DE1110648B - Process for the preparation of disulphide compounds of vitamin B. - Google Patents

Description

Process for the preparation of disulfide derivatives of the vitamin Bt The invention relates to a process for the preparation of compounds of the general formula in which R1 is a methyl or ethyl radical, R2 is a tetrahydrofuryl or tetrahydropyranyl radical, R3 is a hydrogen atom or an acyl radical and A is a low molecular weight alkylene radical.

There are already different types of derivatives of vitamin B1 known whose asymmetric structure is similar to the above formula; these However, instead of the group - A - R2, derivatives have an alkyl, alkenyl, aryl, Aralkyl or similar radical.

In terms of their medicinal effects, such compounds are superior to the vitamin B1 acid salts, but they generally have an ugly one odor similar to hydrogen sulfide.

There have now been new and better disulfide-type vitamin B1 derivatives sought and obtained according to the invention, which have the disadvantages set out above do not have and their medicinal effect is superior to that of the known derivatives is, of course, that of acid salts of vitamin B1.

The superiority of the compounds produced according to the method is shown, for example, in the results of the experiments below. In these Tried were three types of vitamin B1 derivatives of the new group, viz S-t2- [N- (2'-methyl-4'-ammopyrimidyl- (5 ') - methyl) - formamido] - 5-hydroxypentene- (2) - yl- (3)) - tetrahydrofurfuryl disulfide (1), S-1,2- [N- (2'-methyl-4'-aminopyrimidyl- (5 ') -methyl) -formamido] -5-hydroxypenten- (2) -yl- (3)} -y- [tetrahydrofuryl- (2 ") -propyl] disulfide (II) and S- (2- [N- (2'-methyl-4 '-aminopyrimidyl- (5') -methyl) -formamido] -5-hydroxypenten- (2) -yl- (3)} -tetrahydropyranyl - (2 ") - disulfide (III) is used. In these compounds, the symbols have the above given general formula has the following meaning: I: R1 = CH3, R2 = oi-furyl, R3 A = CH2.

II: R1 = CHa, R2 = oc-furyl, R3 A = C3H6.

III: R1 = CH3, R2 = os-pyranyl, R3 = A = CH2.

Control experiments were carried out with vitamin B1 hydrochloride itself and the well-known 5 - {2- [N- (2'-methyl-4'-aminopyrimidyl- (5 ') - methyl) -formamido] - 5-hydroxypenten- (2) -yl- (3)) -n-propyl-disulfide (IV), wherein R1 of the above general Formula has the meaning of CHa, R2 and R3 of H and A of C3H6. The comparison substance IV is the most effective of all known vitamin B1 derivatives of the disulide type.

When injecting compounds I, II or III intravenously into In the ears of rabbits, the vitamin B 1 concentration in the blood is significantly increased and maintain this high concentration for a long time. The trials were carried out with rabbits weighing approximately 2 kg each. The amount of each injected The sample corresponded to 10 mg of vitamin B1 hydrochloride, i.e. H. 11.8 mg I, 13.7 mg II, 12.3 mg III and 10.6mg IV. The vitamin B1 concentration in the blood was increased several times measured after the injection.

The following results were obtained: Vitamin B1 in the blood *) Compound dose cases before and after the injection mg injection 3 minutes 1 10 minutes 1 30 minutes! 60 minutes I 90 minutes I .............. 11.8 4 34.8 2335 2311 2178 1882 1756 II ............. 13.7 8 42.8 1529 1729 1595 1463 1282 III ............ 12.3 8 48.0 2372 2471 2227 1924 1818 IV ............. 10.6 5 63.4 1648 1564 1459 1338 1229 Vitamin B1 hydrochloride. . 10.0 1 46.7 718 1 516 282 156 140 *) Concentration of total vitamin B1 in y 01o per cubic centimeter of total blood.

In the above experiments, the vitamin B1 content in the blood quantitatively determined by means of a chemical process in which the vitamin B1 reduced cysteine in the blood and subsequently using the thiochrome method was determined by cyanide bromide.

