Diphosphonoalkane carboxylic acids, process of preparation and methods of use

Diphosphonoalkane carboxylic acids having the formula ##STR1## wherein R is H or --CH.sub.2 --CH.sub.2 --COOH; as well as their water-soluble salts. The compounds are excellent sequestering agents, especially for alkaline earth and earth metal ions. They are stabilizers for percompounds and are useful in the delaying of the setting times for gypsum. In addition, the compounds are useful in cosmetic preparations, such as toothpastes and mouthwashes where they prevent formation of tartar and plaque and are useful in therapy in the treatment of diseases related to the abnormal deposition or dissolution of difficultly soluble calcium salts in the animal body.

The Related Art 
Compounds of the oligocarboxylic alkane phosphonic acids type have gained 
in importance in recent times owing to their sequestering action. 
Compounds of this type are used as builder substances in cleaning agents, 
a substantial advantage residing in their satisfactory hardness 
stabilization with small dosages, particularly in the cleaning of 
containers and bottles. 2-phosphono-butane-1,2,4-tricarboxylic acid and 
3-phosphono-pentane-1,3,5-tricarboxylic acid have proved to be 
particularly suitable in practice. 
OBJECTS OF THE INVENTION 
An object of the present invention is the obtaining of a diphosphonoalkane 
carboxylic acid selected from the group consisting of (A) a compound of 
the formula 
##STR2## 
wherein R is selected from the group consisting of hydrogen and --CH.sub.2 
--CH.sub.2 --COOH, and (B) a non-toxic, pharmacologically-acceptable 
water-soluble salt thereof. 
Another object of the present invention is the development of a process for 
the production of the above-diphosphonoalkane carboxylic acid by reacting 
an ester of methylene diphosphonic acid with an ester of acrylic acid 
under alkaline conditions and hydrolyzing the resultant ester of 
diphosphonoalkane carboxylic acid. 
A further object of the present invention is the development of a process 
for the delaying or inhibiting of the precipitation of alkaline earth 
metal ions from solution by the use of stoichiometric to 
sub-stoichiometric amounts of the above diphosphonoalkane carboxylic acids 
or their water-soluble salts. 
These and other objects of the present invention will become more apparent 
as the description thereof proceeds. 
DESCRIPTION OF THE INVENTION 
The subject of the invention is new diphosphonoalkane carboxylic acids and 
water-soluble salts thereof. The said compounds are good complex formers 
and have further valuable properties with respect to their technical use. 
Unexpectedly, it was found that the new diphosphonoalkane carboxylic acids 
described hereinafter have considerably better properties than the 
oligocarboxylic alkane phosphonic acids described by the prior art. 
The new diphosphonoalkane carboxylic acids correspond to Formula I: 
##STR3## 
in which R .dbd. --H or represents --CH.sub.2 --CH.sub.2 --COOH, as well 
as their water-soluble salts. More particularly the present invention 
relates to a diphosphonoalkane carboxylic acid selected from the group 
consisting of (A) a compound of the formula 
##STR4## 
wherein R is selected from the group consisting of hydrogen and --CH.sub.2 
--CH.sub.2 --COOH, and (B) a non-toxic pharmacologically-acceptable 
water-soluble salt thereof. 
Compounds of the Formula I, in which R .dbd. -H, can be produced by 
reacting an acrylic acid ester with a methylene diphosphonic acid ester in 
the molar ratio of 1:1 in the presence of basic catalysts, such as, in 
particular, alkali metal lower alkanolates. The reaction product is then 
converted to the desired acid by saponification. 
Diphosphonoalkane carboxylic acids of the Formula I, in which R .dbd. 
--CH.sub.2 --CH.sub.2 --COOH, are obtained in a similar manner by reacting 
an acrylic acid ester with a methylene diphosphonic acid ester in the 
molar ratio of at least 2:1 in the presence of basic catalysts, and 
subsequently saponifying the reaction product. 
More particularly then, the processes are, respectively, a process for the 
production of the diphosphonoalkane carboxylic acid of Formula I wherein R 
is hydrogen, consisting essentially of reacting a lower alkyl ester of 
acrylic acid with a lower alkyl ester of methylene diphosphonic acid in a 
1:1 molar ratio in the presence of a strong basic catalyst, saponifying 
the reaction product under aqueous acidic saponification conditions and 
recovering said diphosphonoalkane carboxylic acid where R is hydrogen, and 
a process for the production of the diphosphonoalkane carboxylic acid of 
Formula I, wherein R is --CH.sub.2 --CH.sub.2 --COOH, consisting 
essentially of reacting a lower alkyl ester of acrylic acid with a lower 
alkyl ester of methylene diphosphonic acid in at least a 2:1 molar ratio 
in the presence of a strongly basic catalyst, saponifying the reaction 
product under aqueous acidic saponification conditions and recovering said 
diphosphonoalkane carboxylic acid where R is --CH.sub.2 --CH.sub.2 --COOH. 
