general formula (IV) at a 
temperature of from 0.degree. to 60.degree. C. and preferably of from 
20.degree. to 40.degree. C. It is possible to work without the use of a 
solvent or also in the presence of inert solvents, for example diethyl 
ether, tetrahydrofuran, dioxan or also halogenated hydrocarbons, for 
example methylene chloride. The acyl phosphonate of general formula (V) 
formed as intermediate can be isolated or also further reacted directly. 
The subsequent reaction is carried out in the presence of a weak base, 
preferably a secondary amine, such as dibutylamine, at a temperature of 
from 0.degree. to 60.degree. C. and preferably of from 10.degree. to 
30.degree. C. 
In the case of process (c), the nitriles of general formula (VIII) are 
reacted with phosphorous acid at a temperature of from 110.degree. to 
180.degree. C. The reaction can be carried out without the use of a 
solvent or in the presence of an aprotic solvent, for example diglycol 
dimethyl ether or diglycol diethyl ether. However, the nitriles can also 
be reacted with a phosphorus trihalide, for example phosphorus tribromide 
or phosphorus trichloride, in an inert solvent, for example dioxan or 
tetrahydrofuran, possibly with the addition of water, at a temperature of 
from 20.degree. to 80.degree. C. Imino ethers of general formula (VIII) 
can be reacted with dialkyl phosphites, preferably in the presence of 
equimolar amounts of sodium, in inert solvents, such as diethyl ether, 
dioxan or also benzene, whereby, as a rule, the reaction takes place at 
the reflux temperature of the solvent used. Acid amides of general formula 
(VIII) can be reacted in inert solvents, for example halogenated 
hydrocarbons or ethers, for example diethyl ether, with a mixture of a 
phosphorus pentahalide/phosphorous acid or also of oxalyl 
chloride/trialkyl phosohite. 
In the case of process (d), the methylenediphosphonic acid ester of general 
formula (XI) is used in the form of its sodium or potassium salt. For this 
purpose, it is reacted with sodium, potassium or the corresponding hydride 
in an inert solvent, for example benzene, toluene or dimethylformamide, at 
a temperature of from 0.degree. to 40.degree. C. and preferably at 
25.degree. C. The alkali salt is reacted, without isolation, with the 
appropriate halide or sulphonate. The temperature is hereby from 
20.degree. to 110.degree. C. 
The tetraalkyl esters possibly obtained in the case of processes (b), (c) 
and (d) can be saponified to diesters or to the free tetraacids. The 
saponification to diesters takes place, as a rule, by treating the 
tetraalkyl esters with an alkali metal halide, preferably sodium iodide, 
in an appropriate solvent, for example acetone, at ambient temperature. 
There is hereby formed the symmetrical diester/disodium salt which can 
possibly be converted by means of an acidic ion exchanger into the 
diester/diacid. 
As a rule, the saponification to free diphosphonic acids takes place by 
boiling with hydrochloric or hydrobromic acid. However, a splitting can 
also be carried with a trimethylsilyl halide, preferably the bromide or 
iodide. On the other hand, the free diphosphonic acids can again be 
converted into the tetraalkyl esters by boiling with orthoformic acid 
alkyl esters. The free diphosphonic acids of general formula (I) can be 
isolated as free acids or in the form of their mono- or dialkali metal 
salts. As a rule, the alkali metal salts can be readily purified by 
reprecipitation from water/methanol or water/acetone. 
The compounds of general formula (I) can possibly be subsequently converted 
from one into another. For example, they can be alkylated or acylated or, 
when X in general formula (I) is an unsubstituted amino group, can be 
converted by diazotisation into compounds of general formula (I) in which 
X is a hydroxyl group. By means of hydrogenolytic splitting off of an 
N-benzyl radical, there can be prepared, for example, the corresponding 
unsubstituted compounds of general formula (I). 
As pharmacologically acceptable salts, there are used, in particular, the 
alkali metal or ammonium salts which are prepared in conventional manner, 
for example by neutralisation of the compounds with inorganic or organic 
bases, for example sodium or potassium hydrogen carbonate, aqueous sodium 
hydroxide solution, aqueous potassium hydroxide solution, aqueous ammonia 
solution or with amines, for example trimethylamine or triethylamine. 
