CA1150280A - Benzimidazole-carbamates - Google Patents
Benzimidazole-carbamatesInfo
- Publication number
- CA1150280A CA1150280A CA000341291A CA341291A CA1150280A CA 1150280 A CA1150280 A CA 1150280A CA 000341291 A CA000341291 A CA 000341291A CA 341291 A CA341291 A CA 341291A CA 1150280 A CA1150280 A CA 1150280A
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- CA
- Canada
- Prior art keywords
- benzimidazole
- carbamates
- compounds
- different
- carbamates according
- 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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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C21/00—Acyclic unsaturated compounds containing halogen atoms
- C07C21/02—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds
- C07C21/04—Chloro-alkenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C21/00—Acyclic unsaturated compounds containing halogen atoms
- C07C21/02—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds
- C07C21/14—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds containing bromine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C21/00—Acyclic unsaturated compounds containing halogen atoms
- C07C21/02—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds
- C07C21/18—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds containing fluorine
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Tropical Medicine & Parasitology (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
The invention relates to benzimidazole-carbamates substituted in position 5 of general formula:
The invention relates to benzimidazole-carbamates substituted in position 5 of general formula:
Description
~5~)Z80 This invention relates to benzimidazole-carbamates endowed with anthelmintic activity; more particularly it relates to new benzimidazole-carbamates substituted in position 5(6) by a diene chain bound to position 5(6) by an atom of oxygen or of sulphur optionally oxidized, and the use thereof as anthelminthes.
Benzimidazole-derivatives exist in tautomeric forms such as ~ B~ -B
For nomemclature convention the substituent A which is in position 5 in a tautomeric form, assumes position 6 in the other tautomeric form~
So a benzimidazole-derivatives having a substituent in the position corresponding to substituent A, is generally defined as "5(6)-substituted".
Several benzimidazole-carbamates variously substituted in position 5(6), as well as their anthelmintic action are known (see for example German patent applications Nos. 2,029,637 and 2,164,690; French patents Nos. 1,556,824 and 2,052,988; US
patents Nos. 3,010,968, 3,915,986 and 4,002,640).
Anthelmintic benzimidazole-carbamates have been described also in German patent applications Nos. 2,816,694 and
Benzimidazole-derivatives exist in tautomeric forms such as ~ B~ -B
For nomemclature convention the substituent A which is in position 5 in a tautomeric form, assumes position 6 in the other tautomeric form~
So a benzimidazole-derivatives having a substituent in the position corresponding to substituent A, is generally defined as "5(6)-substituted".
Several benzimidazole-carbamates variously substituted in position 5(6), as well as their anthelmintic action are known (see for example German patent applications Nos. 2,029,637 and 2,164,690; French patents Nos. 1,556,824 and 2,052,988; US
patents Nos. 3,010,968, 3,915,986 and 4,002,640).
Anthelmintic benzimidazole-carbamates have been described also in German patent applications Nos. 2,816,694 and
2,843,308 in the name of the Applications.
Many benzimidazole-carbamates substituted in position 5(6) have been put on the market, such as for example Albendazole, Oxibendazole and Parbendazole produced by Smith Kline Co.;
Phenbendazole produced by Hoechst; Oxphendazole produced by Syntex; Cambendazole and Thiabendazole produced by Merck, - 1 - ~
z~
and Mebendazole produced by Janssen.
We have now found new benzimidazole-carbamates, which constitute the object of the present invention, substituted in position 5(6), having the general formula:
C=CH-l=C-CH2-X ~ N ~ (I) Rl / ~ J ~ NH-COOR
,' wherein:
R = alkyl Cl-C4;
Rl and R2 (like or unlike each other) = H, halogen, methyl optionally substituted by one or more halogen atoms;
R3 and R4 (like or unlike each other) = H, Cl, CH3;
X = O, S, SO, S02.
The compounds of general formula I are endoxed with an high anthelmintic activity and a wide action spectrum being active against both gastrointestinal and broncho-pulmonary parasites and against hepatic parasites of domestic and breeding animals.
The synthesis of the compounds of general formula (I) is carried out according to simple steps, as results from the following scheme (wherein R, Rl, R2, R3 and R4 have the same meanings indicated in general formula (I); Z and Z' = Cl, Br;
RS = H, CH3CO) :
Rl Z R3 R
I) C / (A)+CH2=C - C=CH2 (B) ___~
R2 z~
Rl . . R3 R4 ,f CH2-C = c cH2z (c, R Z' ~ ~5~Z80 R \ IR3 Rl 4 II) C' bases ) R2/C=CH-C = C-CH2-Z (C) + HZ' III) C + ~ P (E) + NaZ
X Na X-Y
RlR3 R
(X = O, S) (Y = C=CH-C = C-CH2-) ~H2 ~ N02 IV) C ' +D --------~ ~J (E ' ) + NaZ
X-Y' R \ R3 R
~y ' = C -CH2-C = C-CH2-3 V) E' bases_ > E
reducers ~ (F) VI ) E ----~ J
Vl I ) E + N = C - NH - COOR -----> ( I ) ~X=O, S_ 7 COOR _ 3 _ 2~30 VI~ X=S ~ _~er_cldS~ X=SO, SO2_/
The first passage of the scheme of reaction for obtain-ing the compounds of formula (I) (reaction I), i.e. the reaction between a compound of fo~mula C ~whe~ein R1 and R2 have the meanings indicated in general formula (I), and Z and Z' (like or unlike each other) are Cl, Br_/' and a diene of the type CH2=C - C=CH2 ~wherein R3 and R4 have the same meanings specified in general formula (I) ~, is conducted by radical intermediates in the presence of suitable catalysts such as Redox-transfer systems, as for example copper salts and amines, as described by B.M. Asscher et al. / J. Chem. Soc.
page 1887 ~1963) ~ , or in the presence of ruthenium complexes, as more recently described by H. Matsumoto et al. /Chemistry Letters, page 115 (1978) ~ for the reaction between CC14/(A), Rl=R2=Z=Z'+Cl ~ and isoprene CH2=C - CH=CH2 / (B), R3=CH3, R4=H / in the presence of dichloro-tris-triphenyl-phosphine-ruthenium (Ru /P(c6Hs)3 ~ 3C12) It is important to point out that reaction I, both when conducted in the presence of Redox-transfer systems, and when conducted in the presence of ruthenium complexes, is not region-selective, wherefore when in compound B substituent R3 is different from R4, also mixtures of positional isomers, besides mixtures of cis-trans isomers due the presence of the double bond, are obtained.
For example, starting from CC14 and isoprene, mixtures of the following compounds are obtained:
IH3 fH3 Cc13-CH2-C = CH-CH2Cl Ccl3-cH2-cEl=c - CH2Cl ~5~80 /(C'), Rl=R =Z=Z'=Cl; R3=CH3, R4=H and R3=H, R4--C~13 7 Generally the mixture of the positional isomers is separable into the individual isomers by fractionated distillation.
The compounds of formula (C) or (C') are then reacted with the sodium salt of 2-nitro-4-hydroxy-aniline (sodium phenate) / (D), X=O, R5=H~ or of 2-nitro-4-mercapto-aniline (sodium mercaptate) ~ (D), X=S, R5=H~ according to reactions III and IV.
In some cases it is preferable ,to protect the amino group of compounds (D) by acetylation starting then from the corresponding N-acetyl-anilines ~ (D), R5=CH3CoJ , The acetyl group then can be easily removed by hydroli-sis at the more convenient step of the process.
In this manner, nitro-aniline of formula (E) or ~E') are obtained. The latter, when treated with bases, undergoes a dehydrohalogenation on its side chain in position 4 respect to the amino group (X-Y'), so providing the nitro-aniline indicated by letter (E) (reaction V).
Nitro-aniline (E) is then reduced, for example, with sodium hydrosulphite (Na2S2O4), so obtaining phenylenediamine (F) (reaction VI).
Phenylenediamine F is then reacted with 1,3-bis-alkoxycarbonyl-S-methyl-isothiourea, so obtaining benzimidazole-carbamates of general formula (I), in which X = O or X = S
(reaction VII).
By reacting phenylenediamine F with 1,3-bis-methoxycar-bonyl-S-methyl-isothiourea compounds of formula I in which R is methyl are obtained.
In a similar manner by reacting phenylenediamine F with 1,3-bis-ethoxycarbonyl-S-methyl-isothiourea or 1,3-bis-propoxycarbonyl-S-methyl-isothiourea or 1,3-bis-butoxycarbonyl-S-methyl-isothiourea, benzimidazole-carbamates of formula I are prepared in which R is either ethyl, propyl or butyl.
~5~2~30 Finally, from the benzimidazole-carbamates of formula (I), in which X = S, it is possible to obtain, by oxidation with peracids, the compounds of formula (I~ t in which X = SO
or SO2 (reaction VIII).
Reaction VIII is conveniently carried out by dissolving the benzimidazole-carbamate of formula I (in which X=S) in an inert solvent (or in a mixture of inert solvents) and by adding at a temperature of from -30C to room temperature, a peracid such as peracetic acid, perbenzoic acid or 3-chloro-perbenzoic acid.
