CA1110633A - Benzimidazol carbamate active against gastroenteric and lung parasites - Google Patents
Benzimidazol carbamate active against gastroenteric and lung parasitesInfo
- Publication number
- CA1110633A CA1110633A CA312,763A CA312763A CA1110633A CA 1110633 A CA1110633 A CA 1110633A CA 312763 A CA312763 A CA 312763A CA 1110633 A CA1110633 A CA 1110633A
- Authority
- CA
- Canada
- Prior art keywords
- lung
- parasites
- gastroenteric
- active against
- carbamate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
- C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/116—Heterocyclic compounds
- A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/23—Preparation of halogenated hydrocarbons by dehalogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/272—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by addition reactions
- C07C17/275—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by addition reactions of hydrocarbons and halogenated hydrocarbons
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Polymers & Plastics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Husbandry (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
A new benzimidazolcarbamate substituted in 5 (6) position having the formula:
A new benzimidazolcarbamate substituted in 5 (6) position having the formula:
Description
-` 111~;P633 5(~) Substituted benzimidazols are known in the art as is, also, the anti helmintic-action thereof. See, for instance, German patent application Ns. 2,029,637 and
2,164,690, French patents Ns. 1,556,824 and 2,052,988, and United States patents Ns. 3,010,968 and 3,915,986.
Some of those compounds have been introduced into the market, such as, for instance, the Albendazole, Oxy-bendazole and Parbendazole of Smith Kline & French Labora-tories, the Phenbendazole of the Hoechst Company, the Oxphendazole marketed by Syntex, the Cambendazole and Thiabendazole of Merck & Co., Inc., and the Mebendazole of the Janssen Co.
All of the compounds enumerated exhibit good activity against intestinal helminths. However, they exhibit little, if any, effective action against lung nematoda or hepatic trematoda. ;
An objection of the present invention is to provide a new benzimidazolcarbamate substituted in 5(6) position and which is not only particularly active against intestinal helminths but also particularly active against lung nematoda and hepatic trematoda.
That and other objects are achieved by this inven- -tion which provides, as a new benzimidazolcarbamate in the art, 5(6)- rcyclopropylethyl)sulphiny~J-benzimidazol-2-methylcarbamate (CPSBC) of the formula ¦~ s~ 9-NH-CooCH3 H
which exhibits an anti-helminthic action against specific -parasites that infest cattle which is greater than the action of the various benzimidazolcarbamates already adopted in - 1 - ~.k 63~
veterinary practice, and which has a much wider range of activity inasmuch as it is also particularly effective against lung nematoda and hepatic trematoda that are other-wise difficult to combat using the conventional anti-helminthic agents.
In fact, the specific benzimidazolcarbamate of this invention, in addition to exerting exceptional activity against the genera Ostertagia, Oesophagostomum, Trichostrongylus and other intestinal helminths has also proved to be active against Dictyocauli, Metastrongyli, Protostrongyli, lung nematoda, responsible for infections that normally can hardly be dominated in sheep, cattle and equines, and, moreover, it is effective against Fasciolae such as the Fasciola hepatica.
The preparation of the compound according to the invention does not present any particular difficulties. Thus~ :
said compound can be prepared from 2-nitro-4-thiocyano-aniline through the following steps:
\
\
P~633 NH2 2 ~ Cl NH2 NO2 NaBH4 ~ N ~ NO2 SCN Na S
~2 Na2S24 ~ ~ ~ NH2 S~
, ,.
NH2 11_NH COOCH3 ~ ~ -NH-COOCH3 N-COOCH3 ~ ~ N /
S ~ H
S N ~ ~ ~ ~ ~-NH-COOCH3 ~ ~ ~ ~ NH-COOCH3 ~ (CPSBC) : H
~:
The cyclopropylethylchloride may be prepared from CC14 and ethylene according to the following reactions:
CH2 =CH2 CC14 + CH2 = CH2 ~ CC13 - CH2 - CH2 - C1 Zn, gaseous HCl ~ /Cl Cl-CH2-CH2-CC12-CH -CH -Cl --~
The CPSBC proved to be useful both in curing the infested animals and in protecting them from the infection.
It can be administered according to any of the many techniques in use in the veterinary field, for instance by mouth, in the form of bolos, a tablet, a capsule, or a suspension and can be directly ~ixed with the fodder.
