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Publication numberUS3324140 A
Publication typeGrant
Publication dateJun 6, 1967
Filing dateNov 9, 1964
Priority dateNov 9, 1963
Also published asDE1470054A1
Publication numberUS 3324140 A, US 3324140A, US-A-3324140, US3324140 A, US3324140A
InventorsSchorre Gustav
Original AssigneeMerck Ag E
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Pyridoxolyl-hydrocarbon and substituted hydrocarbon disulfides
US 3324140 A
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Description  (OCR text may contain errors)

United States Fatent 3,324,140 PYRIDOXOLYL-HYDROCARBON AND SUB- STITUTED HYDROCARBON DISULFIDES Gustav Schorre, Dannstadt-Eberstadt, Germany, assignor to E. Merck Aktiengesellschaft, Darmstadt, Germany No Drawing. Filed Nov. 9, 1964, Ser. No. 409,950 Claims priority, application Germany, Nov. 9, 1963, M 58,865 Claims. (Cl. 260-2943) This invention relates to sulfur-containing pyridine derivatives, in particular to pyridyl disulfides and their acid addition salts.

The principal object of this invention, therefore, is to provide novel pyridyl disulfides and their acid addition salts.

Another object is to provide processes for their production, including the discovery of novel intermediates therefor.

Still another aspect of this invention is to provide novel pharmaceutical compositions and therapeutic methods, based on the novel compounds of this invention.

Upon further study of the specification and claims, other objects and advantages of the present invention will became apparent.

To attain the objects of the invention, there are provided compounds of the Formula I, and their acid addition salts, as follows:

('lHioRi a N (I) wherein R and R represent hydrogen or acyl; and

R represents: alkyl which can, if desired, be substituted; alkenyl; alkynyl; aryl or aralkyl, either of which can, if desired, be substituted.

The new compounds are derived from vitamin B and its acyl derivatives, respectively.

The acyl residues R and R set forth in Formula I are preferably of saturated or unsaturated aliphatic monocarboxylic acids of up to 18 carbon atoms, particularly preferred residues being derived from the following acids: acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic-acid, pelargonic acid, capric acid, undecylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, acrylic acid, crotonic acid, oleic acid, elaidie acid, undecylenic acid, linoleic acid, and linoleneic acid.

For the preferred embodiments of this invention, R is selected from the group consisting of =(a) unsubstituted alkyl of not more than 20 carbon atoms; (b) alkyl of not more than 20 carbon atoms substituted by at least one member selected from the group consisting of halogen, hydroxyl, lower alkoxy, amino, mono-(lower alkyl)- amino, di-(lower alkyl)-amino, piperidino, morpholino, piperazino and piperazino substituted by lower alkyl, aralkoxy wherein the aryl portion is a hydrocarbon of 6 to 10 carbon atoms and the alkoxy portion is a lower alkoxy, acyloxy of a hydrocarbon monocarboxylic acid of not more than 9 carbon atoms, carbobenzoxy, carboxyl, esterified carboxyl of not more than 9 carbon atoms wherein the alcohol portion is a hydrocarbon alcohol of not morethan 8 carbon atoms, unsubstituted -CONH -CONH substituted by lower alkyl, piperidide, piperazide, and morpholide; (c) alkenyl of not more than 12 carbon atoms; (d) alkynyl of not more than 3 carbon atoms; (e) unsubstituted hydrocarbon aryl of not more than 2 rings with 5 to 6 carbon atoms per ring; (f) unsubstituted aralkyl of the latter unsubstituted hydrocarbon aryl and a lower alkyl; and (g) a member selected from the group consisting of hydrocarbon aryl of not more than 2 rings and 5 to 6 carbon atoms per ring and ar-lower alkyl of said hydrocarbon aryl, the aryl and ar-lower alkyl substituted by at least one member of the group consisting of halogen, lower alkyl, lower alkoXy, hydroxyl, nitro, amino, and lower monoand di-alkylamino.

More particularly, R can represent a straight-chain or branched, substituted or unsubstituted alkyl residue having generally no more than 20 carbon atoms. Suitable alkyl residues are particularly the lower alkyls, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, amyl, and isoamyl, and further those having a longer chain, such as hexyl, heptyl, octyl, nonyl, cetyl, undecyl, dodecyl, or lauryl.

The alkyl group can be monoor poly-substituted. Preferably, only such alkyl groups are substituted which do not contain more than 6 carbon atoms in the alkyl chain. Preferred substituents are halogens, such as, for example, fluorine, chlorine, or bromine; hydroxyl; lower alkoxy groups of up to about 5 carbon atoms, particularly methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and isobutoxy. Also preferred is the amino group wherein one or both hydrogen atoms can likewise be substituted by lower alkyl groups (the alkyl groups being the same or different) having up to about 5 carbon atoms; these latter alkyl groups, in turn, can also be joined with one another, if desired, via a further hetero-atom, particularly a nitrogen or an oxygen atom. Of special impor- .tance are the 2-aminoethyl-, 3-amino-propyl-, 3-amino-2'- methyl-propyl-, and 4-aminobutyl-residues, as well as the corresponding N-methyl-, N-ethyl-, N-propyl-, N-butyl-, N,N-dimethyl-, N,N-diethyl-, N-methyl-N-ethyl-, N,N-dipropyl-, N,N-di-tert.butyl-, and piperidino-derivatives.