When it is desired to convert the thio group to its corresponding sulphinyl group, equimolecular quantities of peracids are used. While when it is desired to convert the thio group to its corresponding sulphonyl group, or to convert the sulphonyl group to its corresponding sulphonyl group, an excess of peracid is used.
As examples of compounds of formula :
R \ / Z
C (A) the following may be cited:
R2 / \ z'
Many benzimidazole-carbamates substituted in position 5(6) have been put on the market, such as for example Albendazole, Oxibendazole and Parbendazole produced by Smith Kline Co.;
Phenbendazole produced by Hoechst; Oxphendazole produced by Syntex; Cambendazole and Thiabendazole produced by Merck, - 1 - ~
z~
and Mebendazole produced by Janssen.
We have now found new benzimidazole-carbamates, which constitute the object of the present invention, substituted in position 5(6), having the general formula:
C=CH-l=C-CH2-X ~ N ~ (I) Rl / ~ J ~ NH-COOR
,' wherein:
R = alkyl Cl-C4;
Rl and R2 (like or unlike each other) = H, halogen, methyl optionally substituted by one or more halogen atoms;
R3 and R4 (like or unlike each other) = H, Cl, CH3;
X = O, S, SO, S02.
The compounds of general formula I are endoxed with an high anthelmintic activity and a wide action spectrum being active against both gastrointestinal and broncho-pulmonary parasites and against hepatic parasites of domestic and breeding animals.
The synthesis of the compounds of general formula (I) is carried out according to simple steps, as results from the following scheme (wherein R, Rl, R2, R3 and R4 have the same meanings indicated in general formula (I); Z and Z' = Cl, Br;
RS = H, CH3CO) :
Rl Z R3 R
I) C / (A)+CH2=C - C=CH2 (B) ___~
R2 z~
Rl . . R3 R4 ,f CH2-C = c cH2z (c, R Z' ~ ~5~Z80 R \ IR3 Rl 4 II) C' bases ) R2/C=CH-C = C-CH2-Z (C) + HZ' III) C + ~ P (E) + NaZ
X Na X-Y
RlR3 R
(X = O, S) (Y = C=CH-C = C-CH2-) ~H2 ~ N02 IV) C ' +D --------~ ~J (E ' ) + NaZ
X-Y' R \ R3 R
~y ' = C -CH2-C = C-CH2-3 V) E' bases_ > E
reducers ~ (F) VI ) E ----~ J
Vl I ) E + N = C - NH - COOR -----> ( I ) ~X=O, S_ 7 COOR _ 3 _ 2~30 VI~ X=S ~ _~er_cldS~ X=SO, SO2_/
The first passage of the scheme of reaction for obtain-ing the compounds of formula (I) (reaction I), i.e. the reaction between a compound of fo~mula C ~whe~ein R1 and R2 have the meanings indicated in general formula (I), and Z and Z' (like or unlike each other) are Cl, Br_/' and a diene of the type CH2=C - C=CH2 ~wherein R3 and R4 have the same meanings specified in general formula (I) ~, is conducted by radical intermediates in the presence of suitable catalysts such as Redox-transfer systems, as for example copper salts and amines, as described by B.M. Asscher et al. / J. Chem. Soc.
page 1887 ~1963) ~ , or in the presence of ruthenium complexes, as more recently described by H. Matsumoto et al. /Chemistry Letters, page 115 (1978) ~ for the reaction between CC14/(A), Rl=R2=Z=Z'+Cl ~ and isoprene CH2=C - CH=CH2 / (B), R3=CH3, R4=H / in the presence of dichloro-tris-triphenyl-phosphine-ruthenium (Ru /P(c6Hs)3 ~ 3C12) It is important to point out that reaction I, both when conducted in the presence of Redox-transfer systems, and when conducted in the presence of ruthenium complexes, is not region-selective, wherefore when in compound B substituent R3 is different from R4, also mixtures of positional isomers, besides mixtures of cis-trans isomers due the presence of the double bond, are obtained.
For example, starting from CC14 and isoprene, mixtures of the following compounds are obtained:
IH3 fH3 Cc13-CH2-C = CH-CH2Cl Ccl3-cH2-cEl=c - CH2Cl ~5~80 /(C'), Rl=R =Z=Z'=Cl; R3=CH3, R4=H and R3=H, R4--C~13 7 Generally the mixture of the positional isomers is separable into the individual isomers by fractionated distillation.
The compounds of formula (C) or (C') are then reacted with the sodium salt of 2-nitro-4-hydroxy-aniline (sodium phenate) / (D), X=O, R5=H~ or of 2-nitro-4-mercapto-aniline (sodium mercaptate) ~ (D), X=S, R5=H~ according to reactions III and IV.
In some cases it is preferable ,to protect the amino group of compounds (D) by acetylation starting then from the corresponding N-acetyl-anilines ~ (D), R5=CH3CoJ , The acetyl group then can be easily removed by hydroli-sis at the more convenient step of the process.
In this manner, nitro-aniline of formula (E) or ~E') are obtained. The latter, when treated with bases, undergoes a dehydrohalogenation on its side chain in position 4 respect to the amino group (X-Y'), so providing the nitro-aniline indicated by letter (E) (reaction V).
Nitro-aniline (E) is then reduced, for example, with sodium hydrosulphite (Na2S2O4), so obtaining phenylenediamine (F) (reaction VI).
Phenylenediamine F is then reacted with 1,3-bis-alkoxycarbonyl-S-methyl-isothiourea, so obtaining benzimidazole-carbamates of general formula (I), in which X = O or X = S
(reaction VII).
By reacting phenylenediamine F with 1,3-bis-methoxycar-bonyl-S-methyl-isothiourea compounds of formula I in which R is methyl are obtained.
In a similar manner by reacting phenylenediamine F with 1,3-bis-ethoxycarbonyl-S-methyl-isothiourea or 1,3-bis-propoxycarbonyl-S-methyl-isothiourea or 1,3-bis-butoxycarbonyl-S-methyl-isothiourea, benzimidazole-carbamates of formula I are prepared in which R is either ethyl, propyl or butyl.
~5~2~30 Finally, from the benzimidazole-carbamates of formula (I), in which X = S, it is possible to obtain, by oxidation with peracids, the compounds of formula (I~ t in which X = SO
or SO2 (reaction VIII).
Reaction VIII is conveniently carried out by dissolving the benzimidazole-carbamate of formula I (in which X=S) in an inert solvent (or in a mixture of inert solvents) and by adding at a temperature of from -30C to room temperature, a peracid such as peracetic acid, perbenzoic acid or 3-chloro-perbenzoic acid.
When it is desired to convert the thio group to its corresponding sulphinyl group, equimolecular quantities of peracids are used. While when it is desired to convert the thio group to its corresponding sulphonyl group, or to convert the sulphonyl group to its corresponding sulphonyl group, an excess of peracid is used.
As examples of compounds of formula :
R \ / Z
C (A) the following may be cited:
R2 / \ z'
3 3, 4, CC14, CH3-CC13, CH3-CHCL2, CF3-CHBr 3 , F3 CFBr2~ CF3-CC13, CF2Cl-CFCl CF CB
CF Br CF Cl-CCl , CF3-CBr2-CF3 CH3-cclBr-cl~3-As examples of compounds of formulal3 IR4 CH2= C=CH2 IB) the following may be cited:
~H3 fl fH3 IH3 CH2= --CH=CH2, CH2=CH-CH=CE~2, CH2=C-CH=CH2, CH2=C-- =CH2, fl cll CH2=C C=CH2.
Some of the compounds indicated by the letters C and C' on scheme 1 are known compounds such as the afore mentioned ~S~280 adduct of carbon tetrachloride and isoprene or l-bromo-exa-2,4-dienetsorbyl bromide) of formula CH3-CH=CH-CH=CH2Br or 5-chloro-1,3-pentadiene of formula cH2=cH-cH=cH-cH2cl described in Russian Patent No 472,926 ~Chemical Abstract 83, 78559 x (1975)_/.
However in the course of the studies carried out on the synthesis of the benzimidazole-carbamates of general formula (I), it has been noticed that many of the intermediates indicated by the letters C and C' on scheme 1 are compounds previously unknown, wherefore the compounds having the general formulae given hereinbelow are a further object of this inven-tion:
R \ R3 R4 C-CH2-C = C-CH2Z (II) and R,2, Z I
Rl' R3 R
\ C=CH-C = C-CH2Z (III) R2~1/
wherein:
Rl = F, methyl substituted by one or more halogen atoms, R2 = halogen, methyl substituted by one or more halogen atoms, Z and Z' (like or unlike each other) = Cl, Br, R3 and R4 (like or unlike each other) = H, CH3.
Some of the compounds of general formulae II and III
can be prepared also by other methods.
For example, compounds in which R3 = H and R4 = CH3 can be prepared by reacting the corresponding compounds in which z = H with N-halo imides (N-bromo-succinimide etc.) in the presence of radical reaction promoters.
As already mentioned hereinbefore, the compounds of ~: .
~s~o general formula (I) are endowed with a high enthelmintic activity and a wide action range, these characteristics permitting to successfully fight infestations in mammals and birds, for example in the domestic and breeding animals.