'6~3 It is compatible with many of the usual diluents or excipients such as, for instance, mais starch, lactosium, saccharose, calcium phosphate, jelly, stearic acid, agar, pectin, etc.
Liquid vehicles which can be used include peanut oil, olive oil, etc., and use of such liquid vehicles would allow the compound to be formulated in the compositions known to those skilled in the art.
The activity of the compound of this invention, in comparison with the activity of the prior art compounds was determined in experiments on sheep preliminarily thoroughly disinfested by administering suitable doses of conventional anti-helminthic products and subsequently infested in a con-trolled way with parasites of the species under examination.
The infested animals were then subdivided into two groups, one' of which was treated with one single dose of the product under examination in the form of an aqueous suspension, by mouth, while the other group was used as a witness for control. After 48 hours from the administering of the anti-helminth, the animals were sacrificed and the parasites present on them were counted according to the techniques usually followed in helmin-thologic practice.
The results, shown in the Table below, are expressed as percentage of disinfestation, according to the following classification:
Classification % of Disinfestation Class 0 0-10, or irrelevant
Some of those compounds have been introduced into the market, such as, for instance, the Albendazole, Oxy-bendazole and Parbendazole of Smith Kline & French Labora-tories, the Phenbendazole of the Hoechst Company, the Oxphendazole marketed by Syntex, the Cambendazole and Thiabendazole of Merck & Co., Inc., and the Mebendazole of the Janssen Co.
All of the compounds enumerated exhibit good activity against intestinal helminths. However, they exhibit little, if any, effective action against lung nematoda or hepatic trematoda. ;
An objection of the present invention is to provide a new benzimidazolcarbamate substituted in 5(6) position and which is not only particularly active against intestinal helminths but also particularly active against lung nematoda and hepatic trematoda.
That and other objects are achieved by this inven- -tion which provides, as a new benzimidazolcarbamate in the art, 5(6)- rcyclopropylethyl)sulphiny~J-benzimidazol-2-methylcarbamate (CPSBC) of the formula ¦~ s~ 9-NH-CooCH3 H
which exhibits an anti-helminthic action against specific -parasites that infest cattle which is greater than the action of the various benzimidazolcarbamates already adopted in - 1 - ~.k 63~
veterinary practice, and which has a much wider range of activity inasmuch as it is also particularly effective against lung nematoda and hepatic trematoda that are other-wise difficult to combat using the conventional anti-helminthic agents.
In fact, the specific benzimidazolcarbamate of this invention, in addition to exerting exceptional activity against the genera Ostertagia, Oesophagostomum, Trichostrongylus and other intestinal helminths has also proved to be active against Dictyocauli, Metastrongyli, Protostrongyli, lung nematoda, responsible for infections that normally can hardly be dominated in sheep, cattle and equines, and, moreover, it is effective against Fasciolae such as the Fasciola hepatica.
The preparation of the compound according to the invention does not present any particular difficulties. Thus~ :
said compound can be prepared from 2-nitro-4-thiocyano-aniline through the following steps:
\
\
P~633 NH2 2 ~ Cl NH2 NO2 NaBH4 ~ N ~ NO2 SCN Na S
~2 Na2S24 ~ ~ ~ NH2 S~
, ,.
NH2 11_NH COOCH3 ~ ~ -NH-COOCH3 N-COOCH3 ~ ~ N /
S ~ H
S N ~ ~ ~ ~ ~-NH-COOCH3 ~ ~ ~ ~ NH-COOCH3 ~ (CPSBC) : H
~:
The cyclopropylethylchloride may be prepared from CC14 and ethylene according to the following reactions:
CH2 =CH2 CC14 + CH2 = CH2 ~ CC13 - CH2 - CH2 - C1 Zn, gaseous HCl ~ /Cl Cl-CH2-CH2-CC12-CH -CH -Cl --~
The CPSBC proved to be useful both in curing the infested animals and in protecting them from the infection.
It can be administered according to any of the many techniques in use in the veterinary field, for instance by mouth, in the form of bolos, a tablet, a capsule, or a suspension and can be directly ~ixed with the fodder.
'6~3 It is compatible with many of the usual diluents or excipients such as, for instance, mais starch, lactosium, saccharose, calcium phosphate, jelly, stearic acid, agar, pectin, etc.
