DE1011428B - Process for the preparation of therapeutically utilizable calcium salts of polyoxyalkylamine-N, N-di- (alkylcarboxylic acids) - Google Patents

Description

It has been found that calcium can be therapeutic Inject particularly well in the form of its salts with poly oxy alkylamine-N, N-di- (alkylcarboxylic acids) can. These salts form stable, aqueous solutions which, for. B. produced in concentrations up to 5% calcium can be. Such solutions are the injectable calcium preparations previously used in therapy superior due to the combination of low toxicity with high calcium effect.

Toxicity, DL ₆₀
Mouse i. ν

Ca Gluco

nat (18 mg

Approx / ccm)

0.10 g / kg

Ca-ethylenediamine-tetraacetic acid Na

0.55 g / kg

Aminoglycerin

diacetic acid approx

(20 mg / ecm) according to Example 1 method of production
of therapeutically usable

Calcium salts of

Polyoxyalkylamine-N, N-di-

(alkyl carboxylic acids)

Applicant:

Paint factories Bayer Aktiengesellschaft, Leverkusen-Bayerwerk

Dr. Friedrich-Johann Meyer and Dr. Wolfgang Wirth,

Wuppertal-Elberfeld,
have been named as inventors

0.40 g / kg _ao

Ca ⁺ + effect on the isolated frog heart
according to Sträub

Influence on the Ca ⁺⁺
Blood level (precipitated as the oxalate at physiological p _H)
in the dog

These calcium salts are obtained by reacting polyoxyalkylamine-N, N-di- (alkylcarboxylic acids) or their Derivatives, such as esters, amides, nitriles or salts, with compounds releasing calcium ions or just as well by polyoxyalkylation of the calcium salts of iminodi- (alkylcarboxylic acids).

As polyoxyalkylamine-N, N-di- (alkylcarboxylic acids), the di- or trioxyalkylamine-N, N-di- (alkyl-a-carboxylic acids), the hydroxyl groups of which are in the α-position to the secondary or tertiary carbon atom to which the amino group is attached. These polyoxyalkylamine-N, N-di- (alkylcarboxylic acids) can be produced z. B. by carboxyalkylation of polyoxyalkylamines or by polyoxyalkylation of Imino-di- (alkyl carboxylic acids) are.

Examples of polyoxyalkylamine-N, N-di- (alkylcarboxylic acids) are 2-methyl-1,3-dioxy-2-aminopropyl-N, N-diacetic acid, 2-oxymethyl-1,3-dioxy-2-aminopropyl-N, N-diacetic acid and 1,3-dioxy-2-aminopropyl-N, N-bis (a-butyric acid) and 2,3-dioxypropylamine-N, N-diacetic acid and glucamine-N, N-diacetic acid. Let save the free acids and their salts their functional derivatives, such as esters, amides or nitriles or their organic or inorganic salts Acids, e.g. B. oxalates, hydrochlorides or sulfates, use for the preparation of the calcium salts, z. B.

by saponifying them in the presence of agents that release calcium ions.

Calcium ions can be used for reaction with the free polyoxyalkylamine-N, N-di- (alkylcarboxylic acids) donating compound advantageously use calcium carbonate, calcium oxide or calcium hydroxide. Should that Calcium salt from another salt, ζ. Β. an alkali or ammonium salt of a polyoxyalkylamine-N, N-di- (alkylcarboxylic acid), it is better to use a calcium salt such as chloride or acetate.

The conversion of a derivative of a polyoxyalkylamine-N, N-di- (alkylcarboxylic acid), e.g. B. an ester, amide or nitrile, which is best converted into the calcium salt by its saponification by means of calcium oxide or hydroxide performed. The polyoxyalkylation of the calcium salts of iminodi- (alkylcarboxylic acids) can, for. B. by Condensation with an oxy- or polyoxyalkyl epoxide, a polyoxyalkyl halide or another reactive Make esters of an aliphatic polyoxy alcohol.

As the simplest oxyalkyl epoxide, glycide is very suitable for this reaction. Epoxies can also be used, derived from higher polyoxy alcohols, e.g. B. from the tetrites, pentites, hexites, heptites, theirs higher analogs or partial deoxy derivatives, provided they still contain at least three hydroxyl groups.