The reactions are preferably conducted in the presence of a saturated 
solution of an alkali metal lower alkanolate in a lower alkanol, such as 
CH.sub.3 ONa/CH.sub.3 OH at an elevated temperature (due to the exothermic 
reaction). The saponification is preferably conducted in a heated acidic 
aqueous solution, such as refluxing concentrated hydrochloric acid. 
The phosphonic acids described above can be converted to the corresponding 
non-toxic, pharmacologically acceptable, water-soluble salts by complete 
or partial neutralization with inorganic, organic or quaternary bases, 
such as alkali metal hydroxide, for example, NaOH, KOH, LiOH; alkali metal 
carbonates, such as Na.sub.2 CO.sub.3 ; NH.sub.4 OH; lower alkylamines, 
such as methylamine; lower alkanolamines, such as monoethanolamine, 
diethanolamine, triethanolamine; and tetra-lower-alkyl-ammonium 
hydroxides, such as tetra-methyl-ammonium hydroxide. 
The new diphosphonoalkane carboxylic acids, including their alkali metal, 
ammonium or alkanolamine salts, are satisfactory complex formers for 
alkaline earth ions, preferably calcium ions, and can, therefore, be 
specifically used for water softening operations. It is unnecessary to 
work with stoichiometric quantities, and calcite precipitations can be 
considerably delayed by using sub-stoichiometric quantities. 
Thus, they are eminently suitable as anti-corrosion and anti-scaling agents 
for cooling water, particularly combined with known additives, such as 
bivalent zinc and/or cadmium salts, orthophosphates, chromates or 
hydrazine hydrate. 
The amount which is to be regarded as stoichiometric according to the 
compound which is used can be readily determined by a simple test. 
Theoretically, 1 mol of the compound should sequester up to 2 mols of 
calcium ions. In general, the complex formers are used in quantities of 
from 1 mol per 2,000 mols of metal ions up to six times the stoichiometric 
quantity. 
Owing to the said properties, the new complex formers can also be used, for 
example, for the descaling of fabrics in which alkali salts have been 
deposited, and to reduce the ash concentration in fabrics. Furthermore, 
they are suitable for processes for cleaning rigid articles such as metal 
or glass. Their use as additive to bottle-rinsing agents is particularly 
important. 
Advantageously, the complex forming capacity can also be used in systems in 
which copper ions have an undesirable influence. Examples of this which 
may be mentioned are the avoidance of the decomposition of percompounds 
or, alternatively, the stabilization of fats and soaps. Furthermore, the 
said compounds are suitable for use as additives to dyeing baths for 
textiles in order to bind, in a complex manner, those metal ions which 
form undesirable tints. 
Finally, the complex forming capacity can also be used to feed so-called 
trace elements to plants. The satisfactory complex forming capacity of 
these compounds is also exhibited by the fact that the known red color, 
which is otherwise observed when adding rhodanide to solutions which 
contain tervalent iron, does not occur. Thus, these properties can also be 
used in an advantageous manner in order to prevent the depositing of iron 
compounds, particularly iron hydroxide, on fabrics or when washing 
bottles. The new compounds can also be used in galvanic baths instead of 
cyanides. 
Finally, they are also suitable as builder substances with complexing 
properties in washing and cleaning agents and can be used in combination 
with known anionic, cationic or non-ionic, surface-active compounds. 
Furthermore, they can be used in combination with caustic alkalies, alkali 
metal carbonates, alkali metal silicates, alkali metal phosphonates, or 
alkali metal borates. 
The diphosphonic acids which have been described are also suitable as 
active substances in pharmaceutical or cosmetic preparations which are 
used for the therapeutic or prophylactic treatment of disorders in the 
calcium or phosphate metabolism and the associated diseases. These 
diseases can be divided into two categories: 
1. Abnormal depositions of difficultly soluble calcium salts, mostly 
calcium phosphate, cause bone malformations, pathological hardening of 
tissues and secretions in organs. 
2. The abnormal dissolution of hard tissues causes losses of hard bone 
substance, which cannot be replaced or are replaced only by incompletely 
crystallized tissue. This dissolution is frequently accompanied by 
pathologically high calcium and phosphate concentrations in the plasma. 
