JPS6117830B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to the compound methyl 6-n-propoxybenzothiazole-2-carbamate, processes for the preparation of this compound, anthelmintic formulations containing this compound and the use of this compound as an active anthelmintic agent in medical and veterinary applications. Benzothiazole carbamate esters of the above type have been described as herbicides or fungicides in the prior literature, for example Swiss Patent No. 505,543, but their pharmaceutical activity (for example as anthelmintic) has has not been disclosed. West German Patent Application No. 2433982 describes ethyl-6-n-propoxybenzothiazole-2
- Anthelmintic agents consisting of carbamates are disclosed. However, this ethyl derivative is significantly inferior in anthelmintic effect compared to the methyl derivative of the present invention. This fact is demonstrated by the following test. Activity against horse roundworm (Parascaris equorum): Comparative test method for pharmacological effects of methyl-6-n-propoxybenzothiazole-2-carbamate; and: ethyl-6-n-propoxybenzothiazole-2-carbamate; High horse roundworm Egg count (EPG, number of eggs/feces 1
Based on g), a suitable naturally parasitized pony was selected. After preparing the test environment, the ponies were administered the test compound along with the appropriate vehicle. The feces excreted after the treatment were examined daily for roundworms that had been exterminated by the drug treatment. This procedure was continued for 7 days, and when the roundworms were eradicated and the EPG decreased, the pony was dissected and the intestinal contents were examined for parasites. If the roundworm egg count remained largely unchanged and few or no roundworms were killed, the pony was allowed to rest for 7 days and the test cycle was restarted with the same compound. Each pony was used as its control in this study. To test the compounds, two animals were infested with horse roundworms, as determined by roundworm eggs.
After the animal was allowed to rest, the drug was suspended in vegetable oil and the suspension was placed into the animal's stomach via a nasal and throat tube. The drug dose rate was 100mg/Kg (body weight) for both animals.
It was hot. In the first animal (Pony A), no roundworms were recovered from the feces and the number of roundworm eggs remained unchanged on day 7 of treatment. This test was repeated as described above. Animals were dissected 7 days after the second treatment. Results The compounds were subjected to the test cycles described above. In this case, the pony was dissected at the end of the first cycle since the horse roundworms had been eradicated.
The test results for the compounds are shown in the table below.

TABLE This test cycle was conducted on Pony B for the same doses of compounds. After a rest period, this cycle was repeated. The results of two types of tests with these compounds are shown in the table.

[Table] Obtained.
As is clear from the above table and the results shown in the table, ethyl-6-n-propoxybenzothiazole-2-carbamate was
mg/Kg is virtually ineffective against horse roundworms.
In contrast, methyl-6-n-propoxybenzothiazole-2-carbamate is highly effective against horse roundworms. formula: Methyl 6-n-propoxybenzothiazole-2-carbamate represented by has not been disclosed so far and is therefore a new compound. The compound can be prepared using known methods, such as the aforementioned Swiss patent.
It can be produced by the method described in No. 505543. Preferred methods are described in 1 to 5 below. 1 (wherein Z ₁ is a reactive group such as a halogen, or a carbon-containing residue that can be easily removed) Preferably, the above process is carried out in a basic solvent such as pyridine at 0°C to room temperature. The reactants are mixed in equimolar proportions, with the compound of formula being added slowly over an extended period of time. After mixing is complete, the reaction mixture is stirred for an extended period of time (preferably overnight) and the desired product is then isolated by methods well known in the art. Purification is preferably carried out by recrystallization from a suitable alcohol. Although pyridine is the preferred solvent for this reaction, other solvents such as acetonitrile and triethylamine and mixtures of acetonitrile and pyridine can be used. 2 This reaction is preferably carried out by stirring and heating the reactants in a suitable solvent such as ethanol at reflux temperature under an inert atmosphere (preferably under nitrogen). 3 This method is also performed using standard methods.