On the other hand, dioxy, trioxy, tetraoxy, pentaoxy, hexaoxyalkyl halides and corresponding reactive esters, e.g. B. Mono-aryl sulfone

709 586/427

3 4

acid esters of glycerol, tetrites, pentites, hexites, water for 2 hours at 25 °, then 30 minutes at 90 °. Heptites and their partial deoxy derivatives, or higher. Then carbonic acid is introduced up to the neutral reac analogue these halides and esters with iminodialkylation, sucks off and falls with alcohol. After drying at carboxylic acids or their derivatives to polyoxyalkylamine- 100 ° are 22 g of the calcium salt of 2, 3-Dioxydi- (alkylcarboxylic acids) in the presence of acid-binding 5-propylamine-N, N-diacetic acid as a water-soluble powder Condense agents in a manner known per se. obtain. .

Finally, in all of the cases listed,

the polyoxyalkylation also includes polyoxyalkyl derivatives. Analysis: C ₇ Hi ₁ O ₆ NCa-H ₂ O., all or some of the hydroxyl groups of which are Calculated: C 32.9, H 4.94, N 5.32, Ca 15.2 ;

Protects are found, for example, by acetal, ester or ether: C 32.81, H 5.45, N 5.26, Ca 15.04. ties. In such a situation, the condensation is followed by a hydrolysis of the latter ^; Ties-on. Example 4

As iminodi- (alkylcarboxylic acids), their calcium salts

come into consideration for the reaction, the man suspended 8.3 g of iminodiacetic acid in 50 ecm

Iminodiacetic acid, iminodipropionic acids which, as the 15 water, adjusted with 2 η-lime milk (about 150 cc) to a, α'-iminodipropionic acid, as a mixture of its optical p _H 10 and stirred for 20 g of glycidol thereto. After two days of isomers, as a racemate or as a mesoform, or like standing at 25 ° and shaking occasionally, ß, ß'-iminodipropionic acid and higher homologous iminodipropionic acid and higher homologous iminodi- use the excess calcium hydroxide by introducing (alkylcarboxylic acids). Carbon dioxide at 90 °, nitrates and evaporates the solution

But there are also mixed iminodi- (alkylcarbon- 20 to 50 ecm.) One falls with 100 ecm of alcohol, sucks the acids) suitable, e.g. B. the alanine-N-acetic acid, the imino precipitate. and dried in vacuo at 100 °. a-butyric acid-acetic acid or the imino-ct-propionic acid yield 12 g. The powder that is easily soluble in water / ^ - butyric acid. after analysis for 4 molecules of the amino

In general, the calcium salts of polyglycerol diacetic acid are 3 atoms of calcium: oxyalkylamino-N, N-di- (alkylcarboxylic acids) in aqueous 25

Make a solution. Such solutions can either be used for analysis: 3 C ₇ H ₁₁ O ₆ NCa · C ₇ H ₁₃ O ₆ N. directly for Caldum therapy or calculated: C 35.6, H 4.88, N 5.94, Ca 12 , 7;

serve to isolate the calcium salts. This isolation found: C 35.51, H 4.31, N 6.00, Ca 12.45.

can e.g. B. by evaporation or by precipitation with a

water-miscible solvents, e.g. B. a 30 example 5

lower alcohol, acetone, dioxane or tetrahydrofuran,
take place. Proceed as in example 4, but turn instead

The calcium salts can be in aqueous solution z. B. of the glycide 15 ecm of a-monochlorohydrin. Sterilize by heating each time. It is often advantageous to stand for one day adds to add another 2 cc of milk of lime to these solutions further substances, be it to p _H 10 to 35th The product must be reprecipitated several times to remove any further increases in the calcium content, be it for stabilizing chlorine ions by dissolving in water and losing concentrated solutions, to protect against exposure to alcohol. The calcium salt of the aminoglycerin, which is easily soluble in microbiological attack during production or in water, is obtained with a pharmaceutical acid other than a colorless powder. Yield 3.7g. combine ecological effects. 40

_p ■ Analysis: C ₇ H ₁₁ O ₆ NCa-V ₂ H ₂ O.

