DE2824386A1 - Antiphlogistic and antiinflammatory compsn. - contains sulphur-contg. acrylic or propionic acid deriv. - Google Patents

Abstract

A drug contg. at least one S-contg. carboxylic acid or ester of formula (I) is new (where X is H, alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, OH or SH; Y is -CH2-CHR- or -CH=CR-; R is H or alkyl; Z is OH, alkoxy or alkylthio; provided that at least one of X and Z contains sulphur). The drug is esp. suitable as an antiphlogistic for the treatment of inflammatory processes. (I) have a considerably broader therapeutic spectrum than previously known inflammation inhibitors. (I) also have few side effects such as heartburn, formation of ulcers, intestinal bleeding, etc. The ED50 for e.g. S-methyl-3-methyl-thiopropionothioate (Ia) is 4.85 mu mol/kg. i.m. in rats with kaolin-induced oedema, cf. LD50 for (Ia) which is 4.587 mu mol/kg. i.m.

Description

New medicines

The present invention relates to the new pharmaceutical use of partially known sulfur-containing organic acids and their esters as Medicines, especially as anti-inflammatory drugs for the treatment of inflammatory processes.

The use of these sulfur-containing organic acids and esters this class of compounds as a drug is not yet known.

It has been found that the sulfur-containing carboxylic acids and their esters of the general formula in which X represents a hydrogen atom, an alkyl group, an alkoxy group, an alkylthio group, an alkylsulfinyl or alkylsulfonyl group or a hydroxy or a mercapto group, Y represents the grouping where R stands for a hydrogen atom or an alkyl group, and Z stands for a hydroxyl group, an alkoxy or alkylthio group, at least one of the substituents of X or Z each being a sulfur-containing radical, having an advantageous anti-inflammatory effect.

The compounds claimed as active pharmaceutical ingredients of the general Some of the formula (I) are known and some are commercially available.

The compounds according to the invention were mainly represented according to the following reaction scheme, as shown in an example: CH3SO2CH2CH2COOH Depending on the concentration of the oxidizing agent and depending on the reaction time used, the individual oxidation stages can be intercepted or mixtures are formed that can be separated by chromatography, as described in detail in the experimental section.

Surprisingly, the sulfur-containing carboxylic acids according to the invention show and esters with a very good anti-inflammatory effect have a much greater therapeutic effect Width than the previously known connections in this field. Also show they have fewer side effects, such as heartburn, formation of tllcera, intestinal bleeding etc.

The compounds according to the invention thus represent an enrichment in pharmacy.