Liquid vehicles which can be used include peanut oil, olive oil, etc., and use of such liquid vehicles would allow the compound to be formulated in the compositions known to those skilled in the art.
The activity of the compound of this invention, in comparison with the activity of the prior art compounds was determined in experiments on sheep preliminarily thoroughly disinfested by administering suitable doses of conventional anti-helminthic products and subsequently infested in a con-trolled way with parasites of the species under examination.
The infested animals were then subdivided into two groups, one' of which was treated with one single dose of the product under examination in the form of an aqueous suspension, by mouth, while the other group was used as a witness for control. After 48 hours from the administering of the anti-helminth, the animals were sacrificed and the parasites present on them were counted according to the techniques usually followed in helmin-thologic practice.
The results, shown in the Table below, are expressed as percentage of disinfestation, according to the following classification:
Classification % of Disinfestation Class 0 0-10, or irrelevant
3 61-90
4 91-100 The results obtained show that the CPSBC has a very J~ 33 high efficacy against all the helminths examined, in particular with regard to the lung nematoda and the trematoda, an efficacy which is only partially realized with oxyphendazol.
The data is evidence that CPSBC, taken in one single dose of 5 mg/kg, allows the full and contemporaneous disinfes-tation in sheep from nematoda, cestoids and trematoda, which so far was impossible to achieve with any of the known products, ;
used singly.
In order to even better illustrate the invention the following examples of the preparation of the 5(6) - ~cyclo-propylethyl~sulphiny~J-benzimidazole-2-methylcarbammate are given. These examples are not intended to be limiting.
: :;
:
\
TABLE I
Efficacy of CPSBC on sheep in comparison with other anti-helminthic benzimidazols:
NematodaCestoids Trematoda Type of R in Gastro- Of entheric theMonie- Fascio-the structure D Osterta- lung ziala hepa-mg/kc Oesofa- , Dcyautluyso tica R ~ /-NH-CO2CH3 go~tomum l O ., .
lo DA~s~ 25.5 4 44(2) -4 -4 \ 25.5 1 3-41 3 3 ~ 5 (3) ' 0 0 0 S- 2.55 42 42 2-3 (4) /~\ .
~ CO- 25.5 (3) 2 3-4 (5) ~ 5 (6) 0 (7) ~ S~ 5 4 4 0 2 ~ -CH2-SO-(1) 5 3 - - 0 .
(1) Obtained following Br. Patent N 1,455,728 (2) At 1 mg~kg there is still complete efficacy.
(3) Effective dose: 12.5 mg~kg.
(~) Effective dose: 5 doses of 10 mg~kg each.
(5~ Requires doses of more than 25 mg/kg.
(6) Requires doses of 20 Mg/kg.
(7) Requires doses of 60 mg/kg.
EX~MPLE 1 Preparation of Cl/A~/ CC12 ~ Cl Into an enameled, 5 liter autoclave, provided with a suitable stirring system and heat regulation, were loaded 2.1 kg (11.5 moles) of CC13-CH2-CH2-Cl, 1 lt. of CH3CN, 20 g of FeC12-4H20, 22 g of (C2H5)2-N~ HCl and 21 g of benzoin.
The air was removed and the autoclave was conditioned with a few atmospheres of ethylene. Thereupon the temperature was raised to 120C and the whole was conditioned with ethylene up to 35 atm. The indicated conditions were maintained for 5 hours and 30 minutes by feeding ethylene according to consump-tion. After filtering the suspended solids, the mixture was fractionated by distillation. It yielded 1300 grams of a fraction of b.p. 80-82C at 2 mm Hg and consisting, for 97%, of Cl ~ CCl2~v/~Cl, Under the above indicated conditions, the conversion, based on the starting CC13CH2CH2Cl, amounted to 65% while the selectivity with respect to the product desired was 80%, corresponding to a yield of 52%.
Preparation of ~
Into a flask fitted with a reflux condenser, a bubler, a stirrer and a thermometer, were loaded 210 g of Cl ~ CC12 ~ Cl, (1 mole), 1000 cc of ethanol and 325 g (5 moles) of Zn powder. This reaction mixture was reflux-heated (temperature of the outside heating bath = 97-98C) and then gaseous HCl was bubbled into the reactor, maintaining a slight, constant flow of it. The reaction was followed by chromato-graphic checking and was interrupted when the Cl ~ CC12 Cl : . . . .