^ ^{els Piel} 1 Calculated: C 33.1, H 4.72, N 5.52, Ca 15.75;

150 g of 2,3-dioxypropylamine-N, N-diacetic- found: C 33.11, H 4.66, N 5.88, Ca 15.6 are dissolved.

acid (M.p. 142 ° decomp.), 50 g of calcium carbonate and 0.4 g. .

p-Oxybenzoic acid methyl ester in 300 ecm double distillation 45 Example ο

lated water and then fills up to 400 ecm. The so man makes by hydrogenating 50 g of glucose in 300 ecm

solution obtained contains 5.13 g calcium per 100 ecm and conc. Ammonia with 2.5 g of Raney nickel at 70 to 80 ° shows a p _H of 5.0. You can also after dilution, a solution of glucamine, which is filtered and after z. B. to a calcium content of 2 g / 100 ecm, in ampoules, remove the excess ammonia in a vacuum and sterilized by heating. 50 is added with 31.2 g of 72 ° / ₀ sodium cyanide. Man drips

to 10 ° 85 g 30% formaldehyde solution at 0 to I and Example _{5 days can stelieil) extracted with ether and} the aqueous t _he hi _tz

150 g of 2,3-dioxypropylamine-N, N-diacetic phase are stirred with 20 g of calcium oxide at 95 ° for several hours. acid with 56.25 g calcium carbonate and 300 ecm distil- Then the excess Calciumhydroxyd lated water falls (at the end at 90 °) until the largest part of the calcium carbonate has dissolved by introducing carbon dioxide, filtered with animal charcoal. It is filtered and the almost colorless solution is precipitated with alcohol. After the calcium salt falls by stirring in the solution, drying in vacuo at 100 ° is obtained in this way in 1500 ecm alcohol. After drying the precipitate of an almost colorless powder, the calcium salt of glucamine in vacuo at 100 °, 165 g of an N, N-diacetic acid in water, which is readily soluble in water, are obtained. Easily soluble powder, in which, according to the analysis to 60 loot 83 g. Moles of 2,3-dioxypropylamine-N, N-diacetic acid about
Atoms of calcium are bound. Analysis: C ₁₀ H ₁₇ O ₉ NCa · 2 H ₂ O.

Calculated: C 32.3, H 5.66, N 3.78, C 10.7;

Analysis: 3 C ₇ H ₁₁ O ₆ NCa-C ₇ H ₁₃ O ₆ -2H ₂ O.. Found: C 32.22, H 5.38, N 3.56, C 9.94.

Calculated: C 34.4, H 5.12, N 5.72, Ca 12.05; ₅ -

Found: C 34.37, H 5.40, N 5.32, Ca 12.72. Example 7

. . 30 g of iminodiacetonitrile and 45 g of glucose are hydrogenated

ü eispiei ό J _{n 400 ccm} 930 ^ g _61n methanol in the presence of Raney

20 g of 2,3-dioxypropylamine-N, N-diacetic-nickel are stirred at 60 ° to 70 ° under pressure. After suction acid with 10 g calcium oxide and 100 ecm distilled 70 from the catalyst, the hot solution of 23 g is added

1 Oil

Oxalic acid in 150 ecm of methanol and sucks off the precipitate formed. After washing with Methanol is dried in a desiccator and obtained as a slightly colored powder with a temperature of 150 ° (darkens from 130 °) N, N-bis-cyanomethyl-glucamine-oxalate.

Analysis: C ₁₀ H ₁₇ O ₅ N ₃ '

C ₂ H ₂ O ₄ -2 H ₂ O.

Calculated: C 38.2, H 5.98, N 10.9;
Found: C 37.23, H 5.98, N 11.02.

16.8 g of the oxalate are heated with 150 ecm 2 η milk of lime 3 hours at 90 °. After precipitating the excess calcium hydroxide by introducing carbon dioxide animal charcoal is added at 90 °, filtered, the solution is concentrated in vacuo to 50 ecm and precipitated with alcohol. Of the Residue, isolated by decantation and dried in vacuo at 100 °, is the calcium salt of glucamine-N, N-diacetic acid. Yield 11.8g.

Analysis: C ₁₀ H ₁₇ O ₉ NCa · 2 H ₂ O.
Calculated: C 32.3, H 5.66, N 3.78, Ca 10.79;
Found: C 32.88, H 5.42, N 3.70, Ca 11.17.

Claims (1)

PATENT CLAIM: Process for the preparation of therapeutically utilizable calcium salts of polyoxyalkylamine-N, N-di- (alkylcarboxylic acids), characterized in that a) polyoxyalkylamine-N, N-di- (alkylcarboxylic acids), their salts or derivatives, such as esters, amides or nitriles, are reacted with calcium compounds or saponified or b) the calcium salts of iminodi- (alkylcarboxylic acids) are polyoxyalkylated on the nitrogen atom. Documents considered :.
U.S. Patent No. 2,712,545. © 709 586/427 6.