The results of the above experiments show that when the compounds obtained according to the method are injected into living bodies, the concentration of total vitamin B1 in the blood increases far more than when vitamin B1 hydrochloride or compound IV is used and this is high in vitamin B1 -Blood level also lasts much longer than with the two comparison substances mentioned. Compound I was administered orally or injected intraperitoneally into rats and the lethal dose was determined. It has been found that the LD50 value in mg / kg is very low, as can be seen below: Vitamin B1 Conditions of use I hydrochloride Oral ...................... 2200 9000 Intraperitoneal injection ... 540 500 To produce the products according to the invention, vitamin B1, homovitamine B1 (a vitamin B1 derivative in which the methyl radical in the pyrimidine nucleus of vitamin B1 is replaced by an ethyl radical) or their O-acyl derivatives (these compounds are hereinafter referred to as »vitamin B1 or this corresponding compounds «) reacted with an active compound, by means of which the - 5 H group is converted into a radical -5-5 - A - R2, in which A and R2 have the meaning given above. Vitamin B1 or the compounds corresponding to it are generally available in the form of their acid salts, such as hydrochloride, nitrate or sulfate, and these acid salts are all suitable according to the invention. Compounds of the general formulas R²-AS-SO3M RA-SS OR R2-ASS O2-R R2-ASSC N R2-ASX are suitable as active compounds for introducing the radical -SSA-R2 into the starting material. In these formulas, R2 and A have the meanings given above, M denotes an alkali or alkaline earth metal atom, R an alkyl radical or the radical R2 and X a halogen atom.

In the process according to the invention, the compounds listed above are reacted with a vitamin B1 of the thiol type or corresponding compounds. It is generally known that in solution vitamin B1 or corresponding compounds are in a state of equilibrium between the ammonium form (V) and the thiol form IV, this equilibrium shifting to the thiol side under alkaline conditions and to the ammonium side under acidic conditions, as shown below . NN NH2 CH-5 N - .N. NH2 R1, CHS R i, CHO N Nx alkaline N / N .SH CH2 c -c acidic CH2 CH, CC f acidic C CH2 CH2CH2OR3 CH3 CH2-CH2OR3 V VI The reaction according to the invention takes place under neutral or alkaline conditions, ie the reaction proceeds slowly at a non-acidic pH. The yield is reduced if the reaction takes place in an excessively alkaline medium, because not only the vitamin B1 or its corresponding compounds, but also the reaction products are decomposed under such conditions.

A pH between 7 and 9 is preferably used.

The reaction is carried out in solvents such as water, alcohols, acetone, Vinegar esters or mixtures these connections carried out, in principle can however, all solvents can be used relating to the reaction system are inert.

Those listed above for the introduction of the -5 - A - R2 group Reactants are almost always used without the addition of other agents.

If the starting compound is an O-acyl derivative of vitamin B1 or of homovitamin B1 is present, the reaction product consists of the corresponding one O-acyl derivative, but the acyl radical can easily be cleaved off in the usual way. When the output connection contains free hydroxyl groups also the reaction product free hydroxyl groups, which, however, if necessary, can be acylated in the usual way.

The invention is illustrated in the following examples. the Parts are parts by weight, the analysis values are given in percent, the temperatures are not corrected.

Example 1 To a solution of 20 parts of vitamin B1 hydrochloride in 30 parts of water, an aqueous solution of 7.2 parts of sodium hydroxide in 30 Parts of water were added and the mixture was cooled with water. It'll be 30 minutes left to stand, then 60 parts of chloroform and then a solution of 30 parts of crude sodium tetrahydrofurfuryl thiosulfate in 30 parts of water were added and stirred for 30 minutes. The chloroform layer is separated and the aqueous layer extracted with 20 parts of chloroform. The chloroform extracts are combined and shaken with 50 parts of 5% hydrochloric acid.