Examples of the compounds which can be used according to the invention are specifically mentioned: 3-methylsulfinylpropionic acid (CH3SOCH2CH2COOH) S-methyl methacrylthioate (CH2 = C (CH3) COSCH3) S-methylcrotonylthioate (CH3CH = CH-COSCH3) S-ethyl acrylthioate (CH2 = CH-COSC2H5) S-ethyl-3-ethylthiopropionylthioate (C2H5SCH2CH2COSC2H5) S-methyl-3-methylthio-2-propylcarbonylthioate (CH3SCH2CH (CH3) COSCH3 3-mercaptopropionic acid (HS-CH2CH2COOH) S-methyl-3-methylthiopropionthioate (CH3S-CH2-CH2-COSCH3) methyl 3-methylthiopropionate (CH3S-CH2-CH2-COOCH3) S-methyl acrylthioate (CH2 = CH-COSCH3) methyl 3-mercaptopropionate (HS-CH2-CH2-COOCH3) 3-methylthiopropionic acid (CH3SCH2CH2COOH) Ethyl 3-methylthiopropionate (CH3SCH2CH2COOC2H5) S-propyl-3-propylthiopropionthioate (C3H7SCH2CH2COSC3H7) S-isopropyl-3-isopropylthiopropionthioate (CH3CH (CH3) SCH3CH2-COSCH (CH3) CH3) S-butyl-3-butylthiopropionthioate (C4H9SCH3CH2COSC4H9) S-sec-butyl-3-sec-butylthiopropionthioate (CH3CH (CH3) SCH3CH2COSCH (CH3) CH2CH3) S-tert-butyl-3-tert-butylthiopropionthioate ((CH3) 3CSCH2CH2COSC (CH3) 3) S-isobutyl-3-isobutylthiopropionthioate (CH3CH (CH3) SCH3CH2COSCH (CH3) 2) S-butyl 3-butylsulfinylpropionthioate (C4H9SOCH2CH2COSC4H9) S-sec-butyl-3-sec-butylsulfinylpropionthioate (CH3CH2CH (CH3) SOCH2CH2COSCH (CH3) = S-isopropyl-3-isopropylsulfinylpropionthioate ((CH3) CHSOCH2CH2COSCH (CH3) 2) S-propyl 3-propylsulfinylpropionthioate (C3H7SOCH2CH2COSC3H7) S-ethyl 3-ethylsulfinylpropionthioate (C2H5SOCH2COSC2H5) S-tert-butyl-3-tert-butylsulfinylpropionthioate ((CH3) CHSOCH2CH2COSC (CH3) 3) S-ethyl-3-ethylsulfonylpropionthioate (C2H5SOCH2COSC2H5) S-sec-butyl-3-sec-butyl-sulfonyl-propionthioate (CH3CH2 (CH3) SO2 = CH2CH2COSCH (CH3) CH2CH3) 3-tert-butylsulfonylpropionic acid ((CH3) 3CSO2CH2CH2COOH) S-isobutyl-3-isobutylsulfonylpropionthioate ((CH3) 2CHCH2SO2CH2CH2COSCH2CH (CH3) 2) S-tert-butyl-3-tert-butylsulfonylpropionthioate ((CH3) 3CSO2CH2CH2COSC (CH3) 3) 3-sec-butylsulfonylpropionic acid (CH3CH2CH (CH3) SO2CH2CH2COOH) S-Butyl-3-butylsulfonylpropionthioate (C4H9SO2CH2CH2COSC4H9) 3-butylsulfonylpropionic acid (C4H9SO2CH2CH2COOH) 3-isobutylsulfonylpropionic acid ((CH3) 2CHCH2SO2CH2CH2COOH) S-isopropyl 3-isopropylsulfonylprophionthioate ((CH3) 2CHSO2CH2CH2COSCH (CH3) 2 S-propyl-3-propylsulfonylpropionthioate (C3H7SO2CH2CH2COSC3H7) S-methyl-3-methylsulfonylpropionthioate (CH3SO2CH2CH2COSCH3) the pharmacological effect is exemplified by means of the S-methyl-3-methylthiopropionthioate (hereinafter designated as A demonstrates.

Substance A has a very pronounced anti-inflammatory effect and is eminently suitable for parenteral use. The anti-inflammatory The effect was demonstrated on the paw edema of the rat caused by the application of kaolin. The value for the DE50 was 4.85 / µmol / kg after IM injection.

This value shows clearly, also in comparison with those of the same Method determined DE50 values for known commercially available anti-inflammatory drugs (see Sect. Table 1) that the compound A inhibits the experimental inflammation to a great extent.

It is well known that almost all nonsteroidal anti-inflammatory drugs cause damage to the mucous membrane of the gastrointestinal tract in humans and animals. It was therefore tested whether the compound A had an ulcerogenic effect after IM administration owns.

A DE50 of 256.41 / µmol / kg was found in the rat.

The distance between the cans between the two DE50 values already shows that, measured by these two criteria, for compound A a great therapeutic Width.

In addition, A is also effective on other models of inflammation. The following DE50 values are determined (mg / kg; i.m) formalin edema 5.4, protein edema 6.3, yeast edema-27/4, cancanavalin edema 3.4, trypsin edema 2.0.

These statements can be reinforced by determining the acute toxicity in rats after i.m injection of compound A.

The DL50 was 4,587 / µmol / kg.

The large difference between this value and the DE50 for kaolin edema underlines the unexpected beneficial therapeutic index for the compound A. The above results are in the table the corresponding values of Flufanamic acid, phenylbutazone and indomethacin compared. The comparison the numbers in the last two columns of the table show the outstanding position of compound A in terms of its therapeutic range.

Table 1 Comparison of the therapeutic index rat thersin animals width Substance kaolin or gastric ulcer applique. DE50 ulges DE50 DL50 µmol / kg DE50 µmol / kg DL50 type DL50 kaolin denomination DL50 kaolin denom µmol / kg S-methyl-5-methylene 4.85 5.76 * 256.41 429.18 4587 4950 1.u. 52.86 945.77 thiopropionthioate 3.36 172.41 4256 Fibrenamic acid 36.2 50.9 55.1 76.7 2037 3065 oral 1.52 56.27 23.9 32.7 1632 Phenylbutazone 122 167.4 181.6 234.9 3217 4803 oral 1.48 26.36 92.8 145.0 2317 Inoometacin 2.9 3.9 11.2 23.0 66 85 oral 2.81 23.44 2.3 6.4 65 m) Figures mean confidence ranges with an intum probability of 5%.

