DE1793545A1 - Dialkylcysteine derivatives and processes for their preparation - Google Patents

Description

The invention relates to metal derivatives and organometallic derivatives of dialkylcysteines and related compounds, as well as their production »

Verschiedsne metals, for example, _c arsenic, bismuth and antimony, impart some compounds thereof have valuable properties as therapeutic agents. However, since they are generally quite toxic, the dose that can be administered without undesirable side effects is quite limited «So their therapeutic index is low ·

It has been known for a long time that thiol compounds contain arsenic Detoxifying substances “Dimercaptopropanol has recently been used as an effective remedy for poisoning administered by arsenic, antimony and mercury compounds. The use of mixtures or complexes of these ihi oil compounds with metal-containing preparations were ye after all So far not possible in therapy, because also the therapeutic one Effectiveness is inhibited and the metal compounds are not only detoxified, but also rendered ineffective

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¹⁴⁰

r / earth, -

The effect of the aforementioned compounds as a blessing in the case of metal poisoning, it appears to be effective as a MetalX binding agent that stir on the ability of in them containing sulfur atoms is based to enter into coordinative bonds with metal, especially heavy metal atoms in particular to form chelates, in which the cooperative effect between the metal compound in question and the fhiol compound to an inclusion of the Metallatoas in one leads heterocyclic ring which has at least one coordinate bond to the metal atom. .

It has now been found that ß, ß-dialkyl-substituted cysteines the formula

R ₁ -C SH

CH ■ = · KHn

0 «C - OH

where R ₁ and R _{2 are} methyl or ethyl, and the acetyl derivatives thereof, as well as the corresponding compounds in which the sulfur atom is formed by selenium or tellurium, reduce the toxicity of metal compounds without significantly impairing the therapeutic effectiveness of the metal residue. This is particularly over-. surprising, since related thiol detoxifying agents such as cysteine itself and diinercaptosuocinate do not have the same effect

This improved therapeutic index increases tolerability of the therapeutically active metal compounds

209811 / 17.19 ^ ₀ original

in the patient, while the side effects are reduced, and also allows the administration of a larger dose Amount of a therapeutic preparation containing metal compounds, thereby increasing the therapeutic effectiveness will"

it was found that the conversion of metal compounds old dialkyloysteines or the analogous compounds, in which the sulfur atom has been replaced by selenium or tellurium, to form compounds, complexes or compound complexes, generally chelates, of low toxicity resulted in Ee it is generally known that certain metal residues, such as trivalent or pentavalent antimony, are effective anti-parasitic Means are. However, their usefulness is limited by the relatively high toxicity of such compounds Now found that dialkyl cysts containing antimony are iva te as Indians anti-parasitic agents with low toxicity are effective. It is believed that dor Dialkylcysteinre et increases the penetration of Metelireatea into the parasite and at the same time facilitates its elimination from the host.

Likewise offer the dialkylcysteine derivatives of other metals or metal-gnischer compounds the possibility of administering such metals and metal compounds in an effective and relatively non-toxic form. The Dlalkylcysteinrest improves the usefulness of the metal residue and at the same time promotes its excretion from the Patient.

Accordingly, the invention relates to new metal derivatives and me tall organic one derivatives of Dialkylcyatelnen and the corresponding selenium and tellurium compounds of the following general? orrael;

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R ₉ OH

3 «r

A _o hey. (R- - C - CH - C * 0) "(R- - C - CH - C" 0)

* »» Ι J'l.l _f

X HHR ₅ XH

or their acid salts, in which Y is equal to 0 or an integer less than or equal to vx, where ν is the valence of the metal, ζ is 0 (except when y is 0) or a whole ZaM> which is less or equal to wy, where w is the maximum number of coordinative bonds that can be formed with the metal, χ is equal to 0 or an integer up to ssu ν, Me antimony (trivalent or pentavalent), arsenic, wisrauth, iron (divalent or trivalent), selenium or Tellurium or mercury is, A represents an organic or inorganic radical or radicals or, if χ is 2 or more, the radical of a heterocyclic ring, which includes Me, R ₁ and E ₂ -CH, or -C ₂ Hc , R3 -B or -COoCH ₅ , and X means sulfur, selenium or tellurium »

In a special respect, the invention relates to dialkyloysteine derivatives of the general formula:

and SaIse thereof, wherein H Sb, As, Bi ₉ Ve, Se or

X ,. that can be present or absent, «Ine Dialkyl

cysteine group dor formula

CH (COOH) (HH ₂ ) ₅

.CH (COOH) (NH ₂ ), C (CH ₅ ) (C ₂ H ₅ ) .S-

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IAD OWGfNAL

Y dimethylcyetein or methylethylcyatein,

Z denotes the radical X, -Sb ₀ Xp or a substituted or unsubstituted alkyl, aryl or aralkyl group bonded to carbon or the remaining part of an organic best which is a heterocyclic ring including M,

k is the number 0, 1 or 2,

η is an integer with the valences of M and Z matches, where Z is the same or different pension can mean «if n. is greater than 1, and

m such an integer that the total number of the present Dialkylcysteinyl groups and complex-forming dialkylcysteine molecules the maximum number of coordinate bonds that can be formed by the metal, does not exceed, or, if X is present, m can be 0, mean.