Further substituents for the substituted alkyls are, for example, aralk-oxy groups wherein the aryl is preferably a hydrocarbon of 6 to 10 carbon atoms and the alkoxy is a lower alkoxy, particularly the benzyloxy residue, as Well as acyloxy groups of aliphatic or aromatic carboxylic acids of up to 9 carbon atoms, preferably monocarboxylic acids, especially acetoxy, n-propanoyloxy, isopropanoyloxy, n-butanoyloxy, isobutanoyloxy, tert. butanoyloXy, and pentanoyloxy, and also benzoyloxy, toluyloxy, carbobenzoxy, or cinnamoyloxy. The alkyl residue R can also be substituted by a free or by an esterified carboxyl group of up to 9 carbon atoms, i.e., for example by carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, also benzyloxycarbonyl, and toloxycarbonyl. The alkyl group can also be substituted by acid amide residues, CONH the hydrogen atoms of the amino group can also be replaced, in this connection, by lower alkyl residues which can also be connected with one another, if desired via another hetero-atom. Particularly suitable are, in addition to CONH the amides of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. butyl, dimethyl, diethyl, di-n-propyl, di-isopropyl, di-n-butyl, methylethyl, methyl-n-butyl, and ethyl-n-butyl, as well as the piperidides and morpholides.

The substituent' R of Formula I can also represent an alkenyl residue of generally not more than about 12 carbon atoms. This alkenyl residue can contain one or several double bonds, but generally no more than two. Preferred alkenyl residues are, for example, vinyl, allyl, butenyl, heptenyl, undecylene and 'butadienyl, hexadienyl, and heptadienyl. Alkynyl residues (R in Formula I) usually contain not more than 3 carbon atoms, and are preferably ethynyl and propa-rgyl.

Additionally, R can represent an aryl residue of not more than 2 rings with 5 to 6 carbon atoms per ring. Hydrocarbon aryl, such as phenyl or naphthyl, is considered preferable. For aralkyl residues the same aryl nuclei can be employed. Particularly suitable are the benzyl and the phenethyl residues. If the aromatic nucleus, particularly the phenyl residue, is mono or poly- (e.g. bi-) substituted, the substituents are preferably halogens, such as fluorine, chlorine, or bromine; or lower alkyl or alkoxy groups of up to 5 carbon atoms, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. butyl and amyl, and the corresponding alkoxy groups; or hydroxyl, nitro, arnino, monoand dialkylamino, preferably lower alkylamino groups, respectively. The following substituted aryl residues are set forth as preferred examples: o-, m-, or p-chlorophenyl; o-, m-, or p-bromophenyl; tolyl; xylyl; p-methoxyphenyl; 0-, rn-, or p-ethoxyphenyl; propoxyphenyl; hydroxyphenyl; nitrophenyl; aminophenyl; aminotolyl; 2-amino-3-hydroxyphenyl; 2-methoXy-3-aminophenyl; N-methyl-aminophenyl; N-ethyl-aminophenyl; N-rnethyl-N-butyl-aminophenyl; N,N-di-tert. butyl-aminophenyl; 2-methyl-4-chlorophenyl; and 2,4-dimethyl-phenyl.

The following structural compounds, as well as their acid addition salts, particularly the hydrochlorides, represent preferred embodiments of this invention:

wherein n=1 or 2.

C H2O R R20- CH1S-S-substituted phenyl HaC CHzO R R O CHz-S-S-substituted benzyl R and R have the previously indicated significance.

Of the compounds included in the above formulae, the following are particularly preferred, the pyridoxolyl radical being represented by Formula I when R and R are both hydrogen:

Pyridoxolyl-methyl-disulfide Pyridoxolyl-ethyl-disulfide Pyridoxolyl-propyl-disulfide Pyridoxolyl-butyl-disulfide Pyridoxolyl-amyl-disulfide Pyridoxolyl-cetyl-disulfide Pyridoxolyl-lauryl-disulfide Pyridoxolyl-vinyl-disulfide Pyridoxolyl-allyl-disulfide PyridoXolyl-crotyl-disulfide Pyridoxolyl-undecylenyl-clisulfide Pyridoxolyl-ethynyl-disulfide Pyridoxolyl-propargyl-disulfide Pyridoxolyl-phenyl-disu1fide Pyridoxolyl-naphthyl-disulfide PyridoxolyLbenzyl-disulfide Pyridoxolyl-phenethyl-disulfide Pyridoxolyl-4' methoxybutyl-disulfide P.yridoxolyl-4-ethoxybutyl-disulfide Pyridoxolyl-4-butoxyzutyl-disulfide Pyridoxolyl-4'-benzyloxybutyl-disulfide Pyridoxolyl-4'-acet0xybutyl-disulfide Pyridoxolyl-4-propoxybutyl-disulfide Pyridoxolyl-3 '-benzoyloxyp ropyl-disulfide Pyridoxolyl-4-cinnamoyloxybutyl-disulfide Pyridox0lyl-3 '-carboxypropyl-disulfide Pyridoxolyl-B-ethoxycarbonylethyl-disulfide PyridoXolyl-Brmethoxycarbonylethyl-disulfide PyridoXolyl-3 '-toloxycarbonylpropyl-disulfide Pyridoxolyl-2-ethoxyheptylpropyl-disulfide Pyridoxolyl-2'-carbamoylethyl-disulfide Pyridoxolyl-4-N,N-dimethylcarbamoylbutyl-disulfide Pyridoxolyl-3 -N,N-di-tert.butyl-carbamoylpropyldisulfide Pyridoxolyl-2 -N-methyl-N-ethylcarbamoylethyl-disulfide Pyridoxolyl-Z'-morpholido-ethyl-disulfide Pyridoxolyl-3 -piperididopropyl-disulfide Pyridoxolyl-2'-hydroxyethyl'disulfide Pyrid0xolyl-2-aminoethyl-disulfide Pyridoxolyl-3 -diethylaminopropy1-disulfide Pyridoxolyl- 3 -N,N-diethylamino-2'-methylpropiyl disulfide Pyridoxolyl-3 '-piperidinopropyl-disulfide Pyridoxolyl-chlorophenyl-disulfide Py-ridoxolyl p-methoxyphenyl-disulfide Pyridoxolyl-o-tolyl-disulfide Pyridoxolyl-p-hydroXyphenyl-disulfide Pyridoxolyl-o-nitrophenyl-disulfide Pyridoxolyl-o-arninophenyl-disulfide Pyridoxolyl-2-amino-3-hydroXyphenyl-disulfide Pyridoxolyl-Z-methoxy-3,-arninophenyl-disulfide Pyridoxolyl-Z-rriethyl-4-chlorophenyl-disulfide Pyridoxolyl-3 ,5 -dimethylphenyl-disulfide Pyridoxolyl-2,3-di methylphenyl-disulfide Pyridoxolyl-2-chloro-4-methylphenyl-disulfide Pyridoxolyl-2-chlore-4,5-dimethylphenyl-disulfide By-ridoxolyl-3 ,4-dimethoxyphenyl-disulfide Pyridoxolyl-2- rnethyl-3 ,o-dichlorophenyl-disulfide Pyridoxolyl-2-trifluoromethyl-4-methylphenyl-disulfide Pyridoxolyl-2-methyl-4-diethylaminophenyl-disulfide Pyn'doxolyl-3-methyl-5-hydroxypheny1-disulfide Pyridoxolyl-2'-piperazinylethyl-disulfide Pyridoxolyl-p-xylyl-disulfide When R and/or R represent acyl, the particularly preferred compounds are 3-acetoxy-4-acetoxymethyl-, 3- butoxy-4-butoxymethyl-, 3-heptoxy-4-heptoxymethyl-, 3- octoXy-4-oct0xymethyl-, 3-undecylenoxy-4-undecylenoxymethyl-, ,and 3-stearyloxy-4-stearyloxymethyl-compounds. These compounds are thus derivatives of the compounds generically and specifically described on Col. 4, lines 4 through 66.

Further specific embodiments are:

[2-methyl-3-acetoxy-4-acetoxymethyl-pyridyl- (5 methyl] -n-butyl-disulfide [2-methyl-3 -acetoxy-4-acetoxymethyl-pyridyl- (5 methyl] -ethyl-disulfide [2-methyl-3 -acetoxy-4-acetoxymethyl-pyridyl- 5 methyl] -allyl-disulfide [2-methyl-3 -acetoxy-4-acetoxymethyl-pyridyl- 5 methyl] -2-methyl-3 ,6-dichlorophenyl-disulfide [2-methyl-3 -propionyloxy-4-propionyloxymethylpy-ridyl- 5 methyl] -ethyl-disulfide [2-methyl-3 -propionyloxy-4-propionyloxymethylpyridyl- (5 methyl] -benzy1-disulfide [2-methyl-3 -propionyloxy-4-propionyloxyrnethylpyridyl- 5 -methyl] -isopropyl-disulfide [2-methyl-3 -propionyloxy-4propionyloxymethylpyridyl- (5 -methyl] -2,3-dimethylphenyl-disulfide [2-methyl-3-palmitoyloxy-4-palmitoyloxymethylpyridyl- 5 -mthyl] -ethyl-sulfide [2-methyl-3-pah11itoyloxy-4-palrnitoyloxymethylpyridyl- 5 -methyl -ethyl-sulfide [Z-methyl-3-palmitoyloxy-4-palmitoyloxymethylpyridyl- 5 -methyl] -benzyl-sulfide [2-methyl-3 -palrnitoy-loxy-4-palmitoyloxymethyL pyridyl- 5 -methyl] -p-xylyl-sulfide [Z-methyl-3-palmitoyloxy-4-palmitoyloxymethylpyridyl- 5 -methyl] -cetyl-sulfide [2-methyl-3 -undecylenoyloxy-4-undecylenoyloxymethylpyridyl- (5 -methyl] -isobutyl-disulfide The novel compounds can be produced as follows: (a) By reacting a pyridine derivative of Formula II:

wherein R and R have the previously indicated meanings, and

R represents hydrogen, ammonium, or an equivalent of .a

metallic atom, preferably an alkali metal such as sodium,

or its acid addition salt, with a sulfur-containing compound of Formula III:

wherein:

Y represents SO R %O R SOR Br, Cl, or

SCN, and R and R have the previously indicated meanings.