~ 6~3 appeared to be completely consumed. The reaction mixture was then diluted with 300 cc of aqueous HCl at 5% concentration, in order to increase its fluidity, and was then extracted with diethyl ether, removing the aqueous phase. The organic phase, after anhydrification, was concentrated and the residue was fractionated at atmospheric pressure gathering a fraction at b.p. 109-111C. Thereby were obtained 86 g of ~ ~ which, on chromatographic analysis, proved to be 98% pure, correspond-ing to a molar yield of 80% on the Cl ~ CC12 Cl.
Preparation of 4-/cyclopropylethyl-thio-7-2-nitro-aniline At room temperature, there were mixed together, under moderate stirring, 51.2 millimoles of 2-nitro-4-thiocyano-aniline dissolved in 25 cc of dimethylformamide (DMF) and 54 millimoles of sodium borohydride dissolved in 25 cc of DMF.
Thereupon the temperature rose autogenously to 30-35C.
The mixture was kept under stirring for one hour at room temperature (15-20C) after which there were introduced 66 millimoles of ~ , regulating the feeding in such a way as to maintain the temperature below 25C. Once the addition had been accomplished, the mixture was heated for 3 hours at 100C. The reaction mass was then cooled down and poured into water under vigorous stirring. Extraction was then carried out with chloroform, the organic extracts were gathered together, dried on Na2SO4 and the solvent removed under vacuum.
The yield in raw product thus obtained amounted to 85% and the product; was useful directly for the successive synthesis.
Preparation of 4- rvcloProPvlethvl-thio-7-ortho-Phenylendiamine 34.4 millimoles of 4-/cyclopropylethylthi~J-2-nitro-aniline were suspended in 340 cc of the mixture 1:1 by volume of methanol and water containing 43 g of Na2S2O4.
63~3 The reaction mixture was heated, under refluxing, the course of the reaction being controlled by thin-layer chromatography. The reaction was completed in about 10-15 minutes. After the reduction was complete, the methanol and part of the water were removed under vacuum, thereby obtaining an oily suspension which was extracted with chloroform.
The organic extracts, after drying on anhydrous ~a2S04, and evaporation of the solvent under vacuum, gave, in practically quantitative yields, raw diamine (a thick, intensely colored oil) which was directly used for the successive step.
Preparation of 5(6)-~(cvclopropvlethyl)-thi o-7- 2-methvl-benzimidazolcarbamate In 20 cc of the mixture C2H5-OH/H20/CH3COOH (40:40:1) were dispersed 16 millimoles of 4-/(cyclopropylethyl)-thio~Jo.
Phenylendiamine and 18 millimoles of 1,3-methoxycarbonyliso-thiourea. The mixture was then refluxed for 4 hours. Thereupon, the solid that formed in the reaction medium was filtered and then recrystallized from methanol and chloroform (l:l) thus obtaining the desired benzimidazolcarbamate (yield = 70%, -m.p. = 187-189C).
Preparation of 5(6) /(cYclopropylethyl)sulphinyl7benzimidazol-2 methyl carbamate In a mixture of CHCl3 (400 cc), methanol (100 cc) and acetic acid (2 cc), 2.3g millimoles of the ester obtained following Example 5 were dissolved. The temperature was kept at 0 and 2.51 millimoles of m-chloroperbenzoic acid were added. After l hour, the reaction was complete, as shown by thin layer chromatography /Silica gel-Eluting solution: mixture of CHC13 3 parts, CH3COOC2H5 2 parts, CH30H 1 par ~.
The organic solution was washed with 150 ml of a . : ~ . . . : . -~ 33 saturated aqueous solution of NaHC03, the organic phase was dried on Na2S04 and evaporated to dryness under vacuum.
The oily residue thus obtained was taken up in methanol. The residue crystallized, yielding the sulphoxide.
Recrystallizing from methanol gave the pure sulphoxide, (m.p. 215C, yield 85%).
The data is evidence that CPSBC, taken in one single dose of 5 mg/kg, allows the full and contemporaneous disinfes-tation in sheep from nematoda, cestoids and trematoda, which so far was impossible to achieve with any of the known products, ;
used singly.