Compounds of formula I are active against gastrointes-tinal parasites such as Ostertaqia spp., T~ichostronqYlus ssp., StronqYloides ssp., Trichuris ssp., Oesophaqostum ssp.,Chabertia ., Nematodirus ssp., Moniezia ssp., Cooperia ssp., ~laemonchus ssp., against broncho-pulmonary parasites such as Dictyocaulus ssP.l and against hepatic parasites such as Fasciola ssp.
The latter characteristic can be dificulty found in the known anthelminthes. The wide field of action of the compounds of general formula (I) represents an important characteristic as the administration of same to infested animals causes a simultaneous liberation o the animal from gastrointes-tinal, hepatic and broncho-pulmonary parasites.
Furthermore, compounds of formula I have been found to be active against-other nematode parasites of the order of fila-rioidea, including Bruqia Pahangi and Dirofilaria immitis.
The activity of compounds according to the present inven-tion was determined in experiments conducted on naturally infested sheeps or, in the case of Fasciola,on artificially infested sheeps.
The animals were divided into two groups, one of which was treated with one dose of the product being tested (orally) while the other untreated group was used as check. During 48-72 houes after treatment with the compound being tested, the excrements of the animals were collected in order to determine the number of parasites or of eggs; successively the animals were killed to determine the reduction of the infestation in comparison with the check.
For veterinary use, the administration of the compounds of this invention to the animals to be treated can be effected according to the usual veterinary techniques for ~15132130 the anthelmintic trea~ment, namely orally in the form of boil, tablets, suspensions, etc., by injections in the form of an injectable liquid or by absorption through the skin (spot on).
It is important to notice that the anthelmintic compounds object oE the present invention are endowed, unlike known anthelminthes, with a good solubility (about 20% by weight) in N-methyl-2-pyrrolidone, an injectable liquid employed in the veterinary technique.
The amounts to be given depend on various actors, among which important are the weight oE the animal to be treated, the nat~re and the severity of the infestation.
Suitable doses are at the discretion of the veterinary physician but may be within the range of 0.5 tolOO mg of the compound of formula I per Kg body weight of the host, preferably 1 to 10 mg/Kg.
Little animals need amounts of a few milligrams of anthelmintic compound, while great animals, such as cattle, sheep, etc., may need amounts of the order of grams per subject.
In practice, the active compound is usually formulated with a vehicle agent (carrier) of veterinary use, or directly in the food for the animal. The active compound may be mixed or dispersed in one of the components of the food, or utilized in the form of boil, tablets easily ingestable or capsules, drenching, suspensions, powders, pastes, salt licks, block licks, granules, pelIets feed premixes. The carrier may be also a pharmaceutic diluent or excipient of the type generally employed in the formulation of medicines; easily available products are, for example, the following: maize starch, terra alba, lactose, saccharose, calcium phosphate, gelatin, stearic acid,magnesium stearate, dextrin, agar, pectines, vegetable oils, injectable liquid carrier such as propylen glycol, N-methyl-2-pyrrolidone, and so on.
If desired other active ingredients such as other anthelmintics, food and mineral supplements may be included in the formulation.
The way of administering may vary remarkably and depends on the specific requirements.
With respect to anthelmintic activity, preferred compounds are thio-derivatives ~X=S) and sulphinyl derivatives (X=SO). Some of the samples tested for anthelmintic activity were mixtures of positional isomers ~R3 different from R4).
However the anthelmintic activity of samples of different composition is practically non-affected by the relative positional isomers ratio (see example 21).
The following examples are given to better illustrate the invention.
PreParation of 1,5,5-trichloro-3-methylhex-2-ene(A) and of 1,5,5-trichloro-2-methylhex-2-ene (B) /Mixture No 1 7 In a "Pfaudler" type autoclave of 2.5 1 capacity the following compounds were introduced under vacuum:
- l,l,l-trichloroethane (CH3-CC13) 1200 ml - isoprene (CH2=C=CH-CH2) 500 ml - Ruthenium-tris-triphenylphosphine-dichloride Ru (C6Hs)3p J 3C12 The content of the autoclave was then stirred and heated up to 90C. At this temperature an exothermic reaction began and the temperature raised to 130C.
The reaction was continued for 2 and half hours keeping the temperature between 120 and 130C, then the autoclave was left to cool at room temperature. The reaction mixture was then concentrated by evaporation at reduced pressure (20 mmHg, 40C)-_ 10 _ ~5~3280 The residue of about 800 g was diluted with 1200 mlof petroleum ether. The ruthenium complex precipitated and was quantitatively recovered by filtration. The filtrate was again concentrated b~ evaporation and the residue was distilled under reduced pressure. The fraction boiling between - 82 and 85C at 5 mmHg was gathered (690 9).
Nuclear Magnetic Resonance (NMR) analysis revealed that the collected fraction was a mixtur~ of compounds (A) an^d (B) in a ratio of about 85:15 CH - CCl - CH2 - C = CH - CH2Cl (A) (cis-trans) `
CH3 CC12 CH2 C 2 (B) (cis-trans) By operating analogously with what described in Example 1, the compounds or mixtures of compounds reported on the following Table 1, were prepared.
~ ~5~80 ~, 1 o ~ ~ ~ ~
~, .U' ~ CO
,c~ , ~
~. ~0'~ ~ ~ In ~
~ o O ~ l ~ r ~O' ~N_ _ ~_ H
C~ U ~~ ~ U ~ ~
~) C) 1:4~ ¢l 1~1 _ ~_, ~
~c m ~ m ~c m ~: m o . ~I ~ ~ ~ ~ ~ ~
~ ~ m m m m m m U) _ ~ S`l~ ~ ~ ~I C~ C~
~ ~ o o 1 i 1 1 ~
~ ~ o ::c m m 5: m m ~
~ c~ m m mm u u ~ :
r~ ~ ~
o~ o ~- J ~. U o H ¦ ~: X _ ~ t~) ~
~1 uz .. I
-2~0 .
.
_ u m o c~
_ ~: m ~ m ~ m ~: m _ _ _ _ _ _ _ _ 5~ ~ ~ I: X X :~
m m ~ ~ o c~ o c~
_ l l l l ~ C~ _ :C ~ ~ ~ ~ ~
C~ C~~ O ~ C~ ~ C~5: U
m 1l :c 1l ~ I o m .
~ _ ~ ~ ~ ~ C~ 5: 1 C~ ~:~ ~ -- ~ --~ ~ Y X ~ ~ ~ ~
-- ~ _ ~:: _ ~ ~ ~ ~::
~: o c~ o ~ ~ m ~ ~: :r: ~ c~l ~ ~ _ ~ ~ ~ ~C ~C X ~ ~ ~ ~
I
:I: ~ ~ ~ ~ ~ ~ X
C~ ~ ~ ~ ~ ~ Y '~ ~
~ ~ ~ ~, ~ ~ C~
m m m l l l l ~ ~ u m ~:
r~ ~ ~C~ ~ C~ U ~ ~ O
C~
-.
, ~ In ~g I_ c~
m~ _ ~ .....
3~81~
_~ _ ~ ~ o I
+ m ~ c~ m H H
u~ ~r ~r c~
m c~ m ~ ~ m ~ o ~ ~ U ~> C~
~: m ~ ~ ~ ~: m ~ â:~
__ .
U h _ _ m~ m ~ ~ m m m :~ :C _ _ c~ ~ ~ m c~ ~: :c ~ ~ ~ ~: :~
uUl~mU~ ~ ml I mm~ ~ U~ ~ ~ I m~mU UU~mm ~ ~ ~ ~ ~ - ~J N ~I ~ t~l O C~ r: ::~ ~ C~ ~ :C ~ ~:
U U ~) ~1 ~ l ~ (r) ~) '1 m m ,1 u ~ ~ ~ ~ u u c~ ~ ~ V m H _ ~1 1~ L~ L~ ~ L~
E~
Z8al Notes to Table 1 (a) Mixture of cis and trans isomers (b) I = isoprene (CH2=C-CH=CH2), B = butadiene ~CH2=CH-CH=CH2) (c) Approximative ratio determined by NMR spectroscopy (d) The preparation of MixtureNo lis described in Example 1 (e) Spectroscopic data of compound No 6 NMR (solvent CDC13, internal standard TMS) d, ppm:
3 1 (d-t., 2EI, JH H =5.66 Hz, JH,F
3.8-4 (m, 2H) 5.3-6.3 (m, 2H) (d.t. = doublet of triplet, m = multiplet, J = coupling constant) (f) Mixture No 9 was isolated as pure (GLC) as residue after distillation from the reactior. crude of unreacted CHC13 and isoprene.
(g) NMR spectroscopic data consistent with the assigned structure.
(h) An analogous preparation has been described by J.Tanaka et al. /Nippon Kagaku Zasshi 90, 803 (1969) ~ (100~ of isomer A).
Preparation of 1,5,5,5-tetrachloro-3-methyl-pent-2-ene (A) and of 1,5,5,5-tetrachloro-2-methyl-pent-2-ene (B) by redox-transfer catalyst.
CuC12.2H2O (2g) was introduced in an enamelled autoclave of 2.5 1 capacity.
The air was elimiriated from the autoclave and, under vacuum, the following compounds were introduced:
- a solution of n.butyl-amine (n.C4Hg-NH2) (3.~5 g) in acetonitrile (CH3C~) (300 ml) - a mixture of carbon tetrachloride (CC14) (600 ml) and isoprene (300 ml) _ 15 _ - carbon tetrachloride (200 ml).
