US3925550A - 1-(5-Nitrothi-alzol-2-yl)-imidazolidine-2-thione having anti-parasitic and anti-microbial properties - Google Patents
1-(5-Nitrothi-alzol-2-yl)-imidazolidine-2-thione having anti-parasitic and anti-microbial properties Download PDFInfo
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- US3925550A US3925550A US381083A US38108373A US3925550A US 3925550 A US3925550 A US 3925550A US 381083 A US381083 A US 381083A US 38108373 A US38108373 A US 38108373A US 3925550 A US3925550 A US 3925550A
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- imidazolidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
Definitions
- This invention is concerned with a new therapeutically useful cyclic thiourea, i.e. l-(5-nitrothiazol-2-yl)- imidazolidine-Z-thione of the formula:
- l-(S-nitrothiazol-Z-yl)-imidazolidine-2-thione is prepared by reacting a compound of the general formula:
- R represents an alkyl radical containing 1 to 6 carbon atoms or the benzyl radical, with sodium hydrogen sulphide (NaSi-l), preferably prepared in situ.
- NaSi-l sodium hydrogen sulphide
- the reaction is carried out in an organic solvent such as an alkanol containing up to 4 carbon atoms, e.g. methanol, and at a temperature between 0 and 50C.
- the sodium hydrogen sulphide may be prepared in situ when an alkanol is the organic solvent by the action of hydrogen sulphide on a sodium alkoxide conwherein X represents the acid residue of a reactive ester such as a halogen atom.
- the reaction is generally carried out in an organic solvent such as an ether (e.g., tetrahydrofuran), an alcohol (e.g., methanol) or an aromatic hydrocarbon (e.g., benzene), at a temperature between C. and the boiling point of the reaction mixture.
- an organic solvent such as an ether (e.g., tetrahydrofuran), an alcohol (e.g., methanol) or an aromatic hydrocarbon (e.g., benzene), at a temperature between C. and the boiling point of the reaction mixture.
- the product of formula I can be purified, if necessary, by physical methods such as distillation, crystallisation or chromatography.
- the new cyclic thiourea of the present invention is less toxic and more active than l-(5-nitrothiazol-2-yl)- irnidazolidin-2-one(niridazole) which is described in the specification of British Pat. No. 986,562 granted to Ciba Limited on an application filed May 22, 1963.
- the compound of formula I administered in suspension once daily for 3 days is half as toxic as niridazole.
- the compound of the present invention is more active than the closely related compound of the prior art.
- a dose of the new compound of 50 mg/kg animal body weight per day for 5 days, administered orally, a total destruction of almost all the worms is observed (the surviving worms being very damaged) whereas niridazole has an action only on the egg-laying of the female wonns.
- the compound of the present invention causes a reduction in the number of worms and a decrease of the egg-laying of the female worms, whereas niridazole only has an action of short duration on the egg-laying of the female worms.
- the compound of fonnula l is active against subcutaneous abscess in mice infected with Trichomonas vaginalis, against intestinal amoebiasis of weanling rats and against hepatic amoebiasis of hamsters infected with Entamoeba histolytica.
- the dose which eliminates 50% of the parasites of the treated animals is between 40 and mg/kg animal body weight per day, administered orally.
- mice In the same way, the dose CD against giardiasis of mice is between 5 and 10 mg/kg animal body weight per day, administered orally.
- the dose CD, against experimental oxyuriasis of mice infected with Aspiculuris tetraptera is about 60 mg/kg animal body weight per day, administered orally.
- the minimum active concentration of the compound of the invention in chicken feedstuffs against experimental coccidiosis of chickens infected with Eimeria tenella is 0.01% by weight.
- the compound of formula 1 exhibits particularly valuable anti-microbial properties. lts activity is exhibited more particularly in vitro, against Escherichia coli, Salmonella typhimurium, Salmonella gallinarum, Welchia perfringens and Clostridium sporogenes.
- EXAMPLE 1 Hydrogen sulphide is bubbled into a solution of sodium methoxide (0.01 mole) in methanol (25 cc.) until the solution is neutral with respect to thymolphthalein. Finely powdered 2-me thylthio- 1 S-nitrothiazol-Z-yl A-imidazoline (2.5 g) is then added, and the mixture stirred for 16 hours at a temperature of about 20C. The suspension is filtered. The solid is washed with methanol (25 cc.), and then dried under reduced pressure (20 mm.I-lg) to give I-(S-nitrothiazol-Z-yhimidazolidine-Z-thione (2 g.), melting at 274C.