In addition to the effects described for compound A, it was also possible it can be demonstrated that the other derivatives (see Table 2) are also strongly anti-inflammatory are effective. Table 2 lists the limit doses, which are not unambiguous cause verifiable influence on the paw edema after kaolin application.

Table 2 Antiphlogistic effect rat, kaolin edema, im, n = 10 / dose group Compound dose mg / kg inhibition in% of controls (DE50 in mg / kg) HSCH2CH2COOH 20.00 8.5 C2H5SCH2CH2COSC2H5 2.50 58.2 (3.75) CH3CH = CHCOSCH3 12.50 16.0 CH2 = C (CH3) COSCH3 5.00 21.8 CH3SOCH2CH2COSCH3 3.12 10.2 (1.8) CH3SCH2CH (CH3) COSCH3 0.65 16.6 (4.5) CH2 = CHCOSC2H5 0.32 18.5 (1.5) Dose inhibition in% compound mg / kg of controls CH3SCH2CH2COOC2H5 25 16 (CH3) 3CsCH2CH2CosC (CH3) 3 12.5 23.3 (CH3) 2CHSCH2CH2COSCH (CH3) 2 25 63.2 C3H7SCH2CH2COSC3H7 25 68.5 C4H9SCH2CH2COSC4H9 50 77.2 CH3CH2CH (CH3) SCH2CH2COSCH (CH3) 72) 2CHCH2SCH2CH2COSCH2CH (CH3) 2 50 77.2 (CH3) 2CHSOCH2CH2COSCH (CH?), 12.5 22.7 (CH3) 2CHCH2SOCH2CH2COSCH2CH (CH3) 2 12.5 17.9 CH3CH2CH (CH3) SO2CH2CH2COSCH (CH3) CH2.5 33 (CH3) 2CHCH2S02CH2CH2COSCH2CH (CH3) 2 12.5 42 C3H7SOCH2CH2COSC3H7 100 73 CH3CH2CH (CH3) SOCH2CH2COSCH (CH3) CH2CH3 100 90.5 C4H9SOCH2CH2COSC4H9 100 73 Of particular interest is the use of compounds of the general formula (1) in which X represents hydrogen, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl or a mercapto group, the aforementioned alkyl and alkoxy groups each containing 1 to 4 carbon atoms; Y for the grouping where R denotes hydrogen or All with 1 to carbon atoms and Z denotes a hydroxyl, alkoxy or alkylthio each with 1 to 4 carbon atoms in the alkoxy and alkyl radicals.

The present invention includes pharmaceutical preparations, which in addition to non-toxic, inert pharmaceutically suitable carrier substances or contain several active ingredients according to the invention or those of one or more according to the invention There are active ingredients and processes for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, e.g. tablets, coated tablets, capsules, pills, suppositories and ampoules are present, whose active ingredient content corresponds to a fraction or a multiple of a single dose. The dosage units can be, for example, 1, 2, 3 or 4 single doses or 1/2, 1/3 or Contain 1/4 of a single dose. A single dose preferably contains the amount Active ingredient that is administered in one application and that usually corresponds to a whole, corresponds to half a day or a third or a quarter of a daily dose.

Among non-toxic, inert pharmaceutically acceptable carriers are solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any kind to understand.

Preferred pharmaceutical preparations are tablets, coated tablets, Capsules, pills, granules, suppositories, solutions, suspensions and emulsions, Called pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, coated tablets, capsules, pills and granules can be the or the active ingredients contain conventional carriers such as fillers and extenders (e.g. starches, milk sugar, cane sugar, glucose, mannitol and silicic acid) binding agent (e.g. carboxymethyl cellulose, alginates, gelatine, polyvinylpyrrolidone), humectants (e.g. glycerine), disintegrants (e.g. agar-agar, calcium carbonate and sodium bicarbonate), Solution retarders (e.g. paraffin) and absorption accelerators (e.g. quaternary Ammonium compounds), adsorbents (e.g. kaolin and bentonite) and lubricants (e.g. talc, calcium and magnesium stearate and solid polyethylene glycols) or mixtures of the listed substances.

