JPS6152154B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel nitroimidazolyl-vinylthiadiazole, a process for its preparation, and a chemotherapeutic agent for treating microbial infections in humans and animals, which contains this compound as an active ingredient. It is known that nitro group-containing heterocyclic compounds, such as nitrofurans, nitrothiazoles or nitroimidazoles, are effective medicaments against bacteria, fungi and protozoa. The minimum inhibitory concentration of known drugs such as metronidazole or tinidazole is of the order of 0.1-2 μg/ml. However, its efficacy and tolerability are not necessarily satisfactory. Therefore, there is a need for the synthesis of new substances with higher efficacy. The inventors have determined that the general formula (In the formula, R ¹ means an alkyl group having 1 to 4 carbon atoms, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, an alkyl group having 1 to 24 carbon atoms, a substituted It has now been found that nitroimidazolyl-vinylthiadiazoles, represented by phenyl or pyridyl, which may be present, have valuable pharmacological properties. Examples of radicals R ¹ include methyl, ethyl, isopropyl or n-butyl. Examples of radicals R ³ as alkyl radicals having 1 to 24 carbon atoms are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, amyl, n-hexyl, n-heptyl, n-octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, octadecyl, cosyl, docosyl and tetradocsyl. If R ³ is a phenyl group, it may be substituted by one or several, preferably one or two, groups which are inert under the production conditions. Inert substituents include, in particular, the following: Halogen atoms such as fluorine, chlorine, bromine, iodine, nitro groups, alkyl groups having 1 to 4 carbon atoms, 1
Optionally substituted with one or several halogen atoms, such as trifluoromethyl, 1 to 4
an acylated or dialkylated amino group in which 1 to 4 carbon atoms are present in the alkyl or acyl group, respectively. Examples of substituted phenyl groups are 2-fluoro-, 4-
Fluoro-, 3-chloro-, 2-bromo-, 3-
Bromo-, 4-iodo-, 2,4-dichloro-,
3,5-dichloro-, 2-methyl, 3-ethyl-, 4-isopropyl-, 2,4-dimethyl-,
3,5-dimethyl-, 4-nitro-, 3,5-dimethoxy-, 4-dimethylamino-, 4-trifluoromethyl- and 4-acetylamino-phenyl. Among the above groups, the following are particularly preferred. R ¹ is a methyl group or ethyl group, R ² is a hydrogen atom or a methyl group, R ³ is 1 to
Alkyl groups with 13 carbon atoms, especially alkyl groups with 1 to 6 carbon atoms and phenyl groups, and pyridine groups in the 2-, 3- or 4-position
Can be combined in position. Particularly preferred substituted phenyl groups are 2-chloro-, 3-chloro-, 4-chloro-, 2-chloro-,
-methyl-, 3-methyl-, 4-methyl-, 4-
dimethylamino- and 4-nitro-phenyl. Particularly preferred are compounds in which R ¹ is a methyl group, R ² is a hydrogen atom or a methyl group, and R ³ is a hydrogen atom, a methyl group, an ethyl group, a phenyl group, or a pyridyl group. The compounds of the present invention have the general formula ² -substituted ^1,3,4 -thiadiazole represented by the general formula 5 represented by (wherein R ¹ has the above meaning)
-nitroimidazole-2-aldehyde at elevated temperature, optionally in the presence of an acidic condensation catalyst and/or a solvent. The aldehydes of the formula can be used as acetals or acyrals, with particular preference given to acetals formed by reaction with methanol or ethanol and acyrals formed by reaction with acetic acid. The reaction is shown by the following equation. 1, 3, 4- of formula used as starting material
Some of thiadiazoles are known compounds, and can be produced, for example, by the method described in Berichte der Deutschen Hemitschen Gesellschaft, Vol. 32 (1899), p. 797. In that case, N.N'-diacylhydrazine is reacted with P ₂ S ₅ in an aromatic hydrocarbon, such as xylene, at elevated temperature. The method for producing the compound of the present invention is preferably carried out as follows. 50 to 220 of a compound of formula or its acetal or acyl
C., preferably in the presence of an acidic condensation catalyst such as a Lewis acid, a mineral acid or an acidic ion exchanger, and optionally in the presence of a solvent. Preferred temperatures are 90-150°C when a solvent is used and 150-200°C in the absence of a solvent. As catalysts, acidic condensation catalysts known for aldehyde condensation are used, at a concentration of 0.005 per mole of starting material.
