DE2424741A1 - Antilipolytic medicaments contg. thiophene derivs - with a thioalkanoic acid, thioalkanol or thioalkanal-acetal gp. - Google Patents

Abstract

Antilipolytic medicaments contain thiophene derivs. of formula (I):- (where one of R1-R4 is Rx, 0, 1 or 2 of R1-R4 are Ry, and the rest are H; Rx is -S-CHR5-COOH, -S-CHR5-CH2OH or -S-CHR5-CH(OAlk)2, where R5 is H or 1-6C alkyl and alk is 1-4C alkyl; Ry is 1-6C alkyl, 1-6C alkylthio or CHO), or enantiomers and/or salts thereof, opt. in combination with conventional additives and carriers. The medicaments inhibit the prodn. of free fatty acids (FFA) due to lipolysis in the fatty tissue, and are thus useful for the treatment of arteriosclerosis (by suppressing the conversion of FFA into triglycerides in the liver) and diabetes mellitus (since FFA interfere with glucose utilisation). Unlike known natilipolytics, they are not subject to tachyphylaxia (loss of activity on repeated administration) or the rebound phenomenon (increase in FFA levels after initial lowering), and they have no effect on the heart frequency.

Description

Antilipolytic Agents The present invention relates to new drugs with antilipolytic effects.

From the literature are through alkyl, alkylthio and formyl groups substituted and unsubstituted (thienylthio) alkanoic acids CGronowitz, Arkiv Kemi 20: 297 (1963); Goldfarb, Chemical Abstracts 59, 583b (1963), Challenger et al., J. Chem. Soc. 1953, 1837; Gronowitz, Acta pharm. Suecica, 2, 65 (1965); Then et al., Chem.

Ber. 87: 373 (1954); Bugge, Acta Chem. Scand. 22, 63 (1968)], (thienylthio) alcohols [Brooks, J. Am. Chem. Soc. 72: 1289 (1950); Schutz et al., J. Org. Chem. 28, 807 (1963)] and the 2- (2-thienylthio) acetaldehyde dimethylacetal Ghaisas, Current Sci. (India) 22, 184 (1953) 7 known without anything about a pharmaceutical usefulness of these substances is stated.

It has now been found that compounds of the general formula I wherein one of the substituents Rt, R2, R3 and R has the meaning Rx, 0, 1 or 2 substituents have the meaning Ry and the remaining substituents are hydrogen atoms, where Rx the groups with R5 meaning a hydrogen atom or an alkyl group with 1-6 carbon atoms and alkyl meaning an alkyl group with 1-4 carbon atoms and Ry an alkyl group with 1-6 carbon atoms, an alkylthio group with 1-6 carbon atoms -Atoms or a formyl group, and, if R5 is an alkyl group, its enar tiomers and, if the compounds are capable of salt formation, their salts with pharmacologically acceptable organic and inorganic bases have a superior antilipolytic effect.

3ei the compounds of general formula I come as Alkyl radical with 1 - 4 carbon atoms, for example, the methyl, ethyl, propyl, isopropyl, butyl or tert-butyl groups. As alkyl radicals with 1 - 6 carbon atoms come above this also preferably the nr-pentyl and n-hexyl radicals.

Among alkylthio groups with 1-6 carbon atoms are the thioethers of the abovementioned To understand alkyl groups, preferably the methylthio and ethylthio group.

Sodium hydroxide, for example, can be used as pharmacologically acceptable bases, Calcium hydroxide magnesium hydroxide, glucamine, N-methylglucamine, N, N-dimethylglucamine; Ethanolamine, diethanolamine, 2-amino-2- (hydroxymethyl) -1, 3-propanediol, morpholine etc. in question.

Pathological increased blood serum concentrations of triglycerides will be e.g. for the development and progression of arteriosclerotic changes in the vascular wall declared responsible. In addition to food, the triglycerides contained in the serum come from from the liver, where they are e.g. T. using free fatty acids (FFS) from the blood can be synthesized.

A decrease in the FFS content in the serum leads to a decrease in the triglyceride concentration in the liver and blood (BIZZI, VENERONI and GARATTINI, J. Pharm. Pharmac., 18, 611, 1966; PAOLETTI and PUGLISI, Naunyn-Schmiedebergs Arch. Pharmak., 269, 317, 1971).

