DE2515424A1 - ISOTHIOURA DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THE PHARMACEUTICAL PRODUCTS CONTAINING THEM - Google Patents

Description

49 S41 - Dr. T

ASPRC-XICIiOLAS LIMITED

225 Bath Road, Sloug h SLl. 4AU / ring land

Isothiourea derivatives, processes for their preparation and pharmaceutical compositions containing them

The invention relates to new heterocyclic compounds, in particular new isothiourea derivatives, which are valuable intermediates for the production of a new class of represent pharmacologically active compounds, as well as processes for their preparation and processes for converting them into a new class of pharmacologically active Compounds and the pharmacologically obtained thereby active connections themselves.

In the new compounds forming an object of the invention they are 3,4-bis-halomethyl-1,2,5-thiadiazoles the general formula

/ v - CH ₀ " ¹ Cj --—— (j - Crl ^ j Λ

N Λΐ Ι

S.
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- 2 V7orin X is bromine or preferably chlorine.

You can, for example, by halogenating 3,4-dimethyl-1,2,5-thiadiazole or by halomethylating 1,2,5-thiadiazole using methods known per se will.

Based on the work: von Weinstock et al in "Advance in Heterocyclic Chemistry ", 1968, 9_, 107, was believed to be. 1,2,5-thiadiazole is resistant to electrophilic substitution, however, it has been found that this compound can be subjected to chlorine or bromine thy formation. In particular such halomethylation can be carried out by Heating 1,2,5-thiadiazole with hydrogen chloride or hydrogen bromide in an anhydrous mixture of a polar acid, preferably glacial acetic acid, and formaldehyde. Will be expedient the process is carried out under reflux conditions.

Another method of making those of the present invention Bis-halomethyl-1,2,5-thiadiazole consists of 3,4-dimethyl-1,2,5-thiadiazole in a perhalohydrocarbon, preferably carbon tetrachloride, and in the presence of a free one Free radical initiator, such as. B. benzoyl peroxide or ultraviolet light, with N-chloro- or N-bromosuccinimide too heat. The reaction is preferably carried out under reflux conditions and / or in an Inertgasunta: carried out exclusion of molecular oxygen.

The bis-halomethyl-1,2,5-thiadiazoles of the formula I can be used in Bis (methylene isothiourea) 1,2,5-thiadiazole hydrohalides

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of the general formula

R ₁ -N = C - S - CH ₀ - CC - CH ₀ - SC = KR ₁ . 2HX

NHR ₀ NN NHR ₀ II

where R .. and R ₀ , which can be the same or different from one another, are each individually hydrogen or a therapeutically acceptable substituent (as defined in more detail below) or together are a divalent therapeutically acceptable substituent and X is bromine or chlorine,

by keeping them, preferably under reflux conditions, preferably in a polar organic solvent, e.g. B. in absolute alcohol, with a thiourea of the general Formula implements

R ₁ IIN -C- NHR ₀
¹ I ² III

wherein R, and R _{0 have} the meanings given above.

The hydrohalide compounds of the general formula II can be converted into the corresponding free by processes known per se Bases are transferred.

The compounds of formula II are new and they have a pharmacological activity insofar as they are in the Phenylbenzoquinone abdominal constriction test (as described by Parkens and Pickens in "Brit. J. Pharmacol. Chemother.", 1964, 2_5, 81,

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and / or in the rat paw volume test (Modified form of the edema test induced by carrageenin, as described by Winter et al in "Proc. Soc. Exp. Biol. Med.", 1962, III, 544), which, among other things, indicate an analgesic and antiinf laminate or i see efficacy, are active. So led z. B. da.s 1,2,5-thiadiazole-3,4-bis (methylene isothiourea) dihydrochloride at an oral dose of 64 mg / kg body weight, a 47% reduction in the comparative edema, which was practically the same as that produced by acetylsalicylic acid.

