FI61881B - PROCEDURE FOR THE FRAMSTATION OF THE PHARMACEUTICALS - Google Patents

Description

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Patents and registries (44) Date of issue of the notice. - 06 82

Patents and registers '' Aiwttktn utlagd och utUkrifttn pubUcarad J

(32) (33) (31) Requested «Bugtnl prlorlttt 09.05.75 USA (US) 576Ο55 (71) Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey, USA (US) ' (72) Conrad Peter Dorn, Plainfield, New Jersey, Howard Jones, Holmdel, New

Jersey, David Penman Jacobus, Princeton, New Jersey, USA (7U) Oy Kolster Ab (5U) Process for the preparation of pharmaceutically acceptable 2-methyl-3-hydroxy-U-hydroxymethyl-5-mercaptomethylpyridine time sulfonates - Förfarande för framställning av farmaceutiskt användbara alkansulfonater av 2-methyl-3-hydroxy-U-hydroxymethyl-5-mercaptomethylpyridine

The invention relates to a process for the preparation of pharmaceutically acceptable alkanesulfonates of 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridine of the formula ch2oh H% ^ S, / CH2SH-H (^ SO3) xCl4-4alkane. wherein X is 1 or 2, and the C 1-4 alkane is straight-chain or branched.

The compound of the invention is a physically, 2,618,81 chemically and pharmaceutically improved form of the known pharmacologically active 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridine (5-mercaptopyridoxine or 5-MP), see U.S. Patent 3,852,454. .

In particular, the invention relates to a process for the preparation of the ethane-1,2-disulfonic acid addition salt (edicylate) of this compound. 5-Mercaptopyridoxine is a known pharmacologically active radiation; as a preservative and an anti-rheumatoid arthritis drug, mainly in the form of a salt of a pharmaceutically acceptable acid. Preferred salts are the hydrochloride and the hydrobromide.

It has been found that most, if not all, previously known salts, and in particular the hydrochloride, a salt previously considered particularly preferred, have serious physical, chemical and / or pharmaceutical disadvantages due to their chemical instability and other undesirable properties. It has now surprisingly been found that the C 1-4 alkanesulfonate and C 1-4 alkanesulfonate salts of 5-mercaptopyridoxine, and in particular the ethane-1,2-disulfonate salts (edicylate), do not have this disadvantage in practice and are therefore much better than previously preferred salts in pharmaceutical dosage unit forms. The improved chemical stability of the salts of this invention has been demonstrated in comparative experiments.

Thus, to evaluate the relative stability of the various salts of 5-mercaptopyridoxine, the salts selected for the experiment (i.e., ethane-1,2-disulfonate, phosphate, sulfamate, nitrate, and hydrochloride) were treated at high temperature as pure, immiscible compounds. The values obtained at high temperatures of 80 ° C and 105 ° C are commonly used in the pharmaceutical industry for screening compounds for sex in the shortest possible time. If several derivatives or salts are available, comparable values can be obtained and the test compounds can be classified in the expected order of stability. The heat-treated salts were subjected to a colorimetrically unreacted thiol group. For the ethanedisulfonate, hydrochloride and sulfamate salts, NMR analysis was also performed to confirm the chemical analysis. NMR values support chemical values. The aggregated values obtained are shown in Table 1 below.

3,61881

Table 1 Thermal stability comparison of 5-MP salts

Thermal stability remaining,% 5-MP salt 105 ° C 80 ° C

3 days .__ 7 days. 1 week 3 weeks

Ethane disulfonate 97.3 99.4 101.0 100.2

Hydrochloride 57.3 - 7 0.5 57.3

Sulfamate 13.0 8.8 94.0 75.7

Phosphate 93.0 58.0

Nitrate - - 87.2

The values clearly show that the ethanedisulfonate salt is the most stable salt at the temperatures used. The salt to be selected on the basis of the apparent advantageous thermal stability indicated by the values shown is ethane disulphate.

