DE2513966C2 - Piperidone-6,6-diphosphonic acid and process for its preparation - Google Patents

Description

CH ₂

in which R denotes a hydrogen atom or an alkyl radical having 1 to 2 carbon atoms, and their water soluble salts.

The invention also relates to a process for the preparation of diphosphonic acids of general Formula I and its water-soluble salts, which is characterized in that one a) Compounds of the general formula 11

10

15th

in which R denotes a hydrogen atom or an alkyl radical having 1 to 2 carbon atoms, and their water-soluble salts.

2. Process for the preparation of diphosphonic acids of the general formula I and their water-soluble salts, characterized in that one

a) Compounds of the general formula II R — N PO (OH)

= C C-NHR

(CH ₂ ), PO (OH) ₂

OD

30th

in which R has the above meaning, alkaline hydrolyzed and the resulting salts possibly converted into acids,

or

b) Dicarboxylic acid derivatives of the general formula

X- (CH ₂ J ₃ -X

in which X denotes the groups —CN or —CONHR and R denotes the above Has meaning, reacts with phosphorus trihalides or phosphorous acid and phosphorus trihalides and the reaction product alkaline hydrolysed and, if necessary, the salts converted into acids, or

c) Glutaric acid monoamides with phosphorus trihalides or phosphorous acid and phosphorus trihalides and the reaction hydrolyzed product and optionally converted the acid into the salts.

55

The invention relates to piperidone-6,6-diphosphonic acids of the general formula I

H ₂ O ₃ P PO ₃ H ₃

CH ₂ NO

CH ₂ C = O

\ / CH ₂

(I)

R-N-

-PO (OH)

O = C

C-NHR

(CH ₂ J ₃ PO (OH) ₂

(Π)

in which R has the above meaning, alkaline hydrolyzed and the resulting salts possibly converted into acids, or

b) Dicarboxylic acid derivatives of the general formula

X- (CH ₂ J ₃ -X

in which X denotes the groups -CN or —CONHR and R has the above meaning with Phosphorus trihalides or phosphorous acid and phosphorus trihalides and that The reaction product is hydrolyzed under alkaline conditions and, if necessary, the salts are converted into acids, or

c) Glutaric acid monoamides are reacted with phosphorus trihalides or phosphorous acid and phosphorus trihalides and the reaction product is hydrolyzed and, if appropriate, the acid is converted into the salts convicted

The preparation can be carried out by reacting suitable derivatives of glutaric acid with phosphorus trihalides or phosphorous acid and phosphorus trihalides and subsequent alkaline hydrolysis of the reaction product. In general, temperatures between 50 and 120 ^° C. are used. Suitable derivatives of glutaric acid are glutaric acid dinitrile and glutaric acid diamide. Glutaric acid diamides in which a hydrogen atom in each amido group has been replaced by an alkyl radical having 1 to 2 carbon atoms are also suitable.

The reaction can be carried out in such a way that, for example, the glutaric acid derivatives mentioned are melted with phosphorous acid and PCI _{3 is} slowly added with stirring. The resulting reaction product is then hydrolyzed under alkaline conditions. This can be done by boiling with a strong base, in particular with sodium or potassium hydroxide solution.

However, it is also possible, in particular, to start from glutaric acid diflitrile, dissolve this in an inert solvent, for example dioxane or chlorinated hydrocarbons, and then dissolve it with phosphorus trihalide offset. Thereafter, phosphorous acid, expediently dissolved in an inert one, is then continued Solvent, added and the reaction product - as described above - hydrolyzed under alkaline conditions. at If necessary, the phosphorous acid can also be omitted from the last-mentioned process a correspondingly larger amount of phosphorus trihalide is used.

Another production method consists in that one glutaric acid monoamides in the described Way with phosphorus trihalides or phosphorous acid and phosphorus trihalides and

finally the reaction product is hydrolyzed. In this case! it doesn't need to be alkaline too hydrolyze, probe, η the hydrolysis can through Addition of water can be carried out with simultaneous heating.