The tablets, coated tablets, capsules, pills and granules can be used with the customary coatings and sheaths, optionally containing opacifying agents be and also be composed so that they only or the active ingredient or preferably in a certain part of the intestinal tract, possibly delayed with embedding materials such as polymer substances and Waxes can be used.

The active ingredient (s) can optionally be combined with one or more the above-mentioned carrier substances are also available in microencapsulated form to achieve this a retard effect.

In addition to the active ingredient (s), suppositories can contain the usual water-soluble ones or water-insoluble carriers, e.g. polyethylene glycols, fats, e.g.

Cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty 14 acid) or mixtures of these substances.

Ointments, pastes, creams and gels can be used in addition to the active ingredient or ingredients contain the usual carriers (e.g.

animal and vegetable fats, waxes, paraffins, starches, tragacanth) or mixtures of these substances.

Powders and spays can be the usual ones in addition to the active ingredient or ingredients Contain carrier substances (e.g. lactose, talc, silica, aluminum hydroxide) or mixtures of these substances.

Sprays can also contain the usual propellants.

Solutions and emulsions can, in addition to the active ingredient or ingredients, the customary carriers such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, ble, especially cottonseed oil, peanut oil, corn oil, Contain olive oil and sesame oil, glycerine, polyethylene glycols or mixtures of these substances.

The solutions and emulsions can also be used for parenteral administration are in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can contain the usual carriers such as liquid diluents (e.g.

Water, ethyl alcohol, propylene glycol), suspending agents (e.g. ethoxylated Isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose) or mixtures of these substances.

The formulation forms mentioned can also contain colorants and preservatives as well as additives that improve smell and taste, e.g. peppermint oil and eucalyptus oil and sweeteners such as saccharin.

The therapeutically active compounds are intended to be in those listed above pharmaceutical preparations preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95 percent by weight of the total mixture be.

The pharmaceutical preparations set out above can also be used the active ingredients according to the invention also contain further pharmaceutical active ingredients.

The manufacture of the pharmaceutical preparations listed above takes place in the usual way by known methods, e.g. by mixing the Active ingredients with the carrier (s).

The present invention also includes the use of the elements according to the invention Active ingredients and pharmaceutical preparations that contain one or more of the invention Contains active ingredients in human and veterinary medicine for smelting and improvement and / or healing of inflammatory processes in the human and animal organism.

The active ingredients or the pharmaceutical preparations can be used locally, administered orally, parenterally, intraperitoneally and / or rectally, preferably parenterally will.

In general, it is to be regarded as advantageous in human medicine, the active ingredient (s) according to the invention in total amounts of about 20 to 800, preferably 100 to 500 m every 24 hours, if necessary in the form of several individual doses to achieve this of the desired results. A single gift contains the one or the other Active ingredients according to the invention, preferably in amounts of about 10 to about 300, in particular 50 to 200 mg / dose.

However, it may be necessary to deviate from the stated dosages depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and application of the drug and the period or interval within which the administration he follows. In some cases it may be sufficient with less than the above Amount of active ingredient get along, while in other cases the amount of active ingredient listed above must be exceeded. Determining the optimal dosage required in each case and type of application of the active ingredients can be carried out by any person skilled in the art on the basis of his specialist knowledge easily done.

Preparation Examples Example 1 S-methyl-3-methylsulfinylpropionthioate CH3SO-CH2-CH2-COSCH3 3 g (0.02 mol) S-methyl-3-methylthiopropionthioate are in dissolved in a mixture of 200 ml of water and 160 ml of acetone, with 3 drops of glacial acetic acid and within 5 1/2 hours dropwise with a solution of 2.83 ml 30 Figem Added hydrogen peroxide and stored overnight. Then the reaction solution evaporated in vacuo and the oily residue stored at 50C for seven days. Of the partially crystalline paste is taken up in ethyl acetate and chromatographed on silica gel. In this way, 0.75 g (22.6 * of theory) of S-methyl-3-methylsulfinylpropionthioate obtained as an oil.

C5II1002S2 (166.3) calcd: C 36.12 *, H 6.06%, S 38.57%; found: C 36.06%, H 5.99%, S 38.54 *.

Example 2 S-methyl 3-methylsulfinylpropionthioate CH3SO2CH2CH2COSCH3 the Compound is used as a faster migrating fraction in the example of chromatography 1 received.