The invention also relates to a process for the preparation of the above dialkylcysteine derivatives by reacting a metal compound or organometallic compound of the formula Α _χ . Me. B _u , where B is an inorganic radical or radicals and u is xv, or, if χ is ν, the number 0 is,

with a dialkylcysteine or a selenium or tellurium analogue thereof of the general formula:

R ₂ OH R

XH NHR-

wherein R ₁ , Rg, R * and X have the meanings given above, or a hydrohalide thereof ·

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A more specific embodiment is in a process for the production of dialkylcysteine substances in general Formula:

Season thereof, wherein II Sb, As ₉ Bi, Fe, Se or $ e, X, which may be present or absent, is a dialkyl-aysteine group of the formula

CH (COOH.) (SH ₂ ) .0 (CH ₃ ) ₂ .S- or CH (COOH) (HH ₂ ). C (CH ₅ ) (C ₂ H ₅ ) .S-

Y dimethylcy et ein or methyl ethyloyatein,

Z denotes the radical X, -Sb.X «or one bonded to carbon substituted or unsubstituted alkyl, aryl * or Aralkyl group or the remaining part of an organic radical which is a heterocyclic ring with a binary ending in M,

k is the number 0, 1 or 2,

α, η is an integer with the valences of K and Z coincides, where Z mean identical or different bests if η is greater than 1, and

m such an integer that the total of the present alkylcysteinyl groups and complex-forming dialkylcysteine molecules the maximum number of coordinate connections which can be formed by the metal, does not exceed, or, if X is present, β be 0 can mean,

which is characterized in that sen or BiBethylcyetein

Methylethylcysteine with a compound of the general

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Formula Z '_. MA _u , wherein A is an inorganic bed or inorganic beds in a total valence of u, and Z ^{1 can} be present or absent, and if present, one or more substituted or unsubstituted alkyl, aryl or Aralkyl groups or the remaining part of an organic radical which comprises a heterocyclic ring including H, denotes the group or groups having an evalence ρ, where ρ + u is the valence of H _# susauaeo gives.

The compounds and method of the invention provide accordingly pharmaceutical preparations that contain one or more the aforementioned. Contain derivatives or are capable of forming such derivatives in aqueous solution. The reaction between the Metallaus caxigsver binding and the dialkylcyetein or Selenium or tellurium analogues can be one or two types of Dictionary tunfassen. First there can be a condensation reaction with elimination of the hydrogen atoms of the thiol or the analogous selenium or tellurium group with an anion bound to the metal in the metal compound take place, «* ■ *» through a direct covalent bond between the metal residue and the sulfur, selenium or tellurium atom in dialkylcysteine or analogs. Equilateral becomes' a coordinative bond is formed between the nitrogen atom in the last-mentioned compound and the metal atom. As an alternative or in addition, a exclusively coordinative bond between the metal atom and the sulfur, selenium or tellurium atom and the nitrogen atom in a dialkyloysteine or analogous molecule be formed·

The derivatives can be obtained by mixing a suitable metal oxide or halide or a hydrohalide

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suitable organometallic compound which is present in water, Alcohol, glycerine or another suitable polar solvent is suspended or dissolved with the selected dialkyl pysteine or dialkyl cyst an analogue hergör will be presented. The condensation compounds formed can - if desired - by adding iron, ether, acetone or another organic liquid in which the product is insoluble, separated

A variation of this method is that in ^ an alkaline solution stoichiometric amounts of one Metal salt and dialkylcysteine or dialkyl * oysteine analogues are dissolved and then - if desired - that Reaction product is isolated as described above with Ither or the like.

An alternative method of working consists in the electrolysis of an inorganic base of the desired metal, which is dissolved in a solution which contains water in a manner analogous to dialkylcytein or dialkyloy et al. The metal ions go into a probe saturation reaction like the dialkyloysteine or dialkylcysteine analogue, and the product is then - if desired - isolated. The Raoeadschen w and dextrorotatory dialkylcysteines kS & nen both for the Synthesis are used, the right-turning spines provide compounds with a high therapeutic index.

The invention is particularly applicable to compounds dee Arsenic, Antimons and Vlsnuts, which are an organic group or groups included. The relationship between the metal compound and the dialkylcysteine ligand is preferably as follows set to achieve the greatest increase in the therapeutic index. The connection or the

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* AD ORIGINAL

tene complex can be in orm of mixtures, solutions and / or Products made by precipitation of solutions of the compound constituents have been received, are used «

The unexpected therapeutic effectiveness is illustrated by the following results:

A lethal dose (LDq ₀ ) of 4 ^ hydroxy-5 ~ aiainophenylaroin oxide, which was reacted with the same amount of dimethyl cysteine, was completely ingeniously detoxified (in spring cases muses 50 mg / kg was indicated subcutaneously) Activity of the minimum effective dose of 4-hydroxy-3-aminophenylarsine oxide, which _{causes the disappearance of the parasites from the blood of mice infected with trypanosomes (T 0} equiperdura), namely 1 to 3 mg / kg if it is maintained after the reaction with the same amount of dimethyl cyst one and even with a considerable excess, namely 100 to 200 mg / kg dimethyl cysteine, was used. It is characteristic of the specificity of this observation that, under appropriate conditions, other thiol antidotes against arsenic poisoning, such as dimercaptopropaol, act in the opposite way, that is, the therapeutic oils counteract the toxic effect of 4-hydroxy-3-amiiophenylarsine oxide 4-Hydroxy-3-aminophenylarsine oxide is 1.0 to 2.7 times more dimercaptopropanol than 4 ~ hydroxy -> - aminophenylarsine oxide required »while the healing effect of the arsine compound disappears even with dimercaptopropanol doses of 11/82 of the arsine compound (Ercoli & Wilson, Journ. Pharmacol · and Experim. Therapeutic $ 2} 121 - 126, 1948) · Mixtures of dimercaptopropanol or dimercaptopropanol glycoside with arsenates or antimonates are therefore not therapeutically useful ·

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The replacement of the oxygen or ChI atoms or aromatic Arsenoxyde or Dichlararsine (aryl AsO; aryl AsClg) forch the dimethyl cysteine or therefore methyl-ethyl CysteiÄ increases its therapeutic index by decreasing your footL- capacity, while the effectiveness of known WirkstoffsiÄ " training is maintained or improved. Other, therapeutically insignificant substituted aryl compounds take on useful properties with the introduction of this new -Ae-Rg-Äestes (where H is a dialkylcyetein residue) ο

This substitution is particularly advantageous in the case of 5-acetainino-4-hydroxyareinoxide to achieve a product of low toxicity for the treatment of amebiaeia and of -arsinobenzaeid to obtain an antifilaral remedy with better therapeutic index.