The autoclave was then heated at 90-130C in three hours keeping the internal pressure a 7-8 atm by adding small amounts of isoprene from a small cylinder.
Then the autoclave was leEt to cool at room tempera-ture, and was opened. The content of the autoclave was distilled at reduced presSue (about 20 mmHg) in order to eliminate the volatile components from tpe reaction mixture ~isoprene, CC14 and CH3CN). The residue was distilled under high vacuum collecting all the distilled material in a single fraction which was then re-distilled collecting the fraction (570 g) boiling at 65 C (1.3 mmHg). NMR analysis revealed that the collected fraction was a mixture of compounds A and B (97% pure by GLC) in a ratio of about 70:30. An analogous preparation has been described by P. Piccardi et al. /Agric.
and Food Chem. ~ 1073 (1977) Preparation of 1,1,5-trichloro-3-methyl-penta-1,3-diene (A) and of l,1,5-trichloro-4-methyl-penta-1,3-diene (B) ~ Reaction II /
200 g of the mixture of compounds, prepared as described in Example 3, were dissolved in benzene ~240 ml).
The solution was added to a solution of NaOH ~162 g) in the presence of tetrabutylammonium iodide (n.C4H9)4N J (1.2 g).
The reaction mixture was maintained under intense stirring at 25-30C for 5 hours.
The organic layer was separated and the aqueous layer, after neutralization with hydrochloric acid, was extracted with diethylether (2 x 100 ml). The organic phases were reunited and anhydrified on anhydrous Na2SO4. The solvents were evaporated under vacuum, the residue was distilled and the fraction boiling at 50-52C (0.7 mmHg) was collected. NMR
_ 16 -~5~80 analysis revealed that the collected fraction was a mixture of compounds A and B in a ratio of about 60:40 (pure at 93% by GLC).
Preparation of 1,1- dichloro-4-methyl-S-bromo-penta-1,3-diene ccl2=cH-cH=f-cH2Br (A) By a procedure analogous to thé one described in Example 1, CC14 (243 ml) was additioned to isopentene CH2=CH-CH(CH3)2 (66 g) in the presence of RuII/(C6H5)3P ~ 3C12 (1.8 g) obtaining 1,1,1,3-tetrachloro-4-methyl-pentane (45 g) 'CCl --CH2-CH-CH-CH3 Cl C~13 The product thus obtained was dehydrohalogenated by treatment with (C2H5)3N (41.4 9) in DMF at reflux temperature - for 10 hours.
The reaction mixture was then poured in H2O (100 ml) and extracted by ethyl ether.
The organic solution was distilled and the fraction boiling at 44C (4 mmHg) consisting of 1,1-dichloro-4-methyl-penta-1,3-diene was collected (NMR consistent with the assigned structure CC12=CH-CH=f-CH3) 16.3 g of the product thus obtained were dissolved in CC14 (50 ml) and additioned with N-bromosuccinimide (19.3 g) in the presence of azobis-isobutyronitrile (100 my).
The reaction mixture was refluxed for 8 hours.
The succinimide was filtered, the solvent was eliminated under vacuum and the residue was distilled.
The fraction boiling at 93-96C/2 mmHg (14.6 g) was collected. NMR data are consistent with the structure _ 17 ~15~280 assigned to compound A.
By operating as described in Example 5 and starting from 2,5-dimethyl-hexa-2,4-diene the compound 1-bromo-2,5-dimethyl-hexa-2,4-diene was obtained (NMR consistent with the assigned structure) H3C / CH2Br / C=CH-CH=C ~
By operating analogously to what described in Example
CF Br CF Cl-CCl , CF3-CBr2-CF3 CH3-cclBr-cl~3-As examples of compounds of formulal3 IR4 CH2= C=CH2 IB) the following may be cited:
~H3 fl fH3 IH3 CH2= --CH=CH2, CH2=CH-CH=CE~2, CH2=C-CH=CH2, CH2=C-- =CH2, fl cll CH2=C C=CH2.
Some of the compounds indicated by the letters C and C' on scheme 1 are known compounds such as the afore mentioned ~S~280 adduct of carbon tetrachloride and isoprene or l-bromo-exa-2,4-dienetsorbyl bromide) of formula CH3-CH=CH-CH=CH2Br or 5-chloro-1,3-pentadiene of formula cH2=cH-cH=cH-cH2cl described in Russian Patent No 472,926 ~Chemical Abstract 83, 78559 x (1975)_/.
However in the course of the studies carried out on the synthesis of the benzimidazole-carbamates of general formula (I), it has been noticed that many of the intermediates indicated by the letters C and C' on scheme 1 are compounds previously unknown, wherefore the compounds having the general formulae given hereinbelow are a further object of this inven-tion:
R \ R3 R4 C-CH2-C = C-CH2Z (II) and R,2, Z I
Rl' R3 R
\ C=CH-C = C-CH2Z (III) R2~1/
wherein:
Rl = F, methyl substituted by one or more halogen atoms, R2 = halogen, methyl substituted by one or more halogen atoms, Z and Z' (like or unlike each other) = Cl, Br, R3 and R4 (like or unlike each other) = H, CH3.
Some of the compounds of general formulae II and III
can be prepared also by other methods.
For example, compounds in which R3 = H and R4 = CH3 can be prepared by reacting the corresponding compounds in which z = H with N-halo imides (N-bromo-succinimide etc.) in the presence of radical reaction promoters.
As already mentioned hereinbefore, the compounds of ~: .
~s~o general formula (I) are endowed with a high enthelmintic activity and a wide action range, these characteristics permitting to successfully fight infestations in mammals and birds, for example in the domestic and breeding animals.
Compounds of formula I are active against gastrointes-tinal parasites such as Ostertaqia spp., T~ichostronqYlus ssp., StronqYloides ssp., Trichuris ssp., Oesophaqostum ssp.,Chabertia ., Nematodirus ssp., Moniezia ssp., Cooperia ssp., ~laemonchus ssp., against broncho-pulmonary parasites such as Dictyocaulus ssP.l and against hepatic parasites such as Fasciola ssp.
The latter characteristic can be dificulty found in the known anthelminthes. The wide field of action of the compounds of general formula (I) represents an important characteristic as the administration of same to infested animals causes a simultaneous liberation o the animal from gastrointes-tinal, hepatic and broncho-pulmonary parasites.
Furthermore, compounds of formula I have been found to be active against-other nematode parasites of the order of fila-rioidea, including Bruqia Pahangi and Dirofilaria immitis.
The activity of compounds according to the present inven-tion was determined in experiments conducted on naturally infested sheeps or, in the case of Fasciola,on artificially infested sheeps.
The animals were divided into two groups, one of which was treated with one dose of the product being tested (orally) while the other untreated group was used as check. During 48-72 houes after treatment with the compound being tested, the excrements of the animals were collected in order to determine the number of parasites or of eggs; successively the animals were killed to determine the reduction of the infestation in comparison with the check.
For veterinary use, the administration of the compounds of this invention to the animals to be treated can be effected according to the usual veterinary techniques for ~15132130 the anthelmintic trea~ment, namely orally in the form of boil, tablets, suspensions, etc., by injections in the form of an injectable liquid or by absorption through the skin (spot on).
It is important to notice that the anthelmintic compounds object oE the present invention are endowed, unlike known anthelminthes, with a good solubility (about 20% by weight) in N-methyl-2-pyrrolidone, an injectable liquid employed in the veterinary technique.
The amounts to be given depend on various actors, among which important are the weight oE the animal to be treated, the nat~re and the severity of the infestation.
Suitable doses are at the discretion of the veterinary physician but may be within the range of 0.5 tolOO mg of the compound of formula I per Kg body weight of the host, preferably 1 to 10 mg/Kg.
Little animals need amounts of a few milligrams of anthelmintic compound, while great animals, such as cattle, sheep, etc., may need amounts of the order of grams per subject.
In practice, the active compound is usually formulated with a vehicle agent (carrier) of veterinary use, or directly in the food for the animal. The active compound may be mixed or dispersed in one of the components of the food, or utilized in the form of boil, tablets easily ingestable or capsules, drenching, suspensions, powders, pastes, salt licks, block licks, granules, pelIets feed premixes. The carrier may be also a pharmaceutic diluent or excipient of the type generally employed in the formulation of medicines; easily available products are, for example, the following: maize starch, terra alba, lactose, saccharose, calcium phosphate, gelatin, stearic acid,magnesium stearate, dextrin, agar, pectines, vegetable oils, injectable liquid carrier such as propylen glycol, N-methyl-2-pyrrolidone, and so on.
If desired other active ingredients such as other anthelmintics, food and mineral supplements may be included in the formulation.
The way of administering may vary remarkably and depends on the specific requirements.
With respect to anthelmintic activity, preferred compounds are thio-derivatives ~X=S) and sulphinyl derivatives (X=SO). Some of the samples tested for anthelmintic activity were mixtures of positional isomers ~R3 different from R4).
However the anthelmintic activity of samples of different composition is practically non-affected by the relative positional isomers ratio (see example 21).
The following examples are given to better illustrate the invention.
