IE43030B1

IE43030B1 - Salts of 5-mercaptopyridoxide

Info

Publication number: IE43030B1
Application number: IE990/76A
Authority: IE
Original assignee: Merck & Co Inc
Priority date: 1975-05-09
Filing date: 1976-05-07
Publication date: 1980-12-03
Also published as: CS189003B2; IL49466A0; DE2620325C3; SE7604580L; PT65061A; SE427033B; DK143335C; PL100306B1; IE43030L; BG25218A3; DK179376A; FR2310130B1; IL49466A; NO144925B; ATA335676A; CH625222A5; FI61881C; NZ180691A; GR59817B; FR2310130A1

Abstract

5-Mercaptopyridoxine alkanesulphonates of the general formula in which X is 1 or 2, and the C1-4-alkane is straight-chain or branched, obtained by treating the corresponding sulphide or sulphide acetal or disulphide or disulphide acetal or the respective acid addition salts thereof with a C1-4-alkanesulphonic acid or an alkali metal or alkaline earth metal salt thereof. The compounds which can be prepared according to the invention can, for example, be used as very effective agents for the treatment of rheumatoid arthritis and similar inflammatory disorders.

Description

This invention is concerned with pharmaceutically acceptable salts of 2 - methyl - 3 - hydroxy - 4 hydroxymethyl - 5 - mercaptomethylpyridine, which is itself a known pharmacologically active compound, also called 5 mercaptopyridoxine or 5-MP. The present invention also concerns the preparation of salts; a method of treating rheumatoid arthritis in non-human animals using the salts and pharmaceutical compositions comprising the salts.

- Mercaptopyridoxine, has been reported to be pharmacologically active 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 stated to be the hydrochloride or hydrobromide.

It has been found that most, if not all, of the - 2 -13 0 30 salts specifically reported in the prior art, and certainly the hydrochloride, suffer serious physical, chemical and/or pharmaceutical disadvantages by virtue of their chemical instability and other undesirable properties.

This invention provides alkanesulfonic and C. . alkanedisulfonic acid addition salts of 5 * 1-4 mercaptopyridoxine, which have the formula: S°3'x C^_^alkane where X is 1 or 2, and alkane is either straight or branched chain. A preferred salt in accordance with the present invention is the ethane - 1,2 - disulfonic acid-addition salt (edisylate) of 5 - mercaptopyridoxine. It has been unexpectedly found that the alkanesulfonate and alkanedisulfonate salts of 5 - mercaptopyridoxine, and particularly the ethane - 1,2 - disulfonate salt (edisylate) are substantially free of the instability observed in the hydrochloride and other known salts and are, therefore, much superior to the previously preferred salts for formulation into pharmaceutical unit dosage forms. The superior chemical stability of the salts of this invention has been confirmed by actual comparative testing.

Thus, in order to evaluate the relative stability of several salts of 5 - mercaptopyridoxine, the test salts selected (i.e., the ethane - 1,2 - disulfonate, the phosphate, the sulfamate, the nitrate and the hydrochloride) were subjected to accelerated conditions Of high temperature as the pure, unformulated, compound. The high temperature data obtained at 8O°C. and at 1O5°C, are conventionally used in the pharmaceutical industry to screen compounds in as short a time as possible. Where a number of derivatives or salts are available, comparative data can be obtained and the test compounds can be ranked in an expected order of stability. The thermally stressed salts were assayed colorimetrically for intact thiol group. The ethane-disulfohate, hydrochloride and sulfamate salts also were subjected to NMR analysis to confirm the chemical analysis. The NMR data supports the chemical data. The accumulated data obtained are shown in the Table 1 below.