In order to even better illustrate the invention the following examples of the preparation of the 5(6) - ~cyclo-propylethyl~sulphiny~J-benzimidazole-2-methylcarbammate are given. These examples are not intended to be limiting.
: :;
:
\
TABLE I
Efficacy of CPSBC on sheep in comparison with other anti-helminthic benzimidazols:
NematodaCestoids Trematoda Type of R in Gastro- Of entheric theMonie- Fascio-the structure D Osterta- lung ziala hepa-mg/kc Oesofa- , Dcyautluyso tica R ~ /-NH-CO2CH3 go~tomum l O ., .
lo DA~s~ 25.5 4 44(2) -4 -4 \ 25.5 1 3-41 3 3 ~ 5 (3) ' 0 0 0 S- 2.55 42 42 2-3 (4) /~\ .
~ CO- 25.5 (3) 2 3-4 (5) ~ 5 (6) 0 (7) ~ S~ 5 4 4 0 2 ~ -CH2-SO-(1) 5 3 - - 0 .
(1) Obtained following Br. Patent N 1,455,728 (2) At 1 mg~kg there is still complete efficacy.
(3) Effective dose: 12.5 mg~kg.
(~) Effective dose: 5 doses of 10 mg~kg each.
(5~ Requires doses of more than 25 mg/kg.
(6) Requires doses of 20 Mg/kg.
(7) Requires doses of 60 mg/kg.
EX~MPLE 1 Preparation of Cl/A~/ CC12 ~ Cl Into an enameled, 5 liter autoclave, provided with a suitable stirring system and heat regulation, were loaded 2.1 kg (11.5 moles) of CC13-CH2-CH2-Cl, 1 lt. of CH3CN, 20 g of FeC12-4H20, 22 g of (C2H5)2-N~ HCl and 21 g of benzoin.
The air was removed and the autoclave was conditioned with a few atmospheres of ethylene. Thereupon the temperature was raised to 120C and the whole was conditioned with ethylene up to 35 atm. The indicated conditions were maintained for 5 hours and 30 minutes by feeding ethylene according to consump-tion. After filtering the suspended solids, the mixture was fractionated by distillation. It yielded 1300 grams of a fraction of b.p. 80-82C at 2 mm Hg and consisting, for 97%, of Cl ~ CCl2~v/~Cl, Under the above indicated conditions, the conversion, based on the starting CC13CH2CH2Cl, amounted to 65% while the selectivity with respect to the product desired was 80%, corresponding to a yield of 52%.
Preparation of ~
Into a flask fitted with a reflux condenser, a bubler, a stirrer and a thermometer, were loaded 210 g of Cl ~ CC12 ~ Cl, (1 mole), 1000 cc of ethanol and 325 g (5 moles) of Zn powder. This reaction mixture was reflux-heated (temperature of the outside heating bath = 97-98C) and then gaseous HCl was bubbled into the reactor, maintaining a slight, constant flow of it. The reaction was followed by chromato-graphic checking and was interrupted when the Cl ~ CC12 Cl : . . . .
~ 6~3 appeared to be completely consumed. The reaction mixture was then diluted with 300 cc of aqueous HCl at 5% concentration, in order to increase its fluidity, and was then extracted with diethyl ether, removing the aqueous phase. The organic phase, after anhydrification, was concentrated and the residue was fractionated at atmospheric pressure gathering a fraction at b.p. 109-111C. Thereby were obtained 86 g of ~ ~ which, on chromatographic analysis, proved to be 98% pure, correspond-ing to a molar yield of 80% on the Cl ~ CC12 Cl.
Preparation of 4-/cyclopropylethyl-thio-7-2-nitro-aniline At room temperature, there were mixed together, under moderate stirring, 51.2 millimoles of 2-nitro-4-thiocyano-aniline dissolved in 25 cc of dimethylformamide (DMF) and 54 millimoles of sodium borohydride dissolved in 25 cc of DMF.
Thereupon the temperature rose autogenously to 30-35C.
The mixture was kept under stirring for one hour at room temperature (15-20C) after which there were introduced 66 millimoles of ~ , regulating the feeding in such a way as to maintain the temperature below 25C. Once the addition had been accomplished, the mixture was heated for 3 hours at 100C. The reaction mass was then cooled down and poured into water under vigorous stirring. Extraction was then carried out with chloroform, the organic extracts were gathered together, dried on Na2SO4 and the solvent removed under vacuum.