Mp 72 to 73 ° C; Yield: 0.5 g (13% of theory).

C5H1003S2 (182.267) calcd: C 32.95%, H 5.53%, S 35.18%; found: C 32.99%, H 5.51%, S 35.18%.

Example 3 S-methyl 3-methoxypropionthioate CH30CH2-CH2COSCH3 One Solution of 20.8 g (0.2 mol) of 3-methoxypropionic acid in 60 ml of dichloromethane is mixed with a solution of 41.2 g (0.2 mol) of dicyclohexylcarbodiimide in 40 ml of dichloromethane and after cooling to -10 ° C with 12 ml (0.22 mol) methanethiol (pre-cooled with acetone / CO2) offset. After standing for 15 hours at room temperature, excess dicyclohexylcarbodiimide becomes destroyed by adding 2 ml of 50% acetic acid, the reaction solution was stirred and a short time later filtered off from the precipitated urea. The filtrate will washed with water, dried and distilled in vacuo.

9.1 g (34% of theory) of S-methyl-3-methoxypropionthioate are obtained obtained as a yellowish oil of bp 12-13 65 to 70 ° C.

C5H1002S (134,201) calcd: C 44.75%, H 7.51%, S 23.89%; found: C 44.87%, H 7.46%, S 23.73%.

Example 4 Ethyl 3-methylthiopropionate A mixture of 20 g (0.2 Mole) of ethyl acrylate in 100 cc of tetrahydrofuran (0.25 mole) and 2.35 g (21 m mole) of potassium tert-butoxide is 8 days at room temperature and then 4 hours at 500C in a laboratory autoclave kept. The reaction mixture is filtered and the filtrate is evaporated in vacuo and the remaining easily mobile oil is distilled.

Bp 12 84-86 ° C; Yield: 24.1 g (81.5% of theory).

(Lit. Kp.18 880C) General manufacturing instructions for S-alkyl-3-alkylthiopropionthioates Example 5 S-methyl-3-methylthiopropionthioate CH3SCH2CH2COSCH3 A solution of 8 g (0.2 mol) of NaOH in 160 ccm of water is cooled to -10 ° C and treated with an acetone / dry ice cooled 25 cc ampoule (0.466 mol) of methyl mercaptan and then in portions 18.1 g = 15.8 ccm (0.2 mol) of acrylic acid chloride were added. After the last encore stirs are 2 hours at room temperature and then left overnight stand.

The separated oil is separated off, the aqueous phase with ether extracted and combined oil and ether phase, dried over Na2SO4 and fractionated.

Bp 20 114-117 ° C; Yield: 24.3 g (81% of theory), pale yellowish Oil.

C5H10OS2 (150.267) calcd: C 39.97%, H 6.71%, S 42.68%; found: C 40.20%, 11 6.63%, S 42.50%.

The following are prepared in a similar manner: Example 6 S-ethyl 3-ethylthiopropionthioate C2H5SCH2CH2COSC2H5 bp 55 157-160 ° C; Yield: 67.4% of theory.

C7H14OS (178.3) calcd: C 47.15%, H 7.91%, S 35.96%; found: c 17, 30%, II 7.85 *, S 35.91%.

Example 7 S-propyl-3-propylthiopropionthioate C3H7SCH2CH2COSC3H7 b.p. 0.08 78-800C; Yield: 78% of theory.

C9H18OS2 (206.4) calcd: C 52.38%, H 8.79%, S 31.08%; found: C 52.47%, EI 8.83%, S 30.97 *.

Example 8 S-Isopropyl-3-isopropylthiopropionthioate (CH3) 2CHSCH2CH2COSCH (CH3) B.p. 0.15 82-83 ° C; Yield: 70% of theory.

C9H18OS2 (206.4) calcd: C 52.38%, H 8.79%, S 31.08%; found: C 52.36%, H 8.66%, S 30.95%.

Example 9 S-butyl 3-butylthiopropionthioate C4H9SCH2CH2COSC4H9 b.p. 0.15 95-102 C; Yield: 80% of theory.

CllH22 ° S2 (234.4) calcd: C 56.36%, H 9.46%, S 27.36%; found: C 56.40%, H 9.44%, S 27.48%.

Example 10 S-sec.Butyl 3-sec.butylthiopropionthioate CH3CH2CH (CH3) SCH2CH2COSCH (CH3) CH2CH3 Bp 0.2 101-105 ° C; Yield: 69% of theory.

