NO144925B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BIS (2-METHYL-3-HYDROXY-4-HYDROXYMETHYL-5-MERCAPTOMETHYL-PYRIDINIUM) -ETHANE-1,2-DISULPHONATE - Google Patents

Description

The present invention relates to an analogous method for the production of a pharmaceutically acceptable ethane-1,2-disulfonic acid addition salt of 2-methyl^3-hydroxy-4-hydroxymethyl-5- mercaptomethylpyridine, a .physically, chemically and ..pharmaceutically improved form of the known pharmacologically active '2-méthyl-3-, ' hydroxy-4-:hydroxymethyl--5-mercaptomethylpyridiri (5-mercaptqpyrid- : oxin or 5-MP) .

The method conjunctions as indicated in the preamble to the claim are useful in processing. of. r.eumatoid arthri-tls-- -

The compound 5-mercaptopyridoxine has been reported to have pharmacological activity as a radiation protective agent, and: an anti-rheumatoid arthritic agent, preferably in the form of a. salt with a pharmaceutically acceptable acid. The preferred salt is indicated to be the hydrochloride or hydrobromide.

.. That. has;'-turned out that--t most, if not all, of the salts specifically', indicated -in' earlier' publications,' and especially the hydrochloride, the previously preferred salt,' suffer from serious physical, chemical'' and/or'^pharmaceutical disadvantages due to their chemical instability and other undesirable properties. Horrifying. enough, it has been shown that the ethane-1, 2-disulfonate salt (edisylate) is essentially free of these defects and is therefore much better than the previously preferred salts for transfer--ing .to pharmaceutical unit dose worms. The better chemical stability of. the salts- have been confirmed by comparative., samples. <;->

Thus, in order to judge therein the relative stability of several salts■ of 5-merca<p>to<p>yrLdoxyri, the selected test salts (ie the ethane-1,2-disulforiate, the phosphate, the sulfamate; the nitrate bg the hydrochloride) were subjected to accelerated conditions at high temperature as the pure, unprocessed compound High temperature data obtained at -80°C and at 105°C are conveniently used in the pharmaceutical industry to screen out compounds in as short a time as possible . When a number of derivatives or salts are available, comparative data can be obtained, and the experimental compounds can be arranged in an expected order of stability. The thermally treated salts were examined for the coiorimetric risk of intact thiol groups. Ethary disulfonate, hydrochloride and sulfamate salts were also subjected to NMR analysis to confirm the chemical analysis.' NMR data support the chemical data. The overall data obtained are shown in Table 1. The above data, where the colorimetric experimental error may be 3-5%, clearly show that the ethanedisulfonate salt is the most stable salt at the temperatures used^ Based on the thermal stability advantages that appear from the table, the ethanedisulfonate is the preferred salt..

The novel process compound can be prepared by mixing 2 molar parts of 5-mercaptopyridoxine or soluble acid addition salt thereof, preferably the hydrochloride, and 1 molar part of ethanedisulfonic acid or an alkali metal or alkaline earth metal salt thereof, preferably the sodium salt, in a liquid medium capable of to some extent to dissolve the two starting materials at a temperature between room temperature and the reflux temperature. The product is isolated by crystallization from the liquid medium by cooling and/or evaporation. if necessary. In a preferred embodiment, a 5-mercaptopyridoxine hydrohalide, preferably the hydrochloride, and an alkali metal or alkaline earth metal salt of ethane disulfonate, preferably the sodium salt, are dissolved in the molar ratio indicated above,

in a minimal amount of water at room temperature and cooled.

Alternatively, the new process compound can be prepared by treating bis-(2,2,8-trimethyl-4-H-m-dioxino-[4,5-c]-pyridyl-5-methyl)-disulfide with a mixture of zinc dust and ethane -1,2-disulfonic acid in water or a suitable organic solvent. The reaction is conveniently carried out by reacting the reaction mixture on a steam bath for 3 to 10 hours, preferably under an inert atmosphere. The reaction mixture is then cooled, filtered and evaporated in vacuo. The residue is extracted in a refluxing organic solvent, and the filtrate is filtered and cooled to precipitate the desired salt.

In a similar way, the process compounds can be prepared by treating bis-(2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl-5-methyl)-disulfide with a mixture of zinc dust and ethane-1,2-disulfonic acid in water or a suitable organic solvent. The reaction is carried out as described above, and the desired salt is recovered in a similar manner.

The process compound can also be prepared by treating 5-mercaptomethyl-2,2,8-trimethyl-4-H-m-dioxino-[4,5-c]-pyridine with ethane-1,2-disulfonic acid in water or a suitable organic solvent. In this case, the reaction mixture is generally heated on a steam bath for 2-10 hours, preferably under an inert atmosphere. The reaction mixture is then concentrated to obtain the desired salt.

The active compound can be administered orally, parenterally, by inhalation or rectally in unit dose preparations containing conventional non-toxic pharmaceutically acceptable carriers, auxiliaries and media. The term parenteral is used herein to include subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion methods. In addition to treating warm-blooded animals such as mice, rats, horses, dogs, cats, etc., it is effective in treating humans.