It was found that analogous to the arsenates »dimethyl- or ß-ethyl-ß-methylcyatein organic antimony preparations (e.g. antimony alkali tartrates, antimony glucoins) detoxifies when it is implemented »without your therapeutic effect impaired. EIa similar effett this was the case when using the N-acetyl derivatives Dialkyl cysteines are observed, albeit to a lesser extent

In contrast, it is known (Chen et al. Jour., Infections Diseases. £ 6: 152-154, 1945) that cysteine itself is the toxi- _{- <| g?} ity of antimonates is reduced to the same extent as the antiparasitic effect. Its positive effect as an antidote is therefore offset by its negative effect on therapeutic effectiveness and the combined treatment is not possible. Similar results were obtained

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• AD ORIGINAL

ait a number of other antidotes for metal poisoning which contain -SE and -HH groups (ö-Benzoylajolno-ß-dimethylacrylthiolic acid undoC-Beneoylattino-ß-mercaptoieovaleranthioleic acid) are tmd et structureaSasig close to the sialkjlcysteines (Ercoli et al-Archiv Internat. Phannaoodyn. 136: 452-462, 1962). With those in the Staeaaaenhang Investigations carried out with the present invention gen was found to have anti-parasitic effects of 10 ag / kg ^ ntlmoakalitnatartret (compared to Srypanoeoxaa equiperdua) is canceled by 0.7 1361 or less in Hatriuadiaeroaptoeuocinat, "honoring 35 BoI or aehr τοπ d- or dl-dinethylcysteine did not affect it. Sinetayloyeteinacetonid turned out to be the cause of the problem of the therapeutic index ale ineffective. You specificity The present invention concerning the epeslellen Pialkylcystein will continue as far as it is the economic effect concerns »by the report · (O.B. Standen in Experimental Cheaotherapj, I »Schnitaer 4 Hawking, JLoadesdo Ire ··, Hew Tork, London, 1965) “It is argued that antlaonyl tartrate by dlaercaptoeuooinate and other dithiols in detoxified in the same way if it is activated

The high toxicity of selene, which, as selenite, prevents liver necrosis when introduced into mirrograss beds and, bound to certain organic beds, acts as qytoetatloua, is changed if ei is in the aforementioned tonal dl » Place of the sulfur elnniaat. In this loza the Me-Se-Bindong a "reverse detoxification" it becomes because relatively, much more toxic selenium (or xellar) is detoxified by the metal bond, and it can be used as an oytostatic or antiaeorotic agent used

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The following examples are also used for further explanations Invention.

Example 1 .

A portion of potassium antimonyl tartrate (Breohwe inst a) is used with 1.5 or 2 parts dl-Dimethyleyetein or d-BiiaetHylcysteia-

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hydrochloride mixed in powder form and hit-sterilized and filled into ampoules as a dry powder, which is stable over a period of years »The product obtained is up to 6.15 % soluble in double-distilled water; the 5 - 6% solution intended for the treatment has a pH value of approx. 6, ^ o

In addition to this reduction in the general toxic effect of the antimonyl residue in this preparation is just disappearing if the local necrosis-sucking effect of the tartrate is such that the product is iujialert intramuscularly can (otherwise emetic tartar can only be administered intravenously), what is connected with the apparent advantages of this property for mass therapy, "the therapeutic and biological properties of the two preparations that 1 (rope Emetic tartar and each 1.5 parts bsw. Containing 2 parts dl-Diaethylcysteine, are shown in Table 1 »

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- Table 1 -/

Suberaitttag

«Stepped CBrechw 9t «in).

! -Antiaonyl-

Leoton. Löag.-. Sb (III) -ireazcatechiu-Sa-disulfoaai;

1.5 ropes? .

Parts ayeteln / Tell

Toxicity in ag / kg Sb

mW .: '

.110

83.5

Kaninczum covenant

8.6 (toac)

8.4

Bacwuaduag ·· - effect

no 6th

eia 6%

panoeomiaeie

reln ^ gend

. j

Try-I

.l «ad.

2.65 11.

20.4

10.1

1.8. 10.1

»■

roini- ^ g * nd le., d

2?

5.5

28

46.5, 7.8

Schistoao-r niiasie Do *

BU iag / lcg

7.5

XiI

7.5

8.8

Therapist <'

Index & £> -. ι

gen j

SeMetosomiaeie)

1.8

2.7

6.9

(1) la titgl. Βοββη from 1.2 - 2. S mg / kg

* ■

Although there is an optimal ratio between the metallarganic compound and the dialkylcysteine to achieve the highest therapeutic index, these ratios can - as shown in the attached figure - vary within a broader range (in the case of emetic tartar and dl. Dimethyleystein the optimal ratio is 1: 4 nolar) _e Among other changes in the biological properties, the direct anti-parasitic effect of the antimony in the solution and dialkylcysteine is also increased to a considerable value. Cercariae of Schlatosoma mansoni, which were treated with tartar emetic, were immobile within 3 hours, if they were exposed to a solution with 10 mol, the 2 files dl. Contained dimethylcysteine (TP2 of Table 1), while a much higher concentration (1 / 70,000 mol) of emetic wines only gave this effect after 5 hours. In the same way the Trpanocidal activity was increased two to three times, whereby both the immobilization and the destruction of the parasites were used as criteria for comparison. (This intensifying effect is probably due to a greater penetration of the parasite by the product formed in the solution with the dialkyloystones). An identical method of preparation can be used when replacing antimonyl tartrate with sodium antimonyl gluoonate.

Example 2

1 part of sodium antimonyl tartrate is mixed with 1.66 parts of dl-dimethylcyetein and heat sterilized and used as filled with dry powder as described in Example 1. The complex compound obtained contains 14.9 # antimony,

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has a Ι ^ γα ^ ^β * subcutaneous administration to mice, which corresponds to 82 to 110 mg / kg of antimony compared to 8 to 10 mg / kg of antimony for the sodium antimony used in its preparation. The degree of detoxification is therefore considerably higher than in the previous example (TP15 and TP2), in which a toxicity reduction in the range of 1:10 is achieved. This highly detoxified complex compound was used clinically (under the name NaP) for the intensive treatment (short-term therapy for 5 to 8 days) of patients who were infected with bilharzia. The patients received an intramuscular injection of 400 mg NaP in 5 ml double-distilled water on 5 consecutive lageii. The injections were painless and well tolerated. The healing results obtained were the highest ever obtained in the treatment of this disease, with an 87 #Lge clearing rate observed in schistosomiasis patients observed for egg shedding over a period of 3 to 6 months. The comparative results with other drugs obtained from the same schistosomiasis service center are listed in Table II, insofar as they relate to tolerance and therapeutic effect.