It has been found that compounds which are analogous to those of the formula II in which the 1,2,5-thiadiazole ring passes through another five-membered aromatic heterocyclic Ring is replaced, are also active in at least one of the above two phenylbenzoquinone abdominal constrictions and rat paw volume tests. For example, the 2,5-dimethylthiophene-3,4-bis (methylene isothiourea) dihydrobromide led at an oral dose of 64 mg / kg body weight, a 27% reduction in comparator edema. These too analog connections are new.

The invention therefore relates to new, pharmacological ones effective bis (methylene isothiourea) compounds in which a five-membered aromatic heterocyclic Ring with 2 or more carbon atoms on each of the two Ring carbon atoms each represent a methylene isothiourea group the general formula is bound

R ₁ N = C - S - CH ₂ -

'NHR ₀

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wherein R or R ₉ , which can be the same or different from one another, individually each denote hydrogen or a therapeutically acceptable substituent (as defined below) or together a divalent therapeutically acceptable substituent, or the acid addition salts thereof, in particular dihydrochlorides or dihydrobromides.

The term used in relation to a substituent "Therapeutically acceptable" means that the presence of this substituent neither reduces the pharmacological effectiveness the molecule still destroys its activity or its toxicity; is increased so that the therapeutic ratio is reduced to a value of 5 or less. The therapeutic tolerance of a specific substituent may be from the desired substitution center in the molecule and / or the presence of other substituents in the molecule. Therefore, a particular substituent can be referred to to one molecule into which it is to be introduced, but it may be therapeutically acceptable with respect to another Molecule incompatible, d. H. have an inactivating effect. The compatibility of a substituent with respect to any Molecule of the formula I can easily be determined by subjecting the respective compound to conventional series tests, such as they are given below. However, it is within the skill of one of ordinary skill in the art Develop new drugs to determine which ones Substituents in pharmacologically active compounds of the formula I may be included.

Examples of the substituents R, and R "are alkyl, cyclo-

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alkyl, phenyl and phenylalkyl and when R., and R.sup.1 together denote a divalent substituent, this is, for example, alkylene. Each of these substituents can itself be substituted by therapeutically acceptable substituents. _{R 1} and R _{9 are} preferably, independently of one another, hydrogen, C 1 -C _x -AIlCyI, cyclohexyl or phenyl or together are C 1 -C 4 -alkylene.

Examples of heterocyclic rings are furan, thiophene, thiazole (especially 1,3-thiazole) and thiadiazole (especially 1,2,5-thiadiazole). When the ring has more than 2 ring carbon atoms has, the carbon atoms which are not bonded to a methylene isothiourea can be bonded thereto have therapeutically acceptable substituents. To suitable Ring substituents include alkyl (especially C.-C, -alkyl), Phenyl or alkoxycarbonyl (in particular C ^ -Cn -AlkOXycarbonyl).

The alkyl groups (including the radicals) in the inventive Compounds can be straight-chain (unbranched) or branched-chain, saturated or unsaturated hydrocarbon radicals having up to 12 carbon atoms, unless the context clearly indicates a limitation in relation to appears on the term "alkyl". In addition, the notice includes to a specific alkyl radical with structural isomers, all isomers and mixtures thereof, if not a specific one Isomer is indicated.

It should be noted that the group of the formula given above is tautomeric with the group of the formula

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R ₁ HN - C - S - CH ₉ - _ ..

I _n 2 IVa

and therefore references to Formula IV also include Formula IVa.

A preferred class of bis (methylene) according to the invention isothiourea) compounds are those of the general formula

T-C-C-T

wherein CC is a five-membered aromatic heterocyclic ring and T is a methylene _{isothiourea group of the formula IV given above, in which R- and R 0 are} as defined above, and the acid addition salts thereof.

The heterocyclic ring C-C preferably denotes furan, thiophene, a thiazole, in particular 1,3-thiazole, or a Thiadiazole, especially a 1,2,5-thiadiazole. The most preferred heterocyclic ring is 1,2,5-thiadiazole.