TABLE 1 Comparison of Thermal Stability of 5-MP Salts Salt of 5-MP Thermal Stability % Remaining 105°C 80°C Ethanedisulfonate 3 days 7 days 1 week 3 weeks 97.3 99.4 101.0 100.2 Hydrochloride 57.3 - 70.5 57.3 Sulfamate 13.0 8.8 94.0 75.7 Phosphate - 93.0 58.0 - - Nitrate - - 87.2 - 3 0 30 The data clearly show that the ethanedisulfonate salt Is the most stable salt at the temperature involved. Based on the thermal stability advantages obviously shown by the data, the ethanedisulfate is the salt of choice.

In accordance with the present invention the novel compounds are prepared by mixing 5 - mercaptopyridoxine (5-MP) or soluble acid-addition salt thereof, preferably the hydrochloride, a C1_j} alkanesulfonic acid or alkanedisulfonic acid or alkali metal or alkaline-earth metal salt thereof, preferably the sodium salt, in a liquid medium capable of dissolving to some degree the two starting materials at a temperature between ambient and reflux temperature. When a C^_4 alkanemonosulfonic acid or salt thereof is used, the preferred molar ratio acid:5-MP is preferably 1:1; when a C^_4 alkanedisulfonic acid or salt thereof is used, the preferred molar ratio acid:5-MP is preferably 1:2. The product is isolated by crystallization from the liquid medium by cooling and/or concentration, if necessary. In a preferred embodiment a 5-mercaptopyridoxine hydrohalide, preferably the hydrochloride,and an alkali metal or alkaline-earth metal alkanesulfonate or disulfonate, preferably the sodium salt, in the above-stated molar ratio, are dissolved in a minimum amount of water at ambient temperature and cooled.

Alternatively, the novel compounds of this invention may be prepared by treating bis(2,2,8 - trimethyl - 4H m - dioxino [4,5-c] pyridyl - 5 - methyl)disulfide with a mixture of zinc or tin dust and the desired C^_4 alkanesulfonic acid or C^_4 alkanedisulfonic acid in water or a suitable organic solvent. The reaction conveniently is - 5 )030 carried out by the reaction mixture on a steam bath for to 10 hours, preferably under an inert atmosphere. The reaction mixture is then cooled, filtered and concentrated in vacuo. The residue is extracted into refluxing organic solvent and the filtrate is filtered and cooled to precipitate the desired salt.

Similarly, the novel compounds of this invention may be prepared by treating bis (2 - methyl - 3 - hydroxy 4 - hydroxymethylpyridyl - 5 - methyl)disulfide with a mixture of zinc or tin dust and the desired C^_4 alkanesulfonic acid or 0χ_4 alkanedisulfonic acid in water or a suitable qrganic solvent. The reaction is carried out as described above and the desired salt is similarly recovered.

The novel compounds of this invention also may be prepared by treating 5-mercaptomethyl - 2,2 - 8 - trimethyl 4 - H - m - dioxino jjS, 5-c] pyridine with the desired C^_4 alkanesulfonic acid or C^_4 alkanedisulfonic acid in water or a suitable organic solvent. In this case, the reaction mixture is usually heated on a steam bath for 2 to 10 hours, preferably under an inert atmosphere. The reaction is then concentrated to. obtain the desired salt.

The active compounds may be administered orally, parenterally, by inhalation or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular or intrasternal injection or infusion techniques. In addition to the treatment of warmblooded animals such as mice, rats, horses, dogs and cats, it 4303ο is effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient are preferably in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders, or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more sweetening agents, flavoring agents, coloring agents, coating agents and preserving agents such as antioxidants in order to provide a pharmaceutically elegant and palatable preparation.

The amount of active ingredient, alone or combined with the carrier materials, to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain from 5 mg. to 5 gm. of active agent either alone or compounded with an appropriate and convenient amount of carrier material which may vary from 0 to 95 percent of the total composition. Dosage unit forms will generally contain from 50 mg. to 1 gm. of active ingredient and preferably 500 mg.