PreParation of 1,5,5-trichloro-3-methylhex-2-ene(A) and of 1,5,5-trichloro-2-methylhex-2-ene (B) /Mixture No 1 7 In a "Pfaudler" type autoclave of 2.5 1 capacity the following compounds were introduced under vacuum:
- l,l,l-trichloroethane (CH3-CC13) 1200 ml - isoprene (CH2=C=CH-CH2) 500 ml - Ruthenium-tris-triphenylphosphine-dichloride Ru (C6Hs)3p J 3C12 The content of the autoclave was then stirred and heated up to 90C. At this temperature an exothermic reaction began and the temperature raised to 130C.
The reaction was continued for 2 and half hours keeping the temperature between 120 and 130C, then the autoclave was left to cool at room temperature. The reaction mixture was then concentrated by evaporation at reduced pressure (20 mmHg, 40C)-_ 10 _ ~5~3280 The residue of about 800 g was diluted with 1200 mlof petroleum ether. The ruthenium complex precipitated and was quantitatively recovered by filtration. The filtrate was again concentrated b~ evaporation and the residue was distilled under reduced pressure. The fraction boiling between - 82 and 85C at 5 mmHg was gathered (690 9).
Nuclear Magnetic Resonance (NMR) analysis revealed that the collected fraction was a mixtur~ of compounds (A) an^d (B) in a ratio of about 85:15 CH - CCl - CH2 - C = CH - CH2Cl (A) (cis-trans) `
CH3 CC12 CH2 C 2 (B) (cis-trans) By operating analogously with what described in Example 1, the compounds or mixtures of compounds reported on the following Table 1, were prepared.
~ ~5~80 ~, 1 o ~ ~ ~ ~
~, .U' ~ CO
,c~ , ~
~. ~0'~ ~ ~ In ~
~ o O ~ l ~ r ~O' ~N_ _ ~_ H
C~ U ~~ ~ U ~ ~
~) C) 1:4~ ¢l 1~1 _ ~_, ~
~c m ~ m ~c m ~: m o . ~I ~ ~ ~ ~ ~ ~
~ ~ m m m m m m U) _ ~ S`l~ ~ ~ ~I C~ C~
~ ~ o o 1 i 1 1 ~
~ ~ o ::c m m 5: m m ~
~ c~ m m mm u u ~ :
r~ ~ ~
o~ o ~- J ~. U o H ¦ ~: X _ ~ t~) ~
~1 uz .. I
-2~0 .
.
_ u m o c~
_ ~: m ~ m ~ m ~: m _ _ _ _ _ _ _ _ 5~ ~ ~ I: X X :~
m m ~ ~ o c~ o c~
_ l l l l ~ C~ _ :C ~ ~ ~ ~ ~
C~ C~~ O ~ C~ ~ C~5: U
m 1l :c 1l ~ I o m .
~ _ ~ ~ ~ ~ C~ 5: 1 C~ ~:~ ~ -- ~ --~ ~ Y X ~ ~ ~ ~
-- ~ _ ~:: _ ~ ~ ~ ~::
~: o c~ o ~ ~ m ~ ~: :r: ~ c~l ~ ~ _ ~ ~ ~ ~C ~C X ~ ~ ~ ~
I
:I: ~ ~ ~ ~ ~ ~ X
C~ ~ ~ ~ ~ ~ Y '~ ~
~ ~ ~ ~, ~ ~ C~
m m m l l l l ~ ~ u m ~:
r~ ~ ~C~ ~ C~ U ~ ~ O
C~
-.
, ~ In ~g I_ c~
m~ _ ~ .....
3~81~
_~ _ ~ ~ o I
+ m ~ c~ m H H
u~ ~r ~r c~
m c~ m ~ ~ m ~ o ~ ~ U ~> C~
~: m ~ ~ ~ ~: m ~ â:~
__ .
U h _ _ m~ m ~ ~ m m m :~ :C _ _ c~ ~ ~ m c~ ~: :c ~ ~ ~ ~: :~
uUl~mU~ ~ ml I mm~ ~ U~ ~ ~ I m~mU UU~mm ~ ~ ~ ~ ~ - ~J N ~I ~ t~l O C~ r: ::~ ~ C~ ~ :C ~ ~:
U U ~) ~1 ~ l ~ (r) ~) '1 m m ,1 u ~ ~ ~ ~ u u c~ ~ ~ V m H _ ~1 1~ L~ L~ ~ L~
E~
Z8al Notes to Table 1 (a) Mixture of cis and trans isomers (b) I = isoprene (CH2=C-CH=CH2), B = butadiene ~CH2=CH-CH=CH2) (c) Approximative ratio determined by NMR spectroscopy (d) The preparation of MixtureNo lis described in Example 1 (e) Spectroscopic data of compound No 6 NMR (solvent CDC13, internal standard TMS) d, ppm:
3 1 (d-t., 2EI, JH H =5.66 Hz, JH,F
3.8-4 (m, 2H) 5.3-6.3 (m, 2H) (d.t. = doublet of triplet, m = multiplet, J = coupling constant) (f) Mixture No 9 was isolated as pure (GLC) as residue after distillation from the reactior. crude of unreacted CHC13 and isoprene.
(g) NMR spectroscopic data consistent with the assigned structure.
(h) An analogous preparation has been described by J.Tanaka et al. /Nippon Kagaku Zasshi 90, 803 (1969) ~ (100~ of isomer A).
Preparation of 1,5,5,5-tetrachloro-3-methyl-pent-2-ene (A) and of 1,5,5,5-tetrachloro-2-methyl-pent-2-ene (B) by redox-transfer catalyst.
CuC12.2H2O (2g) was introduced in an enamelled autoclave of 2.5 1 capacity.
The air was elimiriated from the autoclave and, under vacuum, the following compounds were introduced:
- a solution of n.butyl-amine (n.C4Hg-NH2) (3.~5 g) in acetonitrile (CH3C~) (300 ml) - a mixture of carbon tetrachloride (CC14) (600 ml) and isoprene (300 ml) _ 15 _ - carbon tetrachloride (200 ml).
The autoclave was then heated at 90-130C in three hours keeping the internal pressure a 7-8 atm by adding small amounts of isoprene from a small cylinder.
Then the autoclave was leEt to cool at room tempera-ture, and was opened. The content of the autoclave was distilled at reduced presSue (about 20 mmHg) in order to eliminate the volatile components from tpe reaction mixture ~isoprene, CC14 and CH3CN). The residue was distilled under high vacuum collecting all the distilled material in a single fraction which was then re-distilled collecting the fraction (570 g) boiling at 65 C (1.3 mmHg). NMR analysis revealed that the collected fraction was a mixture of compounds A and B (97% pure by GLC) in a ratio of about 70:30. An analogous preparation has been described by P. Piccardi et al. /Agric.
and Food Chem. ~ 1073 (1977) Preparation of 1,1,5-trichloro-3-methyl-penta-1,3-diene (A) and of l,1,5-trichloro-4-methyl-penta-1,3-diene (B) ~ Reaction II /
200 g of the mixture of compounds, prepared as described in Example 3, were dissolved in benzene ~240 ml).
The solution was added to a solution of NaOH ~162 g) in the presence of tetrabutylammonium iodide (n.C4H9)4N J (1.2 g).
The reaction mixture was maintained under intense stirring at 25-30C for 5 hours.
The organic layer was separated and the aqueous layer, after neutralization with hydrochloric acid, was extracted with diethylether (2 x 100 ml). The organic phases were reunited and anhydrified on anhydrous Na2SO4. The solvents were evaporated under vacuum, the residue was distilled and the fraction boiling at 50-52C (0.7 mmHg) was collected. NMR
_ 16 -~5~80 analysis revealed that the collected fraction was a mixture of compounds A and B in a ratio of about 60:40 (pure at 93% by GLC).
Preparation of 1,1- dichloro-4-methyl-S-bromo-penta-1,3-diene ccl2=cH-cH=f-cH2Br (A) By a procedure analogous to thé one described in Example 1, CC14 (243 ml) was additioned to isopentene CH2=CH-CH(CH3)2 (66 g) in the presence of RuII/(C6H5)3P ~ 3C12 (1.8 g) obtaining 1,1,1,3-tetrachloro-4-methyl-pentane (45 g) 'CCl --CH2-CH-CH-CH3 Cl C~13 The product thus obtained was dehydrohalogenated by treatment with (C2H5)3N (41.4 9) in DMF at reflux temperature - for 10 hours.
The reaction mixture was then poured in H2O (100 ml) and extracted by ethyl ether.
The organic solution was distilled and the fraction boiling at 44C (4 mmHg) consisting of 1,1-dichloro-4-methyl-penta-1,3-diene was collected (NMR consistent with the assigned structure CC12=CH-CH=f-CH3) 16.3 g of the product thus obtained were dissolved in CC14 (50 ml) and additioned with N-bromosuccinimide (19.3 g) in the presence of azobis-isobutyronitrile (100 my).
The reaction mixture was refluxed for 8 hours.
The succinimide was filtered, the solvent was eliminated under vacuum and the residue was distilled.
The fraction boiling at 93-96C/2 mmHg (14.6 g) was collected. NMR data are consistent with the structure _ 17 ~15~280 assigned to compound A.