It is also particularly preferred that R ₁ and R ₀ individually each hydrogen, alkyl, in particular C -C, "alkyl, cycloalkyl, in particular cyclohexyl, phenyl or phenylalkyl, in particular benzyl _v, or together an alkylene group which the isothiourea nitrogen atoms with one another connects, especially a C ₀ -C, alkylene group.

A particularly preferred class of compounds of the above

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-R-

given formula V are those of the formula

R ₁ N = C - S - CH ₀ -CC-CH ₀ -S- C = NR, I ₁ 2 ,, "2, 1 Ha

NHR "NN NHR ₉

wherein R, and R ~, which are the same or different from one another can denote hydrogen, or C, -C, -alkyl, in particular methyl or ethyl, and the dihydrochlorides and dihydrobromides thereof.

Examples of compounds of the formula Ha prepared are the following:

1,2,5-thiadiazole-3,4-bis (methylene isothiourea), 1,2,5-thiadiazole-3,4-bis (N-methyl-methylene-isothiourea), 1,2,5-thiadiazole-3,4- bis (N, N ¹ -dicyclohexyl-methylene-isothiourea),

1,2,5-thiadiazole-3,4-bis (N, N'-dimethylmethyleneisothiourea), 1,2,5-thiadiazole-3,4-bis (N, N-diethyl-methyleneisothiourea f), 1,2, 5-thiadiazole-3,4-bis (N-phenyl-methylene-isothiourea), 1,2,5-thiadiazole-3,4-bis (N, N'diphenyl-methylene-isothiourea), 1,2,5-thiadiazole-3, 4-bis (N, N ¹ -di-n-butyl-methylene isothiourea) and
3,4-bis (2-imidazolin-2-yl-thiomethyl) -1,2,5-thiadiazole.

Another particularly preferred class of compounds of the formula V given above are those in which the heterocyclic Ring has the formula

J «

6 0 9 8 4 4/1 078

where Y is oxygen or sulfur and R _n and R.

3 4 ^y

Substance, C, -C, -alkyl, especially methyl, phenyl or C ₉ -C ₁ -alkoxycarbonyl, especially ethoxycarbonyl ₄ mean.

Examples of compounds of the formula V prepared in which the heterocyclic ring has the formula VI given above, are the following:

2,5-dimethylthiophene-3, 4-bis (niethylenisothiourea), 2-ethoxycarbonylthiophene-4,5-bis (methylene isothiourea) and 2,5-diphenylfuran-3,4-bis (methylene isothiourea).

Another preferred compound of the invention is that 2-phenyl-1,3-thiazole-4,5-bis (methylene isothiourea).

The bis (methvlenisothiourea) compound according to the invention can be prepared by adding a bishalomethyl compound in which a 5-membered aromatic heterocyclic ring with 2 or more carbon atoms has two ring carbon atoms each with a halomethyl group, in particular a chlorine or bromine thy ! group, is bound, preferably in a polar organic solvent, e.g. B. in absolute alcohol, and especially _{heated under reflux conditions 4} with a thiourea of the formula

R ₁ NH - C - NHR ₉

"III

wherein R, and R _{9 have} the meanings given above for the formula IV.

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In the above-mentioned reaction, the hydrohalide is obtained, which can be converted into the free base or another acid addition salt in a manner known per se.

The acid addition salts are preferably pharmaceutically acceptable, non-toxic addition salts with suitable acids, e.g. B. those with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, or those with organic acids such as organic carboxylic acids, e.g. B. glycolic acid, maleic acid, flydroxymaleic acid, malic acid, tartaric acid, citric acid, salicylic acid, o-acetyloxybenzoic acid, nicotinic acid or isonicotinic acid, or with organic sulfonic acids, such as. B. methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, toluene-p-sulfonic acid or naphthalene-2-sulfonic acid.

In addition to the pharmaceutically acceptable acid addition salts, the present invention also encompasses other acid addition salts, e.g. B. those with picric acid or oxalic acid, which can be used as intermediates in the purification of the compounds according to the invention or in the preparation of other, for example pharmaceutically acceptable, acid addition salts or to identify or ■ characterize the bases.