(b) Or by reacting a sulfur-containing pyridine derivative of Formula IV:

(EHzORr wherein Z represents SO R Cl, or Br, and R R and R have the previously indicated meanings,

or its acid addition salt, with a mercaptan derivative of Formula V:

R SR (V) wherein: R and R have the previously indicated meanings.

If desired, a compound of Formula I wherein R and/or R represent hydrogen can be treated with an acylating agent; or a compound of Formula I wherein R and/or R represent acyl can be treated with a saponification agent. Further, a compound of Formula I can be converted, in a conventional manner, to its acid addition salt; or similarly the base compound can be liberated from an acid addition salt if the latter is obtained as a reactio product.

The details of the various processes for producing the compounds of this invention are as follows:

Reaction (a).-The reaction of a 3-mercaptomethylpyridine compound of Formula II with the derivatives of thiosulfuric acid (Y==SO R preferably with Buntes salts (salts of alkylthiosulfuric acids) is advantageously conducted in alkaline solution and in water, or in solvents which are miscible with water, for example in lower aliphatic alcohols, acetone, dimethyl formamide, dioxane, or tetrahydrofuran. It is, of course, also possible to use mixtures of such solvents, particularly mixtures of water and alcohols. Suitable alkaline materials are, for example, sodium hydroxide, potassium hydroxide, or ammo-- nium hydroxide. Normally, the reactions are carried out at temperatures between 0 and C. and under normal pressure.

The reaction between a 3-mercaptomethyl-pyridine compound of Formula II and such sulfur-containing compounds of Formula III wherein Y represents SO R or SOR is suitably carried out in approximately neutral solution. The yields of the desired end products generally decrease substantially in strongly acidic or strongly alkaline solution. Especially suitable for conducting the reaction are polar solvents, particularly alcohols, such as methanol, ethanol, propanol, and isopropanol. The reaction can be conducted in the absolute alcohols, as well as in aqueous alcoholic solution. The reaction temperatures are generally between 0 and about C.; preferably, however, room temperature is employed. Normally, 'it is suflicient to allow the reaction mixture to stand for a few hours.

Also, the reaction of the 3-mercaptomethyl-pyridine derivatives of Formula II with substituted sulfenyl halogenides (Y=Cl or Br) or substituted sulfenyl thiocyanates (Y=SCN) of Formula III is conducted in a solvent; preferably, inert solvents, such as ether, isopropylether, dioxane, dimethyl formamide, methylene chloride, chloroform, carbon tetrachloride, carbon disul fide, or ethyl acetate are added. Normally, the reaction mixture is allowed to stand at room temperature for several hours. However, it is also possible to carry out the reaction at higher temperatures.

solvents are likewise used, such as ether, dioxane, di

methyl formamide, chlorinated hydrocarbons, carbon disulfide or ethyl acetate. Here, too, it is recommended that the reaction mixture be allowed to stand for a longer period of time, for example overnight, at room temperature; however, it is also possible to heat the reaction mixture to increase the rate of reaction.

In contradistinction thereto, if a sulfur-containing pyridine derivative of Formula IV, wherein Z represents SO R is reacted with a mercaptan derivative of Formula V, it is advantageous to conduct the reaction in water and/ or in solvents miscible with water, such as, for example, in lower aliphatic alcohols, acetone, dimethyl formamide, dioxane, or tetrahydrofuran. The pH value of the reaction mixture is advantageously held above 7, preferably between 7 and 11. Generally, aqueous solutions of sodium, potassium, or ammonium hydroxide are added in order to obtain these pH values.

According to this invention, it is possible, in connection with compounds of Formula I wherein R and/ or R represent hydrogen, to substitute these H atoms by acyl groups. For this reaction, any conventional acylating method can be utilized. Particularly advantageous is the reaction with the corresponding acid anhydrides and/or acid chlorides of the above-mentioned acids in the presence of alkaline agents, particularly pyridine. For introducing the acyl residues of longer-chain acids, the acid chlorides are preferably employed.

It is also possible to transform such compounds of Formula I wherein R and/or R represent an acyl residue into the corresponding 3-hydroxy-4-hydroxymethyl compounds by treatment with saponification agents. Such a saponification can be conducted in accordance with any conventional process, for example by the effect of dilute acids or bases. The saponification process is especially smooth if the mixture is allowed to stand for a long period of time at room temperature with dilute acids, such as, for example, hydrochloric acid. However, the saponification can also take place through the efi ect of aqueous or aqueous-alcoholic solutions of, for example, sodium carbonate or bicarbonate.

The isolation of the reaction products is also done in a conventional manner, for example, by precipitating with the addition of a miscible non-solvent; by evaporating the solvent; by extraction; or by chromatographic methods.

The conversion of the compounds of Formula I into their acid addition salts is likewise conventional, for example, by reaction with the corresponding acid in an inert solvent. For pharmaceutical uses, all acids can be employed which yield physiologically compatible acid addition salts. Preferably, the following acids are contemplated: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, and alkylsulfonic acids, such as p-toluenesulfonic acid. In those cases in which the compounds according to the processes of the invention are obtained by acid addition salts, for example as hydrochlorides, they can obviously be converted into the corresponding free bases by any well-known technique, for example by neutralizing the solution of the acid addition salt and subsequently isolating the liberated base.