The new compounds of general formula (I) according to the present invention 
and the salts thereof can be administered enterally and parenterally in 
liquid or solid form. There can hereby be used all conventional forms of 
administration, for example tablets, capsules, dragees, syrups, solutions, 
suspensions and the like. As injection medium, it is preferred to use 
water which contains the additives usual in the case of injection 
solutions, such as stabilising agents, solubilising agents and buffers. 
Such additives include, for example, tartrate and citrate buffers, 
ethanol, complex formers (such as ethylenediamine-tetraacetic acid and the 
nontoxic salts thereof) and high molecular weight polymers (such as liquid 
polyethylene oxide) for viscosity regulation. Liquid carriers for 
injection solutions must be sterile and are preferably placed into 
ampoules. Solid carrier materials include, for example, starch, lactose, 
mannitol, methyl cellulose, talc, highly dispersed silicic acids, high 
molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, 
calcium phosphate, magnesium stearate, animal and vegetable fats and solid 
high molecular weight polymers (such as polyethylene glycols). 
Compositions suitable for oral administration can, if desired, contain 
flavouring and sweetening materials. 
The dosaging can depend upon various factors, such as the mode of 
administration, species, age and/or individual conditions. The doses to be 
administered daily are about 1 to 1000 mg/human and preferably 10 to 200 
mg/human and can be taken one or more times. 
Preferred compounds according to the present invention, apart from the 
compounds mentioned in the following Examples and the compounds derivable 
therefrom by combination of the substituents having the meanings given in 
the claims, include the following diphosphonates: 
1-hydroxy-5-(lH-2-imidazolyl)-pentane-1,1-diphosphonic acid 
1-hydroxy-3-(1,2H-5-methylimidazolin-2-on-4-yl)-propane-1,1-diphosphonic 
acid 
1-hydroxy-4-(1,3H-5-methylimidazolin-2-on-4-yl)-butane-1,1-diphosphonic 
acid 
1-hydroxy-5-(1,3H-5-methylimidazolin-2-on-4-yl)-pentane-1,1-diphosphonic 
acid 
3-(1,3,5-trimethylimidazolin-2-on-4-yl)-1-hydroxypropane-1,1-diphosphonic 
acid 
4-(1,3,5-trimethylimidazolin 2-on-4-yl)-1-hydroxybutane-1,1-diphosphonic 
acid 
5-(1,3,5-trimethylimidazolin-2-on-4-yl)-1-hydroxypentane-1,1-diphosphonic 
acid 
1-hydroxy-3-(1,2,4-triazol-3-yl)-propane-1,1-diphosphonic acid 
1-hydroxy-5-(1,2,4-triazol-3-yl)-pentane-1,1-diphosphonic acid 
1-hydroxy-4(1,2,4-triazol-1-yl)-butane-1,1-diphosphonic acid 
1-hydroxy-4-(1,2,3-triazol-4-yl)-butane-1,1-diphosphonic acid 
1-hydroxy-4-(1-methyl-1,2,3-triazol-4yl)-butane-1,1-diphosphonic acid 
4-(1-benzyl-1,2,3-triazol-4-yl)-1-hydroxybutane-1,1-diphosphonic acid 
3-(5-amino-1,2,3-triazol-4-yl)-1-hydroxypropane-1,1-diphosphonic acid 
5-(5-amino-1,2,3-triazol-4-yl)-1-hydroxypentane-1,1-diphosphonic acid 
3-(5-amino-1-methyl-1,2,3-triazol-4-yl)-1-hydroxypropane-1,1-diphosphonic 
acid 