As indicated above, the bis (methylene isothiourea) compounds of the invention have a pharmacological activity at least insofar as it can be seen in preliminary series tests have proven to be active, among other things, a. disclosed analgesic and anti-inflammatory activity.

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Accordingly, the present invention also relates to pharmaceuticals Agents or pharmaceutical preparations containing at least one bis (methylene isothiourea) compound according to the invention or a pharmaceutically acceptable acid addition salt thereof, optionally in conjunction with a pharmaceutically acceptable one Carriers or diluents.

Such agents or preparations are produced in a manner known per se in the pharmaceutical field. For example the active ingredient (drug) mixed with a carrier or diluted by a carrier or in capsules, Sachets, kachets, paper or other containers can be included or encapsulated. As a carrier or diluent A solid, semi-solid or liquid material can be used as a vehicle (solvent), excipient or can serve as a medium for the active ingredient. Some examples of suitable diluents or carriers are Lactose, dextrose, sucrose, sorbitol, mannitol, starches, Akaziengutnmi, Calcium phosphate, liquid paraffin, cocoa butter ,. Theobroma oil, alginates, tragacanth, gelatine, B.P syrup, methyl cellulose, Polyoxyethylene sorbitan monolaurate, methyl and propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.

The pharmaceutical compositions of the invention (drugs) for administration in any suitable ^ ^e ise, usually orally or rectally, prepared and they may in any patient where treatment is required, such as an animal suffering from an inflammatory condition , in the form of tablets, capsules, suppositories, solutions, suspensions or the like. Administered.

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The dosage required to treat an animal is usually within the range of 0.01 to 250 mg / kg. For the treatment of adult people the lies Dosage of the active ingredient (drug) at about 0.01 to about 15 mg / kg while for the treatment of certain Experimental animals, such as mice and rabbits, a dosage of 10 to 200 mg / kg can be applied. the Preparations according to the invention can be in a unit dosage form are present, each dosage unit preferably 1 to 1000, in particular 5 to 500, especially 20 to 250 mg of the active ingredient according to the invention contains.

As used herein, "unit dosage form" is understood to mean a physically discrete unit containing a certain amount of the active ingredient (active ingredient) hM3 ± ung with or otherwise associated with the carrier, this amount being dosed such that one or more units normally are required for a single therapeutic administration _v or that in the case of multiple units, such as. B. subdivided (scored) tablets, at least a fraction, for example half or a quarter of a multiple unit, are required for a single therapeutic administration.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto. The ones specified therein Temperatures refer to degrees Celsius.

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example 1

3,4-bischloromethyl], 2,5-thiadiazole

A well stirred solution of 19.8 g of 3,4-dimethyl-1,2,5-thiadiazole (prepared by the method of Weinstock et al, "J. Org. Chem.", 1967, 32, 2823) and 24 g of N-chlorosuccinimide in 1 liter of carbon tetrachloride containing about 50 mg of benzoyl peroxide was refluxed under nitrogen for 4 days while using a 100 watt tungsten lamp has been irradiated. A further 7 g of N-chlorosuccinimide and 50 mg of benzoyl peroxide were added and the boiling stopped Reflux was continued. The reaction was monitored by PMR spectroscopy: after 4 days there were singlets at T = 7.36; 5.21, 7.24 and 5.09, according to the starting material, the monochlorinated product or the bis-chloromethyl product observed. Further additions of 7 g of N-chlorosuccinimide and 50 mg of benzoyl peroxide were made at intervals of 2 days added until the PRM spectrum indicated the concentration of the bis-chloromethyl product was maximal. The mixture was then cooled, filtered and the carbon tetrachloride was removed in vacuo to give a pale green yellow oil in 23 g yield. This was fractionated at 0.2 mm and gave 4 fractions:

1. b.p. 30 to 60 ° C; Ratio 2: 3: 5: 0, yield 1.1 g

2. bp 63 to 70 ° C; Ratio 1: 2: 9: 0, yield 13.5 g

3. Bp. 70 to 80 ⁰ C; Ratio 0: 1: 6:10, yield 5.1 g

4. Bp. 120 to 125 ° C, yield 2.0 g

The ratios given above relate to

4 products starting material, monochloromethyl-bischloromethyl- and polychloromethylene compound.