The amount of active ingredient, alone or together with the carrier materials, to form a single dosage form will vary depending on the host being treated and the particular mode of administration. For example, a preparation intended for oral administration to humans can contain from 5 mg to 5 g of active ingredient either alone or prepared with a suitable and convenient amount of carrier material which can vary from 0 to 95% of the total preparation. Unit dosage forms will generally contain between 50 mg and

1 g of active ingredient, and preferably 500 mg.

A preparation as described above is administered to humans in such an amount that it provides 1 mg to 100 mg per kg body weight per day, and preferably 1 - 3 g per day. After a latent period, the effect of the treatment is recognized by significant improvement in clinical and serological symptoms such as a lowering of circulating reutnatoid factor (RF) titers.

However, the specific dosage level for a particular patient will depend on a number of factors including age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, previous therapy and the severity of the particular disease being treated.

Example 1

Bis-(2-methy1-3-hydroxy-4-hydroxymethy1-5-mercaptomethyl-pyridinium)-ethane-1,2-disulfonate.

A solution of 11.1 g (0.05 mol) of 5-mercaptopyridoxine hydrochloride in 40 ml of water was mixed with a solution of 5.85 g (0.025 mol) of disodium ethane-1,2-disulfonate in 40 ml of water at room temperature. The mixture was cooled in an ice bath until evaporation was substantially complete. The precipitate (1) was collected on a filter, and the filtrate was evaporated to approx. 40 ml and again cooled in an ice bath until precipitation was essentially complete. The precipitate (2.) was collected on a filter, and the filtrate was evaporated to approx. 20 ml and cooled in an ice bath until precipitation was essentially complete. The precipitate (3). was.. collected on a filter. The precipitates (1), (2) and (3) were combined and recrystallized from ethanol, which gave 6.5 g of bis-(2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridinium)-ethane-1,2-disulfonate with m.p. 178-180°C. , ■

Sub-application of the method essentially as described in Example 1, but by replacing the disodium ether-1,2-disulfonic acid used there with an equimolar amount of the di-(metal)-alkanesulfonates, the same is formed connection.

'A<®> is an acid anion, and

M is an alkali metal or alkaline earth metal.

Example 2

Bis-(2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethyl-\1 pyridinium) - ethane- 1, 2- disulfonate

A mixture of 9.25 g (0.05 mol) of 5-mercaptopyridoxine, 4.75 g (0.025 mol) of ethane-1,2-disulfonic acid and 40 ml of water was heated briefly until dissolution occurred. The solution was cooled, and the precipitate was collected by filtration. Recrystallization from methanol gave bis-(2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridinium)-ethane-1,2-disulfonate , identical to the compound obtained in Example 1.

Example 3

Bis-(2-methyl-3-hydroxy-4-hydroxymethyl 1-5-mercaptomethyl-pyridinium)-ethane-1,2-disulfonate

Heat a mixture of 0.1 mol bis-(2,2,8-trimethyl-4H-m-dioxino-j 4 ,5-c i -pyridyl-5-methyl 1)-disulfide, 0.2 mol zinc dust, 0.35 mol of ethane-1,2-disulfonic acid and 200 ml of water on a steam bath for approx. 5 hours under a nitrogen atmosphere. Cool the reaction mixture, filter and evaporate in vacuo. Extract the residue with 100 ml of boiling ethanol, filter and cool the filtrate to obtain the title product identical to that in Example 1.

Example 4

Bis-(2-methyl-3-hydroxy-4-hydroxymethy1-5-mercaptomethyl-pyridinuin)-ethane-1,2-disulfonate

Heat a mixture of 0.1 mol of 5-mercaptomethyl-2,2,8-trimethyl-4H-m-dioxino-4,5-c J-pyridine and 0.055 mol of ethane-1,2-disulfonic acid in 100 ml of water at steam bath under a nitrogen atmosphere for approx. 3 hours. Evaporate the reaction mixture to give the title product, which is identical to that of Example 1.

Exerap_el _5

Bis - (2-meth hy 1 -3 -hy droxy-4 -hy dr oxymet hyl -5 -mercaptomethyl - pyridinium)- ethane- 1, 2- disulfonate

Heat a mixture of 0.1 mol of bis-(2-methyl-3-hydroxy-4-hydroxymethylpyridyl-5-methyl)-disulfide, 0.2 mol of zinc dust,

0.35 mol of ethane-1,2-disulfonic acid and 200 ml of water on a steam bath for approx. 6 hours under nitrogen. Cool the reaction mixture, filter and evaporate in vacuo. Extract the residue with 100 ml of boiling methanol, filter and cool the filtrate to obtain the title product, which is identical to that of Example 1.

Claims (1)

Analogous procedure for the preparation of a therapeutically active compound with the structural formula: characterized in that a compound with the structural formula: ' '■ ■ ■■ where and R? is hydroxy, or together is and R,: and A is hydrogen or where R 1 and R 2 are as indicated above, or an acid addition salt thereof, is treated with ethane-1,2-disulfonic acid or an alkali metal or alkaline earth metal salt thereof, when R 1 and R 2 are hydroxy, and A is hydrogen; or treated with ethane-1,2-disulfonic acid in the presence of zinc dust when A is or treated with ethane-1,2-disulfonic acid when and R 2 together are and A is hydrogen.