IL22280A - Asymmetrical pyridoxolyl disulphides and their preparation - Google Patents

Description

PATENTS FORM Γ anraeys PATENTS COMPLETE SPECIFICATION Asymmetrical disulphides and their MERCK a German Body of Frankfurterstrasse do hereby declare the for which we pray that a patent may be granted to and the method by which it is to be to be particularly described in and by the following statement 22280 File 12615 The invention relates to asymmetrical pyridoxolyl disulphides and to methods for thei We have that pyridoxolyl derivatives of the where and H or carboxylic acyl groups and is an optionally acyl or l radical aryloxy an optionally halogen or nitro aryl or radical or an alkenyl or and their salts are pharmacologically active They may be thought of as being vitamin its acyl The present invention provides compounds of the above and their salts new compounds pharmaceutical or their salts these compounds their The novel compounds of formula I can be prepared by reacting a pyridine derivative formula 22280 Pile 12615 where and are previously de ned and is an group or an equivalen of a metal preferably with a compound of formula Y is C or and and are as previously 22280 File 12615 which the acyl groups may be is a branched substituted or unsubstituted alkyl radical which generally not have more tha 20 carbon Suitable alkyl radicals are the lower alkyl radicals preferably with up to 6 carbon atoms such amyl and but also the alkyl groups such as octy When is an alkyl group it ma be unsubstituted or mono or poly substituted in various by acyloxy groups or aliphatic aromatic monocarboxylic acids containing up to carbon more particularly utoxy and amyloxy or carbpbenzoxy or cinnamoylox The alkyl radical may also be substituted by an esterified carboxyl group containing up to carbon for may also denote an alkenyl This may contain one or more double but generally does not contain more than Preferred alkenyl radicals are all 22280 12615 Preferred alkinyl groups are ethinyl and If denotes an aryl then phenyl or naphthyl are Aralkyl are in the benzyl and phenethyl If the aromatic particularly the phenyl is tuents are preferably halogens such as or lower up to carbon more particularly and amyl groups or nitro The following substituted aryl radicals are given by wa of or o The two methods fo the preparation of the novel compounds will now be described in more Reaction A compound of formula II is advantageously reacted with acid derivatives preferably Bunte salts salts of alkylthiosulphuric in alkaline solution in water for example in lower aliphatic dioxan or 22280 alkaline additives for or The reactions are carried out a temperature of from and under normal The reaction between a pyridine compound of formula II and those formula III compounds in which Y denotes is advantageously out i substantially highly acid or highiy alkaline solutions yields of the required products generally fall off Polar solvents more particularly alcohols such as propanol and isopropanol are particularly suitable the The reaction may be performed both in anhydrous and aqueous The reaction temperatures are generally between 0 and but preferably it is carred out at room It is generally sufficient merely to let the reaction mixture stand fo some The reaction of the pyridine derivatives of formula II with substituted sulphonyl or or substituted formula III also carried in a inert solvents advantageously being as the reaction etherj 22280 Pile 12615 carbondisulphide ethyl the reaction mixture left for some hours at room the reaction may carried out at elevated The sulphenyl thiocyanates Y required for the reaction are prepared b reaction of metallic salts anic acid with the corresponding substituted mecaptan derivatives and need not in the form of pure products in the reaction but can used without isolation directly in the solution obtained during their Reaction B Inert as chlorinated carbon disulphide or are again used for the reaction of a pyridine derivative of formula IV Z denotes the mercaptan derivatives of formula Here agai it is advisable to leave the reaction mixture for some for example room although the reaction be heated if on the a pyridine derivative of formula IV in which Z denotes is reacted with a mercaptan derivative of formula V it is advantageous to perform the reaction in water in for example in aliphatic or tetrahyd The pH of the reaction mixture is advantageously above preferably between 7 and aqueous solutions potassium or ammonium hydroxide are added obtain these pH As previously compounds of formula I an be converted to the corresponding acylated Any acylation process may employed for this Particularly advantageous is reaction with the corresponding acid anhydrides or acid chlorides of the requisite acid in the presence of alkaline more particularly the acid chlorides preferably being used for the introduction of the Those compounds I in which R denote an acyl radical may also be converted to the