5-(5-amino-1-methyl-1,2,3-triazol-4-yl)-1-hydroxypentane-1,1-diphosphonic 
acid 
3-(5-amino-1-benzyl-1,2,3-triazol-4-yl)-1-hydroxypropane-1,1-diphosphonic 
acid 
5-(5-amino-1-benzyl-1,2,3-triazol-4-yl)-1-hydroxypentane-1,1-diphosphonic 
acid 
1-hydroxy-3-(1,2,3-triazol-1-yl)-propane 1,1-diphosphonic acid 
1-hydroxy-5-(1,2,3-triazol-1-yl)-pentane-1,1-diphosphonic acid 
3-(2-amino-4-methyl-5-thiazolyl)-1-hydroxypropane-1,1-diphosphonic acid 
4-(2-amino-4-methyl-5-thiazolyl)-1-hydroxybutane-1,1-diphosphonic acid 
5-(2-amino-4-methyl-5-thiazolyl)-1-hydroxypentane-1,1-diphosphonic acid 
1-hydroxy-3-(2-thiazolyl)-propane-1,1-diphosphonic acid 
1-hydroxy-3-(4-thiazolyl)-propane-1,1-diphosphonic acid 
1-hydroxy-3-(5-thiazolyl)-propane-1,1-diphosphonic acid 
3-(2-acetylamino-4-thiazolyl)-1-hydroxypropane-1,1-diphosphonic acid 
3-(2-amino-4-thiazolyl)-1-hydroxypropane-1,1-diphosphonic acid 
4-(2-amino-4-thiazolyl)-1-hydroxybutane-1,1-diphosphonic acid 
5-(2-amino-4-thiazolyl)-1-hydroxypentane-1,1-diphosphonic acid 
5-(1-methyl-1,2,3-triazol-4-yl)-1-propionyloxypentane-1,1-diphosphonic acid 
5-(1-benzyl-1,2,3-triazol-4-yl)-1-propionylpentane-1,1-diphosphonic acid 
5-(1-benzyl-1,2,3-triazol-4-yl)-1-hydroxy-2,4-pentadiene-1,1-diphosphonic 
acid 
1-hydroxy-5-(1,2,3-triazol-2-yl)-pentane-1,1-diphosphonic acid 
1-hydroxy-4-(1,2,3-triazol-2-yl)-butane-1,1-diphosphonic acid 
1-hydroxy-3-(1-methyl-2-benzimidazolyl)-propane-1,1-diphosphonic acid 
1-hydroxy-5-(1-methyl-2-benzimidazolyl)-pentane-1,1-diphosphonic acid 
3-(5-benzimidazolyl)-1-hydroxypropane-1,1-diphosphonic acid 
5-(5-benzimidazolyl)-1-hydroxypentane-1,1-diphosphonic acid 
1-hydroxy-3-(2-methyl-5-benzimidazolyl)-propane-1,1-diphosphonic acid 
1-hydroxy-5-(2-methyl-5-benzimidazolyl)-pentane-1,1-diphosphonic acid 
1-hydroxy-3-(6-methyl-5-benzimidazolyl)-propane-1,1-diphosphonic acid 
1-hydroxy-5-(6-methyl-5-benzimidazolyl)-pentane-1,1-diphosphonic acid 
3-(2,6-dimethyl-5-benzimidazolyl)-1-hydroxypropane-1,1-diphosphonic acid 
5-(2,6-dimethyl-5-benzimidazolyl)-1-hydroxypentane-1,1-diphosphonic acid 
5-(2-benzimidazolyl)-1-hydroxypentane-1,1-diphosphonic acid 
3-(1,3H-benzimidazolin-2-on-5-yl)-1-hydroxypropane-1,1-diphosphonic acid 
5-(1,3H-benzimidazolin-2-on-5-yl)-1-hydroxypentane-1,1-diphosphonic acid 
3-(1,3-dimethylbenzimidazolin-2-on-5-yl)-1-hydroxypropane-1,1-diphosphonic 
acid 
5-(1,3-dimethylbenzimidazolin-2-on-5-yl)-1-hydroxypentane-1,1-diphosphonic 
acid 
1-acetoxy-3-(4-imidazolyl)-propane 1,1-diphosphonic acid 
1-amino-3-(4-imidazolyl)-propane-1,1-diphosphonic acid 
1-dimethylamino-3-(4-imidazolyl)-propane-1,1-diphosphonic acid 
1-acetamido-3-(4-imidazolyl)-propane-1,1-diphosphonic acid 
3-(4-imidazolyl)-propane-1,1-diphosphonic acid 
1-acetoxy-5-[1-benzyl-4-(1,2,3-triazolyl)]-pentane-1,1-diphosphonic acid 
1-amino-5-1-benzyl-4-(1,2,3-triazolyl)]-pentane-1,1-diphosphonic acid 
5-[1-benzyl-4-(1,2,3-triazolyl)]-1-methylaminopentane-1,1-diphosphonic acid 
3-(4-imidazolyl)-1-propionyloxypropane-1,1-diphosphonic acid. 