By operating as described in Example 5 and starting from 2,5-dimethyl-hexa-2,4-diene the compound 1-bromo-2,5-dimethyl-hexa-2,4-diene was obtained (NMR consistent with the assigned structure) H3C / CH2Br / C=CH-CH=C ~
By operating analogously to what described in Example
4, the compounds (or mixtures of compounds) reported in the follbwing Table 2, were prepared.
~S~280 _ .
o ~ o ~ o ~
., ~ m .. ..
~ ~ ~ ~ o C~
.,1 ~ ~ ~ ~D I_ o ~ _, .
.
~ r In ~' P~
, ~0'~ l ,~ er ~ 0 o o~ ~ o a~ o ~ ~ .
U~
Co o~ ~ ~
~ ~ ~ ,. ~ P~ ~
~ o a~ ~ ~ e ~ XX
~1 e t ~5~)280 ~_ 'un. c. .
I N ~1 ~J t~1 . 4~--_ _ _ _ ~: m ~ m .
~ m~ :q ~ ~ m~
c~ a O u N _ _ 11 D~~r) ~_ $~ :~C U U ~C
y U V 5~ ::~ $ .
m ::c ~ Y u ~ ~ u u ~ ~ ~)~
Y ~ u-m y--m ~1~ _ ~ ". ~ ~ ~ ~c ~ ~ u ~ u u u . ., 'l ~ .~ ~ i m~
_ 20 _ Notes to Table 2 (a) Mixture of cis and trans isomers (b) Approximative ratio determined by NMR spectroscopy (c) The preparation is described in Example 4 (d) Compounds of mixture No 20 decompose when distilled, Mass-spectroscopic data (M /e) 248 (10%), 246 (10%), 167 (80~), 147 (56%), 127 (60~), 69 (30%), 53 (100%) (e) Compounds of mixture No 21 decompose when distilled Mass-spectroscopic data (M /e) 310 (8%), 30B (16%), 306 (8~), 229 (50%), 227 (50%), 148 (45%), 147 (90~), 127 (100~).
(f) The preparation is described in Example 5.
(g) The preparation is described in Example 6.
Preparation of 4-/(5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)--thio 7-2-nitro-aniline (A) and of 4- /(5,5-dichloro-2-methyl--penta-2,4-dien-1-yl)-thio 7-2-nitro-aniline (B) ~ Reaction III, X = S, R5 - H 7.
A solution of 10 g (51.2 m.moles) of 2-nitro-4-thio-cyano-aniline in 25 ml of dimethylformamide was added to a solution of 2. 26 g (51 m.moles) of sodium-boron-hydride in 25 ml of dimethylformamide. The reaction mixture was maintained under stirring at room temperature for 1 hour, whereupon 60 m.moles of the mixture of the products obtained as described in Example 3 were added.
The reaction mixture was heated to 100C for 1 hour, then it was allowed to cool down and was poured into 200 ml of H2O-It was extracted with chloroform (3 x 100 ml). The organic extracts were reunited, anhydrified with anhydrous Na2SO4, and the solvent was removed under vacuum.
_ 21 _ ~15~80 A crude product (11.9 g) was obtained, which consisted of compounds A and B in a ratio of about 55:45 (NMR) and resulted sufficiently pure for the successive step (Example 9).
Preparation of 4-/(5,5-dichloro-3-methyl-penta-2,4-dien-1-yl) thio 7-1,2-phenylenediamine (A) and of 4-~ (5,5-dichloro-2-methylpenta-2,4-dien-1-yl)-thioJ -1,2-phenylendiamine (B).
Reaction VI~
11.7 g of the crude product obtained as describecl in example 8 were added to a mixture of 200 ml of H2O and 200 ml of Cll3OH containing 45 g of Na2S2O4.
The reaction mixture was heated to 80C for 15 minutes, whereupon the inorganic salts were filtered and a methanol portion was removed under vacuum.
After extraction with chloroform (3 x 100 ml), the organic phases were reunited, anhydrified with anhydrous Na2SO4, and the solvent was removed, so obtaining a brown viscous oil composed by products A and B in a ratio of about 55:45 (NMR~.
Preparation of 5(6)-/(5,5-dichloro-3-methyl-penta-2,4-dien-1--yl)-thio 7-benzimidazole-2-methylcarbamate (A) and of 5(6)--(5,5-dichloro-2-methyl-penta-2,4-dien-1-yl)-thio ~-benzimi-dazole-2-methylcarbamate (2) Reaction VII 7 _ 8.5 g (29.4 m.moles) of the raw oil obtained as described in Example 9 were dissolved in a mixture of 35 ml of H2O, 35 ml of ethanol, 2 ml of acetic acid and 6.05 g (29.4 m.moles) of 1,3-bis-methoxycarbonyl-S-methyl-isothiourea.
The reaction mixture was heated at reflux for 2 hours.
A solid formed, which was separated by filtration and was re-crystallized by methanol and chloroform (1:1).
7 g of a mixture of compounds A and B in a ratio of ~15~28() about 55:45 (NMR) (melting point 169-170C with decomposition) were obtained.
Preparation of 5(6)-~ (5,5-dichloro-3-methyl-penta-2,4-dien-1--yl)-sulphinyl 7-benzimidazole-2-methylcarbamate (A) and of -
~S~280 _ .
o ~ o ~ o ~
., ~ m .. ..
~ ~ ~ ~ o C~
.,1 ~ ~ ~ ~D I_ o ~ _, .
.
~ r In ~' P~
, ~0'~ l ,~ er ~ 0 o o~ ~ o a~ o ~ ~ .
U~
Co o~ ~ ~
~ ~ ~ ,. ~ P~ ~
~ o a~ ~ ~ e ~ XX
~1 e t ~5~)280 ~_ 'un. c. .
I N ~1 ~J t~1 . 4~--_ _ _ _ ~: m ~ m .
~ m~ :q ~ ~ m~
c~ a O u N _ _ 11 D~~r) ~_ $~ :~C U U ~C
y U V 5~ ::~ $ .
m ::c ~ Y u ~ ~ u u ~ ~ ~)~
Y ~ u-m y--m ~1~ _ ~ ". ~ ~ ~ ~c ~ ~ u ~ u u u . ., 'l ~ .~ ~ i m~
_ 20 _ Notes to Table 2 (a) Mixture of cis and trans isomers (b) Approximative ratio determined by NMR spectroscopy (c) The preparation is described in Example 4 (d) Compounds of mixture No 20 decompose when distilled, Mass-spectroscopic data (M /e) 248 (10%), 246 (10%), 167 (80~), 147 (56%), 127 (60~), 69 (30%), 53 (100%) (e) Compounds of mixture No 21 decompose when distilled Mass-spectroscopic data (M /e) 310 (8%), 30B (16%), 306 (8~), 229 (50%), 227 (50%), 148 (45%), 147 (90~), 127 (100~).
(f) The preparation is described in Example 5.
(g) The preparation is described in Example 6.
Preparation of 4-/(5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)--thio 7-2-nitro-aniline (A) and of 4- /(5,5-dichloro-2-methyl--penta-2,4-dien-1-yl)-thio 7-2-nitro-aniline (B) ~ Reaction III, X = S, R5 - H 7.
A solution of 10 g (51.2 m.moles) of 2-nitro-4-thio-cyano-aniline in 25 ml of dimethylformamide was added to a solution of 2. 26 g (51 m.moles) of sodium-boron-hydride in 25 ml of dimethylformamide. The reaction mixture was maintained under stirring at room temperature for 1 hour, whereupon 60 m.moles of the mixture of the products obtained as described in Example 3 were added.
The reaction mixture was heated to 100C for 1 hour, then it was allowed to cool down and was poured into 200 ml of H2O-It was extracted with chloroform (3 x 100 ml). The organic extracts were reunited, anhydrified with anhydrous Na2SO4, and the solvent was removed under vacuum.
_ 21 _ ~15~80 A crude product (11.9 g) was obtained, which consisted of compounds A and B in a ratio of about 55:45 (NMR) and resulted sufficiently pure for the successive step (Example 9).
Preparation of 4-/(5,5-dichloro-3-methyl-penta-2,4-dien-1-yl) thio 7-1,2-phenylenediamine (A) and of 4-~ (5,5-dichloro-2-methylpenta-2,4-dien-1-yl)-thioJ -1,2-phenylendiamine (B).
Reaction VI~
11.7 g of the crude product obtained as describecl in example 8 were added to a mixture of 200 ml of H2O and 200 ml of Cll3OH containing 45 g of Na2S2O4.
The reaction mixture was heated to 80C for 15 minutes, whereupon the inorganic salts were filtered and a methanol portion was removed under vacuum.
After extraction with chloroform (3 x 100 ml), the organic phases were reunited, anhydrified with anhydrous Na2SO4, and the solvent was removed, so obtaining a brown viscous oil composed by products A and B in a ratio of about 55:45 (NMR~.