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Example 2

1,2,5-thiadiazole-3,4-bis (methylene isothiourea) dihydrochloride

13.5 g of 3,4-bischloromethyl-1,2,5-thiadiazole (fraction No. 2 of Example 1, which contained 10.1 g of the desired material) were together with 11.7 g of thiourea for 3 hours in 350 ml of absolute alcohol refluxed. After cooling, the mixture was filtered and the filtrate became washed with alcohol, then it was dried in vacuo overnight and 14.8 g (81%, based on the bischloromethyl starting material) were obtained the fraction (2)) of a pale yellow solid, F. 243 to 245 C.

Analysis for C _r H ₁₀ Cl ₀ N _r S ₀
^J 6 12 2 6 3

calc .: C 21.5 H 3.6 N 25.1 Cl 21.1 found: 21.6 3.6 25.1 21.0 PMR (D ₆ DMSO) T = 0.55 s (broad) ( 8H); 4.97 s (4H)

Example 3

Production of 3,4-bischloromethyl -], 2,5-thiadiazole

6 g of paraformaldehyde were suspended in 34 ml of glacial acetic acid and hydrogen chloride was bubbled through the solution. 5 g of 1,2,5-thiodiazole was added and the mixture was formed Boiled under reflux for 5 hours. After cooling down the excess paraformaldehyde was filtered off and the solution was concentrated in vacuo. Take part in the extraction 25 ml petroleum ether (40 to 60 C fraction) and the subsequent Filtering and concentrating the extract gave a colorless oil.

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Example 4

Preparation of 1,2,5-thiadiazole-3,4-bis (methylene isothiourea) dihydrochloride

0.7 g of the colorless oil obtained in Example 3 above was dissolved in 2C0 ml of absolute alcohol and taken for 4 hours long with 0.4 g. Thiourea refluxed. The mixture was concentrated to 100 ml, the desired Isothiouronium salt crystallized out, F. 244 C.

The compounds given below were prepared by reacting 3,4-bis (chloromethyl) -1,2,5-thiadiazole with the corresponding thiourea essentially using the procedure described in Example 2 or 4:

1, 2,5-thiadiazole-3, 4-bis (N-methyl-methylenisothiourea) -dihydrochloride, Mp 211-214 ° C.

1,2,5-Thiadiazole-3,4-bis (N, N ^! -Dicyclohexyl-methylene-isothiourea) -dihydrochloride, m.p. 225-227 ° C.

1,2,5-Thiadiazole-3,4-Ms (N, N ¹ -dimethyl-methyleneisothiourea) dihydrochloride, m.p. 145 to 148 C.

1,2,5-thiadiazole-3,4-bis (N, N'-diethyl-methyleneisothiourea) dihydrochloride, M.p. 185 to 187 ° C.

1,2,5-thiadiazole-3,4-bis (N-phenyl-methylene-isothiourea) -dihydrochloride F. 190 to 193 ° C.

1,2,5-thiadiazole-3,4-bis (N, N ¹ -diphenyl-methylene-isothiourea) dihydrochloride.

1,2,5-thiadiazole-3,4-bis (N, N'-di-n-butyl-methylene-isothiourea) dihydrochloride.

3,4-bis (imidazolin-2-yl-thiomethyl) -1,2,5-thiadiazole dihydrochloride, M.p. 256 to 258 ° C.