The starting compounds of Formula II are known from US. Patent No. 3,010,966 (e.g. claim 2) or they can be produced therefrom by conventional reaction with an acylating agent (R and/r R representing acyl) or with an alkali metal or ammonium hydroxide (R representing an alkali metal or ammonium equivalent). Compounds of Formula IV wherein Z represents SO R are obtained by reacting the corresponding 3-bromomethyl-pyridine compound with the desired thiosulfate.

The compounds of Formula III wherein Y=SO R which are used as starting materials, are obtained, in a known manner, by reacting the corresponding halogenides (preferably the bromides such as R Br) with sodium thiosulfate.

The thiosulfinic acid derivatives of Formula III (Y: SOR can be produced, in a known manner, by oxidation of the corresponding disul-fides (-R SSR with perbenzoic acid.

The t'hiosulfonic acid derivatives of Formula III (Y: SO R are formed by heating the correspondingly substituted sulfinic acids (R SO H) in water, the thiosulfonates being precipitated by disproportionation according to the following recation:

The sulfenyl thiocyanates of Formula 111 (Y=SCN) which are further compounds usable as starting materials can be obtained, as mentioned above, by reacting rhodanates with. the correspondingly substituted mercaptan derivatives.

The novel compounds of Formula I and their acid addition slats can be employed as therapeutic drugs and can be particularly utilized in cases wherein vitamin B therapy is indicated, more particularly for the treatment of cerebral malfunctions. In comparison to the known symmetrical pyridoxolyl disulfide, the novel compounds exhibit a higher lipoid solubility. For this reason, they penetrate the cellular membranes more readily and thus are better absorbed by the lipoid-rich nerve tissue.

These compounds can be employed in a mixture with the conventional pharmaceutical excipients. Carrier substances can be such organic or inorganic substances which are suitable for parenteral or enteral application and which do not react with the novel compounds, such as, for example, water, vegetable oils, polyethylene glycols, gelatine, lactose, amylose, magnesium sterate, talcum, Vaseline, cholesterol, etc. For parenteral application, solutions are especially used, preferably oily or aqueous solutions, as well as suspensions or emulsions which, if desired, are used in sterilized form or mixed with auxiliary agents, such as preservatives, stabilizers, or wetting agents, or with salts for influencing the osmotic pressure, or with buffer substances. For enteral ap plication, tablets or dragees are particularly suitable.

It is, of course, also possible to combine the novel compounds with other drugs, the concentration being, of course, compatible. Of special importance are polyvitamin combinations.

With respect to dosage, obviously effective amounts are administered. A unit dosage of a compound of this invention comprises on the order of 10 to 500 mg. preferably 50 to mg.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the specification and claims in any way whatsoever.

Example 1 (a) 2.75 g. 2-methyl-3-hydroxy-4-hydroxymethyl-5- mercaptomethyl-pyridine are dissolved in a mixture of 15 ml. water and 25 ml. of 1 N-sodium hydroxide, and mixed with 3.5 g. butylthiosulfate Buntes salt). The reaction mixture is allowed to stand for 10 minutes at room temperature, and the obtained precipitate is removed by suction. After recrystallization from benzene, the obtained [2-methyl-3-hydroxy-4-hydroxymethyl pyridyl (5)-methyl]-n-butyldisulfide melts at 100 C. Yield: 2.2 g.

(b) 2 g. [2 methyl 3-hydroxy-4-hydroxymethylpyridyl-(5)-methyl]-n-butyl-disulfide are allowed to stand overnight at 0 C. with 10 ml. pyridine and 10 ml. acetic an'hydride. Thereafter, the reaction mixture is mixed with water. The oil which separates during this process is taken up in ethyl acetate. After the solution is dried over sodium sulfate, the solvent is evaporated. The residue of [2-methyl-3acetoxy-4-acetoxymethylpyridyl-(5)-methyl]-n butyl-disulfide melts, after recrystallization, at 3738 C.

Example 2 (a) g. 2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl-(3)-methyl-bromide are slowly added to 800 ml. acetyl chloride in an ice bath and under vigorous stirring; subsequently, the mixture is refluxed for 2 hours. The precipitated 2-methyl-3-acetoxy-4-acetoxymethylpyridyl (3)-methyl-bromide-hydrochloride is removed by suction, and subsequently dissolved in water; the aqueous solution is adjusted to a pH of 7 by means of dilute sodium hydroxide. The 2-methyl-3-acetoxy-4- acetoxymethyl-pyridyl-(5)-methylbromide which precipi- 9 tates is removed by suction and recrystallized from isopropyl ether. M.P. 90 C. Yield: 107 g.

9.15 g. of the compound thus obtained are suspended in 50 ml. alcohol and mixed, under stirring, with a solution of 7.2 g. sodium thiosulfate in 10 ml. water. The mixture is heated for 1% hours to 60 C., is then filtered, and mixed with 20 ml. ether. The 2-methyl-3-acetoxy-4- acetoxy methyl pyridyl-(5)-methyl-thiosulfate-sodium which precipitates is removed 'by suction and recrystallized from methanol/ether. M.P. 238 C. (decomposition). Yield: 9 g.

