DE2102831A1 - New salts of pyridoxine monoesters and processes for their preparation - Google Patents

Description

DR.-ING. WALTER ABITZ DR. DIETER F. MORF DR. HANS-A. BROWN

Patent attorneys

Munich, January 21, 1971 Postal address 8 Munich 86, PO Box 86010?

Pienzenauerstrasse 28 Telephone 483225 and 486415 telegrams! Chemindut Munich

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SOCIETE D ¹ ETUDES DE PRODUITS CHIMIQUES 16 rue Kleber, 92 Issy-les-Moulineaux, France

New salts of pyridoxine monoesters and processes for their preparation

The present invention relates to pyridoxine monoester salts and a process for their preparation and represents a new class of compounds of the general formula:

CH ₂ OH

HO

CH ₂ -OCACOA ₁ -N

Ac

ready to mean in:

A and A ^ each represent an alkylene radical with a chain that has up to 16 carbon atoms, or one

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Amino hydrocarbon residue, e.g. B. an aminoalkylene radical, such as -CH- (CH ₂ ) - or - (CH ₂ ) -CH-,

in which R represents a hydrogen atom or a CH ^ CO group and ρ is 1 or 2;

R ^. and R ^ both (each an alkyl radical with up to 5 carbon atoms, these radicals being separate or forming a heterocyclic ring with the nitrogen atom form;

Ac is a pharmaceutically acceptable acid and η is an integer which takes the value 1, 2 or 3.

The ester salts according to the invention have therapeutic effectiveness and can be prepared according to the invention by adding pyridoxine, the -OH and -CH ₂ OH group of which is blocked in the 3- and 4-position, with a compound of the general formula ClCO-A-COO- A.-HR ^ R _{2 is} implemented, in which the symbols have the meanings given above, and then the blocking of the -OH and -CH ₂ 0H group in the 3- and 4-position of the pyridoxine ring is canceled. The esters so obtained are then treated with a pharmaceutically acceptable acid to obtain an acceptable salt. The reaction sequence is illustrated below using examples:

a) Blocking of two alcohol reactions of the PyridoxLn:

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HO

CH ₂ OH

+ 0 «C

, CH.

HGl

CH,

CH

JO-CH ₀

■ ΓΙ ²

CH ₂ OH

(D

The resulting compound I is obtained in the form of its hydrochloride and is treated with Na _n CO ₂ to obtain the free base.

The choice of acetone is not critical: any "any" conventional blocking agents can alternatively be used.

b) Treatment of the compound obtained under (a) with the appropriate acid chloride:

, -CH ₂ OH

+ ClCO-A-COO-A ₁ -IiIi ₁ R ₂

CH,

.-NR ₁ R ₂

1O98 ⁵ 3O / 2138

(II)

The above chloride is by reacting the anhydride of the corresponding acid with the substituted Aminoalkanol with formation of the substituted aminoalkanol monoester according to the following reaction scheme available:

This monoester, when treated with SOCIp, gives the chloride:

c) Release of OH and CEJJE in the 3- and 4-positions by treatment of the compound (II) with an acid to form a compound according to the invention:

(in)

Another procedure can be used if a different blocking agent is substituted for acetone.

d) The compound (III) can optionally be mixed with an acid to produce a pharmaceutically acceptable acid addition salt implemented.

The following examples illustrate the invention.

^: - 3 ■ · ■; /; ■

I) Dime t ; hyla.Tiinoät; h.anol and 5- <xP: yi'idoxine succinate

a) blocking of alcohol reactions of pyridoxine;

Into a 4 liter flask fitted with a stirrer. was equipped, 2.1 liters of pure anhydrous acetone was poured, and 100 g of dried pyridoxine hydrochloride was added with stirring. The mixture was cooled to 0 ° C with stirring and then gaseous HCl. Bubbled through the solution for 6 hours. After a further hour, the temperature was allowed to rise to room temperature and stirring was continued for a further hour. The mixture was then ^{cooled to -15 ° C.} and the corresponding 5,4-isopropylidene-pyridoxine was obtained in the form of its hydrochloride (100 g). The free base was obtained by treatment with a NapCO, solution.

82 g of base (compound A) which melted at 111 ° C. were obtained.

b) Production and implementation of the chloride of dimethylamino-ethanol monosuccinate:

100 g succinic anhydride, 100 g dimethylaminoethanol and 100 ml of anhydrous acetone were placed in a 2 liter flask and kept in it for 3 hours boiled under reflux for a long time. The solution was then evaporated to one third of its original Concentrated in volume and cooled. A precipitate occurred, which was separated off and recrystallized from acetone became.

140 g of product with a melting point of 78 ° C. were obtained fraud.

The chloride was made from this compound by treatment

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of 420 g of the compound with 1.85 liters of freshly distilled SOCIp produced. After eliminating the unreacted SOCIp, the obtained product became treated with benzene and dried. This resulted in 620 g of the hydrochloride of the chloride acid.