- 2-Bromo-5-nitrothiazole (2.1 g) is added, all at once, to a solution of 2-methylthio-A -imidazoline (2.3 g.) in methanol (25 cc.) and then the mixture is heated under reflux for 1 hour. After cooling, the resulting precipitate is filtered off. 2-Methylthiol-( 5-nitrothiazol-2-yl)- A -imidazoline (1.2 g.), melting at 190C., is thus obtained.
- EXAMPLE 2 Hydrogen sulphide is bubbled into a solution of sodium methoxide (0.14 mole) in methanol (400 cc.) until the solution is neutral with respect to thymolphthalein. Finely powdered 2-benzylthio-l-( S-nitrodriazol-Z-yD-N-imidazoline (45 g.) is then added, and the mixture is stirred for 16 hours at a temperature of about 20C. The suspension is filtered and the resulting solid is washed with methanol (100 cc.) to give l-(5- nitrothiazol-Z-yl)-imidazolidine-2-thione (28 g.), melting at 274C.
- 2-Benzylthio- 1 5-nitrothiazol-2-yl )-A-irnidazoline melting at 160C which is used as starting material, can be prepared by reaching 2-benzylthio-A -imidazoline (154 g.) with 2-bromo-5-nitrothiazole (84 g.).
- the present invention also includes pharmaceutical and veterinary compositions which comprise, as active ingredient, l 5-nitrothiazol-2yl )-imidazolidine-2- thione in association with a carrier or coating generally used in the preparation of pharmaceutical and veterinary compositions.
- the compositions are preferably in a form suitable for oral administration.
- Tablets, pills, powders or granules can be used as solid compositions for oral administration.
- the compound is mixed with one or more inert diluents, such as sucrose, lactose or starch.
- inert diluents such as sucrose, lactose or starch.
- These compositions can also contain substances other than diluents, for example lubricants such as magnesium stearate or a dispersing agent.
- compositions for oral administration can be used as liquid compositions for oral administration.
- inert diluents such as water or paraffin oil
- compositions can also contain substances other than the diluents, such as, for example, wetting agents or sweetening or flavouring agents.
- the compound of the present invention can be used to combat the bilharzioses due to Schistosoma mansoni, Schistosoma haematobium and to Schistosoma japonicum, in daily doses, administered orally, of between 10 and 50 mg/kg body weight. These doses can be repeated at regular intervals of several days or several weeks to achieve complete elimination of the parasite.
- the physician or veterinary surgeon will decide the posology whichis considered most appropriate, depending on the subject to be treated, the age, the weight, the degree of infestation and all other factors peculiar to the subject.
- a method for combatting bilharzioses due to Schistosoma mansom', Schistosoma haematabium or to Schistosoma japonicum, in a patient which comprises administering to the patient 1-(S-nitrothiazol-Z-yl)-imidazolidine-Z-thione in an amount sufficient to improve the condition of the patient.
- a method for combatting infections caused by Salmonella typhimurium or Salmonella gallinarum in a patient which comprises administering to the patient 1- (S-nitrothiazol-Z-yl)-imidazoIidine-2-thione in an amount sufficient to improve the condition of the patient.
- An anti-parasitic and anti-microbial composition comprising an effective amount of l-(5-nitrothiazol-2- yl)-imidazolidine-2-thione in association with a carrier used in the formulation of pharmaceutical or veterinary compositions.
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- Chemical & Material Sciences (AREA)
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Abstract
1-(5-Nitrothiazol-2-yl)-imidazolidine-2-thione, which is a new compound having anti-parasitic and properties, is prepared by reacting a 2-alkylthio-(or 2-benzylthio)-1-(5-nitrothiazol-2-yl)Delta 2-imidazoline with sodium hydrogen sulphide.