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Example 5

2,5 ~ dimethylthiophene-3,4-bis (methylene isothiourea) dihydrochloride

4.2 g of 3,4-bis (chloromethyl) -2,5-dimethylthiophene, prepared by the method of Diraroth, "Chetn. Ber.", 1966, 99 , 634) and 3.1 g of thiourea were added for 6 hours refluxed in 100 ml of ethanol. The mixture was allowed to cool, filtered and the resulting crystalline precipitate washed with cold ethanol and dried in vacuo to give the desired isothiouronium chloride in a yield of 5.6 g, mp 253-254 ° C. Analysis for ^C ] _O ^H i8 ^C1 2 ^N 4 ^S 3

N 15.5 Cl 19.7 S 26.6 15.33 19.5 26.5%.

ber .: C. 33 , 2 H 5 , 00 found: 33 , 3 5 , 00 example 6th

2-ethoxycarbonylthiophene-4,5-bis (methylene isothiourea) dihydrochloride

25.3 g of 2-ethoxycarbonyl-4,5-bis (chloromethyl) thiophene and 15.2 g Thiourea was refluxed in 100 ml of ethanol for 4 days. The solution was concentrated to 150 ml in vacuo and the desired isothiouronium chloride crystallized on standing, then it was recrystallized from ethanol and colorless needles were obtained in a yield of 30 g, mp 233 ° C.

Analysis for C, H, N 0 Sj2HCl

calc .: C 32.6 ^j N4,4 N 13.8 S 23.7 Cl 17.5 Found .: 32.7 4.5 13.6 23.5%

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The ethoxycarbonyl-4,5-bis (chloromethyl) thiophene used as starting material can by the method of Zwanenberg et al in "J. Org. Chem.", 1906, 31_, 3363, from 2-ethoxycarbonylthiophene getting produced.

Example 7

2-phenylthiazole-4,5-bis (methylene isothiourea) dihydrobromide

3.6 g of 2-phenyl-4,5-bis (brotninethyl) thiazole hydrobromide and 1.4 g of thiourea were refluxed in 250 ml of ethanol for 4 hours. The mixture was allowed to cool, filtered, the resulting crystalline precipitate was washed with cold ethanol and dried in vacuo, giving the desired isothiouronium bromide in a yield of 3.8 g, mp 266-28 ° C.
Analysis for CH ₁₇ Br ₂ N ₅ S

calc .: C 31.3 H 3.4 N 14.03 Br 32.00 found: 31.3 3.4 14.19 31.72%.

The 2-phenyl-4,5-bis- (bromomethyl) thiazole hydrobromide used as the starting material can be produced by introducing hydrogen bromide into 2-phenylthiazole-4,5-bismethanol, which in turn can be produced by reducing 2-phenyl-4, 5-diethoxycarbonyl-thiophene with lithium aluminum hydride in tetrahydrofuran (Huntress et al, "J. Amer. Chem. Soc. ¹ , 1943, 65, 2167).

Example 8

2,5-Diphenylfuran-3,4-bis (methylene isothiourea) dihydrochloride dihydrate

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2.2 g of 3,4-bis (chlorine ethyl) -2,5-diphenylfuran (prepared according to the method of 'Lutz et al, ¹¹ J. Amer. Chem. Soc. "1946, 68 , 2002) was together with 1, 1 g of thiourea was refluxed in 500 ml of absolute alcohol for 6 hours, the mixture was concentrated to about 100 ml and allowed to cool to form long acicular crystals of the desired hydrated isothiouronium chloride in 2.8 g yield, mp 245 ° C .
Analysis for ^c ₂ o ^H 24 ^C1 2 ^N 4 ^O 3 ^S 2

Calcd .: C 47.82 H 5.24 N 11.08 Cl 14.03 S 12.69 found: 47.52 5.18 11.08 - 12.62%

In the following examples, in which pharmaceutical agents are described, the term "active ingredient" always to understand the isothiouronium salt of Example 4. This compound can be used in these medicaments by any other bis (iriethylenisothiourea) compounds according to the invention or their pharmaceutically acceptable acid addition salts are replaced. Establishing the amount of Active ingredient can according to desire or requirement in "dependency of the effectiveness of the active ingredient in a manner known per se.