These diseases include: osteoporosis, osteodystrophy, Paget's disease, 
myositis ossificans, Bechterew's disease, cholelithiasis, nephrolithiasis, 
urinary calculus, hardening of the arteries (sclerosis), arthritis, 
bursitis, neuritis, tetany. 
Instead of the free acids, their non-toxic pharmacologically acceptable 
salts, such as sodium, potassium, magnesium, ammonium and substituted 
ammonium salts, such as mono-, di or triethanol ammonium salts, are 
suitable for pharmaceutical use. The partial salts, in which only a 
portion of the acid protons is replaced by other cations, can be used as 
well as full salts, although partial salts, which react substantially 
neutral in aqueous solution (pH 5 to 9) are preferred. Mixtures of the 
aforesaid salts may also be used. 
The dosage of the compounds used is variable and depends upon the 
prevailing conditions, such as the nature and the seriousness of the 
disease, the duration of the treatment and the particular compound. 
Individual doses can be from 0.05 to 500 mg per kg of body weight. The 
preferred dosage is 1 to 50 mg per kg of body weight per day and can be 
administered in up to four doses daily. Owing to the limited resorption, 
the higher dosages are required in the case of oral application. In the 
case of treatment over a long period of time, smaller doses are necessary 
after high initial doses in order to maintain the desired effect. 
Doses of less than 0.05 mg/kg of body weight do not have any significant 
effect upon the pathological calcification or the resolution of calcified 
tissues. Long-term toxic side effects can occur in the case of doses in 
excess of 500 mg/kg of body weight. The described diphosphonic acids or 
their salts may be administered orally in the form of tablets or capsules, 
as well as subcutaneously, intramuscularly or intravenously in hypertonic 
solution. The preferred dosage ranges for these uses are (in mg/kg per 
day): 
Orally 1.0 to 50.0 
Subcutaneously 1.0 to 10.0 
Intramuscularly 0.05 to 10.0 
Intravenously 0.05 to 2.0 
The substances can be formulated for administration in the form of tablets, 
pills, capsules or injection solutions. 
They can be used in combination with the hormone calcitonine for the 
treatment of disorders of calcium or phosphate metabolism. Suitable 
calcitonines are synthetic and natural calcitonine obtained from pigs, 
cattle and salmon. It is also possible to use calcitonines whose 
biological efficacy has been changed by the substitution of individual 
amino acid groups in the peptide chain of the natural calcitonines which 
comprise 32 amino acids. Some of these calcitonines which have been 
mentioned are commercially available. 
In the case of animals, the substances can also be used in fodder and as 
fodder additives. 
When used in cosmetic preparations, such as mouthwashes and toothpastes, 
the diphosphonic acids in accordance with the invention or their 
pharmacologically harmless salts in concentrations of 0.01% to 5% by 
weight, prevent the formation of tartar or plaque. 
Finally, the new diphosphonic acids are also suitable as an additive to 
preparations for producing 99.sup.m technetium radio diagnostics. Diseases 
of the bones and tissues can be recognized and localized by radiography. 
The isotope technetium 99.sup.m, which has a half-life period of six 
hours, has been used for this purpose in recent times. 
Convenient devices are available for its production, from which the 
radioactive isotope in the form of 99.sup.m pertechnetate can be obtained 
by elution with an isotonic solution of common salt. 
Pertechnetate 99.sup.m differs from the radioactive fluorine or strontium 
previously used in that it does not combine specifically in the skeleton 
or in calciferous tumors in the body. It has to be reduced to a low 
oxidation stage for use and then has to be stabilized in this oxidation 
stage by means of a suitable complex former. Furthermore, the complex 
former must have a high selectivity for the preferred absorption by the 
skeleton or by calciferous tumors. 
It has been discovered that the complexing diphosphonic acids described 
above, or pharmaceutically harmless water-soluble salts thereof, are 
particularly suitable for these purposes. The phosphonic acids are used 
together with a pharmaceutically acceptable tin (II), chromium (II) or 
iron (II) salt, the reducing salts being present in stoichiometric 
subordinate quantities relative to the phosphonic acids or water-soluble 
salts thereof. Thus, it is possible to produce, in a simple manner, a 
highly stable product which is suitable for sale in a solid form as 
tablets or in the form of a solution contained in an ampoule. 
After the diphosphonic acid/reduced metal salt preparation has been added 
to a pertechnetate solution, the resultant complex forms a very effective 
means for diagnosing bone tumors, local disorders in bone metabolism and 
calciferous tissue tumors.

The present invention will now be further described by means of the 
following examples, which are not limitative in any manner. 