1-Hydroxy-3-(2-methyl-4-thiazolyl)propane-1.1-diphosphonic acid 
1-Hydroxy-3-(2-methyl-5-thiazolyl)propane-1.1-diphosphonic acid 
1-Hydroxy-3-(2-methyl-4-imidazolyl)propane-1.1-diphosphonic acid 
1-Hydroxy-4-(4-imidazolyl)butane-1.1-diphosphonic acid 
1-Hydroxy-3-(3-methyl-4-isoxazolyl)propane-1.1-diphosphonic acid 
3-(3-Chlor-5-isoxazolyl)-1-hydroxypropane-1.1-diphosphonic acid 
1-Hydroxy-3-(3-methoxy-5-isoxazolyl)propane-1.1-diphosphonic acid 
1-Hydroxy-3-(2-methyl-4-oxazolyl)propane-1.1-diphosphonic acid 
3-(4.5-Dimethyl-2-oxazolyl)-1-hydroxypropane-1.1-diphosphonic acid 
4-(4.5-Dimethyl-2-oxazolyl)-1-hydroxybutane-1.1-diphosphonic acid 
5-(4.5-Dimethyl-2-oxazolyl)-1-hydroxypentane-1.1-diphosphonic acid 
3-(2-Benzyl-4-oxazolyl)-1-hydroxypropane-1.1-diphosphonic acid 
5-(2-Benzyl-4-oxazolyl)-1-hydroxypentane-1.1-diphosphonic acid

The following Examples illustrate some of the process variants which can be 
used for the synthesis of the compounds according to the present 
invention. However, they do not constitute a limitation of the present 
invention. As a rule, the compounds are obtained as solid products with 
high melting points, the structures of which have been verified by H- and 
P-NMR spectroscopy. 
EXAMPLE 1 
1-Hydroxy-3-(4-imidazolyl)-propane-1,1-diphosphonic acid 
3.53 g. (20 mMol) 3-(4-imidazolyl)-propionic acid hydrochloride are heated 
with 2.26 g. phosphorous acid in 10 ml. chlorobenzene to 110.degree. C., 
while stirring. 4.12 g. (30 mMol) phosphorus trichloride are slowly added 
dropwise thereto and heating continued for 4 hours at 110.degree. C. After 
cooling, the chlorobenzene is decanted off and the residue boiled under 
reflux for 5 hours with 15 ml. 6N hydrochloric aci. The reaction mixture 
is allowed to cool, mixed with active charcoal, filtered and the filtrate 
evaporated. The residue is taken up in 10 ml. water, the solution is 
adjusted with an aqueous solution of sodium bicarbonate to a pH value of 
5.5 and mixed with methanol until no further precipitate is formed. The 
precipitate is filtered off with suction, washed with methanol and dried. 
There are obtained 3.23 g. (48% of theory) of the title compound. The 
product is obtained as the monosodium salt with 1 mole of water of 
crystallisation. 
In an analogous manner, there are obtained the following compounds by the 
use of: 
(a) 3-(3-pyridyl) -propionic acid: 
1-hydroxy-3-(3-pyridyl)-propane-1,1-phosphonic acid in a yield of 25% of 
theory. The product is obtained as the monosodium salt with 1.5 moles of 
water of crystallisation. 
(b) 3-[1-benzyl-4-(1,2,3-triazolyl)]-propionic acid (m.p. 