Phosphorus trihalides come in particular Phosphorus trichloride and phosphorus tribromide ■ in question. The latter has proven to be particularly suitable when nitriles are used as reactants. The molar quantity ratio of glutaric acid derivative to phosphorus compound in the reactions described is 1: 2 to 1: 6. When using Glutaric acid dinitrile is preferably a ratio of 1: 4 applied

If the piperidone-6,6-diphosphonic acidix at a alkaline hydrolysis in the form of the corresponding alkali salts, they will if desired after methods known per se, such as, for example, with the aid of cation exchangers, into the corresponding transferred to free acids. For the application areas described below, however, the new Phosphorus compounds also in the form of their water-soluble salts, such as in particular potassium, sodium and Find ammonium salts application. So much for the piperidone-6,6-diphosphonic acids in the form of the acids directly incurred, they can easily be converted into the water-soluble salts, for example by partial or complete neutralization with appropriate bases.

The salts correspond to the formula below

The preparation of the compounds (II) can be carried out in the rest are done by using dicarboxylic acid derivatives of the formula

XO 0 XO / O OX NO
I. / \ ll CH ₂ il / I.
C = O P. CH ₂ P. / \ \ / \ C OX \

CH ₂

Here X = hydrogen, N Η, »- or a Metal cation, but with a maximum of 3 hydrogen atoms.

Finally, it has been found that the piperidone-6,6-diphosphonic acids of the formula I given can also be used can be prepared by adding phosphonic acids of the formula (II)

R —N PO (OH)

I I

O = C C -NHR

(CH ₂ J ₃ PO (OH) ₂

where R denotes a hydrogen atom or an alkyl radical having 1 to 2 C-alkyls, hydrolyzed under alkaline conditions. To This process gives the compounds of the formula I in particularly good yields. The resulting salts can then, if desired, in per se in a known manner, for example using cation exchangers, into the corresponding acids be convicted.

where X = -CN, -CONH ₂ or -CONHR (R = alkyl radical with 1 to 2 carbon atoms), reacts with phosphorous tri-halogenides and hydrolyzes the reaction product under acidic conditions

ίο The preparation of the compounds of formula II is not the subject of the present application.

It was analytically ensured that the products from all the manufacturing methods described correspond to the cyclic formula I and the open-chain

Structure III

PO ₃ H ₂

HOOC-CH ₂ CH ₂ Ch ₂ -C-NHR

PO ₃ H ₂

where R - is a hydrogen atom or an alkyl radical with 1 to 2 carbon atoms means only occurs in minor amounts

The new piperidone-6,6-diphosphonic acids are excellent sequestering agents for polyvalent metal ions, especially divalent and trivalent metal ions. she are particularly suitable as complexing agents for alkaline earth metal ions, so that they are suitable for numerous techni see applications, such as in laundry and Cleaning agents as well as water treatment can be used; act on per connections stabilizing them.

They are also suitable as an additive for setting

35 retardation of gypsum and as a slip liquefaction agent-oa) tel.

In addition to the acids, the potassium, sodium or ammonium salts can also be used to delay the setting of gypsum. Likewise the corresponding LitWumsaL 'ϊ as well as zinc and magnesium salts have been found suitable.

They can also be used in oral and dental hygiene products to prevent the formation of tartar to avoid.

The suitability of the piperidone-6,6-diphosphonic acids to be used according to the invention for combating Tartar and preventing the formation of tartar stems from their ability even in low levels Additional amounts in the precipitation of calcium apatite the To inhibit crystal formation. Calcium apatite of the in The presence of the piperidone-6,6-diphosphonic acids according to the invention is precipitated, is X-ray amorphous in the In contrast to the crystalline apatite usually formed without this addition.

The new piperidone-6,6-diphosphonic acids are suitable as pharmacological active ingredients in pharmaceutical preparations. Namely, they show therapeutic and / or prophylactic effects in the treatment of a number of diseases related to the abnormal Deposition or dissolution of poorly soluble calcium salts in the animal body are connected. These Diseases can be divided into two categories:

Due to anomalous deposition of poorly soluble calcium salts, mostly calcium phosphate, bone deformities, pathological hardening of tissues and deposits in organs occur in the body.