The process according to the invention is characterized in that a compound having the structural formula:

R2 ^ ^ Y ^ CH2 - S "A

ch3 wherein R1 is -CH2OH, R2 is -OH, or R1 and R2 together represent -O-C-O-CHO-; and / CH 3 ch 3 A is -H or 461881 -S 2 H 2 O 2 R 2 N ch 3 or an acid addition salt thereof, wherein R 1 is -CH 2 OH and R 2 is -OH; is treated with a compound having the structural formula: C 1-4 alkane (SO 3 H) x or an alkali metal or alkaline earth metal salt thereof, when R 1 is -CH 2 OH, R 2 is -OH and A is -H; or it is treated with a compound having the structural formula: C 1-4 alkane (Ξ03Η) χ in the presence of zinc dust when A is R 2 N ch 3 or it is treated with a compound having the structural formula: C 1-4 alkane (SO 3 H) x when R 1 and r 2 together correspond -OCO-CH-- / \ 2 CH3 CH3 and A is -H.

In this case, 2 molar parts of 5-mercaptopyridoxine or its soluble acid addition salt, mainly the hydrochloride, and 2 molar parts of C 1-4 alkanesulfonic acid or 1 molar of C 1-4 alkanesulfonic acid are to dissolve both starting materials at a temperature between room temperature and boiling point. The product is isolated by crystallization from a liquid medium by cooling and / or concentration, if necessary. According to a preferred embodiment, the 5-mercaptopyridoxine hydrohalide, preferably the hydrochloride, and the alkali metal salt or alkaline earth metal salt of the C 1-4 alkanesulfonate or disulfonate, preferably the sodium salt, are dissolved in the above molar ratio at room temperature in as little water as possible and cooled.

Alternatively, the novel compounds of this invention can be prepared by treating bis (2,2,8-trimethyl-4-1H-dioxine / 4,5-c7-pyridyl-5-methyl) disulfide with a mixture of zinc dust and the desired C ~ alkanesulfonic acid or C 1-4 alkanesdisulfonic acid in water or a suitable organic solvent. The reaction is most preferably carried out with the reaction mixture in a water bath for about 13 to about 10 hours, preferably protected by a neutral atmosphere.

The reaction mixture is then cooled, filtered and concentrated in vacuo. The residue is extracted into a boiling organic solvent and the filtrate is filtered and cooled to precipitate the desired salt.

The novel compounds of this invention can be prepared in a similar manner by treating bis (2-methyl-3-hydroxy-4-hydroxymethylpyridyl-5-methyl) disulfide with a mixture of zinc dust and the desired C 1-4 alkanesulfonic acid or C 1-4 alkanesulfonic acid. alkanedisulfonic acid in water or a suitable organic solvent. The reaction is carried out as described above and the desired salt is taken in the same manner.

The novel compounds of this invention may also be prepared by treating 5-mercaptomethyl-2,2,8-trimethyl-4-H-m-dioxine / 4,5-c7-pyridine with the desired C1-4 alkanesulfonic acid or C1-4 alkanesulfonic acid in water or a suitable organic solvent. In this case, the reaction mixture is usually heated in a water bath for about 2 to about 10 hours, preferably under the protection of a neutral atmosphere. The reaction mixture is then concentrated to give the desired salt.

The active compounds of the invention may be administered to a patient orally, parenterally, by inhalation or rectally in unit dosage form containing conventional non-toxic pharmaceutically acceptable carriers, excipients and vehicles. Parenteral dosage forms herein include subcutaneous injections, intramuscular, intrasternal injections or infusion injections. In addition to treating warm-blooded animals such as mice, rats, horses, dogs, 6,61881 cats, etc., the compound is also effective in treating humans.

Pharmaceutical compositions containing the active compound are mainly in forms suitable for oral administration, for example tablets, drops, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Mixtures for oral administration may be prepared by any of the methods well known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more substances selected from the group consisting of sweeteners, spices, colorants, coatings and preservatives such as antioxy. dentures to produce a pharmaceutically acceptable and palatable preparation.

The amount of active ingredient used in the preparation of a private dosage form, alone or in combination with carrier materials, will depend on the subject of the treatment and, in particular, the mode of administration. For example, a composition for oral administration to a human may contain from 5 mg to 5 g of active ingredient, alone or in admixture with a suitable amount of carrier, which may be from 0 to 95% of the total amount of the composition. Dosage unit forms generally contain from about 50 mg to about 1 g of active ingredient, preferably 500 mg.