The yield in raw product thus obtained amounted to 85% and the product; was useful directly for the successive synthesis.
Preparation of 4- rvcloProPvlethvl-thio-7-ortho-Phenylendiamine 34.4 millimoles of 4-/cyclopropylethylthi~J-2-nitro-aniline were suspended in 340 cc of the mixture 1:1 by volume of methanol and water containing 43 g of Na2S2O4.
63~3 The reaction mixture was heated, under refluxing, the course of the reaction being controlled by thin-layer chromatography. The reaction was completed in about 10-15 minutes. After the reduction was complete, the methanol and part of the water were removed under vacuum, thereby obtaining an oily suspension which was extracted with chloroform.
The organic extracts, after drying on anhydrous ~a2S04, and evaporation of the solvent under vacuum, gave, in practically quantitative yields, raw diamine (a thick, intensely colored oil) which was directly used for the successive step.
Preparation of 5(6)-~(cvclopropvlethyl)-thi o-7- 2-methvl-benzimidazolcarbamate In 20 cc of the mixture C2H5-OH/H20/CH3COOH (40:40:1) were dispersed 16 millimoles of 4-/(cyclopropylethyl)-thio~Jo.
Phenylendiamine and 18 millimoles of 1,3-methoxycarbonyliso-thiourea. The mixture was then refluxed for 4 hours. Thereupon, the solid that formed in the reaction medium was filtered and then recrystallized from methanol and chloroform (l:l) thus obtaining the desired benzimidazolcarbamate (yield = 70%, -m.p. = 187-189C).
Preparation of 5(6) /(cYclopropylethyl)sulphinyl7benzimidazol-2 methyl carbamate In a mixture of CHCl3 (400 cc), methanol (100 cc) and acetic acid (2 cc), 2.3g millimoles of the ester obtained following Example 5 were dissolved. The temperature was kept at 0 and 2.51 millimoles of m-chloroperbenzoic acid were added. After l hour, the reaction was complete, as shown by thin layer chromatography /Silica gel-Eluting solution: mixture of CHC13 3 parts, CH3COOC2H5 2 parts, CH30H 1 par ~.
The organic solution was washed with 150 ml of a . : ~ . . . : . -~ 33 saturated aqueous solution of NaHC03, the organic phase was dried on Na2S04 and evaporated to dryness under vacuum.
The oily residue thus obtained was taken up in methanol. The residue crystallized, yielding the sulphoxide.
Recrystallizing from methanol gave the pure sulphoxide, (m.p. 215C, yield 85%).
Claims (5)
1. 5(6)-[(cyclopropylethyl)-sulphiny] - benzimida-zol-2-methyl-carbamate of the formula :
2. The process for preparing the compound of claim 1 characterized in that the thio derivative of the formula:
is oxidized in an inert solvent at 0°C.
is oxidized in an inert solvent at 0°C.
3. The process of claim 2, in which the oxidizing agent is selected from the group consisting of hydrogen peroxide and perbenzoic, peracetic and performic acids.
4. The method of combatting infestations of gastro-enteric helminths, lung nematoda and hepatic trematoda in animals, which consists in administering to the infested animals, an anti-helminthically active amount of the substituted benzimidazole carbamate of claim 1.