2, Hard bone loss occurs due to abnormal dissolution of hard tissues, which not replaced or replaced by incompletely crystallized tissue * This dissolution is common of pathologically high calioim and phosphate concentrations accompanied in the plasma

These diseases include;

Osteoporosis ^ ostecdystrophia, Pagef's disease,

Myositis ossificans, Bechterew's disease, Lithiasis of bile, kidney, bladder, hardening of the arteries (sclerosis), Arthritis, bursitis, neuritis, tetany.

For use in pharmaceutical preparations in the treatment of these diseases or for prophylaxis In addition to the free phosphonic acids, there are also their pharmacologically harmless salts such as sodium around-. Potassium, ammonium and substituted ammonium salts such as mono-, di- or triethanolammonium salts in question. Both the partial salts in which only one Part of the arid protons replaced by other cions as well as full salts can be used, but partial salts are approximate to those in aqueous solution react neutrally (pH 5-9), preferably mixtures of the aforementioned salts can also be used.

The dosage of piperidone-6,6-diphosphonic acid can range from 0.05 to 500 mg per kg of body weight betragea The preferred dosage is 1 to 20 mg per kg of body weight and can be used up to 4 times a day administered. The higher doses are for oral administration due to the limited absorption necessary. Dosages below 0.05 mg per kg of body weight influence the pathological calcification or dissolution of bone substance only insignificant. At doses above 500 mg / kg body weight toxic side effects can occur in the long term.

The substances can be administered in tablets, pills, capsules or as injection solutions be formulated. For animals, the substances can also be used as a component of feed or feed additives Find use.

Example 1 Preparation of piperidone-6,6-diphosphonic acid

50 staggered. The precipitated sodium salt of phosphonic acid is separated off and, dissolved in water, passed through a cation exchanger. The solution is concentrated to 100 ml and covered with a layer of ethanol. The substance which crystallizes out is separated off and purified by recrystallization from HiO / methanol. Crude yield of the monohydrate 36 g = 730/0 d. Th,

b) 47 g of glutaric acid (0.5 mol) are dissolved in 100 ml of dioxane and 149 ml of PBr ₃ (1.5 mol) at 35 ° C was slowly added dropwise then the mixture is heated to 7O ⁰ C and slowly treated with a solution of 41 g H ₃ PO ₃ (0.5 mol) in 100 ml dioxane for 16 hours at 70 ⁰ C is hydrolyzed with 125 ml H2O and the reaction mixture with NäÖH to pH brought 12 while passing vori nitrogen is heated up with the steam no ammonia more escapes, the work-up is carried out as described under Ia. Crude yield of monohydrate 12 g = 8.6% of theory, based on glutaric acid dinitrile.

c) 65.5 g Glutarsäuretnonoam'd (0.5 mol) and 41 g H ₃ PO ₃ (0.5 mol) are melted at 70 ⁰ C and slowly with stirring with 43 <5 ml of PCl ₃ (0.5 mol) added After 3 hours at 70 ⁰ C is hydrolyzed with 250 ml H2O and with activated carbon boiled the hot solution is filtered and from the filtrate with 400 ml ethanol and 400 ml of acetone, the phosphoric acid precipitated crude yield of the monohydrate 9 g = 6.5% d. Th.

The piperidone-6,6-diphosphonic acid is obtained as a monohydrate, the molecular weight determined by titration (ber.277.1). In the IR spectrum, the compound shows a yco band at 1625 cm- '. Mp. 245 ° C below Decomposition.