Preparation of 5(6)-/(5,5-dichloro-3-methyl-penta-2,4-dien-1--yl)-thio 7-benzimidazole-2-methylcarbamate (A) and of 5(6)--(5,5-dichloro-2-methyl-penta-2,4-dien-1-yl)-thio ~-benzimi-dazole-2-methylcarbamate (2) Reaction VII 7 _ 8.5 g (29.4 m.moles) of the raw oil obtained as described in Example 9 were dissolved in a mixture of 35 ml of H2O, 35 ml of ethanol, 2 ml of acetic acid and 6.05 g (29.4 m.moles) of 1,3-bis-methoxycarbonyl-S-methyl-isothiourea.
The reaction mixture was heated at reflux for 2 hours.
A solid formed, which was separated by filtration and was re-crystallized by methanol and chloroform (1:1).
7 g of a mixture of compounds A and B in a ratio of ~15~28() about 55:45 (NMR) (melting point 169-170C with decomposition) were obtained.
Preparation of 5(6)-~ (5,5-dichloro-3-methyl-penta-2,4-dien-1--yl)-sulphinyl 7-benzimidazole-2-methylcarbamate (A) and of -
5(6)- (5 5-dichloro-2-methyl-penta-2,4-dien-1-yl)-sulphinyl/-benzimidazole-2-methylcarbamate (B) eaction VIII 7 10.1 m.moles of 3-chloro-perbenzoic acid were rapidly added, under intense stirring, to a solution of 4 g (10.7 m.moles) of the mixture of products obtained as described in example 10, in 400 ml of chloroform, 200 ml of ethanol and 1.5 ml of acetic acid.
The reaction mixture was left at room temperature for 1 hour, then it was treated with an aqueous solution of NaHCO3 and successively with water until a neutral pH was attained. The organic solution was anhydrified with anhydrous Na2SO4 and the solvent was evaporated under vacuum.
The residual oil was washed with methanol and ethyl ether, and the resulting solid was re-crystallized by methanol so obtaining 3.5 g of a mixture of products A and B in a ratio of about 55:45 (melting point = 134-135C with decomposition).
Preparation of 4-/ (5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-. .
dien-l-yl)-thio /-2-nitro-aniline (A) and of 4-/ (5,6,6,6-tetrafluoro-2-methyl-hexa-2,4-dien-1-yl)-thio /-2-nitro-aniline (~) / Reaction IV and V 7.
A solution of 10.5 g of NaBN4 in 15 ml of dimethyl-3 formamide was added, at room temperature, to a solution of 5 g of 2-nitro-4-thiocyano-aniline (25.6 m.molesl in 15 ml of dimethylformamide.
_ 23 _ ~5~280 The reaction mixture was maintained under stirring at room temperature for 1 hour, whereupon 8.85 g (27 m.moles) of mixture No 2 (see Table 1), were added.
The reaction mixture was heated to 100C for 1 hour.
After cooling 4.9 ml (35 m.moles) of triethylamine were added, then it was heated to 100C for 2 hours.
The mixture was cooled and then diluted with 300 ml of H2O and extracted with chloroform (4 x 100 ml). The organic phase was anhydrified with anhydrous Na2SO4, concentrated under vacuum and was chromatographied on silica gel (eluent: ethyl ether - petroleum ether 1:1).
5.~ g (red oil) of a mixture of compounds A and B
in ratio of about 1:1 (NMR) were obtained.
Preparation of 4-/ (5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-dien-l-yl)-thio 7-1,2-phenylenediamine (A) and of 4-/ (5,6,6,6-tetrafluoro-2-methyl-hexa-2,4-dien-1-yl)-thio 7-1,2-phenylene-diamine (B) ~ Reaction VI ~
Starting from 5.7 g of the mixture of the 2-nitro-anilines obtained as described in Example 12 and operating as described in Example 9, 4.6 g of an intensely coloured oil, consisting of a mixture of compounds A and B in a ratio of about 1:1 (NMR), were obtained.
Preparation of S (6) -/ (5, 6, 5, 6-tetrafluoro-3-methyl-hexa-2,4-dien-l-yl)-thio 7-benzimidazole-2-methylcarbamate (A) and of 5(6)-~ (5,6,6,6-tetrafluoro-2-methyl-hexa-2,4-dien-1-yl)-thio 7-benzimidazole-2-methylcarbamate (B) .
~ Reaction VII 7 .
4.6 g (1.5 m.moles) of the mixture of compounds obtained as described in Example 13 were dissolved in a mixture _ 24 _ ~q3Z80 of 20 ml of H2O, 20 ml of ethanol and 0.5 ml of acetic acid containing 3.1 g (1.5 m.moles) of 1,3-bis-methoxycarbonyl-S-methyl-isothiourea. The reaction mixture was heated at reflux for 2 hours, then it was allowed to cool. A solid formed, which was separated by filtration and crystallized by methano-chloroform (1:1), so obtaining 3.7 g of a mixture of compounds A and B in a ratio of about 1:1 (melting point: 167-170 C).
Preparation of 5~6)-~ (5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-dien-1-yl)-sulphinyl 7-benzimidazole-2-methylcarbamate (A) _ and of 5(6)-~ (5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-dien-l-yl)-sulphinyl ~-benzimidazole-2-methylcarbamate (B) _ _ Reaction VIII_ 7 .
Starting from 1.3 g (3.34 m.moles) of the mixture of benzimidazole carbamates obtained as described in Example 14 and operating as described in Example 11, it was possible to obtain 0.95 g of a mixture of compounds A and B in a ratio of about 1:1 (NMR) (melting point : 147-139C~.
Preparation of 4-/ (5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-oxy 7-2-nitro-aniline (A) and of 4-~ (5,5-dichloro-2-methyl-_ penta-2,4-dien-1-yl)-oxy 7-2-nitro-aniline (B) _ .
/ Reaction III, X = O, R5 = CH3CO /.
A mixture of 10.2 g (52 m.moles) of 3-nitro-4-acetamino-phenol, 20 g of Na2CO3, 11.12 g ~60 m.moles) of the mixture No 18 (see Table 2) and 60 ml of acetone was heated at reflux for 48 hours. The reaction mixture was then allowed to cool, the inorganic salts were filtered and a part of the solvent was removed.
The resulting crude product was subjected to chromato-graphied on silica gel (eluent: ethyl ether - petroleum ether 1:1); 7.8 g of a brown crystalline solid consisting of a - ~15~Z80 mixture of compounds A and B in a ratio of about 3:2 (NMR) were obtained.
Preparation of 4-~ (5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-oxy 7-1,2-phenylenediamine (A) and of 4-~ (5,5-dichloro-2-methyl-penta-2,4-dien-1-yl)-oxy 7-1,2-phenylenediamine (B) -Reaction VI~ .
Starting from 7.5 g of the mix~ure of compounds obtained as described in Example 16 and operating as illustrated in Example 9 it was possible to obtain 6.2 g of a thick brown oil consisting of a mixture of compounds A and s in a ratio of about 3:2.
Preparation of 5(6)-~ (5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-oxy /-benzimidazole-2-methylcarbamate (A) and of 5(6)-.
(5,5-dichloro-2-methyl-penta-2,4-dien-1-yl)-oxy_7-benzimidazole-2-methyl-carbamate (B) Reaction VI / .
4.6 g of 1,3-bis-methoxycarbonyl-S-methyl-isothiourea were added to a solution of 6.2 g (22.7 m.moles) of the mixture of products obtained as described in Example 17, in 30 ml of H2O, 30 ml of ethanol and 0.8 ml of acetic acid. The reaction mixture was heated at reflux for 2 hours, whereupon it was allowed to cool. A solid formed, which was filtered and crystal-lized by methanol-chloroform, so obtaining 5.6 9 of a mixture of compounds A and B in a ratio of about 3,2 (NMR) (melting point: 183:185C).
On the following Table 3 benzimidazole-carbamates of general formula I are reported, together with their character-istics and the synthesis procedure.
~ ,~
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æ
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~ \ otn- . er æ z--~c~ ~ om .. ..
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C ~ l o l l l lla) o -- 0~ ~ ~ ~D ~
~ P~ ~_1 ~1 N ~_1 ~1 H .
m u I ~
O ~ O
x æ ~ ~ ,~
U 4~ r~
o ~ ., o u~ .
O ~ ~ In Ln CO OD
~ C Ll ~ ~ ~ ~ r~
m m ~ _ ~
æ~z--5: . ,S m ,s m ~ .