120 g (0.57 mol) of the compound from step (a) described above were dissolved in 0.5 liter of pyridine. After cooling, 170 g (0.69 mol) of the hydrochloride obtained above, dissolved in 0.2 liter of chloroform, were slowly added at about 5 ° ^{C. in the course of 90 minutes.} The solution- was stirred for 10 hours and then evaporated to dryness ($ 50 g). The residue was dissolved in 0.3 liters of water and neutralized by means of an aqueous OTL solution which was saturated in ILJiO ^. An oily substance was obtained, which was extracted with chloroform. The extract was concentrated to dryness (170 g).

c) release of OH and CH ^ , QH in the 5- and 4-position; by treating: the compound (II) with an acid to form a compound according to the invention :

In this stage the blocking group, which bound the OH in the 3-position to the CH ₂ OH in the 4-position of the lyridoxine ring, was opened by hydrolysis with formic acid. 52 g of the product from step (b) described above were treated with 1.650 liters of a 1% strength solution of formic acid and 0.250 liters of ethyl alcohol. The mixture was boiled for 50 minutes, evaporated, treated again with ethyl alcohol and evaporated. 37 g of an oily substance of the following formula were obtained:

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CH ₂ OH

HO _t ^ V ^ _r CH ₂ U-C0- (CH ₂ ) ₂ -C00 (CH ₂ ) ₂ -N (CH ₃ ) ₂

r- ■ - ■ -L

(HD

d) Formation of salts :

1. Maleate

The maleate was prepared by reacting 37 6 (0.115 mol) of the above-described product of step (c), which were dissolved in 120 ml of acetone, with 27 g (0.230 J | mole) of maleic acid, which was dissolved in I30 ml of acetone, obtain. The yield was 51 Si u ^ cL ^ e * ¹ melting point was I34 ⁰ C.

The fumarate was produced by an exactly analogous process .

2. N-acetyl aspartate

The N-acetyl asparaginate was prepared in a manner analogous to the maleate by adding 22 g (0.64 mol) of the Substance from stage (c), dissolved in 0.1 liters of ethyl alcohol, with 22.4 g (1.28 mol) of N-acetyl-asparagine- j | acid dissolved in 0.3 liters of ethyl alcohol. The connection was very hygroscopic. the Yield was 31.5 E-

II) Dimethylamino-ethanol and 5-oc-pyridoxine prlutarate

The step (a) is the same as the step (a) of the example (I). In step (b) glutaric anhydride is used instead of succinic anhydride. Stage (c) is usually like stage (c) of example I). ίί-αη receives such an oily substance .: _? α er v; ie in stage (d) of the

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game (I) is treated with maleic acid. An ocher-white, crystalline product is obtained, which at Melts from 100 to 102 ° C.

III) N-methyl-N'-ethanol-piperazine and 5-a-pyri'doxine succinate

The stage (a) is the same as in example (i). The monochloride of the monosuccinate of N-methyl-N'-ethanolpiperazine is in the same way as in Example (I), step (b), described from the succinic acid. anhydride and N-methyl-N'-ethanol-piperazine in stoichiometric Proportions by refluxing in acetone (this leads to the monosuccinate of N-methyl-N'-ethanol piperazine; Melting point 80 to 82 ° C) and the further treatment of this connection with SOCl ^ manufactured.

Step (c) is carried out as in Example (I), step (c), and an oily substance is obtained in the process a yield of 73% The analysis corresponds to the formula:

^H 2 ^0H 'Ϊ2 f 2

ft-

., - CH ₃

s ₂

Step (d): The compound of step (c) is converted into a by means of maleic acid (as in Example I, step d) Converted to salt. With 3 molecules of maleic acid you get the corresponding tri-maleate, a white one Product with a bitter, salty taste that melts at around 142 ° C.

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These compounds have interesting psycho-stimulatory properties Properties such as dimethylamino-ethanol and 5-a-pyridoxine succinate maleate shows. The connection shows at doses of 10 mg / kg per os an antagonistic effect against the hypothermic and ptosis effects of reserpine. J Moreover, it has a very beneficial effect on the dysfunction of memory was noted in the rat, and high levels of effectiveness were observed on the cat's cortex • at dose levels of 25 mg / kg i.v. noticed.

These compounds also show a low toxicity (in the case of the above-mentioned compound it is: LD ₁ -Q in mice 1.55 g / kg per os or 1.0 g / kg ip). '

In human therapy there have been very good results in patients suffering from psychasthenia, neurotonic, depressive Suffered from syndrome or subjective traumatic skull syndrome, achieved through a treatment according to the per diem 4 x to 6 gelatin capsules, each 0.250 g of the same compound contained, were administered. In all cases dor Administration, the tolerance was perfect.

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Claims (1)

Patent claims in which: A and A. each represent an alkylene radical having a chain containing up to 16 carbon atoms, or an amino hydrocarbon radical, e.g. B. an aminoalkylene radical, such as -CH- (CH ₂ ) - or - (CH ₂ ) -CH-, HHR HHR in which R is a hydrogen atom or a CiL, CO group and ρ is 1 · or 2; R ₁ and Rp each represent an alkyl radical with up to 5 Carbon atoms, these radicals being separate or a heterocyclic one with the nitrogen atom Form ring; Ac is a pharmaceutically acceptable acid; and η is an integer that is 1, 2, or 3. Process for preparing the compounds according to Claim 1, characterized in that the two alcohol functions in the 3- and 4-positions are blocked, then the compound obtained in this way with the compound of the formula ClCO-A-COO-A ₁ -NR ₁ R ₂ converts, in which the symbols A, A ₁ , R ₁ and Rp have the same meanings as in claim 1, then in the new compound thus obtained the block 109830/2131 marking of the "two alcohol functions in the 3- and 4-position opens and finally treated with the selected acid to produce the appropriate pharmaceutically acceptable To obtain addition salt. - 11 - Often KHNAL INSPECTED 109830/2 138