One preferred method consists of heating the thiourea compound in a suitable solvent such as chloroform at reflux temperature in the presence of bromine. Instead of heating, the reaction mixture can also be irradiated. Isolation of the product is also carried out by standard methods. The mixture was brought to room temperature, washed with aqueous Na ₂ CO ₃ and then aqueous NaCl, and dried over sodium sulfate. Evaporation of the solvent yielded the desired product. Intramolecular cyclization can also be achieved by adding an aqueous solution of potassium ferricyanide to a stirred, moderately heated mixture of the thiourea compound, NaOH and water. After the addition of potassium ferricyanide is complete, add potassium carbonate and continue stirring. The reaction mixture is then extracted with a suitable solvent (preferably chloroform). The extract is dried over sodium sulfate and the solvent is evaporated to yield the desired product. 4 The etherification is preferably carried out by heating a mixture of methyl 6-n-propoxybenzothiazole-2-carbamate, anhydrous potassium carbonate, n-propyl bromide and a suitable solvent (eg acetone) at reflux temperature. The solvent is then distilled off and the residue is filtered in water.
The pure product is obtained by recrystallization from ethanol. 5 Another method is the formula: of the corresponding benzothiazole-2-isocyanate or a reactive derivative thereof with methanol. This reaction is preferably carried out by stirring the mixture of anhydrous reactants in an excess of a solvent such as methanol or benzene at room temperature. Preferred reactive derivatives of the compounds of formula X above are those in which the group -N=C=O is

[Formula] is substituted with [Formula]. The starting compounds for methods 1 to 5 above can be obtained by methods well known in the art. Expression 2
-Amino-benzothiazoles can be obtained by cyclizing the appropriate thiourea by heating with liquid bromine in boiling chloroform or chlorobenzene. The thiourea is prepared by condensing the appropriate aniline with an alkali metal isothiocyanate. The starting compound of the formula can be obtained by the following reaction scheme. Starting compounds with formulas are well known in the art. The following examples illustrate the methods described above. Example 1 A round 1 flask equipped with a reflux condenser, magnetic stirrer and heating mantle contains 45.75
g of 2-mercapto-4-propoxyaniline,
45.25 g of methyl N-[di(methylthio)-methylene]carbamate and 250 ml of absolute ethanol were charged. This mixture was heated under an inert atmosphere of nitrogen for 12
Heat to boil for an hour. It was then cooled and the white crystalline solid formed was isolated by filtration, washed with cold ethanol and dried. mp178~180℃. Example 2 26.8 g of 1-carbamethoxy-3-(p-n-
A solution of propoxyphenyl)thiourea in chloroform (containing 16 g of bromine) was heated under reflux for 5 hours. It was then brought to room temperature and washed with 100 ml of a 10% aqueous solution of Na ₂ SO ₃ , 200 ml of a 10% aqueous solution of NaCO ₃ and a saturated aqueous solution of NaCl. Drying over anhydrous sodium sulfate followed by evaporation of the solvent gave 25 g of a white solid. mp178~180℃. Example 3 26.8 g of 1-carbamethoxy-3-(p-n-
propoxyphenyl) thiourea and 16 g of bromine.
It was dissolved in 700 ml of chloroform and irradiated with a 450 W medium pressure mercury lamp in a quartz container until the bromine color disappeared. The reaction mixture was then treated in the manner described in Example 2 to obtain the target compound. mp 178-180℃. Example 4 NaOH at 64°C (by water bath) in a triangular kolben
(2.4 g) in water (35 ml), stirred and suspended 2.1 g of 1-carbamethoxy-3-(p-n-propoxyphenyl)thiourea, and added potassium ferricyanide (8.8 g) in water (20 ml). Ta. Stirring was continued for an additional 2 hours. Then add 6g of potassium carbonate,
Stirring was continued for a further 2 hours. It was then extracted twice with 50 ml of chloroform. The chloroform extract was dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the product. mp178~180℃. Example 5 9.45 g of methyl chloroformate was added dropwise to a solution of 2-amino-6-n-propoxybenzothiazole HCl (24.45 g) in dry pyridine (100 ml) while stirring and cooling (0° C.). Then, it was left to stand at room temperature for 8 hours. Pour into 300g ice-water. The solid product was separated and dried. crystallized from ethanol
20 g of product was obtained. mp178~180℃. Example 6 2.24 g of 6-hydroxybenzothiazole-2