It is used in an amount of ~1 mol, preferably 0.05-0.2 mol. Acidic condensation catalysts are, for example, polyphosphoric acid, boron fluoride and zinc chloride, with zinc chloride being particularly preferred. The starting materials are usually used in stoichiometric proportions, but it is also possible to use an excess of one compound.
The reaction is generally carried out at normal pressure, but elevated or reduced pressure may also be advantageous in special cases. The reaction is carried out with or without solvent. As solvents, in particular lower carboxylic acids such as acetic acid or propionic acid,
Preferred are its anhydrides or mixtures of lower carboxylic acids or their anhydrides. In the carboxylic acid/carboxylic acid anhydride mixture, the ratio is preferably from 9:1 to 1:9. Generally, the reaction is completed within a few hours. Work-up is not particularly difficult and can be carried out, for example, by adding a precipitant, especially water or acetone, to the reaction mixture, precipitating the reaction product, filtering it off with suction, washing with water and alcohol and recrystallizing it from a suitable solvent. It is carried out with The compounds of the invention exhibit a good action against microorganisms and are highly effective in the treatment of infections caused by flagellates, especially trichomonads and trypanosomas, and Entamoeba histolytica in humans and animals. Additionally, the present compounds are effective in treating Leishmania infections. For example, the compounds of Examples 6 and 7 have good antibacterial activity even at concentrations of 10 ^-5 or less. The minimum inhibitory concentration (MHK) against Trichomonas vaginalis is shown in the table below.

[Table] It is completely unexpected that the efficacy of commercially available trichomonad infection treatments such as metronidazole and trinidazole is increased by more than 10 times by the introduction of a thiadiazole residue linked via an ethylene bridge. Ta. In terms of efficacy against trichomonades, the compounds of Examples 1, 5, 7 and 10 are particularly excellent. Effects on infections caused by trypanosomes and Entamoeba histolytica, published in Handbuzfufuer Experimentere Pharmacologia 16th Edition, "Experimental Generation of Disease States", Part 9, pp. 150-292 (Schuplinger Verlag, Berlin-Göttingen-Heidelberg). This can be demonstrated using mice (NMRI species) using the method described in (1964). 1 Trypanosoma brucei (infection of mice)
Various formulations were tested. Cure of the infection was confirmed by microscopy and culture. In addition, in order to check for recurrence, the treatment was discontinued and
Post-observation was performed 25 days later. The results are shown in the table below.

[Table] Rule 2 Trypanosoma gambiense (infection of mice) The experimental method is the same as for Trypanosoma brucei.

[Table] Intraperitoneal 3 Trypanosoma congolense (infection of mice) The experimental method is the same as for Trypanosoma brucei.

【table】

[Table] Intraperitoneal 4 Entamoeba histolytica (serial dilution test) PN and Q strains were tested. The minimum inhibitory concentrations were as follows. Example 1 <0.01μg/ml 〃 2 0.1 〃 〃 5 <0.01〃 〃 10 <0.01〃 〃 6 <0.01〃 〃 7 <0.01〃 Metronidazole 0.1 〃 The experiment was carried out in the same manner as above using the in vitro serial dilution test method. It was conducted. From these results, it is known that the compounds of Examples 1 and 10 are excellent, especially compared to, for example, germanin, which is a commercially available preparation, and suramin, which is a component of naganol. It was also known that the effect against amoebic dysentery was very good to good in vitro. As shown in the table, the compounds of the present invention are 10 times more effective than known metronidazole. 5. Trichomonas vaginalis (infection of mice) Various formulations were tested. The diagnosis of infection was confirmed by microscopy and culture.

[Table] The toxicity value LD50 of the compounds of Examples 1, 7, and 10 was 1500 mg/Kg when administered orally to mice (NMRJ species) and measured during a one-week observation period.
That's all. The following compounds are also preferred as effective substances. 2-phenyl-5-[2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1.
3,4-thiadiazole 2-(4-pyridyl)-5-[2-(1-methyl-
5-nitroimidazol-2-yl)-vinyl]-
1,3,4-thiadiazole 2-[2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole 2-ethyl-5-[2-(1-methyl -5-nitroimidazol-2-yl)-vinyl]-1.3.
