DE1301003B - Use of dialkyl cysteines to reduce the toxicity of pharmacologically active metal compounds - Google Patents

Description

1 2

The invention relates to the use of dialkyl alkyl cysteine is preferably adjusted so that the

cysteines of the general formula, greatest increase that can be determined experimentally

of the therapeutic index is achieved.

_R Q _H The unexpected therapeutic effectiveness will

^ ₁ 5 illustrated by the following results:

_ A lethal dose (LD ₉₀ ) of 4-hydroxy-3-amino-

¹ C- (J phenylarsine oxide, which with the same amount of dimethyl

cysteine was converted, was completely detoxified (in

SH NHR _{3 in} each case was injected subcutaneously with 50 mg / kg of mice.

lo adorned). On the other hand, the therapeutic activity

in which R ₁ and R _a denote the methyl or ethyl radical and R ₃ denote the minimally effective dose of 4-hydroxy-3-aminoein hydrogen atom or the acetyl group, phenylarsine oxide, the disappearance of the parasites to reduce the toxicity of pharmacologically from the blood of with trypanosomes (T. equiperdum) effective compounds of the trivalent or pentavalent infected mice, namely 1 to 3 mg / kg, valuable antimony, arsenic, bismuth, bivalent or trivalent 15 retained if it is retained after the reaction with the same valued iron or mercury or their Ge amount of dimethylcysteine and even with a considerable mix, borrowed excess, namely 100 to 200 mg / kg di-It is known that certain metals valuable methyleysteine were used. It is part of the character of therapeutic agents. However, since they are realistic for the specificity of this observation, which are generally quite poisonous, the administered or other thiolable dose under appropriate conditions is quite limited. So your therapeutic index antidote to arsenic poisoning, such as dimercapto, is low. propanol, act in the opposite way, ie it has been known for a long time that thiol compounds detoxify the therapeutic rather than the toxic effect of substances containing arsenic. So in the last 4-hydroxy-3-aminophenylarsine oxide was canceled. At present, dimercaptopropanol as an effective agent against detoxification of 4-hydroxy-3-aminophenylarsine oxide poisoning by arsenic, antimony and mercury is administered 1.0 to 2.7 times more dimercaptopropanol than silver compounds. The use of 4-hydroxy-3-aminophenylarsine oxide is necessary, while mixtures or complexes of these thiol compounds the healing effect of the arsine compounds with metal-containing preparations was previously not possible in therapy with dimercaptopropanol doses of 11/82, as the thera- 30 of the compound disappears (Er c ο II - Wilson, peutic effectiveness is inhibited and the metal Jour. Pharmacol, and Experim. Therapeutic 92 [1948] compounds not only detoxified, but also un- p. 121 to 126). Mixtures of dimercaptopropanol can be made effective. or dimercaptopropanol glycoside with arsenates or it has now been found that the antimonates mentioned at the outset are therefore not therapeutically useful. Dialkylcysteines of the general formula 35 The same effect as with aromatic arsine

oxides are also obtained with dichloroarsine compounds,

R ₂ OH where ethyl methyl cysteine as well as dimethyl

: cysteine works.

η Q CH C = O * ^ ^{e he} inventive use of dialkyl

¹ 40 cysteines is particularly beneficial for 3-acetaminophen

QH MHR 4-hydroxyarsine oxide for the treatment of amebiasis

JNnK _{3 unc} j | j _e j _ _ars j _no 5 _enzam j (i to achieve an anti-

filarial drug with better therapeutic

without significant impairment of the therapeu index.

the effectiveness of the metal compounds to a 45 Investigations on antimony compounds with Diviel better compatibility of these metal preparations methyleysteine and ethyl-methyl-cysteine (with antimony leads, the effectiveness of the acetyl compound alkali tartrates and antimony gluconate) showed the somewhat lower than that of the non-acetylated comparisons. Detoxification effect without impairment bond is. Surprisingly show chemically - the therapeutic effect. When using the closely related compounds such as cysteine itself and 50 N-acetyl derivatives of these dialkylcysteines is the effect Dimercaptosuccinate doesn't have the same effect. a little less.

In contrast, it is known (Chen et al. Jour, with a simultaneous reduction in the side effects of Infections Diseases. 76 [1945], pp. 152 to 154) that gen is the administration of larger amounts and thus the toxicity of antimonates im cysteine itself an increase in therapeutic effectiveness 55 possible to the same extent as the anti-parasitic effect, diminishes. A combined treatment is therefore not possible at the same time, because the detoxification effect also appears to be possible Metal compound from the patient by the pre-therapeutic effectiveness cancels. Appropriate The mentioned dialkylcysteines are promoted to results were with other compounds will. It was found that antimony containing 60 -SH and -NH groups, such as ^ -Benzoylamino - ^ - dider-like Dialkylcysteine derivatives as anti-parasitic methylacrylthiolic acid and benzoylamino - /? - mer agents lower toxicity are effective, with the captoisovalerianthiolic acid, which is structurally preserved Dialkylcysteine residue the penetration of the metal residue are close to the dialkylcysteines (Ercoli et al: Archive, increase in the parasite and at the same time its training boarding. Pharmacodyn. 136 [1962], pp. 452 to 462). Divorce from the host should facilitate. 65 Upon investigation, it was found that the anti-Die The invention is particularly suitable for the compound parasitic effect of 10 mg / kg potassium antimonyl dung of arsenic, antimony and bismuth, with tartrate against Trypanosoma equiperdum by 0.7 mol the ratio between metal compound and di- or less sodium dimercaptosuccinate

is raised, while 35 moles or more of d- or dl-dimethylcysteine have no influence on the therapeutic effect. Dimethylcysteine acetonide on the other hand had no effect on the therapeutic index. It is also known (O. D. Standen, Experimental Chemotherapy, Academic Press, New York, London, 1963) that antimonyl tartrate is replaced by dimercaptosuccinate and other dithiols are simultaneously detoxified and deactivated, which is the specificity of the Use of dimethyl, diethyl and methyl ethyl dialkyl cysteine as well as the acetyl derivative thereof still emphasized.