Since the FFS concentration in the serum depends primarily on the extent of triglyceride cleavage (Lipolysis) in the adipose tissue, represents a pharmacological inhibition of this process an effective measure to lower and prevent serum triglyceride levels arteriosclerotic) changes in blood vessels. This was animal experiments proved (BIZZI, VENERONI and GARATTINI, J. Pharm. Pharmac., 18, 611, 1966; BIZZI, GARATTINI, VENERONI, HOWARD, GRESHAM and JENNINGS, Atherosclerosis, in press, 1974). A decrease in the serum triglyceride concentration was also observed in humans Treatment with lipolysis inhibitors measured (BERINGER, BANDER, GLANINGER, MAYRHOFER and SCHNACK, Horm. Metab. Res., 2, 81, 1970).

A decrease in the FFS concentration in the serum due to lipolysis inhibition In adipose tissue there is also a useful therapeutic principle for treatment of diabetes mellitus. According to investigations by RANDLE and employees (RANDLE, P.J. in: B. S. LEIBEL and G.A. WRENSHALL, Editors: On the Nature and Treatment of Diabetes, Excerpta Medica Foundation, Amsterdam -New York - London - Milan- - Tokyo - Buenoes Aires, p. 361, 1965) FFS interfere with the utilization of glucose for the purpose of generating energy in the body periphery (muscles).

The uptake of glucose by muscle cells is dependent on insulin Occurrence. Since insulin also takes place in lipolysis and thus the release of FFS from the Adipose genes inhibit the blood, is in diabetes mellitus, which is restricted by a Insulin secretion and production is characterized by the utilization of glucose Body periphery disturbed for two reasons.

The insulin deficiency primarily leads to a glucose uptake disorder into the muscle cells. It is reinforced by the simultaneous increase in FFS concentration in the blood and the associated increased FFS supply to the body periphery. With a pharmacological inhibition of lipolysis in adipose tissue if this factor disappears, the glucose utilization is improved and the increased Blood glucose concentration decreases. This was first used in animal studies shown in rats with an insulin deficiency (FROESCH, WALDVOGEL, MEYER, JAKOB and LABHART, Mol. Pharmacology,, 442, 1967) and was able to use a clear on diabetics Improvement and reduction of urinary glucose excretion are confirmed. Here Lipolysis inhibitors have been shown to be effective or either with monotherapy were able to undergo therapy with ß-cytotropic sulfonylureas in secondary failures respectively.

Sulphonylureas and biguanides in combination with these drugs to normalize the derailed carbohydrate metabolism (BERINGER, BÄNDER, GIANINGER, MAYRHOFER and SCHNACK, Horm. Metab. Res., 2, 81, 1970; -GEYER and SOKOPP, Vienna. clin. Wschr., 81, 701, 1969; GEYER and SOKOPP, Med. And Nutrition, 10, 115, 1969; NEUMANN, MICHAELIS, BIBERGEIL and WULFERT, Dtsch. Ges.

Wesen, 27, 972, 1972).

Previously used as lipolysis inhibitors in such investigations Compounds such as nicotinic acid, 3-pyridinemethanol, 5- (3-pyridyl-) tetrazole, 3,5-dimethylpyrazole, 3,5-Dimethylisoxazole, the result of the last two substances mentioned in the organism resulting active metabolites 5-methylpyrazole-3-carboxylic acid and 5-methylisoxazole-3-carboxylic acid2 various other pyrazole and isoxazole derivatives as well as a number of adenosine derivatives All of them cause an initial lowering of the FFS content in the serum, but they come for various reasons not for long-term therapy for metabolic abnormalities in question. With the exception of the adenosine derivatives, all of the substances mentioned lead to especially nicotinic acid and compounds derived from it, after they have subsided FFS-lowering effect leads to an excessive increase in free fatty acids in the Serum above the initial level (rebound phenomenon) and thus raise the positive consequences their initial effect again (BIZZI and GARATTINI, in: Metabolic Effects of Nicotine Acid and Its Derivatives, Hans-Huber-Verlag, Bern, p. 207, 1971).