The preparation NaP administered orally to a man in the form of intestinal pills or capsules (entero-coated pills or capsules) was used in daily doses corresponding to about 100 mg Sb, and the highest dose tested is, well tolerated.

The preparation (NaP) contains the compound sodium antimonyl dimethyl cysteinyl tartrate with the probable structural formula

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COOH
ι CH-
» J HC CL
I s
HC O ^ S C - CH,
<ι ³
NHg-OH COONa COOH

and the molecular weight of 440.04, together with 0.8 parts of excess dirne thylcy st, which is 2.4 times the molar Excess of dirnethylcysteine corresponds to that with the compound forms a complex through coordinative bonds with the Sb atom.

Table II

Clinical activity of the new antimony complex compounds NaP (Example 2) and TP2 (Example 1) in comparison with other modern antimony preparations _{or similar}

The results were collected by the "Centro De Lucha Antibilharziana", Ministry De Sanidad Y Asistencia Social, Venezuela, Caracas, under the direction of Dr Miguel Ron Pedrique _o

No drug clin »active intolerance

sameness

1) Sb (III) -catechol- 46 i> + + + (cases of sodium disulfonate (Fuadin) fatal toxicity)

2) ASTIBAN (500 mg Sb total) 71 ^ + + + +

3) Li-Sb thiomalate

(Anthioaalin) 30 3S ++

4) TP2 (200 mg Sb total) 51 ί> + (almost zero)

5) NAP (298 mg Sb total) 87 1 ° ± (almost zero)

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-ie- 1793S45

Pie statistical results are based on TP2 and HaP on 220 bilharzia cases, while the baügliöh the arena agent Mr. 1 and 2 dae result tob ötfä ÄJ * jMn * extensive experience in the center listening to thousands of patients * put «Astiban was created by Dr, Ron Pedri ^ taö and tested on 95 cases

Example 3

One gram of potassium antimonyl tartrate and 1.5 g dl. cysteine are dissolved in 40 ecm of distilled water at 40 °, the addition of 300 ecm acetone or 400 ecm ethyl alcohol forms a crystalline precipitate with a Sb Gefcalt of 14 to 15 pounds and an LDc ₀ corresponding to 40 to 50 mg / kg Sb with subcutaneous Injection in mice (approximately as much as antimonyl tartrate) with a healing index against Trypano-Bomiasia that is 100 to 150 i> higher than that of the antimony tartrate used for the preparation «

The antimony content of the crystalline preparations thus obtained can be varied with regard to the ratio of the antimony and dialkyloysteine used, all of which have an increased therapeutic index relative to the toxicity of the antimony content used as a reference. The optimal preparations for therapeutic uses are those which contain 10 to 20 $> antimony and which are obtained by the method described from the original organic compounds, 36 to 39 »5 i> antimony (antimonyl potassium tartrate 36» 5 #; a.ntimonyl sodium tartrate 39, 4 $>% sodium antimonyl gluconate 36 #) contain, obtained., Are o These materials are suitable for the production, heating and isolation of chemical compounds with a defined structural formula, the antimony and two organic

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Contain radicals, one of which is dialkylcysteine and the other 3ev; eils for example tartaric acid or gluoic acid bind.

Example 4

a) 1 g of SA.niino-ij.-hydroxyphenyl arsenic oxide (arsenic oxide) with de evenly mixed with 2 g of d-dimethylcysteine hydrochloride, 3.0 g of cane sugar, 0.18 g of sodium carbonate and 0.03 g of ascorbic acid · The preparation was filled into ampoules and contained 60 mg of arsenic oxides for a single adult dose (162 µg of the mixture) and was dissolved in distilled water prior to use. The! «D») of the arsenic oxydedimethyleysteine derivatives in this preparation was 150 Ωg / kg for mice, ie _o the toxicity of the preparation was reduced by 2.7 times, true ** .. * the activity was identical to that of the starting material which represents a corresponding (2.7-fold) increase in security. An increase in the safety factor to various degrees is obtained when 1 part of arsenic oxides and 0.5 to 6 parts of the d-dimethylcysteine hydrochloride are used.

The lower toxicity of the product extends not only to the systemic, but also to the local effect the arsenic compound, which in the form of the present composition is also used for intramuscular injection T / can earth. While arsenic oxides in 1 to 2 mg / ml concentrations (administered subcutaneously) various necrotic Caused damage to rabbit skin produced 20 mg / ml of the arsenic compound in the presence of the pialkylcyetein no damages"

The intramuscular use of arsenic oxide is in shape

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the preparations described here are possible and permitted the combined treatment with other drugs in the form of a single pharmaceutical preparation without it is necessary to resort to two different routes of administration. (Z, B. Intravenous for areenocytes and intramuscular for penicillin) "

t>) Similar improved therapeutic products can be obtained if one part of 3-amino-4-hydroxyphenyldichlorareenhydrochloride (dichlorophenarsine) is used with two parts of dl-dimethylcysteine. The eubcutaneously tolerated dose of dichlorophenarsine increased from 12 mg / kg As to over 32 mg / kg As (Table III), while the trypanocidal activity remained unchanged in vivo and became even higher in vitro; 0.09 micrograms / ml As in the form of the dimethyloysteine preparation compared to 0.14 microgrejun / ml As of dlohlorarsine.