3.17 g. of the thus-obtained thiosulfate are added to a solution of 0.9 g. n-butyl-mercaptan in 25 ml. 0.5 N NaOH. The reaction mixture is allowed to stand for 5 minutes at room temperature, and the oil which is separated is taken up in ethyl acetate. The reaction mixture is dried over sodium sulfate and concentrated by evaporation. The oily residue of [2-methyl-3-acetoxy-4-acetoxymethyl-pyridyl- (5 -methyl] -n-butyl-disulfide crystallizes by trituration with hexane. M.P. 37-38 C. (hexane). Yield: 2.3 g.

(b) 0.3 g. [2-methyl-3-acetoxy-4-acetoxymethyl-pyridyl-(S)-methyl]-n-buty1-disulfide is allowed to stand in cc. 1 N-hydnochloric acid for 24 hours at room temperature. The solution is neutralized in 2 N-solution of sodium bicarbonate. After the mixture is worked up in conventional manner, 0.17 g. pyridoxolyl-n-butyldisulfide is obtained, M.P. 100 C.

Example 3 2.75 g. 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethyl-pyridine are dissolved in 40 ml. 0.5 N NaOH and mixed with 4.5 g. lauryl thiosulfate. The reaction mixture is heated for 15 minutes to 50-55 C. The precipitated [2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl- 5 methyl]-lauryl-disulfide is removed by suction and re crystallized from benzene. M.P. 114-115 C. Yield: 2.8 g.

Example 4 8.7 g. l-propanethiosulfinic acid propyl ester are dissolved in 150 ml. methanol and mixed with a solution of 22.1 g. 2-methyl-3-hydroxy-4 hydroxymethyl-S-mercaptomethyl-pyridine-hydrochloride in 100 ml. methanol. After the mixture has been allowed to stand at room temperature for 6- hours, 50* ml. ether are added. The [2-methyl-3- hydroxy-4-hydroxymethyl-pyridyl-( 5 methyH-n-propyldisulfide-hydrochloride which precipitates is removed by suction and recrystallized from isopropyl alcohol/ether. M.P. 117-118 C. Yield: 19' g.

If the ethereal solution is adjusted to a pH of approximately 7 by the addition of NaOH, the free base can be isolated. M.P. 114 C. (benzene).

Example 5 11.9 g. isopentanethiosulfonic acid isoamyl ester are dissolved in 30 ml. absolute alcohol and mixed with a solution of 9 g. 2-methyl-3-hydroxy-4-hydroxymethyl-S- mercaptornethyl-pyridine in 50 ml. absolute alchol. After the mixture has been allowed to stand for 12 hours at room temperature, it is evaporated to dryness under vacuurn. The residue is mixed with 2 N-aqueous solution of sodium bicarbonate. The [2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl- (5 -methyl] -isoamyl-disulfide which separates is removed by suction and recrystallized from benzene. M.P. 114-115 C. Yield: 7.4 g.

Example 6 22.5 g. lead rhodanate are suspended in 150 ml. ab solute ether and mixed with 3 ml. bromine at 5-10 C. Once the mixture loses its color, the precipitated lead bromide is removed by suction. A solution of 5.5 g. thiophenol in 100 ml. dimethyl formamide is slowly added,

dropwise, to the filtrate at 10 C. The reaction is subsequently mixed with a solution of 9.2 g. 2-methyl-3- hydroxy-4-hydroxy-methyl-S-mercaptomethyl pyridine m ml. dimethyl formarnide. After the mixture has been allowed to stand overnight, 2.5 l. ether are added. The separated oil is dissolved in 50 ml. 2 N-hydrocholoric acid. The portion which does not dissolve (diphenyl disulfide) is removed by suction. The filtrate is evaporated to dryness, and the residue is taken up in water, neutralized, and extracted with ethyl acetate. The ethyl acetate solution is freed from precipitating by-products and dried over sodium sulfate. After concentration and recrystalliztation from ethyl acetate, the [2-methyl-3-hydroxy 4 hydroxymethyl-pyridyl-(S)-methyl] -phenyl-disulfide melts at 108 C. Yield: 4 g.

Example 7 9.2 g. 2-methyl-3-hydroxy-4-hydroxymethyI-S-mercaptomethyl-pyridine are dissolved in 100 ml. dimethyl formamide. The solution is mixed with 4.8 g. o-nitrobenzene sulfenylchloride in 50 ml. dimethyl formamide. The reaction mixture is stirred for 2 hours at room temperature and is then allowed to stand overnight. The obtained precipitate is removed by suction, and the filtrate is concentrated to about /s its volume and mixed with 500 ml. water. The precipitating substance is removed by suction, washed with 20ml. 1 N-hydrohloric acid, and recrystallized from methanol/ether. The obtained [2-methyl-3-hydroxy-4-hydroxymethyl pyridyl-(5)-methyl]-onitrophenyl-disulfide melts at 163 C. Yield: 1.3 g.

Example 8 Analogously to Example 1, the following compoundsare obtained by reaction of 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethyl-pyridine with the corresponding alkylthio sulfates (a) [2-methyl-3 -hydroxy-4-hydroxyme thyl-pyridyl- (5 hydrochloride: M.P. 97 C. (isopropanol/ether).

(e) [2 methyl-3-hydroxy-4-hydroxymethyl pyridyl- (5)-methyl]-allyl-disu1fide: M.P. 118 C. (benzene).