Pyrazole and isoxazole derivatives as well as pyridyl tetrazole lose in addition, if it is applied several times consecutive Days after a shorter or longer period of time their ability to inhibit lipolysis and thus lowering the FFS concentration in the serum. This is known as tachyphylaxis Behavior was observed in animal experiments (BIZZI and GARATTINI, in: Metabolic Effects of Nicotinic Acid and its Derivatives, Hans Huber-Verlag, Bern, 1971, 5. 207; FROESCH, WALDVOGEL, MEYER, JAKOB and LABHART, Mol. Pharmacol.,, 442, 1967 SCHILLINGER and LOGE, B; iochem. Pharmacol. in print 1974) and found in clinical Use of 5-methylpyrazole-3-carboxylic acid and 5-methylisoxazole-3-carboxylic acid Confirmation on humans (NEUMANN, MICHAELIS, BIBERGEIL and WULFERT, Dtsch. Ges. Wesen, 27, 972, 1972; GEYER and SOKOPP, Acta endocr. (Kbh.) Suppl. 173, 127, 1973). The phenomenon of tachyphylaxis does not necessarily have to be according to the findings given above related to the rebound phenomenon, just like this however it is for one permanent therapy prohibitive.

Antilipolytically effective adenosine derivatives have neither after initial decrease is an excessive increase in the FFS in the serum above the initial level result in a loss of effectiveness after repeated application (SCHILLINGER and LOGE, Biochem. Pharmacol., In press 1974).

However, they have only an extremely low therapeutic level times because they are already in lipolytically effective doses or only slightly higher affect the heart's activity and lead to a decrease in the heart rate (MANNESMANN, Publication in preparation, 1974). Because of this dangerous effect on the Cardiovascular system, adenosine derivatives come for long-term therapy in humans therefore out of the question.

Looking for lipolysis inhibitors that will last for the long term Suitable for use in humans, it was surprisingly found that compounds of the general formula I neither the phenomenon of tachyphylaxis nor of overshooting of free fatty acids after an initial reduction (rebound phenomenon). aside from that no influence on the heart rate was found; the therapeutic breadth is very great in this regard.

The compounds of general formula I are therefore suitable for permanent Reduction of the free fatty acids in the blood plasma of animals and humans without it after initial decrease leads to an excessive rise again or with undesirable effects or harmful influences on the cardiovascular system are to be expected. The connections open up a completely new treatment option for metabolic diseases in principle such as B. diabetes mellitus, hyperlipemia and arteriosclerosis. In the treatment of Diabetes mellitus is one of the three treatment options common therapies (insulin, sulfonylamino compounds and biguanides) as an equal fourth option aside.

The compounds according to the invention are of particular importance here in combination therapy with those commonly used in the treatment of diabetes mellitus Medication.

In the table below is one of the compounds according to the invention the reference substance designated as the standard 5-methylisoxazole-3-carboxylic acid in your 'day profile' of the FFS lowering (with multiple applications) and in your Profile of the FFS lowering with daily application over 8 days - "" Tachyphylaxis profile " - juxtaposed.

The (2-thienylthio) acetic acid selected as an example lowers how from Table I and Fig. I, after a single oral application, the free Fatty acids (FFS) in the serum of fasting rats were significant. In the inventive- Connection - there is no unwanted increase again after the initial lowering of the FFS, as observed after treatment with the reference substance 5-methylisoxazole-3-carboxylic acid will. This was also observed with other conventional lipolysis inhibitors and was independent of the dose "Rebounds" phenomenon cancels the positive effects of the initial lowering and makes the therapeutic value of such a compound is doubtful.

In Fig. II is the antilipolytic effect of (2-thienyl) thioacetic acid shown after several days of treatment.

The connection shows after 8 days, at a time when the Reference substance 5-methyl-isoxazole -) - carboxylic acid no longer lowering the FFA causes unchanged antilipolytic effect. This for the invention Compounds characteristic lack of tachyphylactic effects is unconditional Prerequisite for the chronic use of a lipolysis inhibitor.

Table I Daily profile of free fatty acids (FFA) in serum 24 hours. fasting rats after oral treatment with 2-thienylthioacetic acid (I + II) and 3-methyl isoxazole -5-carboxylic acid (III) compared to the untreated control group (IV).