C11H22OS2 (234.4) calcd: C 56.36%, H 9.46%, S 27.36%; found: C 56.30%, H 9.46%, S 27.35%.

Example 11 S-tert-Butyl 3-tert-butylthiopropionthioate (CH3) 3CSCH2CH2COSC (CH3) 3 Bp 28 160-162 ° C (lit. bp11 135-136 °); Yield: 50% of theory.

C11H220S2 (234.4) calcd: C 56.36%, H 9.46%, S 27.36%; found: C 56.48%, H 9.35%, S 27.14%.

Example 12 S-Isobutyl-3-isobutylthiopropionthioate CH3CH2CH (CH3) SCH2CH2COSCH2CH (CH3) CH3 Bp 012 107-110 ° C; Yield: 64% of theory.

C11H22O52 (234.4) calcd: C 56.36%, H 9.46%, S 27.36%; found: C 56.30 *, H 9.41%, S 27.40%.

4th

Oxidation of the above S-alkyl-3-alkylthiopropionthioate method A: in glacial acetic acid with 1 mol of hydrogen peroxide.

Example 13 S-Butyl 3-butylsulfinylpropionthioate C4H9SOCH2CH2CO-SC4H9 9.37 g (40 mol) of S-butyl-3-butylthiopropionthioate are dissolved in 9 cc of glacial acetic acid and with stirring and cooling in an ice bath, dropwise with 4 cc (40 mol) of 30% hydrogen peroxide offset. After warming to room temperature, the mixture is allowed to react for 2 hours and diluted then with water and then extracted the product with methylene chloride. To Evaporation of the solvent in vacuo on silica gel chromatographed. By washing with ether, small amounts of S-butyl-3-butylthiopropionthioate and S-butyl-3-butylsulfonypropionthioate was separated off. Subsequent elution with methylene chloride and evaporation of the solvent in vacuo gives 5.75 g (57.5% of theory) of oily S-butyl 3-butylsulfinylpropionthioate.

C11H22O2S2 (250.4) calculated: C 52.76%, II 8.85%, S 25.61%; found: C 52.99%, H 8.48%, S 24.32%.

The following are produced in a similar manner: Example 14 S-sec. -Buty 1- 3 - sec. -butylsu Lfinylpropionthioat CH3CH2CH (CH3) SCH2CH2COSCH (CH3) CH2CH3 Yield: 89 5 of theory; bl.

C11H22O2S2 (250.4) calcd: C 52.76 i, EI 8.85%, S 25.61%; found: C 52.84, EI 9.89 t, S 25.63%.

Example 15 S-Isopropyl 3-isopropylsulfinylpropionthioate (CH3) 2CHSOCH2CH2COSCH (CH3) 2 Yield: 62.5% of theory; oil.

C9H18O2S2 (222.4) calcd: C 48.61%, H 8.16%, S 28.84%; found: C 48.84%, H 8.00%, S 28.84%.

Example 16 S-PropyL-3-propylsuieinylpropionthioate C3H7SOCH2CH2COSC3H7 Yield: 56.3% of theory; oil.

C9H18O2S2 (222.4) calcd: C 48.61%, H 8.16%, S 28.84 *; found: C 48.58%, H 8.26%, S 28.75 *.

Example 17 S-Ethyl 3-ethylsulfinylpropionthioate C2H5SOCH2CH2COSC2H5 Mp 35.5-36 ° C; Yield: 55.4% of theory.

C7H14 ° 2S2 (194.3) calcd: C 43.27%, H 7.26%, S 33.00%; found: C 43.15%, H 7.30%, S 32.97%.

Example 18 S-tert -Butyl 3-tert-butylsulfinylpropionthioate (CH3) 3CSOCH2CH2COSC (CH3) 3 Mp 72.5-73.5 ° C; Yield: 61.9% of theory.

C11H2202S2 (250.4) calcd: C 52.76%, H 8.85%, S 25.61%; found: C 52.85%, H 8.70%, S 25.51%.

Method B: in glacial acetic acid with 2 mol of hydrogen peroxide, reaction time 3 to 4 days.

Example 19 S-ethyl 3-ethylsulfinylpropionthioate and S-ethyl-3-ethylsulfonylpropionthioate C2 1 '5S0 2CH2CH2COSC2H5 7.13 g (40 m mol) of S-ethyl-3-ethylthiopropionthioate dissolved in 5 cc of glacial acetic acid and added dropwise with stirring and cooling in an ice bath 8 ccm (80 m mol) of 30% hydrogen peroxide were added. The reaction solution is left react for three days at room temperature, dilute with water, extract the reaction mixture with methylene chloride and chromatographed after evaporation of the solvent remaining oil on silica gel.