EXAMPLE 1 
57.6 gm (0.2 mol) of tetraethyl methylenediphosphonate and 34.4 gm (0.4 
mol) of methyl acrylate were mixed and 12 to 14 ml of freshly prepared 
saturated CH.sub.3 ONa/CH.sub.3 OH solution were added drop by drop under 
agitation. The reaction temperature reached 90.degree. C. Agitation was 
continued for 2 hours at 90.degree. C to 100.degree. C after the 
exothermic reaction had ceased. The reaction product was then subject to 
vacuum fractionation. The main fraction of the ester obtained had a 
boiling point of 210.degree. C to 216.degree. C/0.09 Torr. The density 
n.sub.D.sup.20 was 1.4513. The yield was 88%. 
The ester obtained was subsequently saponified by refluxing for a long 
period of time with concentrated hydrochloric acid and the free acid was 
separated. The yield upon saponification was approximately 86%. In 
accordance with potentiometric titration, the diphosphonoalkane 
dicarboxylic acid of the formula 
##STR5## 
(I, R .dbd. --CH.sub.2 --CH.sub.2 --COOH) which was obtained had a 
molecular weight of 330 (calculated 320). 
Analysis Values: Calculated: C 26.25% H 4.36% P 19.38%; Found: C 26.31% H 
4.72% P 18.67%. 
EXAMPLE 2 
57.6 gm (0.2 mol) of tetraethyl methylenediphosphonate and 17.2 gm (0.2 
mol) of methyl acrylate were mixed, and 10 ml of saturated sodium 
ethanolate solution were added drop by drop under agitation. The reaction 
temperature increased to 60.degree. C. The additive reaction was completed 
by postheating to 80.degree. C to 90.degree. C for 21/2 hours. 
The reaction product was subject to vacuum fractionation. The main fraction 
of the ester obtained had a boiling point of 180.degree. C to 188.degree. 
C/0.4 Torr and a density of n.sub.D.sup.20 = 1,4510. The yield was 33%. 
The ester obtained was subsequently saponified by refluxing for a long 
period of time with concentrated hydrochloric acid and the free acid was 
separated. The yield upon saponification was approximately 87%. In 
accordance with potentiometric titration, the molecular weight of the 
1,1-diphosphonopropane-3-carboxylic acid of the formula 
##STR6## 
(I, R .dbd. H), obtained in the form of dihydrate, was 280.3 (calculated 
284). 
Analysis Values: Calculated: C 16.90% H 4.93% P 21.83%; Found: C 17.16% H 
4.90% P 21.06%. 
EXAMPLE 3 
The acids of Examples 1 and 2 in aqueous solution were mixed with the 
stoichiometric amount of sodium hydroxide solution and evaporated to 
dryness to obtain, respectively: 
Hexasodium 3,3-diphosphonate-pentane-1,5-dicarboxylate and 
Pentasodium 1,1-diphosphonate-propane-3-carboxylate. 
EXAMPLE 4 
Threshold Effect - Modified Hampshire Test 
The determining of the complex binding capacity by means of the modified 
Hampshire test, that is, the dissolving of freshly precipitated 
CaCO.sub.3, clearly shows the efficacy of the new complex formers (III and 
IV). 
The compounds I to IV utilized in the test were the following: 
I 2-phosphono-butane-1,2,4-tricarboxylic acid 
Ii 3-phosphono-pentane-1,3,5-tricarboxylic acid 
Iii 3,3-diphosphono-pentane-1,5-dicarboxylic acid 
Iv 1,1-diphosphono-propane-3-carboxylic acid. 
200 mgm of the sequestering agent were dissolved in 10 ml of H.sub.2 O 
(which has been adjusted with NaOH to pHll); and 100 ml of sodium 
carbonate solution (14.3 gm of Na.sub.2 CO.sub.3 . H.sub.2 O/liter) were 
added. A calcium solution (36.8 gm of CaCl.sub.2 . 2H.sub.2 O/liter) was 
added dropwise from a burette until the cloudiness formed barely remains. 
The results are given in Table I. 
TABLE I 
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MHT Values at pH 11 
Complex Former in gm-ions of Ca/Mol Acid 
______________________________________ 
I 1.60 
II 1.26 
III 2.91 
IV 2.20 
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EXAMPLE 5 
Threshold Effect - Carbonate/Silicate Test 
The hardness-stabilizing effect in sub-stoichiometric quantities was 
determined at 60.degree. C and 95.degree. C in a sodium carbonate-silicate 
builder substance formulation. 