Description
United States Patent Tchelitcheff Dec. 9, 1975 l-(S-NITROTHl-ALZOL-2-YL)- [58] Field of Search 424/270 IMIDAZOLIDINE-2-THIONE HAVING ANTl-PARASITIC AND ANTLMICROBIAL [56] References Cited PROPERTIES UNITED STATES PATENTS Inventor: Serge Rhelitcheff, hia s, France 3,297,699 1/1967 Schmidt 424/270 Assignee: e ulenc, s-A. a s, ran e 3,298,9l4 l/l967 Schmidt 424/270 [22] Filed: July 20, 1973 Primary ExaminerFrederick E. Waddell [2]] pp NO: 381,083 fiitgzziy, Agent, or Firm-Stevens, Davis. Miller &
Related U.S. Application Data [62] Division of sci, No. 236,579, March 21, 1972, Pat. [57] ABSTRACT 1810908 l-(5-Nitr0thiaz0l-2-yl)-imidazolidine-2-thi0ne, which is a new compound having anti-parasitic and pmper- [30] Foreign Application Priority Data ties, is prepared by reacting a 2-alkylthi0-(0r 2- Mat 1971 France 71-10150 benzylthio)-l-(S-nitrothiazol-Z-ylJ-N-imidazoline with sodium hydrogen sulphide. [52] U.S. Cl. 424/270 Int. Cl. A61K 27/00 4 Claims, No Drawings l-( S-NITROTHI-ALZOL- 2-YL )JMIDA ZOLIDINE-Z- THIONE HAVING ANTl-PARASITIC AND ANTI-MICROBIAL PROPERTIES This is a division of application Ser. No. 236,579, filed Mar. 21, 1972, now [1.8. Pat. No. 3,810,908.
This invention is concerned with a new therapeutically useful cyclic thiourea, i.e. l-(5-nitrothiazol-2-yl)- imidazolidine-Z-thione of the formula:
to a process for its preparation and to therapeutic compositions containing it.
According to a feature of the invention, l-(S-nitrothiazol-Z-yl)-imidazolidine-2-thione is prepared by reacting a compound of the general formula:
wherein R represents an alkyl radical containing 1 to 6 carbon atoms or the benzyl radical, with sodium hydrogen sulphide (NaSi-l), preferably prepared in situ. Generally the reaction is carried out in an organic solvent such as an alkanol containing up to 4 carbon atoms, e.g. methanol, and at a temperature between 0 and 50C. The sodium hydrogen sulphide may be prepared in situ when an alkanol is the organic solvent by the action of hydrogen sulphide on a sodium alkoxide conwherein X represents the acid residue of a reactive ester such as a halogen atom. The reaction is generally carried out in an organic solvent such as an ether (e.g., tetrahydrofuran), an alcohol (e.g., methanol) or an aromatic hydrocarbon (e.g., benzene), at a temperature between C. and the boiling point of the reaction mixture.
The product of formula I can be purified, if necessary, by physical methods such as distillation, crystallisation or chromatography.
l 5-Nitrothiazol-2-yl )-imidazolidin e-2-thione possesses valuable therapeutic properties: it has proved particularly active as an anti-bilharzia agent, as an antitrichomonas agent, as an anti-amoeboid agent, as an anthelmintic agent, as an anti-giardiasis agent, as an anti-coccidial agent and as an anti-microbial agent.
The new cyclic thiourea of the present invention is less toxic and more active than l-(5-nitrothiazol-2-yl)- irnidazolidin-2-one(niridazole) which is described in the specification of British Pat. No. 986,562 granted to Ciba Limited on an application filed May 22, 1963.
Thus, in the case of mice, the compound of formula I administered in suspension once daily for 3 days is half as toxic as niridazole.
In the case of monkeys [Maccaca mulatta (rhesus variety)] infested with Schisrosoma mansom', the compound of the present invention is more active than the closely related compound of the prior art. At a dose of the new compound of 50 mg/kg animal body weight per day for 5 days, administered orally, a total destruction of almost all the worms is observed (the surviving worms being very damaged) whereas niridazole has an action only on the egg-laying of the female wonns. At a dose of 30 mg/kg animal body weight per day for 5 days, administered orally, the compound of the present invention causes a reduction in the number of worms and a decrease of the egg-laying of the female worms, whereas niridazole only has an action of short duration on the egg-laying of the female worms.
The compound of fonnula l is active against subcutaneous abscess in mice infected with Trichomonas vaginalis, against intestinal amoebiasis of weanling rats and against hepatic amoebiasis of hamsters infected with Entamoeba histolytica. The dose which eliminates 50% of the parasites of the treated animals (CD is between 40 and mg/kg animal body weight per day, administered orally.