Elution with ether gives 1.5 g (17.8% of theory) of S-ethyl 3-ethyosulfonyl propionthioate from m.p. 35-36 ° C.

C5H1003S2 (182.3) calcd: C 39.98%, H 6.71%, S 30.49%; found: C 40.17%, H 6.71%, S 30.40%.

Subsequent elution with acetone gives 2.8 g (36.1% of theory) S-ethyl 3-ethylsulfinylpropionthioate of melting point 35.5-360C was obtained.

The following are prepared in a similar manner: Example 20 S-sec-butyl-3-sec-butylsulfonylpropionthioate CH3CH2CH (CH3) SO2CH2CH2COCH (CH3) CH2CH3 from S-sec-butyl-3-sec-butylthiopropionthioate.

Yield: 31.1% of theory; oil.

C11H22O3S2 (266.4) calculated: C 49.59%, H 8.32%, S 24.07%; found: C 50.35%, H 8.29%, S 23.71%.

In addition: S-sec-butyl-3-sec-butylsulfinylpropionthioate Yield: 30% of theory.

Example 21 S-Isobutyl 3-isobutylsulfonylpropionthioate (CH3) 2CHCH2 SO2CH2CH2COSCH2CH (CH3) 2 from S-isobutyl-3-isobutylthiopropionthioate.

M.p. 43-440C; Yield: 20% of theory.

C11H2203S2 (266.4) calcd: C 49.59%, H 9.32%, S 24.07%; found: C 49.70%, H 8.29%, S 24.01%.

In addition: S-isobutyl-3-isobutylsulfinylpropionthioate Yield: 30% the theory; waxy substance.

C11H2202S2 (250.4) calcd: C 52.76%, H 8.85%, S 25.61%; found: C 52.94%, H 8.91%, S 25.68%.

Example 22 S-tert -butyl-3-tert-butylsulfonylpropionthioate (CH3) 3CSo2CH2CH2CoSC (CH3) 3 from tert-butyl 3-tert-butylthiopropionthioate.

Mp 98-99 ° C; Yield: 22.6% of theory.

C11H2203S2 (266.4) calcd: C 49.59%, H 8.32%, S 24.07 S; found: C 49.47%, H 8.18%, S 24.24%.

In addition: S-tert-butyl-3-tert-butylsulfonylpropionthioate, melting point 73-74 0C; Yield: 34% of theory.

If the dropwise addition of the hydrogen peroxide is not cooled, the result is in an exothermic reaction only 3-tert-butylsulfonypropionic acid.

(CH3) 3CSO2CH2COOH m.p. 103 ° C; Yield: 14.2% of theory.

C7H14O3S (194.3) calcd: C 43.28%, H 7.26%, S 16.51%; found: C 43.57%, H 7.33%, S 16.61%.

Method C: in glacial acetic acid with 2 mol of hydrogen peroxide; reaction time 10-14 days.

Example 23 S-sec-butyl-3-tert-butylsulfonylpropionthioate and S-sec-butylsulfonylpropionic acid CH3CH2CH (CH3) SO2CH2CH2COOH 9.37 g (40 mol) of S-sec-butyl 3-sec-butylthiopropionthioate are dissolved in 17 cc of glacial acetic acid and stirred and cooled in the 8 cc (80 m mol) of 30% hydrogen peroxide are added dropwise to the ice bath. Man allowed to react for 14 days at room temperature, diluted with water and extracted the reaction mixture with methylene chloride and the oily residue from evaporation of the extract is chromatographed on silica gel.

Elution with diisopropyl ether gives 2.35 g (22.2% of theory) S-sec-butyl-3-sec-butylsulfonylpropionthioate was obtained.

Subsequent washing of the column with acetone yields 2 g (25.8% of Theory) 3-sec-butylsulfonylpropionic acid of m.p. 66-670C.

C7H1404 (194.3) calcd: C 43.28%, H 7.26%, S 16.61%; found: C 43.22%, H 7.15%, S 16.66%.

In a similar manner are prepared: Example 24 S-Butyl-3-butylsulfonylpropionthioate from S-butyl-3-butylthiopropionthioate.