In practicing the method of the present invention, for example, the prescription mixture described above is administered in a dosage amount of 1 mg to 100 mg per kilogram of body weight per day, and in the case of a human, mainly 1 to 3 grams per patient per day. At the end of the latent period, the benefits of treatment manifest themselves as a significant improvement in clinical and serological symptoms, such as a reduction in rheumatoid factor (RF) levels.

However, it will be appreciated that the specific dosage level for any particular patient will depend on various factors including age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug composition, previous treatment and severity of disease being treated.

Example 1

Bi s (2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridinium) ethane-1,2-disulfonate

A solution of 11.1 g (0.05 mol) of 5-mercaptopyridoxine hydrochloride in 40 ml of water was stirred at room temperature with a solution of 5.85 g (0.025 mol) of disodium ethane-1,2-7 61881 disulfonate in 40 ml of water. The mixture was cooled in an ice bath until precipitation was virtually complete. The precipitate was collected by filtration and the filtrate was concentrated to about 40 ml and again cooled in an ice bath until precipitation was virtually complete. The precipitate (2) was collected on a filter and the filtrate was concentrated to about 20 ml and cooled in an ice bath until precipitation was virtually complete. The precipitate (3) was collected on a filter. Precipitates (1), (2) and (3) were combined and recrystallized from methanol to give 6.5 g of bis (2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpuridinium methane-1,2-disulfonate, mp 178-180 ° C.

Using essentially the procedure described in Example 1, but replacing the disodium ethane-1,2-disulfonic acid used therein with an equivalent molar amount of di (metal) alkane disulfonates, or with two molar equivalents of the metal alkane sulfonates mentioned in Table I, the corresponding 5-mercapto-pyridoxide which are also mentioned in Table I.

Equation I

ch2oh hVVch2sh χ f | + C 1-4 alkane (SO 3 M) x Λ®

CH 2 OH

HO i. CH2SH

* Il (®SOO „C. 4-time

CHS HU

wherein X is 1 or 2, and A ® is an acid anion, and M is an alkali metal or alkaline earth metal.

8 61881

Table I

A ® M X C 1-4 alkane

Cl K 2 -CH2CH2- C1 Na 2 "CH2"

Cl Na 2 - (CH2) 3-

Br Na 2 - (CH2) 4 ~ C1 K 1 ch3-

Br K 1 CH3CH2- C1 Na 1 CH3CH2CH2-

Br Ca 2 -CH- ch3

Cl Ca 2 -CH-CH-- I ^ CH3 CH3

Br Na 2 -C- έίί3

Example 2

Bis (2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridinium) 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 is heated briefly until dissolution has taken place. The solution is cooled and the precipitate is collected by filtration. Recrystallization from methanol gives bis (2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridinium) ethane-1,2-disulfonate.

Using essentially the procedure described in Example 2, but replacing the ethane-1,2-disulfonic acid used therein with the corresponding molar amount of alkanesdisulfonic acids listed in Table II or with two molar equivalents of alkanesulfonic acids, the corresponding acid addition salts also mentioned in Table II are prepared according to Equation II.

61 881 9

Equation II

ch2oh HO 1. ch2sh χ 1 + C1_4 ~ alkane (SO3H) x CH3 "n ch2oh

ho ch2SH

-> L (© 03S) xC1_4-alkane ch3 g ©

X

_ _

Table II

X C1-4 alkane 1 -CH2-2 - (CH2) 3-2 - (CH2) 4-1 ch3-1 CH3CH2-1 CH3CH2CH2-2 -CH- ch3 2 -CH-CH- I ^ CH3 CH, I 3 2 -C- ch3 61 881 ίο

Example 3

Bi s (2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridinium) ethane-1,2-disulfonate

A mixture of 0.1 mole of bis (2,2,8-trimethyl-4H-m-dioxin- [4,5-c] pyridyl-5-methyl) disulfide, 0.2 mole of zinc dust, 0.35 mole of ethane-1 , 2-disulfonic acid and 200 ml of water, are heated in a water bath for about 5 hours under nitrogen. The reaction mixture is cooled, filtered and concentrated in vacuo. The residue is extracted with 100 ml of boiling methanol, filtered and the filtrate is cooled to give the title product.