corresponding compounds by with saponification The saponification can be carried out by any for example by the action of dilute acids or Saponification by leaving the mixture at room temperature for a relatively long period with dilute for example hydrochloric is particularly Saponification can also be carried out by the action of aqueous or solutions for carbonate or sodium hydrogen carbonate the acyl The reaction products are in each case isolated by procedures known to those skilled in the for by precipitation an appropriate by evaporation of the by extraction or by chromatographic Conversion ormula I compounds to their salts is also carried out in a manner known in the for reaction with the appropriate acid in a inert In principle any acid which yields a physiologically compatible salt may be used this The following acids are particularly nitric and methane sulphonic acid and alkylsulphonic acids such as If the novel compounds are isolated in the form they can be converted into the free bases by any conventional methods such as neutralisation the solution of the acid addition salt followed by isolation the liberated The formula II starting materials are known from File 12615 Patent Spedification or can be prepared om treatment with an agent or with hydroxide or ammonium Formula compounds i which denotes obtained by reaction of the basic me compound with the corresponding The starting materials of formula III in which Y denotes may be obtained by reaction of the corresponding halides with solium The thiosulphate acid derivatives of formula can be prepared by oxidation of the with The hiosulphonic acid derivatives of formula III finally form when the correspondingly substituted thiosulphinic acids are heated in thiosulphonates precipitating by The sulphenylthiocyanates of formula III which are also used as starting material as already by reaction of rhodanides with correspondingly substituted mercaptan The following formulae illustrate certain examples of the novel i 22280 File 12615 where substituted pplysubstituted with pre erable not more than 6 carbon atoms in the The substitutes may be acyloxy groups acyls or aliphatic or aromatic monocarboxylic con taining up to 9 carbon atoms or a esterifled group containin up to 9 carbon atoms ethinyl or prdpargyl 22280 12615 lkyl where n 1 phenyl where substituted phenyl is polysubstituted substituted by or lower alkyl with up to 5 carbon atoms or nitro 22280 12615 where benzyl may be or substituted by halogens or lower with up to 5 carbon atoms or In each of the above formulae and meanings previously ascribed to If are the following compounds will be of particular and The new compounds and their salts may be used as drugs and be applied wherever vitamin therapy is They are used more particularly for the treatment of disorders of cerebral As compared with known symmetrical pyridixolyldlsulphides the new compounds have better They therefore penetrate the cell membranes more easil and thus absorbed more satisfactorily by the rich nerve They can be used in admixture with conventional drug excipients in human 6r veterinary The excipients will be those organic or inorganic substances which are suitable parenteral or enteral application which do not react with the new for example vegetable polyethyleneglycols magnesium petroleum jelly and parenteral application there will be in solutions preferably oil or and suspensions or emulsions if may be sterilised or mixed with such as stabilisers or wetting or salts for influencing osmotic pressure or buffer Tablets or pills are particularly suitable for enteral The new compounds can of course be combined with other drugs if they are compatible Combinations with vitamins are particularly In order the invention may be more fully understood the following Examples are given by way of illustration Example 1 g of are dissolved in a mixture of 15 ml of water and 25 ml of hydroxide solution and g of butyl thiosulphate are The reaction mixture is left for 10 minutes at temperature and precipitate filtered off After the resultant melts 2 g of are left overnight at with 10 ml of pyridine and 10 ml of acetic Water is then added to the reaction The oil which separates in these conditions is taken up in ethyl The solution is dried over sodium sulphate and the solvent is The residue melts at after recrystallisati Example 2 120 g of oxymeth are slowly added to 800 ml of acetyl chloride with intensive agitation and cooling with and the mixture is then boiled for 2 hours under The precipitated is filtered off by dissolved in and the aqueous solution adjusted to a of with dilute The precipitated is filtered off by suction and recrystallised from Melting point Yield g the compound obtained in this way are suspended in ml of alcohol a solution of g sodium thiosulphate in 10 ml of water is added with The mixture is heated at for then filtered and ml of ether are The precipitated is removed by suction and recrystallised from