Calc .: C 21.67 H 4.73 N 5.05 P 2236%
Found: C21.43 H 4.71 N 5.01 P 20.87%

Example 2

Production of
N-methylpiperidone-6,6-diphosphonic acid

PO ₃ H ₂ C. \ NH
I. / C = O CHj / CH ₂ CH ₂ \

55

60

a) 49 g of 2-hydroxy-2,7-dioxo-3-amino-3-phosphono-1,2-azaphosphacycloheptane monohydrate (0.178 mol) is _{adjusted to pH 12 in 400 ml of H 2} O with 2 η NaOH so long while passing e ¹ ; Nitrogen is heated until no more ammonia escapes with the steam. The solution, concentrated to 100 ml, is mixed with 300 ml of acetone H ₂ O ₃ P

PO ₃ H ₂

CH ₂ N-CH ₃

I I

CH ₂ C = O

CH ₂

g of l-methyl ^ f-dioxo ^ -hydroxy-S-methylamine-S-phosphono-l ^ -azaphosphacycloheptane (0.27 Mo!) are heated with 600 ml of 2 η KOH until no more methylamine escapes Filtration, the potassium phosphonate is separated from the alkaline solution by precipitation with ethanol and acetone, redissolved in H ₂ O and passed through a cation exchanger. The N-methylpiperidone-ee-diphosphonic acid is isolated from the solution concentrated to 100 ml with ethanol and acetone. Yield 43.2 g & 55% of theory. Th.

After drying at 50 ° C., the substance is titrimetrically determined as a monohydrate with its molecular weight of 292 (calc. 291.1). In the IR spectrum

shows the connection a yco band at 1640 cm ¹ . Mp. 258 ° C.

Calc .: C 24.75 H 5.19 N 4.81%
Found: C 24.67 H 4.91 N 4.53%

Example 3

Making the
N-ethylpiperidone-6,6-diphosphonic acid

H ₂ O ₃ P

PO ₃ H ₂

10

H ₂ O ₃ P PO ₃ H ₂

CHj NO

CH, C = O

CHj

R = H, C ₁ -C ₂ alkyl

specified.

CH,

NC ₂ H ₅

Tabel

CH ₂ C = O

\ /
CH ₂

25th

) n

20th

Phosphono-i ^ -azaphosphacycloheptane (0.06 mol) are boiled with 140 ml of 2η NaOH until no more ethylamine escapes. It is then filtered with activated charcoal and the sodium phosphonate is precipitated with ethanol and acetone. The substance is redissolved in H ₂ O, passed through a cation exchanger and the phosphonic acid is isolated from the eluate with ethanol and acetone. Yield 3.7 gs 20.4% of theory Th.

After drying at 50 ^° C., the substance is obtained as a monohydrate with a titrimetrically determined molecular weight of 300 (calc. 305.1). In the IR spectrum, the compound shows a y _C o band at 1655 cm - '.

Example 4 "

a) 12.5 g of piperidone-6,6-diphosphonic acid are dissolved with 50 ml of water and with 50 ml of 4 η LiOH solution offset. The tetralithium salt of piperidone-6,6-diphosphonic acid is obtained by adding 200 ml of ethanol failed.

b) 10.0 g of N-methylpiperidone-6,6-diphosphonic acid (0.036 mol) are dissolved with 50 ml of water. A solution of 4 g of ZnCl ₂ (0.036 mol), dissolved in 50 ml of H ₂ O, is added to this. The precipitation of the i \ Zinkphosphonats is completed by addition of 300 ml of ethanol.

c) The corresponding magnesium phosphonate is obtained if one works in the same way as under

b) described the ZnCl ₂ replaced by 3.1 g of MgCl ₂ (0.033 w mol).

Example 5
Calcium complexation

The modified Hampshire test was used to investigate calcium complexation and worked as indicated below:

1 g of the complexing agent is dissolved in 50 ml H ₂ O, adjusted with NaOH to pH 11, dissolved 50 ml of a Ca ²⁺ solution (1470 mg CaCl ₂ · 2 H 2 O / I) is in one piece, with 100 ml of a sodium carbonate solution (7 , 15 g Na ₂ CO ₃ · IOH2O / I) added. The solution of the complexing agent is then added dropwise from a burette until the calcium carbonate precipitate has dissolved again

For the sake of simplicity, only the individual substituents for are shown in the left-hand column of the table below R according to formula (I)

55

60

65

substance
R- consumption
Complexing agent solution
(mil mg CaCO ₃ H
CH ₃
C ₂ H, 3.0
2.9
2.9 g substance 830
865
865

Practically consistent results are obtained if, instead of the acids, the corresponding sodium, potassium oc ^{r 1} ammonium salts are used.