In practising the novel method of treatment of this invention, a formulation such as described above is administered at such a rate as to provide 1 mg. to 100 mg. per kilogram of body weight per day and preferably 1 3 grams per human patient per day. After a latent period the benefits of treatment are realized by significant improvement 3 0 3 0 in clinical and serological symptoms such, as a lowering of circulating rheumatoid factor (RF) titer.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the 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 undergoing: therapy.

Example 1.

Bis(2-methyl-3-hydroxy-4-hydroxyraethyl-5mercaptomethyl-pyridinium) ethane-1,2-disulfonate A solution of 11.1 g. (0.05 mole) of 5 mercaptopyridoxine hydrochloride in 40 ml. of water was mixed with a solution of 5.85 g. (0.025 mole) of disodium ethane - 1,2 - disulfonate in 40 ml. of water at room temperature. The mixture was cooled in an ice-bath until precipitation was substantially complete. The precipitate (1, was collected on a filter and the filtrate was concentrated to about 40 ml. and again cooled in an ice-bath until precipitation was substantially 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 substantially 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 mercaptomethylpyridinium ethane - 1,2 - disulfonate, m.p. 178 — 180°C.

By the procedure substantially as described in Example 1, but substituting for the disodium ethane - 1,2 disulfonic acid used therein, an equimolar amount of the di(metal) alkanedisulfonates, or two equimolar amounts of the metal alkane sulfonates depicted in Table I, there are produced the corresponding acid addition salts of -mercaptopyridoxine, also depicted in Table T,in accordance with Equation I.

Equation I ( θ S03)χ alkane /As/ CH3 H ® where X is 1 or 2, A A is an acid anion, and M is an alkali metal or alkaline-earth metal. 3 0 3 0 TABLE I Αθ M X C^_4 alkane Cl K 2 -ch2ch2- Cl Na 2 -CH2- Cl Na 2 -(ch2)3- Br Na 2 -(ch2)4- Cl K 1 ch3- Br K 1 ch3ch2- Cl Na 1CH3CH2CH2- Br Ca 2 -CH- 1 ch3 Cl Ca 2 -CH-CH,- 1 CH3 CH, ι J Br Na 2 -ο- Ι CH3 Example 2.

Bis(2-methy1-3-hydroxy-4-hydroxymethyl-5mercaptomethyl-pyridinium) ethane-1,2-disulfonate A mixture of 9.25 gm. (0.05 m)of 5 mercaptopyridoxine, 4.75 gm. (0.025 m) of ethane -1,2 disulfonic acid, and 40 ml. of water is heated briefly until solution occurs. The solution is cooled and the precipitate collected by filtration. Recrystallization from methanol gives bis(2 - methyl - 3 - hydroxy - 4 - hydroxymethyl 5 - mercaptomethylpyridinium)ethane - 1,2 - disulfonate. - 10 43030 By the procedure substantially as described in Example 2, but substituting for the ethane - 1,2 - disulfonic acid used therein, an equimolar amount of the alkanedisulfonic acids or two equimolar amounts of the alkanesulfonic acids depicted in Table II, there are produced the corresponding acid-addition salts also depicted in Table II, in accordance with Equation II.

Equation II X C1-4 alkane ( SO3H )x TABLE II C^_4alkane -ch2“ -ωΗ2)3-(ch2)4ch3CH3CH2CH3CH2CH2-CHI CH* -CH-CHgCH3 I 3 -εΙ CH* Example 3.

Bis (2-methy1-3-hydroxy-4-hydroxymethy1-5mercaptomethyl-pyridinium) - ethane-1,2-disulfonate A mixture of 0.1 mole of bis(2,2,8 - trimethyl 4H - m - dioxino[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 is heated on a steam bath for about 5 hours under an atomsphere of nitrogen. The reaction mixture is cooled, filtered and concentrated in vacuo. The residue is extracted with 100 ml. of boiling methanol and filtered. The filtrate is cooled to obtain the title product.

Example 4.