The acidic solution is decolorized and neutralized with alkali carbonate, after which the compound 1 is deposited in a resinous state, but without solidifying (Melting point 1290 C with decomposition). The yield is 16 parts. When recrystallizing from ethyl acetate colorless prisms are obtained which decompose melt at 132 ° C.

Analysis for C17H26O3N4S2: Calculated ... C 51.22, H 6.58%; found .. CSl, 11, H6,450 / 0.

Example 2 3 parts of tetrahydrofurfurylthiosulfinic acid tetrahydrofurfuryl ester are added to 100 parts of 50% ethanol and 2 parts of vitamin hydrochloride added and the mixture with a 100 / 0eigen aqueous sodium hydroxide solution adjusted to a p: value of 8.

This p-value is maintained during the mixture for 1 hour is heated to a temperature between 50 and 600 C until the thiochrome reaction the mix is negative. After decolorization, the mixture is reduced under Pressure was evaporated and then a small amount of water was added to the residue dissolve the inorganic impurities. What remains is an oily substance that however, solidified after washing. Melting point 129 ° C with decomposition. The yield is 1.2 parts.

When recrystallizing from ethyl acetate, colorless prisms become of the compound I with a melting point of 132 "C obtained with decomposition.

There is no lowering of the melting point upon melting of the product with that obtained according to Example 1 was determined.

Example 3 To a solution of 3.4 parts of vitamin B1 hydrochloride in 5 parts of water, a solution of 1.2 parts of sodium hydroxide in 5 parts of water is made given and the mixture left to stand for 30 minutes.

To this mixture are added 12 parts of chloroform and then with stirring a solution of 4.7 parts of sodium y- [tetrahydrofuryl (2) propyl] thiosulfate in Given 5 parts of water. 30 minutes later the chloroform layer is separated and the aqueous layer was extracted with 12 parts of chloroform. The chloroform extracts are combined and shaken with 25 parts of 5% hydrochloric acid. The acidic solution is neutralized with alkali carbonate after decolorization.

Compound II separates out in a resinous state. the Yield is 3 parts.

Recrystallization from ethyl acetate gives colorless ones Prisms that melt at 110 "C with decomposition.

Analysis for C38H2803N4S2: Calculated ... C 52.40, H 6.84%; found ... C52.47, H6.76% Example 4 To a solution of 3.4 parts of vitamin B1 hydrochloride in 5 parts of water, a solution of 1.2 parts of sodium hydroxide in 5 parts of water is made given. The mixture is left to stand for 30 minutes and then 12 parts of chloroform and then, with stirring, 6 parts of crude sodium tetrahydropyranyl (2) methylthiosulfate admitted. After 30 minutes the chloroform layer is separated and the aqueous one Layer extracted with 12 parts of chloroform. The chloroform extracts are combined and shaken with 15 parts of 50/0 strength hydrochloric acid. The acidic solution is decolorized and neutralized with alkali carbonate, the compound III being in the form of a separates resin-like substance, which, however, soon crystallizes into colorless prisms, which melt at 126 to 1270 C with decomposition. The yield is 1.4 parts. When recrystallizing from benzene, large, colorless flakes are obtained.

Claims (2)

PATENT CLAIM: 1. Process for the preparation of disulfide derivatives of vitamin B1 of the general formula in which R1 is a methyl or ethyl radical, R2 is a tetrahydrofuryl or tetrahydropyranyl radical, R3 is a hydrogen atom or an acyl radical and A is a low molecular weight alkylene radical, characterized in that compounds of the general formulas in which R1 and R3 have the meaning given above, with a pE value above 7 in an inert solvent with compounds of the general formulas R2-AS-SO3M, R2-AS-OSR, R2-AS O2-SR, R2-ASS- CN or R 2-ASX in which R is an alkyl radical or the radical R2, X is a halogen atom and M is an alkali or alkaline earth metal atom and R2 is as defined above. 2. The method according to claim 1, characterized in that at pn values between 7 and 9 is worked. Documents considered: French patent specification No. 1,068,459.