In the same way, the dose CD against giardiasis of mice is between 5 and 10 mg/kg animal body weight per day, administered orally.
The dose CD, against experimental oxyuriasis of mice infected with Aspiculuris tetraptera is about 60 mg/kg animal body weight per day, administered orally.
The minimum active concentration of the compound of the invention in chicken feedstuffs against experimental coccidiosis of chickens infected with Eimeria tenella is 0.01% by weight.
As well as its very pronounced anti-parasitic activity, the compound of formula 1 exhibits particularly valuable anti-microbial properties. lts activity is exhibited more particularly in vitro, against Escherichia coli, Salmonella typhimurium, Salmonella gallinarum, Welchia perfringens and Clostridium sporogenes.
The following Examples illustrate the preparation of the compound of the invention.
EXAMPLE 1 Hydrogen sulphide is bubbled into a solution of sodium methoxide (0.01 mole) in methanol (25 cc.) until the solution is neutral with respect to thymolphthalein. Finely powdered 2-me thylthio- 1 S-nitrothiazol-Z-yl A-imidazoline (2.5 g) is then added, and the mixture stirred for 16 hours at a temperature of about 20C. The suspension is filtered. The solid is washed with methanol (25 cc.), and then dried under reduced pressure (20 mm.I-lg) to give I-(S-nitrothiazol-Z-yhimidazolidine-Z-thione (2 g.), melting at 274C.
2-Methylthio-1-(5-nitrothiazol-2-yl)-A -imidazoline, employed as starting material, can be prepared in the following manner:
2-Bromo-5-nitrothiazole (2.1 g) is added, all at once, to a solution of 2-methylthio-A -imidazoline (2.3 g.) in methanol (25 cc.) and then the mixture is heated under reflux for 1 hour. After cooling, the resulting precipitate is filtered off. 2-Methylthiol-( 5-nitrothiazol-2-yl)- A -imidazoline (1.2 g.), melting at 190C., is thus obtained.
EXAMPLE 2 Hydrogen sulphide is bubbled into a solution of sodium methoxide (0.14 mole) in methanol (400 cc.) until the solution is neutral with respect to thymolphthalein. Finely powdered 2-benzylthio-l-( S-nitrodriazol-Z-yD-N-imidazoline (45 g.) is then added, and the mixture is stirred for 16 hours at a temperature of about 20C. The suspension is filtered and the resulting solid is washed with methanol (100 cc.) to give l-(5- nitrothiazol-Z-yl)-imidazolidine-2-thione (28 g.), melting at 274C.
2-Benzylthio- 1 5-nitrothiazol-2-yl )-A-irnidazoline melting at 160C, which is used as starting material, can be prepared by reaching 2-benzylthio-A -imidazoline (154 g.) with 2-bromo-5-nitrothiazole (84 g.).
The present invention also includes pharmaceutical and veterinary compositions which comprise, as active ingredient, l 5-nitrothiazol-2yl )-imidazolidine-2- thione in association with a carrier or coating generally used in the preparation of pharmaceutical and veterinary compositions. The compositions are preferably in a form suitable for oral administration.
Tablets, pills, powders or granules can be used as solid compositions for oral administration. In these compositions the compound is mixed with one or more inert diluents, such as sucrose, lactose or starch. These compositions can also contain substances other than diluents, for example lubricants such as magnesium stearate or a dispersing agent.
Pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, containing inert diluents such as water or paraffin oil, can be used as liquid compositions for oral administration. These compositions can also contain substances other than the diluents, such as, for example, wetting agents or sweetening or flavouring agents.
The percentage of l-(5-nitrothiazol-2-yl)-imidazolidine-Z-thione in the compositions may be varied, it
4 being necessary that it should constitute a proportion such that a suitable dosage shall be obtained.
In human therapy, the compound of the present invention can be used to combat the bilharzioses due to Schistosoma mansoni, Schistosoma haematobium and to Schistosoma japonicum, in daily doses, administered orally, of between 10 and 50 mg/kg body weight. These doses can be repeated at regular intervals of several days or several weeks to achieve complete elimination of the parasite.
Generally, the physician or veterinary surgeon will decide the posology whichis considered most appropriate, depending on the subject to be treated, the age, the weight, the degree of infestation and all other factors peculiar to the subject.
The following Example illustrates therapeutic compositions according to the invention.