Central values of 10 animals Kon-FFS according to FFS in @ mVal / 1 according to trolle Hours 1, 250 mg / kg II, 50 mg / kg III, 1 mg / kg IV 0.5 0.335 0.730 0.420 1.000 1 -0.465 0.520 0.415 0.700 2 0.485 0.635 0.785 0.775 3 0.405 0.605 0.620 0.710 4 0.425 0.875 0.850 1.115 5 0.350 0.650 0.700 1.030 6 0.445 0.490 0.920 0.630 7 0.430 0.500 0.785 0.665 9 0.285 0.545 0.750 0.900 11 0.300 0.545 0.785 0.760 13 0.250 0.600 0.615 0.670 16 0.425 0.690 0.935 0.970 19 0.415 0.685 0.610 0.670 24 0.685 0.760 0.745 0.685 -: significantly different from the control group.

Fig. I Daily profile of free fatty acids (FFA) in serum 24 hours, more sober Rats after oral treatment with 2-thienylthioacetic acid (I + II) and 3-methylisoxazole-5-carboxylic acid (III) compared to the untreated control group (IV).

-II 50 mg / kg --IV contr.

---- III 1 mg / kg -NN I 250 mg / kg The new active ingredients can be administered orally or parentally. The packaging can be carried out without additives or with the additives, carrier substances, flavor corrections etc. customary in galenic pharmacy

take place, for example in powder form, as tablets, dragees, Capsules, pills, in the form of suspensions or solutions.

The amount of active ingredient to be administered can be between 1 and 100 mg / kg, preferably vary between 1 and 30 mg / kg body weight per day. Dose units can contain 10 mg to 1 g of active ingredient, preferably 50-550 mg of active ingredient.

The compounds of the general formula I are either known from the literature or can be prepared by processes known from the literature.

It has proven to be particularly advantageous to use an appropriately substituted Thienylthiol or an alkali salt, preferably the lithium salt, of which with halocarboxylic acid, Halo alcohols or haloaldehyde dialkyl acetal to give compounds of the general Formula I to implement.

The thienylthioic acid derivatives can also be produced will, by first the thienylthiol or an alkali salt thereof with a halogen ester reacted and then saponified the thienyl thioester obtained.

The substituted or unsubstituted thienylthio alcohols can further obtained by reducing the corresponding thiocarboxylic acids will.

The substituted or unsubstituted ones used as starting materials Thienylthiols or their alkali salts are either known from the literature or can be used according to processes described in the literature.

The following process has proven to be advantageous: Unsubstituted or appropriately substituted thiophene is lithiated with butyllithium and then converted into the thiol with sulfur. This method has the advantage that the Lithium salt accruing thiol does not need to be isolated, but processed directly can be.

Example 1 (2-thienylthio) acetic acid.

At - 200 C under nitrogen, 22.7 g (270 mmol) of thiophene are obtained in 50 ml dry ether 100 ml (c.230 mmol) # 22% igs butyllithium solution (in hexane) given. The mixture is allowed to warm to room temperature, stirred for a further 2 hours and then cooled to -600 ° C. and 7.5 g (230 mmol) of dry sulfur are added in portions. The mixture is then stirred for one hour at 00 ° C. and poured into 200 ml of ice water. The ether-hexane phase is separated and extracted once with 40 ml of water. The combined aqueous Phases become a solution of 22.5 g (234 mmol) of chloroacetic acid and 16.3 g (117 mmol) of potassium carbonate in 150 ml of water and stirred overnight. Then it will be gageschüttelt with ether, the ether discarded and the aqueous alkaline phase with concentrated hydrochloric acid adjusted to pH 2. The exuding brown oil is extracted with ether, the ether is washed acid-free with water and dried over Na2SO4 and narrowed.

Distillation (bp 0.8 = 132 - 134 ° c) gives a colorless 1, the solidified into crystals with a melting point of 440 C.

Yield: 62 ffi of theory.

For example 2 (3-thienylthio) acetic acid.