Example 4

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

A mixture of 0.1 mol of 5-mercaptomethyl-2,2,8-trimethyl-4H-m-dioxine / 4,5-c7-pyridine and 0.055 mol of ethane-1,2-disulfonic acid in 100 ml of water is heated in a water bath under nitrogen. protected for about 3 hours. The reaction mixture is concentrated to give the title product.

Example 5

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

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, heated on a water bath for about 6 hours under nitrogen. The reaction mixture is cooled, filtered and concentrated in vacuo. The residue is extracted with 100 ml of boiling methanol, filtered and the filtrate is cooled to give the title product. Using essentially the procedure described in Examples 3, 4 or 5, but replacing the ethane-1,2-disulfonic acid used therein with an equivalent amount of the alkanesulfonic acids listed in Table II above or with two molar equivalents of alkanesulfonic acids, the corresponding acid addition salts listed in Table II are prepared according to Equation II.

Claims (2)

61881 11 1. A process for the preparation of pharmaceutically acceptable alkanesulfonates of 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridinine having the formula: ch 2oh H ° YT 2SH CH 2 · H 2 O 2 wherein X is 1 or 2 , and the C 1-4 alkane is straight-chain or branched, characterized in that the compound having the structural formula: t 1 R 2 \ AS AS / CH 2 ~ S “A Jk i / N ch 3 having -CH 2 OH, R 2 is -OH, or R 1 and R 2 together correspond to the group -O-C 0 -CH 9 and X 1 CH 3 ch 3 A is -H or -S-CH-I R 0 is N 1 CH 3 or an acid addition salt thereof, wherein R 1 is -CH 2 OH and R 2 is -OH; is treated with a compound having the structural formula: C 1-4 alkane (SO 3 H) x or an alkali metal or alkaline earth metal salt thereof, when R 1 JL 61 881 12 is -CH 2 OH, R 2 is -OH and A is -H; or it is treated with a compound having the structural formula: C 1-4 alkane (SO 3 H) x in the presence of zinc dust when A is -8 ^ yL' 2 CH 2 or is treated with a compound having the structural formula: C 1-4 alkane (εο3Η) χ when ^ and R 2 together correspond -O-C-O-CH0- / CH2-CH3 and A is -H. Process for the preparation of bis (5-mercaptopyridoxine) ethane-1,2-disulfonate according to Claim 1, characterized in that the 5-mercaptopyridoxine halide is treated with di- (alkali metal) ethane-1,2-disulfonate. Process for the preparation of bis (5-mercapto-pyridoxine) ethane-1,2-disulfonate according to Claim 1, characterized in that bis (2,2,8-trimethyl-4H-m-dioxin / 3,5- C 7-Pyridyl-5-methyl) disulfide is treated with ethane-1,2-disulfonic acid in the presence of zinc dust. Process for the preparation of bis (5-mercapto-pyridoxine) ethane-1,2-disulfonate according to Claim 1, characterized in that 5-mercaptomethyl-2,2,8-trimethyl-4H-m-dioxin- 1,5-c7pyridine is treated with ethane-1,2-disulfonic acid. Process for the preparation of bis (5-mercapto-pyridoxine) ethane-1,2-disulfonate according to Claim 1, characterized in that bis- (2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl) -methyl) disulfide is treated with ethane-1,2-disulfonic acid in the presence of zinc dust. 61881 13 A process for the preparation of a pharmaceutical composition containing an alkanesulfonate of 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridine, having the formula: r— - ch2oh HCL J. CH2SH Jk Jl (® SO3) xC1_4-Alkan ch3 * © X ^ L- color X is 1 or 2, and C1-4-Alkan is used to form a solid, the first of which is derived from the structure: <"N 1 color R1 is -CH2OH, R2 is -OH, or R ^ and R2 tillsammans raotsvarar Group - 0 -.C - 0 - CH ~ -f / \ 2 CHj CH3 and A is -H or er -S — CH0 «. ly. R-, XX ch3 eller et cyradditionssalt därav, color R3 is -CH2OH and R2 is -OH; behandlas med en förening med structuralformeln: C1-4-Alkan (δ03Η) χ