Comparative experiment

Complexing ability of phosphonic acids against calcium in the modified Hampshire test

Phosphonic acid mg CaCO ₃ / g substance Piperidop-6,6-diphosphonic acid 830 3-amino-l-hydroxypropane-l, l-di- 470 phosphonic acid Aminometnanediphosphonic acid 210 Azacycloheptane diphosphonic acid 255 Iminopyrrolidone-5,5-diphosphonic acid 725 Example 6 Threshold effect

The prevention of the precipitation of poorly soluble calcium compounds by sub-stoichiometric Amounts of the complexing agent were investigated using the Hampshire test at room temperature. How follows worked

50 mg of the complexing agent are dissolved in 10 ml of H ₂ O (adjusted to pH 11 with NaOH), and 100 ml of soda solution are added (14.3 g of NaCO ₃ · W H ₂ OzT). A calcium solution (36.8 g CaCl ₂ · 2 H2O / l) is then added dropwise from a burette until a permanent cloudiness occurs

With regard to the information in the left column of the Table see example 5.

Table II

substance
R =

consumption
Ca solution

(ml)

mg CaCOj

mg CaCOj g substance

2.2
2.6
2.8

3 y

65
70

1100 1300 1400

Table III lot
(mg) Setting time
(Min.) substance
R = 30th
30th 125
110 H
CH,

The results are summarized in the following Table IV:

Table IV

Substance R ⁼

10

Practically the same result? «Is obtained if, instead of the acids, the corresponding sodium, Potassium or ammonium salts can be used.

Ii

Example 7 Gypsum Set Retardation

Plaster of paris in the form of plaster of paris, plaster of paris or mixed with additives such as lime, sand, perlite or cellulose set relatively quickly. so that rapid processing must take place. A delay the setting time can be achieved if the phosphonic acids described are added to the gypsum masses will. This makes processing the materials easier for Ji.

In the following experiments, the phosphonic acids were added to the water before the plaster of paris was mixed. It can be mixed with the gypsum or shortly added after mixing of the gypsum instead be water-soluble salts of phosphonic acids, particularly the lithium, m sodium, potassium and ammonium salts. The following setting values were found in the eir.zclr.cn, using 20.0 g of plaster of paris and 9 ml of H2O in each case. The setting time is given as the J5 period in which the plaster was easy to spread and easy to work with.

With regard to the information in the left column of the table, see Example 5.

40

45

Comparable results are obtained when using the corresponding magnesium and zinc salts.

Example 8 Pharmaceutical Use

An essential test for the effectiveness of the compounds in physiological systems are in-vitro experiments to redissolve freshly precipitated "CaHPO ₄ " at a pH of 7.4. The test is carried out as follows: *> o

By combining 25 ml of a phosphate solution (138 g of NaH ₂ PO ₄ .H ₂ O, adjusted to pH 7.4) and 25 ml of a calcium solution (1.47 g of CaCl ₂ · 2 H ₂ O, pH 7.4) a precipitate of "CaHPO" is produced in one pour. So much solution of the complexing agent (10 mg / ml) is added dropwise from a burette that after! Hour delay time a clear. Solution has arisen

consumption
Complexing agent solution

(ml)

mg "CaHPO ₄ " g substance

4.2 4.6

815
740

With regard to the information in the left column of Table IV, see Example 5.