4-thiadiazole A particularly preferred compound is 2-methyl-5-[2
-(1-methyl-5-nitroimidazole-2-
yl)-vinyl]-1,3,4-thiadiazole and 2-ethyl-5-[1-methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4 - Thiadiazole. The chemotherapeutic agents or preparations are prepared in the appropriate doses and in the conventional manner using conventional excipients or diluents and conventional pharmaceutical auxiliaries depending on the desired application. Preferred formulations are in dosage forms suitable for oral administration. Such dosage forms are, for example, tablets, film tablets, dragees, capsules, pills, powders or suspensions. The compounds of the present invention are relatively poorly soluble and are therefore suitable for oral administration. Parenteral preparations such as injection solutions can of course also be used.
Other preparations include suppositories. Additionally, for the treatment of trichomoniasis, vaginal preparations such as vaginal tablets,
Balls and powders are also used. The dose is determined depending on the nature and extent of the disease. The daily dose is up to 5g. Single dose is 50 to 1000 mg, sometimes administered several times a day.
is preferred. The single dose is 500-1000 mg for trypanosome infection, and for Entamoeba histolytica infection.
100-500 mg, and for trichomonad infections
100-300mg is preferred. Usually this single dose is used two to five times a day, and the duration of treatment is generally 14 to 20 days for trypanosome infections, 5 to 8 days for Entamoeba histolytica infections, and 5 to 8 days for trichomonad infections.
It is day. For practical use, the compounds of the invention are processed using conventional excipients in galenic formulations. For example, tablets contain the active substance in combination with known auxiliary substances such as inert diluents such as dextrose, sugar, sorbitate, mannitol, PVP, calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch. or by mixing with gelatin, lubricants such as magnesium stearate or talc and/or substances with a depot effect such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate-phthalate or polyvinyl acetate. The tablet may consist of several layers. Dragee-coated tablets are produced by coating particles produced in a manner similar to tablets with those commonly used for dragee coatings, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The dragee coating may consist of several layers, in which case the upper layer can be the auxiliary substances mentioned for the tablets. The active substance suspensions according to the invention can contain taste improvers, such as saccharin, cyclamate or sugar, and, for example, flavoring agents, such as vanillin or orange extract. In addition, they may contain suspension aids such as sodium carboxymethyl cellulose or preservative substances such as p-oxybenzoic acid esters. Active substance-containing capsules are produced, for example, by mixing the active substance with an inert excipient, such as lactose or sorbitol, and encapsulating it in gelatin capsules. Suitable suppositories are prepared, for example, by mixing the active substance with suitable excipients, such as neutral fats or polyethylene glycols or derivatives thereof. Example 1 2-Methyl-5-[2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1.
3,4-thiadiazole 2,5-dimethyl-1,3,4 in a stirred vessel
- 11.4 g of thiadiazole and 15.5 g of 1-methyl-5-nitroimidazole-2-aldehyde are mixed with zinc oxide in a mixture of 50 ml of glacial acetic acid and 20 ml of acetic anhydride.
Heat at reflux temperature for 10 hours with 0.2 g. After cooling, the precipitated solid was separated and washed with glacial acetic acid,
When recrystallized from dimethylformamide, the melting point
15.6 g (62% of theory) of colored crystals at 248° C. are obtained. Example 2 2-phenyl-5-[2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1.
3,4-thiadiazole 17.6 g of 2-methyl-5-phenyl-1,3,4-thiadiazole, 15.5 g of 1-methyl-5-nitroimidazole-2-aldehyde and zinc chloride
0.5 g is heated in 100 ml of acetic acid and 50 ml of acetic anhydride at reflux temperature for 7 hours. After adding water to the reaction mixture, the precipitated solid is recrystallized from glacial acetic acid.
17.5 g (56% of theory) of product with a melting point of 257° C. are obtained. Example 3 2-(2-chlorophenyl)-5-[2-(1-methyl-5-nitroimidazol-2-yl)-
Vinyl]-1,3,4-thiadiazole 2-methyl-5-(2-chlorophenyl)-1.
21 g of 3,4-thiadiazole and 1-methyl-5
-Nitroimidazole-2-aldehyde 15.5g
in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride,
Heat at reflux temperature for 6 hours with 0.5 g of zinc chloride. After cooling, ether was added to the reaction mixture and the precipitated solid was washed with water and recrystallized from dimethylformamide, yielding 18.5 g of product with a melting point of 239°C.