5. The method of Claim 4, in which to the infested animal is given one or more doses of 2.5 mg/kg and upwards of the substituted carbamate of claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT28322A/77 | 1977-10-06 | ||
| IT28322/77A IT1107749B (en) | 1977-10-06 | 1977-10-06 | BENZIMIDAZOLCARBAMMATE PARTICULARLY ACTIVE AGAINST GASTROENTERIC AND PULMONARY PARASITES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1110633A true CA1110633A (en) | 1981-10-13 |
Family
ID=11223358
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA312,763A Expired CA1110633A (en) | 1977-10-06 | 1978-10-05 | Benzimidazol carbamate active against gastroenteric and lung parasites |
Country Status (15)
| Country | Link |
|---|---|
| AR (1) | AR219768A1 (en) |
| AT (1) | AT359518B (en) |
| AU (1) | AU523667B2 (en) |
| BR (1) | BR7806559A (en) |
| CA (1) | CA1110633A (en) |
| DE (1) | DE2843008A1 (en) |
| DK (1) | DK145121C (en) |
| FR (1) | FR2405248A1 (en) |
| GB (1) | GB1573072A (en) |
| IE (1) | IE47239B1 (en) |
| IT (1) | IT1107749B (en) |
| NL (1) | NL7809973A (en) |
| NZ (1) | NZ188560A (en) |
| SU (1) | SU799660A3 (en) |
| ZA (1) | ZA785663B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4599428A (en) * | 1979-10-19 | 1986-07-08 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt | Process for the preparation of 5(6)-thio substituted benzimidazoles |
| US4299837A (en) | 1979-12-05 | 1981-11-10 | Montedison S.P.A. | Anthelmintic benzimidazole-carbamates |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3929821A (en) * | 1972-12-29 | 1975-12-30 | Syntex Inc | 5 (6)-Benzene ring substituted benzimidazole-2-carbamate derivatives |
| DE2334631A1 (en) * | 1973-07-07 | 1975-03-27 | Hoechst Ag | 5-PHENYLSULFINYL-2-BENZIMIDAZOLE CARBAMIC ACID ESTERS AND THE METHOD FOR THEIR MANUFACTURE |
| US3915986A (en) * | 1974-06-19 | 1975-10-28 | Smithkline Corp | Methyl 5-propylthio-2-benzimidazolecarbamate |
| US4025638A (en) * | 1975-03-10 | 1977-05-24 | Smithkline Corporation | Methods and compositions using 5-cycloalkylthio- and oxy-2-carbalkoxy-aminobenzimidazole |
| US4076828A (en) * | 1977-02-17 | 1978-02-28 | E. R. Squibb & Sons, Inc. | Method of treating helminthiasis by parenteral administration of sulfoxide derivatives of benzimidazoles |
| US4093732A (en) * | 1977-02-17 | 1978-06-06 | E. R. Squibb & Sons, Inc. | Sulfoxide derivatives of benzimidazoles |
-
1977
- 1977-10-06 IT IT28322/77A patent/IT1107749B/en active
-
1978
- 1978-01-18 GB GB2073/78A patent/GB1573072A/en not_active Expired
- 1978-08-15 IE IE1644/78A patent/IE47239B1/en unknown
- 1978-10-02 AR AR273917A patent/AR219768A1/en active
- 1978-10-02 FR FR7828067A patent/FR2405248A1/en active Granted
- 1978-10-02 NZ NZ188560A patent/NZ188560A/en unknown
- 1978-10-02 SU SU782667050A patent/SU799660A3/en active
- 1978-10-03 NL NL7809973A patent/NL7809973A/en not_active Application Discontinuation
- 1978-10-03 BR BR7806559A patent/BR7806559A/en unknown
- 1978-10-03 DE DE19782843008 patent/DE2843008A1/en active Granted
- 1978-10-03 AU AU40342/78A patent/AU523667B2/en not_active Expired
- 1978-10-05 AT AT717278A patent/AT359518B/en not_active IP Right Cessation
- 1978-10-05 CA CA312,763A patent/CA1110633A/en not_active Expired
- 1978-10-05 DK DK442378A patent/DK145121C/en not_active IP Right Cessation
- 1978-10-06 ZA ZA00785663A patent/ZA785663B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ188560A (en) | 1981-04-24 |
| AU523667B2 (en) | 1982-08-12 |
| FR2405248A1 (en) | 1979-05-04 |
| ATA717278A (en) | 1980-04-15 |
| DE2843008C2 (en) | 1988-07-14 |
| AU4034278A (en) | 1980-04-17 |
| FR2405248B1 (en) | 1982-10-08 |
| ZA785663B (en) | 1979-09-26 |
| AT359518B (en) | 1980-11-10 |
| BR7806559A (en) | 1979-05-02 |
| IE47239B1 (en) | 1984-01-25 |
| IT1107749B (en) | 1985-11-25 |
| DK145121B (en) | 1982-09-06 |
| AR219768A1 (en) | 1980-09-15 |
| GB1573072A (en) | 1980-08-13 |
| DE2843008A1 (en) | 1979-04-19 |
| DK145121C (en) | 1983-02-07 |
| IE781644L (en) | 1979-04-06 |
| NL7809973A (en) | 1979-04-10 |
| SU799660A3 (en) | 1981-01-23 |
| DK442378A (en) | 1979-04-07 |
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| MKEX | Expiry |