Melting point 9 S the thiosulphate obtained in this way are added to a solution of S of in 25 ml of reaction mixture is left at room temperature for five minutes and the separated oil is taken up in ethyl It is dried over sodium sulphate and The oily residue disulphide crystallises on rubbing with Melting point Yield g of are left for 2 hours at room temperature in IN hydrochloric The solution is neutralised 2N sodium bicarbonate After processing g of is Melting point Example 3 g mercapto dissolved 0 ml of NaOH and g of laurylthiosulphate is The reaction mixture is heated for minutes at The precipitated is filtered off by suction and from Melting Yield Example 4 g propyl ester are dissolved in of methanol and a solution of g of in 100 ml of methanol is being left at room temperature for 6 ml of ether is The precipitated is filtered off by suction and recrystallised from Melting point Yield 19 If the ether is adjusted to about by the addition of the free base can be Melting point 11 Example g of isopentane thiosulphonic ester are dissolved in 30 ml of absolute alcohol and a solution of g of of absolute alcohol After being left for 12 hours at room temperature the reaction mixture is inspissated in vacuo until 2N aqueous sodium hydrogen carbonate solution is added to the The precipitated is filtered by suction and recrystallised from Melting point Yield Example 6 g of lead rhodanide are suspended in 150 ml of absolute ether of bromine is added at When the solution has lost colour the precipitated lead bromide is filtered off by suction and a solution S in 100 ml of slowly added the filtrate at a temperature of A solution of Pile 12615 in 100 of then added to the reaction After the been left overnight of ethe The separated oil is dissolved in 50 ml of hydrochloric The undissolved fraction filtered off by The filtrate is inspissated until the residue taken up in and then extracted with ethyl acetate The precipitated are eliminated from the ethyl acetate solution and the latter is dried over After inspissation and recrystallisation from ethyl acetate the melts at 108 Yield 4 Example g of are dissolved in 100 ml of dimethylformamidei g of benzene sulphonyl chloride in 50 ml of ormamide is added to the The reaction mixture is agitated at room temperature for 2 hours and then left The precipitate is filtered off by suction and the filtrate inspissated to about of its original volume and 500 ml tered off by with 20 ml of chloric acid and recrystallised from The resultant melts at Yield i Example compounds prepared in the same way as in Example 1 by reaction of with the corresponding thiosulphates Melting point Melting point Melting point Melting point Melting point 1 Melting point Melting Melting point Melting point Example By the process described in Example S of pyridine are reacted with benzylthiosulphate to Melting point 1 10 By described in Example S pyridine are reacted phenylthiosulphate to form Melting point Example 11 By the process described in Example S of pyridine are reacted with to form Melting point Example 12 By the process described in Example S pyridine are reacted with sulphate to form Melting point Example 13 By the process described in Example g of pyridine are reacted with g of thiosulphate to form pyrid Melting point 1 Example By the process described in Example g of pyridine are reacted g of sulphate to Melting point Example 1 By the process described in Example 1 g of pyridine are reacted with 9 g of to point Example 16 By the process described in Example 1 g of 1 pyridine are reacted with g of to form Melting point Example 1 By the process described in Example 1 g of pyridine are reacted with 8 g of thiosulphate to point insufficientOCRQuality

Claims (1)

1. 22280 Pilel2615 NOW particularly described and ascertained the nature of our said invention and in what manner the same to be we declare tha what claim A compound of the earboxylic acyl or aryloxy substituted allcyl radical alkyl an alkinyl radical or an optionally halogen or nitro aryl or aralkyl A compound according to Claim in which the substituted alkyl group contains not more than 6 carbon atoms in its A salt a compound according to any of Claims 1 and 20 22280 Pile 12615 lp ide 22280 12615 A process for the of a compound of the where and have the meanings ascribed to them in which process comprises the step of reacting a compound of the where an ammonium an equivalent of a metal with compound of the where T is or process according to Claim in which metal is A process for production of a compound of the y 12615 process for the preparation of a compound according to Claim substantially as herein described in any of the Examples A process for the preparation of a compound according to substantially as herein a o E A pharmaceutical composition comprising a compound according to any of Claims 1 to association with an pharmaceutical A preparation according to Claim which also comprises a insufficientOCRQuality