Under nitrogen and at -700 ° C., 37.5 g (230 mmol) of 3-bromothiophene are obtained in .100 ml of dry tetrahydrofuran 100 ml (i 230 mmol) of 22% strength butyllithium solution (in hexane) dripped. Stirring is continued for 15 minutes at -600 ° C. and then 7.5 g (230 mmol) of dry sulfur - 700 ° C. was added in portions. The mixture is then stirred for 1 hour at - 700 C and 28 g (230 mmol) of ethyl chloroacetate are added dropwise at this temperature to. The mixture is allowed to warm to room temperature, stirred for 1 1/2 hours and then poured into a mixture of 250 g of ice and 100 ml of 5N hydrochloric acid. It is extracted three times with 150 ml of ether each, washes the ether three times with 80 ml of saturated sodium bicarbonate solution each time and three times with 50 ml of saturated saline each time. The Atherextrakt is about CaSO4 dried, concentrated and treated as a crude product with an equimolar amount of 1N NaOH in saponified ethanol. After the alcohol has been stripped off, it becomes the aqueous-alkaline phase extracted with ethyl acetate, adjusted to pH 2 with 6 N HC1 and three times with Ethyl acetate extracted. The combined ethyl acetate extracts are saturated with Washed sodium chloride solution, dried over CaSO4, concentrated and distilled.

Kp = 122 - 1230 C.

Yield: 86% of theory (based on the crude ester).

The (3-thienylthio) acetic acid crystallizes during the Standing at room temperature and has after. Recrystallization from benzene - petroleum ether Melting point of 510 C.

B ei sp i e 1 D: 2- (2-thienylthio) acetic acid.-Production takes place analogously to Example 3 from thiophene and α-bromopropionic acid.

Melting point: 71 - 74 ° C.

Example 4: (5-Methyl-2-thienylthio) acetic acid.

Production takes place analogously to Example 1 from 2-methylthiophene and Chloroacetic acid.

Bp 0.05: 11 - 112 ° C B e 1 s p i e 1 5: (4-methyl-2-thienylthio) acetic acid.

Production takes place analogously to Example 1 from 3-methylthiophene and Chloroacetic acid.

M.p. 540 C.

B e 1 5 1 e 1 6: (5-ethyl-2-thienylthio) acetic acid.

Production takes place analogously to Example 1 from 5-ethylthiophene and Chloroacetic acid.

Kp5: 172 - 1730 C.

Ex. 7 2- (3-thienylthio) propionic acid.

The preparation takes place analogously to Example 1 from 3-bromothiophene and α-bromopropionic acid.

Mp. 77-780 C.

B e-i s 2 i e 1 8 2- (3-thienylthio) ethanol The production takes place analogously to Example 2 from 3-bromothiophene and 2-chloroethanol.

Kpi: 123-1250 C. Example 9 (S "Methyl-3-thienylthio) acetic acid.

Production takes place analogously to Example 1 from 2-methyl-4-bromothiophene and chloroacetic acid m.p. 74-760 C.

13 e 1 s p 1 e 1 10 2- (2-thienylthio) acetaldehyde dimethyl acetal Die Production takes place analogously to Example 2 from thiophene and chloroacetaldehyde dimethyl acetal.

Kp0.05 87 - 930 C.

EXAMPLE 11 2- (4-Methylthio-3-thienylthio) propionic acid Production takes place analogously to Example 1 from (3-mercapto-4-thiomethyl) thiophene and α-Bromopropionic acid Melting point: 750 C.

13 e 1 5 p 1 e 1 12 2- (2-methylthio-3-thienylthio) propionic acid Die Production takes place analogously to Example 1 from (3-mercapto-2-thiomethyl) thiophene and α-bromopropionic acid.

Melting point: 410 C.

Example 1 13 (5-methylthio-2-thienylthio) acetic acid The production takes place analogously to Example 1 from (2-thiomethyl) thiophene and chloroacetic acid.

Bp 0.1: 1600 C, for example 1 14 (2,5-dimethyl-3-thienylthio) acetic acid It is added with stirring. a solution of 28.8 g (200 mmol) of 3-mercapto-2,5-dimethylthiophene and 8.8 g (220 mmol) of NaOH in 50 ml of water, a solution of 19.9 g (200 mmol) of chloroacetic acid and 10.6 g (100 mmol) Na2CO3 in 35 ml water.

After standing overnight, the mixture is acidified with 6 N HC1 and extracted three times with 150 ml of ether each time. The ether extracts washed with water the ether is dried over Na2SO4, stripped off and the oily residue is distilled.