(53% of the theoretical value) is obtained. Example 4 2-(4-chlorophenyl)-5-[2-(1-methyl-5-nitroimidazol-2-yl)-
Vinyl]-1,3,4-thiadiazole 2-methyl-5-(4-chlorophenyl)-1.
21 g of 3,4-thiadiazole and 1-methyl-5
-Nitroimidazole-2-aldehyde 22.8g
in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride,
Heat to reflux temperature for 5 hours with 0.5 g of zinc chloride. After cooling, ether is added to the reaction mixture and the precipitated solid is separated, washed with water and recrystallized from dimethylformamide to give a product with a melting point of 268°C 27.5
g (77% of the theoretical value) is obtained. Example 5 2-(4-pyridyl)-5-[2-(1-methyl-
5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole 2-methyl-5-(4-pyridyl)-1,3,4
- 8.8 g of thiadiazole and 7.7 g of 1-methyl-5-nitroimidazole-2-aldehyde are heated with 0.2 g of zinc chloride at reflux temperature for 6 hours in a mixture of 50 ml of glacial acetic acid and 25 ml of acetic anhydride. After cooling, the precipitated solid is filtered off with suction, washed with concentrated aqueous ammonia and recrystallized from dimethylformamide. Melting point 240-241℃. Example 6 2-[2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole 10 g of 2-methyl-1,3,4-thiadiazole
was dissolved in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride, 0.3 g of zinc chloride was added, and then 1-methyl-5-nitroimidazole-2-aldehyde was added.
A solution of 15.5 g in 100 ml of acetic acid and 50 ml of acetic anhydride is added dropwise at reflux temperature over a period of 45 hours. The reaction mixture is concentrated after 24 hours to remove the solvent and ether is added. After washing the precipitate with water, the crude product is recrystallized from xylene, giving 9.3 g (39% of theory) of product with a melting point of 214°C. Example 7 2-ethyl-5-[2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1.
3,4-thiadiazole 12.8 g of 5-ethyl-2-ethyl-1,3,4-thiadiazole and 0.5 g of zinc chloride were added to 100 ml of glacial acetic acid.
and dissolved in 50 ml of acetic anhydride, and added 1% to this at reflux temperature.
A solution of 15.5 g of methyl-5-nitroimidazole-2-aldehyde in 50 ml of glacial acetic acid and 25 ml of acetic anhydride is added over the course of 10 hours. After the mixture is kept at reflux temperature for an additional 20 hours, the solvent is evaporated off, the residue is washed with acetone, and purified using a silicic acid gel packed column (Type A manufactured by Merck & Co.).
Elution with CHCl ₃ /CH ₃ OH (98:2) gives 5.6 g (21% of theory) of product, melting point 165°C. Example 8 2-Methyl-5-[1-methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole Evaporating the acetone solution from Example 7 After concentration, the residue is poured into a column packed with silicic acid gel (Merck Type A) and eluted with CHCl ₃ /CH ₃ OH (98:2). The yield of product with a melting point of 249° C. is 5.4 g. In addition, 3.4 g of a stereoisomeric compound with a melting point of 155° C. is obtained. Overall yield from Examples 7 and 8 is 54% of theory
It is. Example 9 2-n-tridecyl-5-[2-(1-methyl-
5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole 2-tridecyl-5-methyl-1,3,4-thiadiazole 8.45 g, 1-methyl-5-nitroimidazole-2-aldehyde 4.65g and zinc chloride
0.5 g is heated in 40 ml of acetic acid and 15 ml of acetic anhydride at reflux temperature for 24 hours. After removal of the solvent, the residue is recrystallized from alcohol to give 7.1 g (61% of theory) of product with a melting point of 91°C. Example 10 2-ethyl-5-[1-methyl-2-(1-(methyl-5-nitroimidazol-2-yl)-
Vinyl]-1,3,4-thiadiazole 17.1 g of 2,5-diethyl-1,3,4-thiadiazole was added to 60 ml of acetic acid, 25 ml of acetic anhydride and zinc chloride.
0.5 g of 1-methyl-5-nitroimidazole-2-aldehyde dissolved in 80 ml of glacial acetic acid and 35 ml of acetic anhydride.