The following examples serve to further illustrate the invention.

example 1

One part of potassium antimonyl tartrate (emetic tartar) is mixed with 1.5 or 2 parts of dl-dimethylcysteine or d-Dimethylcysteine hydrochloride mixed in powder form

and heat-sterilized and filled as a dry powder in ampoules, which over a period of Years is stable. The product obtained is up to 6.15% soluble in double-distilled water; the for the 5 to 6% solution intended for treatment has a pH of about 6.4.

In addition to this reduction in the general toxic effect of the antimonyl radical in this preparation the local necrosis-producing effect of the tartrate also disappears in such a way that the Product can be injected intramuscularly (otherwise tartar emetic can only be given intravenously what the advantages of this property of the products according to the invention for mass therapy makes apparent. The therapeutic and biological properties of the two preparations that 1 part emetic tartar and each 1.5 parts or 2 parts dl-dimethylcysteine are shown in the table.

toxicity Rabbit fur
chen
ver
wear kg Pnt Therapeutic TT ₀ M.-, J 10.1 j Indices Hey Schistoso-
miasis Dos. Therapeu in mg / Sb per intra dog fiery
manic
weather-
kung Dose against
Trypanosomiasis
Sb rag / kg rieUena 1.8 I 10.1 Reini lend table index
against
Billharziosis
(Schistoso- preparation LD ₆₀
mouse
sub- venous Reini gend Sb mg / kg miasis) cutan gend 2.65 11 1.7 3.6 6.7 7.3 K-antimonyl tartrate 5J5 ¹ ) o, i 7o 1.8 (Emetic tartar) 18th high 5.3 Isotonic. Solution of 27 41 Sb (III) catechol no 2.7 Na disulfonate 110 5 / o 4.1 20.4 4th 1.5 parts dl-dimethyl 8.6 28 7.5 cysteine / part break tox no 6.8 Weinstein (TP 15) 51 67o 1.8 7.8 2 parts dl-dimethyl 8.4 46.5 QQ
ο, ο cysteine / part break 28!) no 9.5 Weinstein (TP 2). . 83.5 i. m. 6%

*) In daily doses of 1.2 to 2.8 mg / kg.

The optimal ratio of emetic tartar to dl-dimethylcysteine is 1: 4 mol.

Although there is an optimal ratio between the organometallic compound and the dialkylcysteine to achieve the highest therapeutic index, these ratios can - as in shown in the figure - can be varied within a broader range (in the case of emetic tartar and dl-dimethylcysteine is the optimal ratio

1: 4 molar). Among other changes in biological properties is the direct anti-parasitic The effect of the antimony in the solution with the dialkylcysteine also has a considerable effect Increased value. Cercariae of Schistosoma mansoni that have been treated with emetic tartar were immobile within 3 hours when exposed to a 10 "mole solution which

Contained 2 parts dl-dimethylcysteine (TP 2 of Table 1), while a much higher concentration (1/70 000 mol) of Brechweinstein alone only showed this effect after 5 hours. In the same way it was the tripanocidal activity increased two to three times, with both as a criterion for comparison the immobilization and destruction of the parasite was taken. (This reinforcing Effect is likely to result in greater penetration of the parasite by having that in the solution the product formed by the dialkylcysteines). An identical procedure for the preparation can be used when sodium antimonyl gluconate is substituted for antimonyl tartrate.

Further evidence of technical progress

The use of 1.66 parts of dl-dimethylcysteine with 1 part of sodium antimonyl tartrate according to Example 1 resulted in a ten-fold increase in the tolerance of antimony (determined by LD ₅₀ subcutaneously on mice).

The use of dimethylcysteine hydrochloride with 3-amino-4-hydroxyphenyl arsenic oxide in a weight ratio of 2: 1 reduced the toxicity of the arsenic

compound by 2.7 times without changing the therapeutic index. Similar results were found for Use of 0.5 to 6 parts by weight of dimethylcysteine hydrochloride per part of 3-amino-4-hydroxyphenyl arsenic oxide obtain. The results when used together with S-amino ^ -hydroxyphenyldichloroarsenic hydrochloride were even better because the tolerated dose was increased from 12 to 32 mg / kg As and the trypanocodial effect in vivo was unchanged remained and even increased by 50% in vitro.

Similar increases in the therapeutic index occurred together with 4-carbamylphenyldichlorarsine, S-acetamino ^ -hydroxyphenyldichlorarsine and p-ureido-phenyldichlorarsine, being the d-compound of dialkylcysteine reduced the toxicity even more.

The use of 1 to 3 parts of methyl ethyl cysteine or dimethylcysteine per part 4-carbamidophenyldicarboxymethylthioarsenite results in an injectable Preparation of this arsenic compound. Further ao attempts were made with sodium bismuth thioglycolate, Antimony trichloride, mercury (II) chloride and ferrous and ferric sulfate, each time the toxicity is considerable was reduced.

Claims (1)

Claim: Use of dialkylcysteines of the general formula R ₂ OH R ₁ -C- CH-C = O SH NHR ₃ in which R ₁ and R ₂ denote the methyl or ethyl radical and R ₃ denote a hydrogen atom or the acetyl group, to reduce the toxicity of pharmacologically active compounds of trivalent or pentavalent antimony, arsenic, bismuth, bivalent or trivalent iron or mercury or mixtures thereof . 1 sheet of drawings