The effectiveness of piperidone-6,6-diphosphonic acids in preventing abnormal calcium deposits can be demonstrated in vivo in rats as follows:

This test is based on the observation that high doses of vitamin D3 cause severe calcification in the aorta of rats. 30 female rats weighing 150-200 g are divided into three groups of 10 animals each. You will be given a normal diet and tap water ad libitum during the trial period. A group of 10 animals received no further treatment. Another group of animals receives 75,000 units of vitamin Dj per kg of body weight from the 3rd to the 7th day through a tube probe. The third group also receives 75,000 units of vitamin D ₃ per body weight from the 3rd to the 7th day and additionally - also orally - 10 mg per kg weight of a piperidone-6,6-diphosphonic acid from the 1st to the 10th day. After 10 days, the animals are sacrificed and their aortas are dissected and dried at 105 ° C. for 12 hours. After determining the dry weight, the aortas are incinerated, the residue is dissolved and the calcium is determined by flame photometry. All of the piperidone-6,6-diphosphonic acids mentioned in this invention reduce the vitamin D3-induced calcification of the rat ^aortas . considerable.

The effectiveness of the compounds according to the invention for the purposes mentioned was also in vitro demonstrated by a crystallization delay test.

Supersaturated solutions of Ca ²⁺ and HPO ₄ ² ions are relatively stable, but crystallize again when apatite nuclei are added

5Ca ²⁺ + 3HPO ² T + H ₂ O
> Ca ₅ (PO ₄ ) JOH + 4H ⁺

with the release of protons. The reaction can therefore be easily carried out by base titration at constant pH follow.

400 ml of a 0.0008 molar KH ₂ PO ₄ solution are mixed with 45 ml of a 0.012 molar CaCl ₂ solution and the clear solution is adjusted to pH 7.4 with KOH after it has been heated to 35 ° C. After 30 minutes, during which the pH did not change, a suspension of 100 mg of hydroxyapatite in 50 ml of H ₂ O is added. The crystallization which started immediately is followed by pH stat titration with 0.05 η KOH

If a small amount of a piperidone-6,6-diphosphonic acid is added to the solution before the apatite is added,

so there is a strong delay in crystallization. The inhibition of crystallization is 2 mg Piperidone-6,6-diphosphonic acid in the period of 8 hours. Over 90%, with 2 mg N-methylpiperidone-6,6-diphosphonic acid over 80% in a period of 8 hours.

For the production of pharmaceutical preparations in the form of capsules according to known methods the following composition suitable as capsule content:

Piperidone-6,6-diphosphonic acid 100 mg

Strength 20 mg

Sodium Lauryl Sulphate 1 mg

Essential oils 1.0 sweetener 0.4 Piperidone-6,6-d'phosphonic acid 2.5 Glycerin 30.0 water 18.5 N at rium carboxymethy! Cellulose 1.0 Aluminum hydroxide 44.0 Sodium lauryl sulfate 1.0 Silica fumed 1.5 Essential oils 1.5 sweetener 0.5 Piperidone-6,6-diphosphonic acid 2.0

15 The following basic recipe for mouthwash is suitable for making tablets following formulation: combination suitable:

N-methylpiperidone-6,6-di- 50 mg 20th Ethyl alcohol Parts by weight phosphonic acid 100 mg Glycerin 19.5 ti Lactose OC ~. ~
- »-» " ¹ B ti / ™ .— ~ - 7.5 otäfKc 2 mg Essential oils 700 Magnesium stearate Sodium lauryl sulfate 0.2 ..: Antiseptic (chlorothymol) 0.1 sweetener 0.1 Example 9 Piperidone-6,6-diphosphonic acid 0.1 Cosmetic preparations 2.5

The following formulations are suitable as basic formulations for toothpastes:

Parts by weight a) glycerin 60.0 water 13.5 Sodium carboxymethyl cellulose 0.6 Silicic acid xerogel 20.0 Sodium lauryl sulfate 2.0

Instead of piperidone-6,6-diphosphonic acid, the corresponding amount of N-alkylpiperidone-6,6-diphosphonic acid can also be used in each case (Alkyl radical with 1–2 carbon atoms) can be used. By regularly using the mouthwash and / or toothpaste with a content of piperidone-6,6-diphosphonic acid of the type indicated, the formation of tartar can be significantly and the formation of hard, compact plaque is largely prevented.

Claims (1)

Claims; 1, Pjperidon-6,6-dipbosphonic acids of the general formula I. H ₂ O ₃ P PO ₃ H ₂ CH ₂ NO I I σ) CH ₂ C = O