The therapeutic properties of the product can be explained by the formation of 3-amino-4-hydrary-phenarein-ai-ß, ß-dimethylcysteine in the solution. This compound has a tolerance dose corresponding to 18 mg / kg As, but it has been further detoxified to 35 mg / kg As (Table B) by the presence of an excess of dl-Dlmethylcysteln, which by means of coordination bonds formed a complex of the new compound with the As atom

loxicity of dichlorophenarsine alone and with dl-disiethyl cyeteln and compared with the trichlorohydrate dee 3-amino-Φ-hydroxy-di-ß, β-dimethylcysteine

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preparation

As content Total number of drug and injection eggs killed dose tor mice mg / kg mice subcutaneously

Dichlorophenarsine 25.8 96 50 12th
Q O
7th 100 J
8th I.
8th 1 part dichlorophenarsine
+ 1 part dl-dimethyl
cysteine $ 12.9> 150
250
500 6th
3
3 O
3
3 1 part dichlorophenarsine
+ 2 parts dl-dimethyl-
cysteine 8.65 1- 3OO
400
600
800 6th
3
3
3 O
O
3
3 3-amino-4-hydroxy
phenarsine-di-ß, ß-
dieethyloysteine-3HGl $ 12.08 150
POO 4th O
p 300 4th C.
4th

c) trichlorohydrate of 3-amino-4-hydroxy-phenarsine-di-ß, fldimethylcysteine (or 3-Amino-4 ^ hydroxyphenylarsenide-dlß-mercapto-valine).

2.2 g of dl-dimethylcysteine contained in 9 nl of ethanol were slowly added 2 g of 3-amino-4-hydroxyphenyldichlorarsine hydrochloride dissolved in 6 ml of ethanol given. The mixture was refluxed for 1 hour and then heated remaining insoluble material was removed by vacuum filtration. To the Piltrat were initially 10 ml of ethanol and then 50 ml of chloroform was added, resulting in the formation of a

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Goat precipitation causes. This was filtered off and dried in vacuo, losing its resinous consistency and turning into a white-gray powder. When drying to the weight constant at 40 C in vacuo it lost 4.4 * # of its weight «The analysis yielded values that of the formula

As "(.8C ₅ H ₁₀

corresponded, calculates As $ 12.7> i C $ 32.2 1 H 7.1 ^

S 10.7 #; H 4t95 t; 0.13.6 #i Cl 18 f>. Found: As 12.08 #j

C 29.75 * H 6.6 *>; S £ 10.2; H 4.54 % t 0 15.2 * f Cl 21.65 *

The minimum lethal dose of this compound against mice is 200 mg / kg, while in the same genus it is the Trypanosoiia equiperduii infection with sutaratane doses of 2.5 to 3> 0 mg / kg and 12 mg / kg cleans a permanent one Causes healing. Compared to the corresponding arsenic-OSO- (AsO) compound, arsenic oxides (Mapharside), 1st therapeutic index uia not less than 100 ^ increased been. The improvement in the therapeutic index is even greater with the clockwise connection.

Similar increases in therapeutic indices occur when used as starting material for the production of p-arsenosobenzamide-dialkylcysteines 4-CarbsjHyl-phenyldichlorarsine or for the condensation with the dialkylcysteine 3-Acetamino-4-hydroxyphenyldichlorarsine and p-T3reidophenyldichlorarsine can be used. As with the antimony compounds, the clockwise fora of the selected Dialkyl cysteine to the less toxic compound Alt a higher therapeutic index.

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Example 6

Arsenamid (4 ~ CarbaB & do-phenyldicarboxy-me1äiyl-thioarsenit) is an ^H v7irksames antifilariales drug, but it is too toxic for general use "(Brit" Med. Dictionary, Sir · Arthur Salisbury, Caxton Publishing Comp. London, 1961).

Effective products with reduced toxicity are made (a) by dissolving 1 to 3 ropes of methyl-ethylcysteine or dimethyleysteine powder, which is filled into sterile ampoules, in a commercial solution of the arsenamide just before its use. A vial with 160 mg dl-dimethylcysteine _y is suitable to be dissolved into 6 to 8 cc of a 1 #igen Arsenamidlösung at a pH of. 7 At another alternai. In a method, which consists in the preparation of dry mixtures of the sodium salt of arsenamide, 80 mg filled into ampoules are dissolved with 150 mg of the dl-dimethylcysteine before the injection «

Example 7

One part of H-carbamylarsanilic acid (Carbarsone) is 0.2 Parts of calcium glucoxide and 0.7 parts of dl-dimethylcyetein mixed. The composition is used in the form of capsules (500 ag) for the treatment of voxi amebiasis.

Example 8

A part of sodium bismuth / thioglycolate (thiobismol) is used with 0.75 parts of d-dimethyloysteine mixed. The product will in the form of capsules of 400 mg (in Yicent angina) given intramuscularly «It can be stored in ampoules

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the example, "in doses of 400" to 600 mg _o The therapy may be supplemented by a higher Calciumzufiihr ₀

Example 9

a is) 1 part Antimontrichiarid _o mixed with 2.4 parts of dl-Dimethylcyetein and 2 parts of sodium carbonate under carefully trokkenen Bedinglangen snowy The obtained powder dissolves rapidly in water to release cog ₀ 5 #ige The solution of the mixture has a pH -of 6.8 and can be injected without damage »your!" den corresponds "in mice (subcutaneously) to slightly more than 100 mg / kg Sb (Table IV).

The reaction that takes place when the mixture is dissolved in the water, leads to the formation of antimony tri-dl-ß, ß-dimethylcyst one which has a lethal dose that is 30 mg / kg Sb corresponds to α, but this can be increased considerably by adding a 25 to 50% excess of dl-dimethylcysteine can be increased (Table IV).

In the mixture of the present example this is theoretical ratio for the reaction between SbCl »and Diriethylcysteine 1.9 »while, however, an excess of 2.4 Parts of dialkylcysteine was used, which is highly tolerated of the new product explained, because in the solution with the excess dirnethylcysteine a complex was formed.

In the Bern example it was found that a connection has been formed by the excess dl-dimethylcysteine is further detoxified, which forms a complex with the newly formed compound in the solution «.

209811/1719

; ORKatNAL

The new compound complex is antimony tri-dl-ß, ß-dimethyl ~ cysteine, whose antimony has coordinative bonds with the excess dl-Dimethyloyeteln is connected.

An increase in the content of dimethyloysteine in the mixture with antimony tri-dl-dimethyleysteine did not result in any further detoxification (in fact, a decrease occurred), which confirms that the toxicity and biological properties of the mixture obtained in aqueous solution
is determined by the equilibrium between the new chemical structure and the bound dl-dimethylcysteine.