110.degree.-112.degree. C.; prepared by hydrogenation of 
3-[1-benzyl-4-(1,2,3-triazolyl)]-acrylic acid): 
3-[1-benzyl-4-(1,2,3-triazolyl)]-1-hydroxypropane-1,1-diphosphonic acid in 
a yield of 48% of theory. The product is obtained as the dosodium salt 
with 1 mole water of crystallisation. 
(c) 5-[1-benzyl-4-(1,2,3-triazolyl)]-valerianic acid (m.p. 
84.degree.-85.degree. C.; prepared by hydrogenation of 
5-[1-benzyl-4-(1,2,3-triazolyl)]-2,4-pentadienoic acid): 
5-[1-benzyl-4-(1,2,3-triazolyl)]-1-hydroxypentane-1,1-diphosphonic acid in 
a yield of 53% of theory. The product is obtained as the disodium salt 
with 1 mole of water of crystallisation. 
(d) 3-(4-pyridyl)-propionic acid: 
1-hydroxy-3-(4-pyridyl)-propane-1,1-diphosphonic acid in a yield of 56% of 
theory. The product is obtained as the monosodium salt with 2 moles water 
of crystallisation. 
(e) 3-(2-pyridyl)-propionic acid: 
1-hydroxy-3-2-pyridyl)-propane-1,1-diphosphonic acid in a yield of 54% of 
theory. The product is obtained as the monosodium salt with 2 moles water 
of crystallisation. 
(f) 3-(2-benzimidazolyl)-propionic acid: 
3-(2-benzimidazolyl)-1-hydroxypropane 1,1-diphosphonic acid in a yield of 
24% of theory. The product is obtained as the monosodium salt with 1.5 
moles water of crystallisation. 
(g) 5-(1-methyl-1,2,3-triazol-4-yl)-valerionic acid (m.p. 
74.degree.-76.degree. C.): 
1-hydroxy-5-(1-methyl-1,2,3-triazol-4-yl)-pentane-1,1-diphosphonic acid in 
a yield of 36% of theory. The product is obtained as the disodium salt 
with 2 moles water of crystallisation. 
(h) 3-(1-methyl-1,2,3-triazol-4-yl)-propionic acid: 
1-hydroxy-3-(1-methyl-1,2,3-triazol-4-yl)-propane-1,1-diphosphonic acid in 
a yield of 50% of theory. The product is obtained as the disodium salt 
with 2 moles water of crystallisation. 
(i) 3-(1-ethyl-1,2,3-triazol-4-yl)-propionic acid: 
3-(1-ethyl-1,2,3-triazol-4-yl)-hydroxypropane-1,1diphosphonic acid in a 
yield of 54% of theory. The product is obtained as the disodium salt with 
1 mole water of crystallisation. 
(j) 3-[1-(4-methylbenzyl)-1,2,3-triazol-4-yl]-propionic acid: 
1-hydroxy-3-[1-(4-methylbenzyl)-1,2,3-triazol-4-yl]-propane-1,1-diphosphoni 
c acid in a yield of 40% of theory. The product is obtained as the disodium 
salt with 1.5 moles water of crystallisation. 
(k) 3-[1-(4-aminomethylbenzyl)-1,2,3-triazol-4-yl]-propionic acid (m.p. 
207.degree.-210.degree. C.; prepared by catalytic hydrogenation of 
3-[1-(4-cyanobenzyl)-1,2,3-triazol-4-yl]-acrylic acid (m.p. 
168.degree.-170.degree. C.) which is obtained by oxidation of the 
corresponding 3-[1-(4-cyanobenzyl)-1,2,3-triazol-4-yl]-acrolein (m.p. 
152.degree.-155.degree. C.)): 
3-[1-(4-aminomethylbenzyl)-1,2,3-triazol-4-yl]-1-hydroxypropane-1,1-diphosp 
honic acid in a yield of 41% of theory. The product is obtained as the 
disodium salt with 1 mole water of crystallisation. 
(1) 3-[1-(3-nitrobenzyl)-1,2,3-triazol-4-yl]-propionic acid (m.p. 