Example 9

TableLter preparation

mg / tablet

Active ingredient 15

Lactose 86

Corn starch (dried) 45.5 gelatin 2.5

Magnesia tearat 1.0

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The active ingredient was pulverized and then passed through a sieve with a mesh size of 0.152 mm (B.S. sieve No. 100) and with the lactose and 30 mg of the corn starch, both of which have been passed through a sieve with a mesh size of 0.353 mm (B.S. sieve Kr. 44) were well mixed.

The mixed powders were washed with a warm gelatin solution, which have been prepared by stirring the gelatin in water and heating to produce a 10 vol / vol% solution was mixed up. The mass was granulated by passing it through a sieve with a mesh size of 1.405 mm (B. S. sieve Mr. 12) and the moist granules dried at 40 C.

The dried granules were granulated again by passing them through a sieve with a mesh size of 1.204 mm (B.S. sieve Mr. 14) and the rest of the passed through a sieve with a mesh size of 0.353 mm (B.S. sieve No. 44) The starch passed through and the magnesium stearate passed through a sieve with a mesh size of 0.251 mm (B.S.sieve No. 60) was added and mixed thoroughly.

The granules were compressed into tablets each weighing 150 mg.

Example 10
Tablet preparation

mg / tablet active ingredient '100

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^ ait

T5T5424

Lactose corn starch (dried) gelatin Magnesium stearate

39

80
4.0 2.0

The same procedure was used as in Example 9, but this time using 60 mg in the granulation procedure Starch and 20 mg of starch were used during tableting.

Example 11 Capsule Preparation

Active ingredient lactose

mg / capsule 250 150

The active ingredient and the lactose were passed through a sieve with a mesh size of 0.353 mm (B.S.sieve No. 44) and the powders were mixed well together before filling into hard gelatin capsules of an appropriate size, so that each capsule contained 40 mg of the mixed powders.

Example 12 suppositories

Active ingredient theobroma oil

mg / suppo s i torium

50 950;

The active ingredient was powdered and passed through a sieve with a mesh size of 0.152 mm (B.S. sieve No. 100)

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and at 45 C rait melted theobroma oil triturated under Formation of a smooth suspension.

The mixture was stirred well and used to prepare suppositories in forms with the respective nominal Cast capacity 1G.

Example 13
Kachets

mg / cachet

Active ingredient '100

Lactose 400

The active ingredient was passed through a sieve with a mesh size of 0.390 mm (B.S. sieve No. 40), with the previously passed through a sieve with a mesh size of 0.353 mm (B.S. sieve Kr. 44) mixed lactose and filled in cachets of a suitable size so that each cachet contained 500 mg.

Patent claims:

509844/1 078

Claims (16)