Toxicity of antimony tri-dl-ß ^ -dimethylcysteine / Sb
(DMC) - / and its dl-dimethyloysteine complexa, compared with the preparation of Example 9a).

2 0 9811/1719 ° * ^iqi * al

Table IV preparation

Sb Total Aranei- ftthahl number Salary MitteldoBia In ^ i ·. getdmg / kg subotitan Haöae fet er

Chewing

Part I Sb (ISKi) 0.25 part dl-dimethyloysteine

1 part Sb (DMO), + 0.5 part SL- dimethylcyetein

1 part Sb (DMD) - + 1 part -Ul-DitMI oyetein

Example 9a 1st sample

SbCl-Z-diinethyloysteine Verh & tnia 2.4

2nd sample

SbCl_ / DiBMthylcT8tein ratio 2.7 19.5

15.6

12.9 9.25

15.5

14.6 100 150 200

200-500

400

500 600-790

250 500 600

300 500 600

300 600 800

3 4th

6th 3

8th 4th

4th 8th

2 5

1 1

0 0 3

3 2

0 0 7

0 0 4

0 0 0 5 7

Sb (imcji β itself is against its fatal, effect 4iüvch pretreatment with Dinethyloyetein geai * Utn _t dhm 'i »Ä it its therapeutic effectiveness rm% imt% *

Pretreatment with 200 mg / kg dimethylcyetein immediately followed by Sb (DIB) ₃

400

209811/1719

ORIGINAL INSPECTED

b) Analogous preparations can be made with a mixture of Antimony oxide and dialkyloystelnen are obtained, however these go into solution more slowly and generally require heating.

c) 20 g of Sb Cl were added to 100 ml of water to form a mass of 16 g of "wet trioxide" (a mixture of Sb2 ° 3 and hydrochloric acid). This mass was quickly washed on a filter (with approx. 20 ml of water ), then added to 100 ml of distilled water in which 10 g of dl-dimethylcysteine were dissolved. The mixture was heated in an autoclave at 120.degree. And a pressure of 15 1 »05 atIi for 2 hours, then filtered and the filtrate evaporated in vacuo in order to stimulate the formation of crystals, which were formed as heavy Ilasee on the addition of alcohol . By successive Tfakristalllslerangen from water-alcohol Hischungen welsse crystals were obtained which melted with decomposition at 165 to 170 ⁰ C. The analysis gave values which corresponded to a monochloride of the expected compound SbC ₁ ^ _HJOgS-.HCl (H. g. 602.26). Theoretical values: Sb £ 20.2; C £ 29.9 {H £ 5.15} H £ 6.9; 0 $ 15.9> \ S 15.9 ^; Cl 5.9 ^. The values found experimentally were: Sb 19t5 # 5 ^c 31 »68 £ (in other samples 29.43 and 30.17 t); H. 4.71 * (4.91 and 5.01 * h * 6.37 * j 0 17.25 i »% S 15.30 <f> (15.9 and 15.62 *) j Cl 5, 48 * In two of the three preparations analyzed, which had been prepared with various modifications of the method described above (refluxing instead of autoclaving), the Cl values were lower ( $ 2.95 and $ 2.5), which indicates a was due to prolonged washing of the "wet trioxide" leaving insufficient HCl to remove all of the free amine

209811/1719

to bind in the form of the hydrochloride

The lethal dose (LDc ₀ ) <* of the compound was 150 mg / kg when 0u.bou.taner was administered to mice, while the cleaning dose of a Trypanosoma equiperdura infection was 10 mg / kg, ie 1/15 of the lethal dose. The toxicity of the compound could be further reduced to a 1 "Dc ₀ of 400 mg / kg by adding 0.25 parts of dimethylcysteine to one part of the compound, which corresponds to a 1 molar excess of dimethylcysteine, with which excess the compound forms a complex.

The therapeutic effect is retained in full.

The product containing an excess of dialkylcysteine is particularly suitable for oral administration by the tendency of the organic derivatives and the chelates to decompose at the low pH of the stomach contents counteracts. Treatment with orally tolerated and absorbed antimonates leads alongside the obvious Advantage for mass therapy also to relatively high concentrations of ilntimony in the portal system, where the Schistoeomas localized in a.S, Iflansoni infection are.

d) 9.34 g of dl-dimethylcysteine were placed in a 500 ml three-necked round bottom flask dissolved in 100 ml Y / water and stirred while nitrogen gas was passed through the bottle to remove the To reduce air oxidation. After 4 »98 g of KaOH had been added, 4> 75 g of SbCl-, dissolved in 25 ml of absolute Alcohol, slowly added from a dropping triohter. A precipitate appeared briefly, but it calmed off immediately

BAD ORIGINAL .. «? 209811/1719

loosed down. Stirring was continued for 30 minutes and the solution was then refluxed on a water bath for 1 hour. Alcohol was added to the reaction solution, which had been concentrated to a small volume in a Sohnell evaporator. The precipitate was filtered off, washed with Λ-alcohol and dried under vacuum. The product, a white solid, was readily soluble in neutral pH water. This preparation (the free hnljx) has the same biological properties as the Monochlorld. In doses of 200 mg / kg it killed 75 $> of the mice, it was administered (ie be LD "^ was 200 mg / kg), while 12.5 mg / kg in all treated animals äqulperdum with Trypanosoma were infected, caused a cleansing.