(f) [2 methyl-3-hydroxy-4-hydroxymethyl pyridyl- (5)-Inethyl]-cetyl-disulfide: M.P. C.

Example 9 Analogously to the method described in Example 1,

2.75 g. 2-methyl-3-hydroxy-4-hydroxyrnethyl-5-mercaptomethyl-pyridine are reacted with benzylthiosulfate to form [2-methyl-3-hydroxy 4 hydroxymethyl pyridiyl (5)- methyl]-benzyl-disulfide. M.P. C. (methanol).

Example 10 Analogously to the method set forth in Example 1, 2.75 g. 2-methyl-3-hydroxy 4 hydroxymethyl-S-mercaptornethyl-pyridine are reacted with phenylthiosulfate to form [2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl- (5)-methyl]-phenyl-disulfide. M.P. 108 C. (ethyl acetate).

Example 11 Analogously to the method described in Example 1, 2.75 g. 2-methyl-3-hydroxy-4-hydroxymethyl-5-rnercaptomethyl-pyridine are reacted with 4'-acetoxy-butylthiosulfate to yield [2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl-(5)-methyl]-4'-acetoxybutyl-disulfide. M.P. 71-72 C. I

(benzene/isopropyl ether).

C. (benzene);

Example 12 Analogously to the method mentioned in Example 1, 2.75 g. 2-methyl-3-hydroxy-4-hydroxymethyl-S-mercaptomethyl-pyridine are reacted with fl-et'hoxy-carbonylethylthiosulfate to yield [2 methyl 3.- hydroxy-4-hydroxymethyl pyridyl (5 methyl] J8 ethoxy-carbonylethyldisulfide. M.P. 71 C. (isopropyl ether/hexane).

Example 13 Analogously to the method described in Example 1, 5.4 g. 2-methyl-3-hydroxy 4 hydroxymethyl-S-mercaptomethylpyridine are reacted. with 11.6 g. p-chlorophenoxyethylthiosulfate to form ['2-methyl-3-hydroxy-4-hydroxymethylpyridyl (5) methyl] p chlorophenoxyethyldisulfide. M.P. 145-146" C. (methanol).

Example 14 Analogously to the method set forth in Example 1, 5. 4 g. 2-methyl 3 hydroxy 4 hydroxymethyl-S-mercaptomethylpyridine are reacted with 8.78 g. benzoyl-methylt-hiosulfate to produce [2-methyl-3-hydroxy-4-hydroxymethyl pyridyl (5) methyl]-benzoylmethyl-disulfide. M.P. 142 C. (190 C. decomposition)-(methanol).

Example 15 Analogously to the method described in Example 1', 3.6 g. 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridine are reacted with 9 g. p-bromobenzylthiosulfate to yield [2 methyl- 3 -hydroxy-4-hydroxyl methyl pyridyl (5)-methyl]-p=brom0benzyl disulfide. M.P. 156 -157" C. (methanol).

Example 16 Analogously to the method set forth in Example 1, 5.4 g. 2 methyl 3 hydroxy 4-hydroxymethyl- 5- mercaptomethylpyridine are reacted with 9.6 g. p-xylylt-hiosulfate toproduce [2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl-(5)-methyl]-p-xylyl-disulfide. M.P. 135- 136 C. (methanol).

Example 17 Analogously to the method mentioned in Example 1, 5.4 g. 2 methyl 3 hydroxy 4 hydroxymethyl-S- mercaptomethylpyridine are reacted with 8 g. B-naphthylmethyl-thiosulfate to form [2 methyl 3 hydroxy-4- hydroxymethyl pyridyl (5)-methyl]-B-naphthylmethyldisulfide. M.P. 195196 C. (methanol).

Example 18 Analogously to Example 1, the following compounds are obtained by reaction, of 2 methyl-3 -hydroxy-4- hydroxymethyl-5-mercaptomethyl-pyridine with the corresponding thiosulfates:

Pyridoxolyl-methyl-disulfide Pyridoxolyl-vinyl-disulfide Pyridoxolyl-crotyl-disulfide Pyridoxolyl-undecylenyl-disulfide Pyridoxolyl-ethynyl-disulfide Pyridoxolyl-propargyl-disulfide Pyridoxolyl-naphthyl-disulfide Pyridoxolyl-phenethyl-disulfide Pyridoxolyl-4-methoxybutyl-disulfide Pyrid0xolyl-4-ethoxybutyl-disulfide Pyridoxolyl-4-butoxybutyl-disulfide Pyridoxolyl-4-benzyloxybutyl-disulfide Pyridoxolyl-4-propoxybutyl-disulfide Pyridoxolyl-3-benzoyloxypropyl-disulfide Pyrid0xolyl-4'-cinnamoyl-disulfide Pyridoxolyl-3'-carboxypropyl-disulfide Pyridoxolyl-p-methoxycarbonylethyl-disulfide Pyridoxolyl-3-toloxycarbonylpropyl-disulfide Pyridoxolyl-Z'-ethoxyheptylpropy1-disulfide Pyridoxolyl-2'-carbamoylethyl-disulfide Pyridoxolyl-4-N,N-dimethylcarbamoylbutyl-disulfide By repeating the preceding examples, using the required starting materials, all of the specifically and generically described compounds can be produced. The reaction conditions can, of course, be routinely varied by those skilled in the art to give more Weight to certain variables of the process, such as reaction time, inhibition of side reactions, yield, and so on.