Bp 0.9: 172 T 1760 C The 3-mercapto-2,5-dimethylthiophene is after Process known from the literature [Dann, Dimmling, Chem. Ber. 87, 373 (1954J7 from 2,5-dimethylthiophene produced by sulfochlorination and subsequent reduction of the sulfochloride.

13 e i 5 p i e 1 15 2-- (2-thienylthio) ethanol under nitrogen 22.7 g (270 mmol) of thiophene in 50 ml of dry ether at -200 C with 100 ml (230 mmol) 22% butyllithium solution (added in hexane and 2 hours at room temperature held. After cooling to -600 ° C., 7.5 g (230 mmol) of sulfur are added in portions added and stirred at 00 C for 30 minutes. Then 18.4 g (230 mmol) of chloroethanol, the temperature should not exceed - 100 C. Man stirs for one hour at room temperature and then refluxes for three hours. After pouring into 200 ml of ice-cold 1N HCl, it is extracted with ether, the ether three times washed with 100 ml of water each time, over sodium sulfate dried and narrowed. Kugelrohr distillation at 0.04 Torr (T bath: 87 - 920 C) gives the desired alcohol as a pale yellow oil.

Yield: 2T% of theory.

B e i s P i e 1 16 2- (3-thienylthio) propanol To a suspension of 11.4 g (300 mmol) of lithium aluminum hydride in 250 ml of dry ether is taken under Ice cooling a solution of 43.2 g (200 mmol) of ethyl 2- (3-thienylthio) propionate dripped. The mixture is subsequently stirred for one hour at room temperature, cooled to −0 ° C. and given 20 ml of ethyl acetate are added dropwise. The mixture is then poured into 850 ml of ice-cold 10% strength Poured sulfuric acid, extracted three times with 200 ml of ether each time, the ether three times washed with 150 ml of 5% sodium bicarbonate solution each time and dried over Na2S04. After evaporation of the ether, the product distills at bp 0.6: 1520 C.

The 2- (3-thienylthio) propionic acid ethyl ester is analogous to the example 2 made from 3-bromothiophene, butyllithium, sulfur and ethyl bromopropionate.

Kp1: 115 - 1160 C.

B e 1 5 p 1 e 1 17 2- (3-Thienylthio) -butanol Starting from 2- (3-Thienylthio) -butyric acid ethyl ester (Bp 0.5: 116 ° C) the connection is carried out analogously to Example 16 reduction made with lithium aluminum hydride.

Bp 6: 122 - 1250 C.

0.0 13 e i 5 n i e 1 18 2- (3-thienylthio) pentanol Starting from Ethyl 2- (3-thienylthio) valerate (boiling point 0.1: 112-1160 C) is the compound prepared analogously to Example 16 by reduction with lithium aluminum hydride.

Bp 0.5: 133-134 ° C 0.5 e i si e 1 19 (2-formyl-3-thienylthio) acetic acid With ice cooling, 176 g (1.15 mol) of POC13 are added dropwise to 84 g (1.15 mol) N, N-dimethylformamide given.

The mixture is stirred for a further 30 minutes and then added dropwise while cooling with ice with 202 g (1.0 mol) of (3-thienylthio) acetic acid ethyl ester. The mixture will last 24 hours stirred at room temperature, poured onto 500 g of ice and 12 hours at room temperature touched. Extract three times with 200 ml of ether each time and shake the ether once with 150 ml of water, then three times with 180 ml of concentrated sodium bicarbonate solution each time. The bicarbonate extracts are extracted once with 150 ml of ether and concentrated with HC1 added up to pH 1. The precipitated crude acid is recrystallized twice from water. Melting point 170-1710 C (water).

EXAMPLE 1 20 (3-Formyl-2 thienySthio) acetic acid The compound is analogous to Example 2 from 3-formylthiophenethylene glycol acetal, butyllithium, sulfur and ethyl chloroacetate. The one obtained after treatment with 5 N HCl (3-Formyl-2-thienylthio) acetic acid ethyl ester is used in the saponification in crude form used with methanolic potassium hydroxide solution and gives after the usual work-up Carboxylic acid that is recrystallized from acetic acid / water.

Melting point: 133-1360 C (acetic acid / water).

Yield: 79% of theory.

Ex. 1 21 (5-Formyl-2-thienylthio) acetic acid Starting from 2-formylthiophene dimethylacetal, the compound is prepared analogously to Example 20.