Bis (2-methyl-3-hydroxy-4-hydroxymethyl-5mercaptomethyl-pyridinium)-ethane-1,2-disulfonate A mixture of 0.1 mole of 5 - mercaptomethyl 2,2 - 8 - trimethyl - 4H - m - dioxino{4,5-c]pyridine and 0.055 mole of ethane - 1,2 - disulfonic acid in 100 ml. of water is heated on a steam bath under an atomosphere of nitrogen for about 3 hours. The reaction mixture is concentrated to obtain the title product.

Example 5.

Bis(2-methyl-3-hydroxy-4-hydroxymethyl-5mercaptomethyl-pyridinium)-ethane-1,2-disulfonate A mixture of 0.1 mole of bis(2 - methyl - 3 - hydroxy - 4 - hydroxymethyl - pyridyl - 5 - methyl) disulfide, 0.2 mole of zinc dust, 0.35 mole of ethane - 1,2 - disulfonic acid and 200 ml. of water is heated on a steam bath for about 6 hours under a nitrogen atmosphere. The reaction mixture is cooled, filtered and concentrated in vacuo. The residue is extracted with 100 ml. of boiling methanol. The extract is filtered and the filtrate is cooled to obtain the title product.

By employing the procedure substantially as described in Examples 3, 4, or 5, but substituting for the ethane 1,2 - disulfonic acid used therein, an equimolar amount of the alkanedisulfonic acids or two equimolar amounts of the alkanesulfonic acids depicted in Table II above, there are produced the corresponding acid addition salts as depicted in Table II in accordance with Equation II.

Example 6. (1) Tablets - 10,000 scored tablets for oral use, each containing 500 mg of active ingredient are prepared from the following ingredients: Gm. bis (5-mercaptopyridoxine) ethane-1,2-disulfonate 5000 Starch, U.S.P. 350 Talc, U.S.P. 250 Calcium stearate 35 The powdered bis(5 - mercaptopyridoxine) ethane 1,2 - disulfonate is granulated with a 4% w./v. aqueous solution of methylcellulose U.S.P. (1500 cps.). To the dried granules is added a mixture of the remainder of the ingredients and the final mixture compressed into tablets of proper weight. (2) Capsules - 10,000 two-piece hard gelatine capsules for oral use, each containing 250 mg. of bis(5 mercaptopyridoxine) ethane-1,2-disulfonate are prepared from the following ingredients: Gm. bis(5-mercaptopyridoxine) ethane-1,2-disulfonate 2500 Lactose, U.S.P. 1000 Starch, U.S.P, 300 Talc, U.S.P, 65 Calcium stearate 25 The powdered bis(5 - mercaptopyridoxine) ethane 1,2 - disulfonate is mixed with the starch-lactose mixture followed by the talc and calcium stearate. The final mixture is then encapsulated in the usual manner. Capsules containing 10, 25, 50, and 100 mg. of 5 - mercaptopyridoxine ethane - 1,2 - disulfonate are also prepared by substituting, 100, 250, 500, and 1000 gm. for 2500 gm. in the above formulation. (3) Soft elastic capsules - One-piece soft elastic capsules for oral use, each containing 500 mg. of bis(5 mercaptopyridoxine) ethane - 1,2 - disulfonate are prepared in the usual mahner by first dispersing the powdered active material in sufficient corn oil to render the material encapsulable. (4) Aqueous suspension - An aqueous suspension for oral use containing in each 5 ml., 1 gm. of bis(5 - mercaptopyridoxine) ethane - 1,2 - disulfonate i from the following ingredients: ,s prepared bis(5-mercaptopyridoxine) ethane-1,2-disulphonate gm. 2000 Methylparaben, U.S.P. gm. 7.5 Propylparaben, U.S.P. gm. 2.5 Saccharin sodium gm. 12.5 Glycerin ml. 3000 'fragacanth powder gm. 10 Orange oil flavour gm. 10 F.D. & C. orange dye gm. 7.5 Deionized water, q.s. to 10 liters

Claims

1. A compound of formula: S0 3 ) X 1-4 alkane in which X is 1 or 2, and the C^_ 4 alkane is a straight or branched radical.