147.degree.-150.degree. C.; prepared by reduction by means of 
hydroxylamine-O-sulphonic acid of 
3-[1-(3-nitrobenzyl)-1,2,3-triazol-4-yl]-acrylic acid (m.p. 
155.degree.-158.degree. C.), which is obtained by oxidation of the 
corresponding 3-[1-(3-nitrobenzyl)-1,2,3-triazol-4-yl]-acrolein (m.p. 
136.degree.-140.degree. C.): 
1-hydroxy-3-[1-(3-nitrobenzyl)-1,2,3-triazol-4-yl]-propane-1,1-diphosphonic 
acid in a yield of 22% of theory. The product is obtained as the disodium 
salt with 2 moles water of crystallisation. 
(m) 3-(1,2,4-triazol-1-yl)-propionic acid: 
1-hydroxy-3-(1,2,4-triazol-1-yl)-propane-1,1-diphosohonic acid in a yield 
of 45% of theory. The product is obtained as the disodium salt with 1.5 
moles water of crystallisation. 
(n) 3-(1,2,4-triazole-1-yl)-butyric acid: 
1-hydroxy-3-(1,2,4-triazol-1-yl)-butane-1,1-diphosphonic acid in a yield of 
44% of theory. The product is obtained as the disodium salt with 1.5 moles 
water of crystallisation. 
(o) 5-(1,2,4-triazol-1-yl)-valerianic acid: 
1-hydroxy-5-(1,2,4-triazol-1-yl)-pentane-1,1-diphosphonic acid in a yield 
of 53% of theory. The product is obtained as the disodium salt with 1.5 
moles water of crystallisation. 
(p) 3-(1-benzylimidazol-2-yl)-propionic acid: 
3-(1-benzylimidazol-2-yl)-1-hydroxypropane-1,1-diphosphonic acid in a yield 
of 71% of theory. The product is isolated as the free acid with the m.p. 
230.degree.-232.degree. C. (foaming up). 
EXAMPLE 2 
1-Hydroxy-3-[4-(1,2,3-triazolyl)]-propane-1,1-diphosphonic acid. 
1 g. 3-[1-benzyl-4-(1,2,3-triazolyl)]-1-hydroxypropane-1,1-diphosphonic 
acid (see Example 1 (b)) is dissolved in 40 ml. water and hydrogenated at 
ambient temperature in the presence of 0.5 g. 10% palladium on charcoal. 
The take up of hydrogen is finished after about 6 hours. The catalyst is 
filtered off with suction, the filtrate is evaporated, dried and the 
residue is triturated with methanol. There are obtained 0.74 g. (99% of 
theory) of the title compound. The product is obtained as the monosodium 
salt with 1 mole water of crystallisation. 
In an analogous manner, there are obtained by the hydrogenation of: 
(a) 5-[1-benzyl-(1,2,3-triazol-4-yl)-1-hydroxypentane-1,1-diphosphonic acid 
(disodium salt; see Example 1 (c)): 
1-hydroxy-5-(1,2,3-triazol-4-yl)-pentane-1,1-diphosphonic acid in a yield 
of 86% of theory. The product is obtained as the disodium salt with 2 
moles water of crystallisation. 
(b) 3-(1-benzylimidazol-2-yl)-1-hydroxypropane-1,1-diphosphonic acid (see 
Example 1 (p)): 
1-hydroxy-3-(imidazol-2-yl)-propane-1,1-diphosphonic acid in a yield of 26% 
of theory; m.p. 238.degree. C. sintering, 240.degree.-244.degree.C. with 
foaming. 
(c) 
1-hydroxy-3-[1-(3-nitrobenzyl)-1,2,3-triazol-4-yl]-propane-1,1-diphosphoni 
c acid (disodium salt; see Example 1 (l)): 
3-[1-(3-aminobenzyl)-1,2,3-triazol-4-yl]-1-hydroxypropane-1,1-diphosphonic 
acid in a yield of 60% of theory. The product is obtained as the disodium 
salt with 2 moles water of crystallisation.