Example 10 Antimony-d-dimethylcysteine hydrochloride.

a) It has been found that the reduced toxicity of the product obtained when antimony trioxide is mixed with d-dimethyleysteine hydrochloride is due to the formation of antimony-d-dimethylcysteine hydrochloride. The tolerability of this compound was the highest that has ever been encountered, corresponding to an LD ₅₀ (in the mouse) of 245 mg / kg Sb, with an excellent therapeutic index against trypanosomiasis. Infected mice were cleaned with 1 / 4-0 of the lethal dose, ie 25 mg / kg of the preparation corresponding to 6.2 mg / kg Sb.

b) 1 g of d-dimethyloysteine hydrochloride was dissolved in 10 ml of distilled water and 1 g of freshly precipitated (from SbO1-), moist Sb ₂ O. was added to this solution. The suspension was refluxed over a water bath for 3 hours

209811/1719

heated. After filtration, it was concentrated by yakunm centrifugation, leaving a lot of material sarttok; this lake was dissolved in ethyl alcohol and precipitated with Xther. The we i see powder melted under Zersetsung at 168-170 ⁰ C. Microanalysis found values corresponding to the following formula:

(HCl. C ₅ H ₁₀ HO ₂ S) ₂ * Sb-Sb- (SO ₂ NH ₁₀ C ₅ O ₂ OHCl) ₂

Found; C 23 #; Sb 24.4 * i H 3.7 #; H 5 _f 8 +% 0 12.9 ti s $ 12.9; ei 1?, 4 #.

Calculated ^: 24.5 * »Sb 24.7 #i H 4.4 * f W 5.7 * f 0 13.0 f>; S 13.0? Ss; Cl 14.6 #.

Example 11 Mercury-d-dimethylcyetein hydrochloride.

2 g of HgCl ₂ were added to 100 ml of de et lasser gel Ost and 16 ml of HaOH-LCsung. The insoluble BeO precipitated and was repeatedly washed with distilled water on a filter and then resuspended in 15-1 of distilled water Suspension was slowly added to 60 ml of a solution containing 1.5 g

chlorld contained and was erhitet to 70 ⁰ C. The mercury oxide immediately dissolved. The reaction product can be crystallized by gradual cooling or quantitatively recovered by adding two to three times the volume of a dose of botyl alcohol and ether or by adding ethyl alcohol. The white product precipitated by: Hlkofaol "erBetete see 1""i 177 1) 1" 185 ° 0, the product by the butyl alcohol-Xther-Mieohette "KftfalXie product at 180 to 190 °. Eb a peculiar, characteristic odor arises which causes decomposition; this metaUorganl-

iAD 209811/1719

see connections accompanied, and a black one forms Backlog of HgS,

Example 12 Mercury dl-dimethylcysteine hydrochloride.

2.01 g of HgGl «were dissolved in 30 ml of absolute Λ-alcohol and 2.3 g of dl-dimethylcysteine were suspended in 105 ml of the same medium in an Erlenmayer flask. The HgClg solution was heated on the water bath while the alcoholic dimethylcysteine suspension was slowly added to it. The suspension immediately went into solution as a result of the reaction with the HgCl «. The reaction product could be collected by slow crystallization after cooling or by precipitation with ether. The observation of the white crystals formed under a microscope on a heated plate showed that it began at 170 ⁰ C without melting, to sodium 5 to curse before the temperature reached 180 °, a black residue was formed · The compound was soluble in water " On heating the solution became cloudy due to the addition of NaOH; however, a clarification. HgS was polished out by introducing HgS into the acidic solution. Their formula * was Hg (SvJ ₅ H ₁₀ O ₂ TI _e HCl) ₂ . Calculated: Hg 35.2 #>; H 3 _t 85 ti C 21.2 ^; S 11.3 #j Cl 12.4 #

The microanalysis gave the following experimental values: Hg 38.75 £ f H 4.17 * 5 C 22.26 *; S 11.18 #; Cl 12.45 *. The material can be used alone or in combination with dialkylcysteine as an antibacterial cb.es tmd / or "diuretiachee agent be used.

209811/1719

Example 15

Ferro- and Ferri- & - and dl-dimethyloysteine «,

a) 1 g of ferric sulfate was dissolved by heating in 200 μl of water and mixed with 10 ml of 5% NH. _o 0H ferric oxide precipitated. The ferric oxide formed was washed on the filter until neutral, then suspended in 60 ml of water. 600 mg of dl-Dimethyloysteln (or the free amine) dissolved in 45 ml of water were added to this suspension. After heating to the boiling point for 10 minutes, the mixture assumed a dark purple color. It was filtered and 100 ml of ethanol and 200 ml of ether were added to the filtrate. The two layers formed, the upper one of which was colorless and the lower one purple in color and containing the compound, were separated. 80 ml of alcohol and 100 ml of ether were added to the purple liquid, causing the expected compound to precipitate. Fe (CcH ₁₀ NO ₂ S) -, which was brown in color, was soluble in alkalis and was filled with HgS after neutralization. It had a strong tendency to hydrolyze and to regress insoluble iron oxide.

~ b) 500 mg Fe SG ₄ ° 7H ₂ O (KLg. 278.03) were dissolved in 5 ml glycerol and 550 mg dl-dimethylcysteine (M. 151.18) in 15 ml glycerol. A stream of hydrogen was bubbled through the solutions before they were mixed and the combined solution was saturated with ammonia until the original purple color turned yellow. Aue of this solution, by adding a mixture of 2 parts by volume of alcohol and 408 parts by volume of ether, an initially oily-yellow precipitate was obtained which, on successive treatment, gave a solid material, which was mainly the expected reaction product: Fe (C ₅ H ₁₀ NO ₂ S) ₂

209811/1719 ^ ₀ owGfNAL

Ji'VH '' -I "'J: Γ d iS £

· J Ο J -r .,;

■ his proa. "^ V - ;;. R iasi ^ r-. ■:. ■ 'i all' 1.,. · ■ \: '. V, ona; oat urit- ■ * - ■ ·· s: - '\: ^ ::, ^ <-k ^s ar ; - - '■. .: · CV :. b ^ da gerc

:;.,. . ■■■ ■. -.3 FeSO.-THgO and "? 0: rg ■ - ^; · ^; - ^ xyceri :: ij des 1 n? L V *" -: - ■; » -sr ^ u-

■ and 200 volts in one Π -? ::; η * r.shm

osu- ^ r; to dsr "K.a1n.

.aii-nelt -und Iiο A.usfs.llung init 2 VcI. -'Cv?, ■ "= ■ -. ■ Iko-> Vol, ~ Divide. Ethylätiier yielded a" bIr. ".: ·.! ..: .-. ■■ ^; = .. '■■ *? $ ■■■

BATH

2 0 9 811/17 19

all hematopoietic derivatives (hematopoietio agents) are used will"

The selenium and tellurium derivatives of dialkyl stones can can be produced by similar processes.