2. Bis(5-mercaptopyridoxine) ethane-1,2-disulfonate.

3. A method of preparing a compound as claimed in Claim 1 that comprises treating 2 - methyl - 3 - hydroxy 4 - hydroxymethyl - 5 - mercaptomethylpyridine or an acidaddition salt thereof with a compound of formula C^_ 4 alkane (SO 3 H) X or an alkali metal or alkaline-earth metal salt thereof, where C^_ 4 alkane and x are as defined in Claim 1, in a liquid medium capable of dissolving the reactants to some degree and at a temperature between ambient and reflux.

4. A method of preparing a compound as claimed in Claim 1 that comprises treating the compound of formula 4333ο viz. 5 - mercaptomethyl - 2,2,8 - trimethyl dioxino[4,5-cJpyridine, with a compound of formula C^_ 4 alkane (30 3 Η) χ where Cj_ 4 alkane and x are as defined in 5. Claim 1, in water or an organic solvent.

5. A method of preparing a compound as claimed in Claim 1 that comprises treating a compound of formula: in which is hydroxymethyl and R 2 is hydroxy or R·^ and 10 R 2 together represent a radical of formula -0—C(CH 3 ) 2 0—CH 2 -, with a compound of formula C 1-4 alkane (δΟ 3 Η) χ , where C x _ 4 alkane and x are as defined in Claim 1, in the presence of zinc dust and in water or an organic solvent.

6. A method of preparing bis(5 - mercaptopyridoxine)ethane - 1,2 - disulfonate that comprises treating a 5 mercaptopyridoxine hydrogen halide salt with a di(alkali metal) ethane - 1,2 - disulfonate in a liquid medium capable of dissolving the reactants to some degree and at a temperature between ambient and reflux.

7. A method of preparing bis(5 - mercaptopyridoxine)ethane - 1,2 - disulfonate that comprises treating bis(2,2,8 trimethyl - 4H - m - dioxino[4,5-cJpyridyl - 5 - methyl) disulfide with ethane - 1,2 - disulfonic acid in the presence of zinc dust and in water or an organic solvent.

8. A method of preparing bis(5 - mercaptopyridoxine)ethane - 1,2 - disulfonate that comprises treating 5 mercaptomethyl - 2,2,8 - trimethyl - 4H - m - dioxino[4,5-c]pyridine with ethane - 1,2 - disulfonic acid in water or an organic solvent.

9. A method of preparing bis(5 - mercaptopyridoxine)ethane - 1 - 2 - disulfonate that comprises treating bis(2 methyl - 3 - hydroxy - 4 - hydroxymethylpyridyl - 5 - methyl) disulfide with ethane - 1,2 - disulfonic acid in the presence of zinc dust and in water or an organic solvent.

10. A method of preparing a compound as claimed in Claim 1 substantially as hereinbefore described in any one of Examples 1 to 5.

11. A compound as claimed in Claim 1 when prepared by a method as claimed in any one of Claims 3 to 10.

12. A pharmaceutical composition comprising a carrier and an effective amount of a compound as claimed in Claim 1.

13. A composition as claimed in Claim 12 in which the compound is bis(5 - mercaptopyridoxine) ethane-1,2disulfonate.

14. A composition as claimed in Claim 12 in which the compound has been prepared by a method as claimed in any one of Claims 3 to 10.

15. A composition as claimed in any one of Claims 12 5 to 14 in orally administrable form.

16. A composition as claimed in Claim 15 in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders, or granules, emulsions, hard or soft capsules, syrups or elixirs. 10

17. A composition as claimed in Claim 12 substantially as hereinbefore described in any one of parts 1 to 4 of Example 6.

18. A method of treating rheumatoid arthritis in a non-human animal that comprises the administration to the 15 animal of an effective amount of a compound as claimed in Claim 1, 2 or 10.