EXAMPLE 3 Tablets having the following composition are prepared in accordance with the usual technique:
1-( 5-nitrothiazol-2-yl )-imidazolidine-2-thione 500 mg. wheat starch mg. colloidal silica 40 mg. magnesium stearate 10 mg.
1 claim:
1 A method for combatting bilharzioses due to Schistosoma mansom', Schistosoma haematabium or to Schistosoma japonicum, in a patient which comprises administering to the patient 1-(S-nitrothiazol-Z-yl)-imidazolidine-Z-thione in an amount sufficient to improve the condition of the patient.
2. A method according to claim 1 in which a dose of l S-nitrothiazol-Z-yl)-imidazolidine-2-thione between 10 and 50 mg. per kilogramme body weight of the patient is administered orally during a day to the patient.
3. A method for combatting infections caused by Salmonella typhimurium or Salmonella gallinarum in a patient which comprises administering to the patient 1- (S-nitrothiazol-Z-yl)-imidazoIidine-2-thione in an amount sufficient to improve the condition of the patient.
4. An anti-parasitic and anti-microbial composition comprising an effective amount of l-(5-nitrothiazol-2- yl)-imidazolidine-2-thione in association with a carrier used in the formulation of pharmaceutical or veterinary compositions.
Claims (4)
1. A METHOD FOR COMBATTING BILHARZIOSES DUE TO SCHISTOSOMA MANSONI, SCHISTOSOMA HAEMATOBIUM OR TO SCHISOTOSOMA JAPONICUM, IN A PATIENT WHICH COMPRISES ADMINISTERING TO THE PATIENT 1-(5-NITROTHIAZOL-2-YL)-IMIDAZOLIDINE-2-THIONE IN AN AMOUNT SUFFICIENT TO IMPROVE THE CONDITION OF THE PATIENT.
2. A method according to claim 1 in which a dose of 1-(5-nitrothiazol-2-yl)-imidazolidine-2-thione between 10 and 50 mg. per kilogramme body weight of the patient is administered orally during a day to the patient.
3. A method for combatting infections caused by Salmonella typhimurium or Salmonella gallinarum in a patient which comprises administering to the patient 1-(5-nitrothiazol-2-yl)-imidazolidine-2-thione in an amount sufficient to improve the condition of the patient.
4. An anti-parasitic and anti-microbial composition comprising an effective amount of 1-(5-nitrothiazol-2-yl)-imidazolidine-2-thione in association with a carrier used in the formulation of pharmaceutical or veterinary compositions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US381083A US3925550A (en) | 1971-03-23 | 1973-07-20 | 1-(5-Nitrothi-alzol-2-yl)-imidazolidine-2-thione having anti-parasitic and anti-microbial properties |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7110150A FR2129953B1 (en) | 1971-03-23 | 1971-03-23 | |
| US00236579A US3810908A (en) | 1971-03-23 | 1972-03-21 | 1-(5-nitrothiazol-2-yl)-imidazolidine-2-thione |
| US381083A US3925550A (en) | 1971-03-23 | 1973-07-20 | 1-(5-Nitrothi-alzol-2-yl)-imidazolidine-2-thione having anti-parasitic and anti-microbial properties |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3925550A true US3925550A (en) | 1975-12-09 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US381083A Expired - Lifetime US3925550A (en) | 1971-03-23 | 1973-07-20 | 1-(5-Nitrothi-alzol-2-yl)-imidazolidine-2-thione having anti-parasitic and anti-microbial properties |
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| Country | Link |
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| US (1) | US3925550A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3297699A (en) * | 1964-04-24 | 1967-01-10 | Ciba Geigy Corp | 5-nitrothiazolyl-dioxo-diazacycloalkanes |
| US3298914A (en) * | 1962-05-30 | 1967-01-17 | Ciba Geigy Corp | Anti-parasitic 5-nitrothiazolyl oxodiazacycloalkane compositions |
-
1973
- 1973-07-20 US US381083A patent/US3925550A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3298914A (en) * | 1962-05-30 | 1967-01-17 | Ciba Geigy Corp | Anti-parasitic 5-nitrothiazolyl oxodiazacycloalkane compositions |
| US3297699A (en) * | 1964-04-24 | 1967-01-10 | Ciba Geigy Corp | 5-nitrothiazolyl-dioxo-diazacycloalkanes |
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