- 22 claims '. 3,4-bis-halomethyl-1,2,5-thiadiazole, characterized by the general formula X - CH ₂ - C - C - CH ₂ - X ^ N ^(I) wherein X is bromine or chlorine. 2. Process for the preparation of a 3,4-bis-halomethyl-1,2,5-thiadiazole according to claim 1, characterized in that a 1,2,5-thiadiazole is used in an anhydrous mixture from a polar acid and formaldehyde heated with hydrogen chloride or hydrogen bromide. 3. Process for the preparation of a 3,4-bis-halomethyl-1,2,5-thiadiazole according to claim 1, characterized in that a 3,4-dimethyl-1,2,5-thiadiazole is used in a perhalohydrocarbon and heated with N-chloro- or N-bromosuccinimide in the presence of a catalyst which produces free radicals, 4. Bis (methylene isothiourea) compound, labeled by a 5-membered aromatic heterocyclic ring with 2 or more carbon atoms in which there are two ring carbon atoms are each bonded to a methylene isothiourea group of the general formula R ₁ N = C - S - CH ₂ - NHR ₀ 509844/1078 wherein R 'and R ", which are the same or different from one another can, individually in each case hydrogen or a therapeutically acceptable substituent or together a divalent one mean therapeutically acceptable substituents, and the acid addition salts thereof. 5. bis (methylene isothiourea) compound according to claim 4, characterized by the general formula J. ~ * \ -> ■ " Kj " * JL wherein C-C is a 5-membered aromatic heterocyclic Ring and T is a methylene isothiourea group of the formula mean R ₁ N = C-S-CH ₀ wherein R, and R ", which are the same or different from one another can, individually in each case hydrogen or a therapeutically acceptable substituent or together a divalent one mean therapeutically acceptable substituents, and the acid addition salts thereof. 6. A compound according to claim 5, characterized in that it is a furan ·? Thiophene, thiazole or contains thiadiazole ring. 7. A compound according to claim 5 and / or 6, characterized in that in the formula IV.R, and R ₂ are each hydrogen} 509844/1078 Alkyl, cycloalkyl, phenyl or phenylalkyl or together alkylene denote which is the isothiourea nitrogen atoms connects with each other. 8. A compound according to claim 7, characterized in that R, and R ₀ individually each denote hydrogen, C -C, alkyl, cyclohexyl or phenyl or together are C ₉ -C, alkylene. 9. Bis- (methylenisothiourea) -l, 2,5-thiadiazole, marked by the general formula RN = C - S - CH - C - C - CH ₉ - S - C = NR ₁ NHR ₀ NN NHR ₀ ^ ^; Z _{χ y} Z in which R ₁ and R 0, which can be the same or different from one another, are each hydrogen or C 1 -C 4 -alkyl, and the dihydrochloride or dihydrobromide thereof. 10. A compound according to claim 9, characterized in that it is one of the following compounds: 1,2,5-thiadiazo1-3,4-bis (methylene isothiourea), 1,2,5-thiadiazole-3,4-bis (N-methy1-methylenisothiourea), l, 2,5-thiadiazole-3,4-bisO ', I \' -dicyclohexy 1-methyleni so thiourea), 1,2,5-thiadiazole-3,4-bis (N, N'-dimethyl-methylene-isothiourea), 1,2,5-thiadiazole-3,4-bis (N, N'-diethylmethylene isothiourea), 1,2,5-Thiadiazole-3,4-bis (N-phenyl-methyleniso-thiourea)., 1,2,5-thiadiazole-3,4-bis (N, N'-diphenylmethylene isothiourea), 1,2,5-thiadiazole-3,4-bis (N, N'-di-n-butyl-methylene isothiourea) and 509844/1078 - 25 3,4-bis (2-imidazolin-2-yl-thiomethyl) -1,2,5-thiadiazole. 11. A compound according to claim 5, characterized in that it is such as a 5-membered heterocyclic ring Contains formula -R v / orin Y oxygen or sulfur and R ₀ and R, because water 3 4 ^a Substance, C, -C, alkyl, phenyl or C ^ -Cr -alkoxycarbonyl mean. 12. A compound according to claim 11, characterized in that it is one of the following compounds: 2, 5-dimethylthiophene-3,4-bis (iaethyleneisothiourea), 2-ethoxycarbon3 ^ 1-thiophene-4, 5-bis (methyleneisothiourea f and
2,5-diphenylfuran-3,4-bis (methylene isothiourea). 13. 2-Phenyl-1,3-thiazole-4,5-bis (methylene isothiourea) 14. Process for the preparation of a bis (methylene isothiourea) compound according to at least one of claims 4 to 13, characterized in that a Bishaiοgenmethy1 compound having a 5-membered aromatic heterocyclic ring containing two or more carbon atoms, where an every two ring carbon atoms each have a halomethyl group is bound, heated with a thiourea of the general formula 509844/1078 R ₁ HN - C - NHR (III) wherein R, and R_ are those given in claims 5 to 9 Have meanings. 15. Pharmaceutical agent, characterized in that it in conjunction with a pharmaceutically acceptable one Carrier at least one compound according to at least one of claims 4 to 8 and 11 to 13 and / or at least one contains pharmaceutically acceptable salt thereof. 16. Pharmaceutical agent, characterized in that it contains at least one compound according to claim 9 and / or 10 in association with a pharmaceutically acceptable carrier. 509844/1078