For a specific preferred embodiment of a pharmaceutical composition of this invention, the following is presented:

I. Tablets: Each tablet contains- Mg. Pyridoxolyl-allyl-disulfide Lactose 200 Corn-starch 35 Magnesium stearate S Talc 20 II. Coated tablets: The core contains Pyridoxolylether-disulfide 150 Lactose 100 Potato starch 50 Gelatine 4 The core is coated according to standard techniques with a mixture of sugar and arabic gum to make up a coated tablet with a total weight of 500 mg.

III. Syrup:

Pyridoxolyl-benzyl-disulfide g 100 Sugar syrup l 15 Saccharin g 0.5 Para-hydroxy benzoic acid methyl ester g 10 Para-hydroxy benzoic acid propyl ester g 7 Aromatic stuffs (The usual dosage is 15 m1.)

IV. Hard gelatine capsules: A mixture of- Mg. Pyridoxolyl 2 methyl 3,6 dichlorophenyldisulfide Lactose 50 Talc 15 Vanillin 1 is filled into hard gelatine capsules having 3 mm. in diameter.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and Without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Consequently, such changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of the following claims.

What is claimed is: 1. A member of the group consisting of a compound of the following formula and the acid addition salts thereof,

Hac \N (I) wherein:

R and R are each selected from the group consisting of hydrogen and acyl of an aliphatic hydrocarbon carboxylic acid of not more than 18 carbon atoms, and

R is selected from the group consisting of (a) unsubstituted alkyl of not more than 20 carbon atoms; (b) alkyl of not more than 20 carbon atoms substituted by at least one member selected from the group consisting of halogen, hydroxyl, lower alkoxy, amino, mono-(lower a1kyl)-amiuo, di-(lower alkyl)-amino, piperidino, morpholino, piperazino and piperazino substituted by lower alkyl, aralkoxy wherein the aryl portion is a hydrocarbon of 6 to carbon atoms and the alkoxy portion is a lower alkoxy, acyloxy of a hydrocarbon monocarboxylic acid of not more than 9 carbon atoms, carbobenzoxy, carboxyl, esterified carboXyl of not more than 9 carbon atoms wherein the alcohol portion is a hydrocarbon alcohol of not more than 8 carbon atoms, unsubstituted -CONH CONH substituted by lower alkyl, piperidino carbonyl, piperazino carbonyl, and mor-pholino carbonyl; (c) alkenyl of not more than 12 carbon atoms; (d) alkynyl of not more than 3 carbon atoms; (e) x-carbocyclic aryl of up to 12 carbon atoms; (f) x-carbocyclic ar-lower alkyl of up to 12 carbon atoms in the carbocyclic portion; and x is selected from the group consisting of hydrogen and at least one of halogen, lower alkyl, lower alkoxy, hydroxy, nitro, amino, mono-(lower alkyDamino, and di-(lower alkyl) amino.

2. A compound as defined in claim 1 wherein R and R designate hydrogen and R is allyl.

3. A compound as defined in claim 1 wherein R and R designate hydrogen and R is benzyl.

4. A compound selected from the group consisting of pyridoxolyl ethyl disulfide, pyridoxolyl propyl disulfide, pyridoXolyl-butyl-disulfide, pyridoXolyl-cetyl-disulfide, pyridoxolyl-lauryLdisulfide, and pyridoxolyl-allyldisulfide.

5. A compound selected from the group consisting of pyridoXolyl-benZyl-disulfide, pyridoXolyl-p-xylyl-disulfide, pyridoxolyl 2 methyl 3,6 dichloro phenyl -i disulfide, and pyridoXolyl-2,3-dimethylphenyl-disulfide.

References Cited UNITED STATES PATENTS 1,915,334 6/1933 Salzberg et al. 260-243 2,075,359 3/1937 Salzberg et a1. l6722 3,010,966 11/1961 Zima et a1. 260294. 8 3,039,930 6/1962 Gray 167-65 ALEX MAZEL, Primary Examiner.

J. TOVAR, Assistant Examiner.

Patent Citations
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US1915334 *Oct 16, 1930Jun 27, 1933Du PontFluosilicate of organic heterocyclic bases and process of making it
US2075359 *Oct 16, 1930Mar 30, 1937Du PontInsecticide
US3010966 *Mar 19, 1959Nov 28, 1961Merck Ag EDerivatives of vitamin b6
US3039930 *Apr 6, 1960Jun 19, 1962Irwin Neisler And CoPyridyl carbamyl lower alkane derivatives: analgesic process
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US5137877 *May 14, 1990Aug 11, 1992Bristol-Myers SquibbBifunctional linking compounds, conjugates and methods for their production
US7282590Feb 8, 2005Oct 16, 2007The Research Foundation Of State University Of New YorkDrug conjugates
US7847119Sep 17, 2007Dec 7, 2010The Research Foundation Of State University Of New YorkDrug conjugates
Classifications
U.S. Classification546/294, 544/360, 544/158, 546/301, 546/302, 544/124, 544/364, 544/357, 424/481, 546/193, 424/479, 424/456, 546/300
International ClassificationC07D213/66
Cooperative ClassificationC07D213/66
European ClassificationC07D213/66