Addition is carried out over a period of 5 hours at reflux temperature. 24 at reflux temperature
After heating for an hour, the reaction mixture was concentrated by evaporation to remove the solvent, and the precipitated product was separated by addition of water, sublimated, and recrystallized from propanol, yielding 2.9 g of product with a melting point of 125 °C (theoretical). 35%). The following formulation examples are manufactured by conventional methods. 1 tablet: (1) Active substance of formula 120mg Lactose 200mg Methylcellulose 15mg Corn starch 50mg Talc 11mg Magnesium stearate 4mg 400mg (2) Active substance of formula 120mg Lactose 178mg Avicel (cellulose powder) 80mg Polywax 6000 20mg Magnesium stearate 2 mg 400 mg 2 Vaginal tablet: (1) Active substance of formula 80 mg Lactic acid 30 mg Glucose 670 mg Lactose 200 mg Hydroxypropyl methyl cellulose 20 mg 1 g (2) Active substance of formula 80 mg Boric acid 30 mg Lactose 890 mg 1 g 3 Tablet: Example 1 or 10 Compound of 200mg polyvinylpyrrolidone (average molecular weight 25000)
20mg polyethylene glycol (average molecular weight 4000)
14 mg hydroxypropyl methylcellulose 40 mg talc 4 mg magnesium stearate 2 mg 280 mg The active substance was moistened with a 10% aqueous solution of polyvinylpyrrolidone and extruded through a sieve with a mesh width of 1 mm.
Dry at 50℃. The particles are mixed with polyethylene glycol, hydroxypropyl methylcellulose, talc and magnesium stearate and compressed into tablets of 280 mg each. 4 Compound of Dragee Example 1 or 10 150 mg Lactose 60 mg Corn starch 30 mg Polyvinylpyrrolidone 4mg Magnesium stearate 1mg 245mg A mixture of active substance, lactose and corn starch was moistened with 8% polyvinylpyrrolidone aqueous solution and passed through a 1.5 mm sieve. without particles, 50℃
Dry and pass through a 1.0 mm sieve. The particles thus obtained are mixed with magnesium stearate and compressed into dragee cores.
This is coated with a coating of sugar and talc in the usual manner. 5 Suppositories (per 1 piece) Active substance 250mg Base (e.g. Vitepsol H19) 1500mg 1750mg Suppository base (Vetepsol H19 mentioned above contains neutral fat properties) is melted and heated to 38°C.
to uniformly disperse the finely divided active substance. this
Pour into suppository molds pre-chilled at 35°C.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ means an alkyl group having 1 to 4 carbon atoms, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, an alkyl group having 1 to 24 carbon atoms, a substituted a nitroimidazolyl-vinylthiadiazole represented by a phenyl group or a pyridyl group which may be a phenyl group or a pyridyl group. 2. Nitroimidazolyl according to claim 1, wherein R ² is a methyl group, R ³ is a hydrogen atom or a methyl group, and R ³ is a hydrogen atom, a methyl group, an ethyl group, a phenyl group, or a pyridyl group. Vinylthiadiazole. 3 General formula ² -substituted ^1,3,4 -thiadiazole represented by the general formula 5 represented by (in the formula, R ¹ has the meaning below)
- general formula characterized by reaction with nitroimidazole-2-aldehyde or its acetal or acyl at elevated temperature (In the formula, R ¹ means an alkyl group having 1 to 4 carbon atoms, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, an alkyl group having 1 to 24 carbon atoms, a substituted A method for producing nitroimidazolyl-vinylthiadiazole represented by a phenyl group or a pyridyl group, which may be a phenyl group or a pyridyl group. 4. Claim 3, characterized in that R ¹ is a methyl group, R ² is a hydrogen atom or a methyl group, and R ³ is a hydrogen atom, a methyl group, an ethyl group, a phenyl group, or a pyridyl group. The method described in. 5 General formula (In the formula, R ¹ means an alkyl group having 1 to 4 carbon atoms, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, an alkyl group having 1 to 24 carbon atoms, a substituted An antiprotozoal agent containing as an active ingredient a nitroimidazolyl-vinylthiadiazole represented by a phenyl group or a pyridyl group, which may be a phenyl group or a pyridyl group. 6 In the compound of the general formula, R ¹ is a methyl group,
Claim 5, characterized in that R ² is a hydrogen atom or a methyl group, and R ³ is a hydrogen atom, a methyl group, an ethyl group, a phenyl group, or a pyridyl group. Antiprotozoal agents as described. 7 Active ingredient content is 50 to 1000 per dose
Claim 5, characterized in that mg.
Chemotherapeutic agents as described in Section.