Melting point: 132-133 ° C (ethyl acetate Bonzin) Yield: 11% of the Theory.

13 e i 5 p i e 1 22 500 g (2-thielylthio) - acetic acid-3 g disperse Silicic acid (Aerosil #) and 47 g of corn starch are sieved, mixed homogeneously and filled in hard gelatin capsules with a net filling of 550 mg / capsule.

For example 1 23 500 g (2-thienylthio) acetic acid, 3 g disperse silica (Aerosil 45 g corn starch, 50 g dry binder cellulose (Avicel PH 101 #) and 2 g magnesium stearate are mixed homogeneously and in the usual way on a tablet press to form tablets of 600 mg pressed. The tablets are then made up with a coating varnish of 8 parts of hydroxypropyl cellulose (Klucel LF #), one part of castor oil and one Part of the talc.

Claims (22)

Claims to fatigue 1) Medicinal product consisting of a compound of the general formula I. wherein one of the substituents R1, R2, R3 and R4 has the meaning Rx, 0, 1 or 2 substituents have the meaning Ry and the remaining substituents are hydrogen atoms, where Rx the groups with R5 meaning a hydrogen atom or an alkyl group with 1-6 carbon atoms and alkyl meaning an alkyl group with 1-4 carbon atoms and Ry an alkyl group with 1-6 carbon atoms, a thioalkyl group with 1-6 carbon atoms -Atoms or a formyl group, and, if R5 is an alkyl group, their enantiomers and, if the compounds are capable of salt formation, their salts with pharmacologically acceptable organic and inorganic bases and pharmaceutically customary auxiliaries and carriers. 2) Medicament according to claim 1, characterized in that it is as Active ingredient (2-thienylthio) acetic acid contains. 3) Medicament according to claim 1, characterized in that it is as Active ingredient () -thienylthio) acetic acid contains. 4) drugs) according to claim 1, characterized in that it is as Active ingredient 2- (2-thienylthio) propionic acid contains. 5) Medicament according to claim 1, characterized in that it is as Active ingredient (5-methyl-2-thienylthio) acetic acid contains. 6) medicament according to claim 1, characterized in that it contains (5-ethyl-2-thienylthio) acetic acid as active ingredient. 7) Medicament according to claim 1, characterized in that that it contains (4-methyl-2-thienylthio) acetic acid as an active ingredient. 8) Medicament according to claim 1, characterized in that it is as Active ingredient 2- (3-thienylthio) propionic acid contains. 9) Medicament according to claim 1, characterized in that it is as The active ingredient contains 2- (3-thzenylthio) ethanol. 10) Medicament according to claim 1, characterized in that it is as Active ingredient (5-methyl-3-thienylthio) acetic acid contains. 11) Medicament according to claim 1, characterized in that it contains 2- (2-thienylthio) acetaldehyde dimethylacetal as active ingredient. 12) Medicament according to claim 1, characterized in that it is as Active ingredient 2- (4-methylthio-3-thienylthio) propionic acid contains. 13) Medicament according to claim 1, characterized in that it is as Active ingredient 2- (2-methylthio -3-thienylthio) propionic acid contains. 14) Medicament according to claim 1, characterized in that it is as Active ingredient (5-methylthio-2-thienylthio) acetic acid contains. 15) Medicament according to claim 1, characterized in that it is as Active ingredient (2,5-dimethyl-3-thienylthio) acetic acid contains. 16) Medicament according to claim 1, characterized in that it is as Active ingredient 2- (2-thienylthio) ethanol contains. 17) Medicament according to claim 1, characterized in that it is as Active ingredient 2- (3-thienylthio) propanol contains. 18) Medicament according to claim 1, characterized in that it is as Active ingredient 2- (3-thienylthio) -butanol contains. 19) Medicament according to claim 1, characterized in that it is as Active ingredient 2- (3-thienylthio) pentanol contains. 20) Medicament according to claim 1, characterized in that it is as Active ingredient (2-formyl-3-thienylthio) acetic acid contains. 21) Medicament according to claim 1, characterized in that it is as Active ingredient (3-formyl-2-thienylthio) acetic acid contains. 22) Medicament according to claim 1, characterized in that it is as Active ingredient (5-formyl-2-thienylthio) acetic acid contains.