- Methyl carbamate, 1.3 g of 1-bromopropane, 2 g of anhydrous potassium carbonate and 50 ml of anhydrous acetone. A mixture was heated under reflux for 72 hours. The acetone was then distilled off and the solid residue was mixed with 100 ml of water and filtered. The desired product was obtained by crystallization from ethanol. mp178~180℃. Example 7 A mixture of 11.5 g of anhydrous 6-n-propoxybenzothiazole-2-isocyanate, 3.5 g of methanol and 50 ml of benzene is stirred at room temperature for 4-5 hours, then poured into ice-water and stirred for 30 minutes. did. The white solid product was perisolated and recrystallized from ethanol. mp178~180℃. Methyl 6-n-propoxybenzothiazole-2-carbamate has a high degree of anthelmintic activity against parasites and low toxicity to the host. This compound can be administered to host animals in a preventive and/or therapeutic setting to eliminate nematodes. It is useful for exterminating the gastrointestinal tract of parasites and for dealing with invaded humans and other animals. This compound is particularly unique because it is effective against the three most common nematodes known to invade mammals, and is therefore of great value. That is, this compound exhibits an effective anthelmintic effect against types of insects such as Arachillidae (e.g., arthropods), Decoaridinae (e.g., hookworms), and Trichuriae (e.g., whipworms). The anthelmintic activity of this compound is described by H.B.Whitlock and H.Mcl.Gordon in J.Council Scientific Industrial Research (Australia) p. 12, 50 (1939) and by H.B.
J.Council Scientific Research by B.Whitlock
(Australia) 21, p. 177 (1948), a modification of the McMaster egg counting method. In these methods (and similar methods) anthelmintic efficacy is assessed by measuring the number of eggs in the stool after treatment with the compound. These tests have shown that the compounds of the present invention exhibit significant toxicity when administered to a host (e.g., a horse) at a dosage of 30 to 100 mg/Kg/day over one to several days by methods well known in the art. It has been confirmed that it has an anthelmintic effect. The compounds of the present invention can be administered in the form of suspensions, capsules, feed additives, tablets, etc., which are well known to those skilled in the medical and veterinary arts. Additionally, this compound can be used as an injectable anthelmintic preparation. For this purpose, the active ingredient is mixed with a suitable sterile carrier such as sterile water, isotonic saline, and the like. The compounds of the invention have low toxicity and therefore exhibit favorable therapeutic indices. In mice and dogs, 200 mg/Kg was a non-lethal dose. Suitable pharmaceutical formulations containing the benzothiazoles of the present invention can be administered orally in the form of tablets, capsules, elixirs, and the like. For example, they can be mixed with inert carriers such as gums, starches, sugars, incorporated into gelatin capsules, or formulated into elixirs. Elixirs have the advantage that their scent can be easily modified by the addition of standard natural or synthetic flavoring agents. Particularly useful veterinary deworming formulations embodying the compounds of this invention for the treatment of parasitic diseases may be either ready-to-use liquid suspensions or wettable or water-dispersible powders that are mixed with water prior to use. Liquid suspension formulations can contain 50-55% W/V of active compound along with dispersants and stabilizers. A typical process is as follows. Active compound: 50 to 55 parts by weight Dispersion: 1/2 to 2 parts by weight Stabilizer: 1 to 3 parts by weight Preservative: Required amount Water: To make the total 100 parts by volume Sufficient Amounts Suitable dispersants are those with sulfonate groups, such as sodium lignosulfonate or sulfonated phenols or naphthol formaldehyde polymers. Bentonite can be used as a stabilizer, but protective colloids such as carboxymethyl cellulose, sodium alginate, etc. can also be used. The above formulations can be prepared by mixing very vigorously the active compound with water containing the dispersant dissolved therein in a suitable mechanical mixing device. Wettable or water-dispersible powder formulations can contain about 90-95% W/W of active compound along with wetting and dispersing agents. Approximately 98W/W
If a lower concentration than % is required, a diluent such as kaoquin can be added. Defoamers and optionally stabilizers may also be present. A typical recipe is as follows. Active compound: 90-95% by weight Wetting agent: 1/2-4 Stabilizer: 0-2 Antifoaming agent: 0.01-1 Water: 0-5 A suitable wetting agent is , nonionic alkylphenol-ethylene oxide adducts, such as condensates of 1 mole of octylphenol or nonylphenol with 10 moles of ethylene oxide, or synthetic arylalkyl sulfonates, examples of which are sodium dodecylbenzenesulfonate or sodium dibutylnaphthalenesulfonate. ) is an anionic substance such as Is the antifoaming agent used silicone?