Example 14

Further examples of Malkyleystein-Berivaten von Metall- © rganieehen Yerbihdungan are listed below: Biphenyläthjlffl®thylciaca? Arsin CgH ₅ -CgH ^. CH ₂ .As. ClOH reacts ä ^ taa Mall löystein and produces A.rylalkyl-Ä-lkyl- (iaono) -Rein * Bie Arylantimonhalogenide (Ä.rSbCl ₂₎ the Arylssostibina (IHgGgH-.S-bO) form the dialkyl "3 ^ I3T © in-Terl> ladttQgen · - Chlordipihenylatibine (CgHc) «-SWl

eia I '£ s ^ yl (mono) ~ dialkylcysteine8tibine. Corresponding "-1" 3-dithia-2-arsa-oyclo-pentane

AsCl

. ^[ 1 lyy. ^ Yp

P _LCiierw @ i39 * she the stibiacyclopentane - "BerlVe * d ·· Diaer-

t ^ prjpanels (BAL) »in which 2 bonds of the trivalent 2 in © inem inner bithiol ring and the third binary & stisgewglil * ® Bialkyloystein" are bound. C3 Äeteresyelisell's Hstalloarganische connections, the.

indicis.! 1 _f 5 «B £ iäiia & reaoyelopentan _t 1 _f 3-StiTaiacyclo _f Shenotltiarsin or Diaercaptopropanol-cyolische-Ii3m% tring6haltea ,, can also be used, friptenylwisnatdichlorid (CgH ₅ ) ^ iCl ₂ gives a triaryl)

209811/1719

Claims (1)

1o ant! Parasitic preparations, characterized by a Contains 3- or 5-valent antimony, arsenic, bismuth, 2- or three-quarters of iron, selenium, tellurium or mercury or organometallic compounds thereof, and a compound the general formula ? 2 H- - 0 - CH - COOH XH SHR- where Ί. Sulfur, selenium or £ ellur, H ₁ and l _gf or the Tsrsohieden can be methyl or Äthyljtsnd R "is hydrogen or the Acetylreat mean in form of a mixture or Terblndung · 2 * preparation according to claim 1, characterized in that it is a mixture of 1.5 or 2 parts dl-Diiaethyloyatein or d-dimethylcysteine hydrochloride and 1 part potassium antimonyyl tartrate. 3ο preparation according to claim 1, characterized in that that there is a mixture of 1.66 files dl-dimethyleystein and 1 feil Hatriumantimonyl tar is stepped 4 »Process for the production of antiparasitic general or organometallic derivatives of dialkylcystoins and the analogous Se and ΐβ compounds of general formula 209811/1719 R ₉ Rp OH Me ₀ (R, -C - CH »C s OV (R ₁ - C ~ CH - C a 0) • «« ν ■ y · 9 ■ » -X NHR, OH XH NHR- . 5 3 or their acid salts, in which y "is 0 or an integer Number is less than or equal to v-x, where ν represents the valence of the metal Me, ζ equals O (except when y «0) φ or an integer less than or equal to wy, where w is the maximum number of coordinate bonds that can be formed with the metal, χ is 0 or an integer up to ν, Me is trivalent or pentavalent antimony 'Arsenic * is bismuth, bivalent or trivalent iron, selenium, tellurium or mercury. A is an organic or inorganic radical or radicals, or, if χ is the number 2 or more, the radical of a heterocyclic ring in which Me is included, X is sulfur, selenium or tellurium and R ₁ and R _{2 are} methyl - or ethyl radical and R- represent a hydrogen atom or an acetyl group, characterized in that a metal compound or organometallic compound of the formula A- Me ₀ B, in which B is an inorganic radical or radicals and u «χ« · ν or, if χ « B is the number O, with a compound of the general formula ^R 2 R ₁ - C - OH - CQOH ' XH wherein X, R ₁ , R ₂ and Rj have the meanings given above, or a hydrohalide thereof is reacted « 2 0 9811/1719 «AD okignal 37-17935-5 5o method according to claim 4 »characterized! that one for the preparation of compounds of the general formula and salts thereof, wherein M Sb, As, Bi, Pe, Se or Te, X, which may be present or absent, is a cyatein group of the formula CH (COOH) (HH ₂ ) 0C (CH ₃ ) ₂ oS- or CH (COOH) I dimethylcysteine or methylethylcysteine, Z denotes X, -Sb ₀ X ₂ or a substituted or unsubstituted alkyl, aryl or aralkyl group bonded to carbon or the remaining part of an organic radical which is a heterocyclic ring including M,
k is the number O, 1 or 2, η is an integer with the valences of M and Z Matches, where Z is the same or different radicals mean, if η is greater than 1, and m such an integer that the total number of dialkylcysteinyl groups and complex-forming dialkylcysteinyl molecules does not exceed the maximum number of coordinate bonds that can be formed by the metal, or, if X is present, m can be? · Dimethyl cysteine or methyl ethyl cysteine with a compound of the general formula Z ¹ "pföoA ^, where A is an inorganic 20 981 1/1719 niBo remainder or inorganic remainders in a total valence of u is or «are, and Z * can be present or absent, and if present one or more substituted or unsubstituted alkyl, aryl or aralkyl groups or the remaining part of an organic radical which comprises a heterocyclic ring including M, means, where the group or groups has or have an overall valence ρ, in which ρ + u is the valence of M is, implements 60 The method according to claim 4 or 5 »characterized in that that a metal oxy d or halide or a hydrohalide an organometallic compound, in water, alcohol, glycerine or another suitable polar solvent suspended or dissolved is reacted with the dialkylcysteine or the corresponding selenium or tellurium compound « 7 ο method according to claim 4 to 6, characterized by records that in an alkaline solution it is stoichiometric Amounts of a metal salt and the dialkylcysteine or the corresponding selenium or tellurium compound are dissolved and implemented ο ■ AD 209811/1719