M.p. 46-470C; Yield: 10.4% of theory.

C11H22O3S2 (266.4) calculated: C 49.59%, H 8.32%, S 24.07%; found: C 49.82%, J 8.38%, S 23.87%.

In addition: 3-butylsulfonylpropionic acid C4H9SO2CH2CH2COOH melting point 111-111.50C; Yield: 24.5% of theory.

C7H1404S (194.3) calcd: C 43.28%, H 7.26%, S 16.61%; found: C 43.34%, H 7.31%, S 16.48%.

Example 25 S-isobutyl-3-isobutylsulfonylpropionthioate from S-isobutyl-3-isobutylthiopropionthioate.

M.p. 42-430C; Yield: 6.1% of theory.

In addition: 3-isobutylsulfonylpropionic acid.

M.p. 106-1070C; Yield: 11.6% of theory.

C7H14 ° 4S (194.3) calcd: C 43.28%, H 7.26%, S 16.51%; found: C 43.43%, El 7.25%, S 16.48%.

Method D: in aqueous acetone with 2 moles of hydrogen peroxide.

Example 26 S-Isobutyl-3-isobutylsulfonylpropionthioate (CH3) 2CHSO2CH2CH2COSCH (CH3) 2 and S-isopropyl-3-isopropylsulfynylpropionthioate 4.12 g (20 mol) of S-isopropyl-3-isopropylthiopropionthioate are dissolved in a mixture of 20 ccm water and 60 ccm acetone and after cooling on OOC with a few drops of glacial acetic acid and dropwise while stirring with 4 ccm (40 m mol) added 30% hydrogen peroxide. The reaction mixture is 8 days at room temperature stored, to destroy excess hydrogen peroxide with a split point Treated platinum black, filtered, evaporated in vacuo and chromatographed on silica gel.

Elution with ether gives 1.9 g (39.9% of theory) of S-isopropyl-3-isopropylsulfonylpropionthioate obtained at m.p. 45-470C.

c911180352 (238.4) calcd: C 45.34%, H 7.62%, S 26.90%; found: C 45.53%, H 7.56%, S 26.80%.

Subsequent elution with acetone gives 1.2 g (27% of theory) of oily S-isopropyl 3-isopropylsulfinylpropionthioate.

The following are prepared in a similar manner: Example 27 S-propyl-3-propylsulfonylpropionthioate C3H7S02CH2CH2COSC3H7 from S-propyl-3-propylthiopropionthioate.

M.p. 55-560C; Yield: 18.5% of theory.

C8H1803S2 (238.4) calcd: C 45.34%, H 7.62%, S 26.90%; found: C 45.63%, H 7.59%, S 26.91%.

Claims (1)

Claims 1) Medicines contain at least one sulfur-containing carboxylic acid or an ester of the general formula (I) in which X stands for a hydrogen atom, an alkyl group, an alkoxy group, an alkylthio group, an alkylsulfinyl or alkylsulfonyl group or for a hydroxyl or a mercapto group, for the grouping where R stands for a hydrogen atom or an alkyl group, and Z stands for a hydroxyl group, an alkoxy or alkylthio group, at least one of the substituents of X or Z each being a sulfur-containing radical 2) Anti-inflammatory drug according to claim 1. 3) Process for the production of pharmaceuticals, characterized in that that sulfur-containing carboxylic acids or their esters according to formula (I) are claimed 1 if necessary with the addition of inert, pharmaceutically harmless auxiliaries and carriers converted into a suitable application form. 4) Medicines containing at least one sulfur-containing carboxylic acid or its ester of the general formula (1) in which X stands for hydrogen, alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl or a mercapto group, said alkyl and alkoxy groups each containing 1 to 4 carbon atoms, Y for the grouping where R is hydrogen or alkyl having 1 to 4 carbon atoms and Z is hydroxy, alkoxy or alkylthio each having 1 to 4 carbon atoms in the alkyl and alkoxy group, at least one of the substituents of X or Z each being a sulfur-containing radical . 5) Use of sulfur-containing carboxylic acids and their esters general formula (r) according to claim 1 in combating diseases. 6) Use of sulfur-containing carboxylic acids and their esters general formula (1) according to claim 1 in the treatment of inflammatory processes. 7) method for the treatment of inflammatory processes, characterized in that then sulfur-containing carboxylic acids or their esters of the formula (t) according to claim Applied to humans and animals if necessary.