The stabilizer may be any substance such as ethylhexanol, octanol, etc., and the stabilizer may be selected from water-soluble gums such as bentonite. Wettable or water-dispersible powder formulations are prepared by carefully and thoroughly mixing the active compound and other ingredients, with or without the addition of some water, using typical powder mixing equipment such as a ribbon blender. Ru. This powder is stirred into water by the user before actual use. The following examples illustrate particularly useful formulations. A tablet formulation g/1000 tablets 6-n-propoxybenzothiazole-2-methylcarbamate 200.0 Lactose 90.0 Hydrous dicalcium phosphate 122.5 Polyvinylpyrrolidone 25.0 Polyethylene glycol 1500 7.5 Cornstarch 50.0 Magnesium stearate 5.0 500.0 Carbamate, lactose , mixed with dicalcium phosphate (powder). Approximately 20ml of polyethylene glycol 1500 and polyvinylpyrrolidone
dissolved in water (aqueous solution). If necessary, more water was added and the powder was granulated using an aqueous solution to produce a wet mass. The mixture was passed through a 12-mesh screen, spread on a tray, and air-dried at 35°C. The resulting dry granules were mixed with starch and magnesium stearate. It was compressed into 500 mg tablets. B Capsule Formulation g/1000 Capsules Methyl 6-n-propoxybenzothiazole-2-carbamate 200.0 Lactose 198.0 Magnesium Stearate 2.0 400.0 Ingredients were mixed and filled into hard gelatin capsules. Methyl 6-n-propoxybenzothiazole-2-carbamate 40.0g Sodium citrate 10.0g Sugar 500.0g Glycerin 200.0g Complex orange peel essence 10.0ml Alcohol 100.0ml Amarant 0.1ml Water remaining 1000.0ml Per 1000ml of C elixir formulation

Claims (1)

[Scope of Claims] 1. In a pharmaceutically active composition useful for curing parasitic diseases in mammals, the compound methyl 6-n-propoxybenzothiazole-2-carbamate as an active ingredient compositions containing in combination with suitable carriers that are acceptable to 2. The composition of claim 1, wherein the pharmaceutically acceptable carrier is sterile. 3. The composition of claim 1, wherein the sterile carrier is a carrier suitable for injection. 4. The composition according to claims 1 to 3, characterized in that, in addition to the active ingredient and the pharmaceutically acceptable carrier, flavoring agents and/or coloring agents are added. 5. The composition of claims 1 to 4 in a suitable dosage form. 6. Suitable dosage forms are tablets or capsules;
The composition of claim 5. 7. The composition of claim 5, wherein the suitable dosage form is a suppository. 8. The composition of claim 1 in the form of an elixir. 9 6-n-propoxybenzothiazole-2-
Methyl carbamate. 10 Formula: 6-n-, characterized in that the compound is reacted with a compound of the formula: Z ₁ COOCH ₃ (wherein Z ₁ represents an easily substitutable group).
A method for producing methyl propoxybenzothiazole-2-carbamate. 11. The manufacturing method according to claim 10, characterized in that Z ₁ is halogen. 12 Formula: The formula for the compound is: (wherein Z ₂ and Z ₃ represent unstable groups that can be eliminated together with one hydrogen atom under the applicable reaction conditions). Method for producing methyl 2-carbamate. 13 Z ₂ and Z ₃ are groups -SCH ₃ , -OCH ₃ and -N
Process according to claim 12, characterized in that it represents one of (CH ₃ ) ₂ . 14 Formula: characterized by subjecting the compound to intramolecular condensation,
Method for producing methyl 6-n-propoxybenzothiazole-2-carbamate. 15 Formula: 6-n-propoxybenzothiazole-2-, characterized in that the compound is subjected to n-propylation.
Method for producing methyl carbamate. 16 Formula: A method for producing methyl 6-n-propoxybenzothiazole-2-carbamate, which comprises reacting a compound or a reactive derivative thereof with methanol.