25 ml of water having a German hardness of 80.degree. C (Ca:Mg = 4:1) in a 
100 ml graduated cylinder were treated with the sequestering agent 
solution (7.5 mgm or 15.0 mgm). After dilution with distilled water up to 
a volume of 65 to 70 ml, 25 ml of a sodium carbonate-sodium silicate 
solution having a concentration of 4.5 gm of Na.sub.2 CO.sub.3 /liter and 
600 mgm of sodium silicate/liter (in a ratio of SiO.sub.2 :Na.sub.2 O 
.dbd. 3.36:1) were added. After filling up to the 100 ml mark, the sample 
was either heated to 60.degree. C within 20 minutes and maintained at this 
temperature for an additional ten minutes (see Table II for the results of 
this procedure); or the sample was heated to 95.degree. C within 25 to 30 
minutes and maintained at 95.degree. C for an additional 30 minutes. (See 
Table III for the results of this procedure.) 
Subsequently, the solution, the precipitated portion, and the incrustation 
tightly adhering to the glass were analyzed as to their calcium content. 
In Table II and Table III, the results of the analyses are expressed in 
percent whereby the sum of the resulting values is set equal to 100%. The 
compounds employed are identified above in Example 4. 
TABLE II 
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150 mg/liter - 60.degree. C 
Complex % CaO % CaO % CaO 
Former Dissolved Precipitated Incrustation 
______________________________________ 
I 98.8 1.0 0.2 
II 27.4 54.7 17.9 
III 100.0 0 0 
IV 100.0 0 0 
______________________________________ 
TABLE III 
______________________________________ 
150 mg/liter - 95.degree. C 
Complex % CaO % CaO % CaO 
Former Dissolved Precipitated Incrustation 
______________________________________ 
I 98.9 0.9 0.2 
II 6.1 4.4 89.5 
III 100.0 0 0 
IV 98.0 2.0 0 
______________________________________ 
EXAMPLE 6 
Pharmaceutical Preparations 
For the production of pharmaceutical preparations in the form of a tablet, 
the known methods of preparation were followed to produce a tablet having 
an effective dosage unit composition as follows: 
______________________________________ 
Compound of Example 1 100 mgm 
Lactose 100 mgm 
Starch 47 mgm 
Magnesium stearate 3 mgm 
______________________________________ 
For the production of pharmaceutical preparations in the form of a capsule, 
the known methods of preparation are followed to produce a capsule having 
an effective dosage unit composition as follows: 
______________________________________ 
Compound of Example 2 100 mgm 
Starch 20 mgm 
Sodium lauryl sulfate 1 mgm 
______________________________________ 
The compounds of the invention are interchangeable in the above 
formulations. In another series of compositions, the free acids in the 
above formulations were replaced by the corresponding amounts of the 
tetrasodium or trisodium salts of the acids, respectively. 
EXAMPLE 7 
Cosmetic Preparations 
The following recipes are suitable as a basic formula for toothpastes: 
______________________________________ 
Parts by 
Weight 
______________________________________ 
(a) Glycerin 60.0 
Water 13.5 
Sodium carboxymethyl-cellulose 
0.6 
Silicic acid zerogel 20.0 
Sodium laurylsulfate 2.0 
Essential oils 1.0 
Sweetening agent 0.4 
Compound of Example 2 2.5 
(b) Glycerin 30.0 
Water 18.5 
Sodium carboxymethyl-cellulose 
1.0 
Aluminum hydroxide 44.0 
Sodium laurylsulfate 1.0 
Pyrogenic silicic acid 1.5 
Essential oils 1.5 
Sweetening agent 0.5 
Compound of Example 1 2.0 
______________________________________ 
Suitable as a basic formulation for mouthwashes is the following recipe: 
______________________________________ 
Parts by 
Weight 
______________________________________ 
Ethyl alcohol 19.5 
Glycerin 7.5 
Water 70.0 
Essential oils 0.2 
Sodium laurylsulfate 0.1 
Antiseptic (chlorothymol) 
0.1 
Sweetening agent 0.1 
Compound of Example 2 2.5 
______________________________________ 
The corresponding neutral salts such as the sodium salts can also be 
employed. 
By regular use of the mouthwashes and/or toothpastes containing the 
above-mentioned diphosphonoalkane carboxylic acids, according to the 
invention, the formation of tartar could be considerably reduced. The 
formation of hard compact plaque on the teeth was to a great extent 
prevented. 
The preceding specific embodiments are illustrative of the practice of the 
invention. It is to be understood, however, that other expedients known to 
those skilled in the art or discussed herein may be employed without 
departing from the spirit of the invention or the scope of the appended 
claims.