1~
X ~ ~ rS rS
,_1 rS ~S H H
P~--t,) ~ ~rS fS H H lo mO
E~ H H m, u~ u~ u~ tn u m o o . ~ X
~.\ o lu~ ~n Y Y Y Y ., / \ ~ ~ ~ ~. :~ ~ ~ ~
r~ / ~ $ ~ ~ U r~) t~ ~
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Y Y Y C~ y Y Y
o X
~ ~ ~ ~ C) ~ ~ ~
ll ll11 4~ ~ ~ ~ ~ ~r.
o r~ ~ ~ r~ ~ r~
U~ O ~ O '~ .~, 'U
r~ ,~ _ _ _ 0~ ~ O ~n ~ r co o~
m ~ ~ æ
r~ C~ U~
:~5~30 ~ K :1; K :~ :~:
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U~ ~ ~ o o o In ~ ~ ~ In LO
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~ ~ ~ ~ ~ m ~ ~ ~ m ~ ~
C~ V ~ ~C C~ U H H m m H H V C~ ~~3 m m l l H H m m~C ~ H H l l O O
m m l l H H m mu, u~ cn u, l l o o m m cn c~ u~ ~n u~ I cn u~ ~ ~ ~
C~ C~ V
~ ~ ~ X ~ ~ ~ ~ l l V V U U ~ X X X
X I ~ IC~ y U ~UlUI :C~ C~ ~
U ~) C~ ~ :~ ~::C ^ ~ U ^ U
11 U 1' U U ~ U~ $ C~ ~:~ U
-- ~-- ~ U ~ U U 11 U 11 ~: U X U ~ -- ~ -- _ ~ _ C~ 11 C~ 11 ~ C~ ~: C~ U U C~
_ ~ _ ~: U 11 U 11 I
~â Y Y c~ ~) u u c~ u u $ u u ~ ~: ~ l l I ~ 11 ll 11 11 U U C,l U X ~1: I~ C 1~ ~ 1~
ll ll 11 ll U U U U U U C~ U
O ~ ~ ~ I ll ll 11 ll l I
~ ~ ~ ~ ~I ~ ~ ~r) ~ ~ r~
u u m U u u u u c~ u c~ u .
_ _ _ I
m o ~ ~ r~ ~r u7 ~3 5~280 .
~ :~ ~ ~ ~ X
_ ul u~ O ~ , ,n In ~r. ~ ~ ,1 L~ o Ln U~ ".
~o ~ o~ o~
~ r ~o l u~ ~n, ~ l U~ ~o CO U~ ~ ~
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. _ o~ ~ ~ ~o a~ a~
.
_ _ _ _ ~ m ~: m ~: m ~ m C~ O ~ ~
C.) O '¢ ~ ~1 ~ ~HS ~ H
C H H H H m m H H m mc~ u m m m m l l ~ l l o o o o l l O O H HU~U~ U~ U~ U~ U~
. u~u~ u~u~ m m o o ~ ~ ~ :~ X~
~~C ~ ~ ~ ~ ) C~ t~ ~ o ~ Y, c I ~ ~ ~ ~C I ~ ~
11 ~ 11 5: 11 :~
11 ~ '' C) ~ ~ _ ~ _ ~ _ C~
r~ ~ ~ ~ 11 ~C ~ ~ ~C O
~ C~ XO ~ ~ o ~ ~ ~: ~ ~
-- :~ _$ ~ t~ ~ ~ o o C~ C~
Y Y C~ ~U ~ X :~ 5: ~ ~ X
X ~ ~Y Y ~, ~ v ~ c~
~ $ ~C ~ ~ lC C~ ~ C~ C~ ~ ~
~ ~ ~ ~ O C~ ~ ~C ~C X ~ $
C~ ~ ~ ~ C~ ~ ~ o C~ ~ C~ C~
~3 ~ ~D I_ 0~ a~ o ~
.
115~1280 . ~: _ U~ ~ ~
~ H P-l Z Z Z :ZI: PZ 1 O
_ . O ~
O ' O
t~ 11~ t`~ ~ _ (~ CO
o ~ Lr~ ' r~
o~ ~r o _ CO ~ 0~ ~ ~ ~ C~
~J LO
~r ~ ~:r ~ ~r ' .'1 ~ ~r H H t.) ~ H H C,) H m m ~
m ~ H
~ ~ m l ~ o o m m l o cn u~ u~ u~
. ~ ~ ~ ~: X
~r~ $ ~ :~ C~
m m ~ Y ~ ~c _ _, :~ $ :~ U
O ~ $ C~ ll ^~7 - _ Y Y Y Y Y ~C ~ O
::~ ~~ :~ ~ 5~:, O ~ ~ Y Y Y
~ ~ ~ ~7 ~ ~1 ~ Vl ~ O ~ $ :I: C~ o o ~ .
~ _ ~ ~ ~ ~ n ~D ~ 00 m ~ ~ ~ ~ ~r ~ ~r ~ _ _. _ ~5~Z80 Notes to Table 3 (a) Mixture of cis and trans isomers (b) Products 1-17 and 18-24 are reported on Table 1 and Table 2 respectively (c) Melting points have not been corrected.
dec. = decomposition, n.d. = not determined (d) Approximative ratio determined by NMR spectroscopy (e) Structures confirmed by the performed analysis NMR = Nuclear Magnetic Resonance spectroscopy IR = Infra-red spectroscopy MS = Mass spectroscopy EA = Elemental analysis (f) Prepared by a procedure analogous to the one described in Example 11, by using two equivalents of 3-chloro-perbenzoic acid.
(g) Mixture 28/3 is described in Example No 21 Compounds of general formula I were tested for anthelmintic activity acc~rding to the procedure described at page 11.
Samples No 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 44, 45 and 47 (see Table 3) tested against Gut-nematodes in infested sheeps, proved to be completely effective (90-100~ reduction of infestation) at the dose of 5 mg/Kg of body weight.
Samples No 28, 29, 35 and 40 tested against Flukes (Fasciola) in infested sheeps, proved to be completely effective (90-100% reduction oE infestation) at the dose of 5 ~g/Kg of body weight.
Samples No 32 and 44 tested against Lungworms (Dictyocaulus) in infested sheeps, proved to be completely effective (90-100% reduction of infestation) at the dose of 31 ~
l~S~Z80 5 and 2.5 mg/Kg of body weight respectively.
Anthelmintic activity of positional isomers mixtures having different isomeric composition.
Sample No 28 (see Table 3) is a mixture of compound A
and compound B in the ratio A/B = 55:45 CC12=CH-C(CH3)=CH-cH2-s ~ NH-coocH3 (A) H
CC12=CH-CH=C(CH3)-CH2-S ~ O X ~ NH-COOCH3 (B) ~, N
Sample No 48 (see Table 3) is compound B (100%).
A mixture consisting of compounds a and b in the ratio a/b = 75:25 (NMR) CC12=CH-C(CH3)=CH-CH2Cl (a) CC12=CH-CH=C(CH3)-CH2Cl (b) was distilled at reduced pressure.
The following fractions were collected:
Fraction B.p. Composition No (C/mmHg) a/b (NMR) , 1 50-54/0.5 90:10 2 54-57/0.5 80:20 3 5?/0.5 70:30 From fractions 1 and 3 independently and by operating as described in Examples 8-10, the corresponding benzimidazole-carbamate derivatives (Samples 28/1 and 28/3) were prepared.
Sample 28/1 A/B = 90:10 (NMR) m.p. = 163-5 C
Sample 28/3 AJB = 70:30 (NMR) m.p. = 160-5 C
Samples 28, 28/1, 28/3 and 48 were separately tested for anthelmintic activity against Gut-nematodes in infested sheeps.
The obtained activity data are reported on tne following Table 4 and are expressed according to the following scale of values:
O O-10~ reduction o infestation 1 Il-25% reduction 2 26-60~ reduction 3 61-90% reduction 4 91-100% reduction Sample Compositions dose Activity No of Sample (~) (mg/Kg) l 28 A=55, B=45 5 4 28/1 A=90, B=10 5 4 - 28/3 A=70, B=30 5 4 48 A=0 , B=100 3 SUPPL~;M~;~TARY DISCLOSVRE
Example 22 Activity against ~rugia pahangi (Filarioidea) n vivo Brugia pahangi adult worm transplant screen.
Young male adult birds were infested with large numbers of larvae by the intraperitoneal route. 60 days later adult worm were rec~vered, washed, sexed and counted into groups of 10 female and 5 male. These were then transplanted into the peritoneal cavities of naive (normal) birds. Following a recovery period, the compound to be tested was administered at 100 mg/kg for 5 consecutiye days by subcutaneous injection.
The compound was formulated in 1~ Tween 80 (trademark).
Each compound was tested in two animals. If the compound was inactive a worm recovery of 85-90% was expected;
this was then considered to be a pseudo-control. In this way control~> groups of 20 or more animals can be used, against which active compounds were compared. The selection of pseudo-controls is thus subjective but the hypothesis tha~t a compound i8 inactive was tested by the <sF test. If the variances of the pseudo-con-trols were homogeneous, then the active compounds were tested against thi~group by the <~student t test.
At autopsy (32 days after administration of the final dose of compound), the peritoneal fluid was also examined for the presence of microfilariae.
When these were absent, present in only small numbers, or abnorma~, the adult worms were examlned to determine if the compound has effected em~ryogenesis and/or spermetogenesis.
Reference to the F test and <~student t test maybefound in Snedecor and Cochran, Statistical Methods, published by Iowa State University Press at pages 258-268.
- _ 34 _ llSV~30 The following scores were allocated according to the pe~ce~tage worm reduc~ion observed.
Percentage worm reduction . Score 0 - 10% 0 11 - 25%
26 - 60% 2 61- 90% 3 91 -100% 4 ^ Samples n~ 25, 29, 35, 44 and 45 (see Table 3' reported ~ereinafter) tested against Brugia ~ahangi according to the above reported procedure proved to be completely effective (91-100~ reduct~on o~ infes~ion, score 4). - -z80 ~: I
o I l ¦
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The reaction mixture was left at room temperature for 1 hour, then it was treated with an aqueous solution of NaHCO3 and successively with water until a neutral pH was attained. The organic solution was anhydrified with anhydrous Na2SO4 and the solvent was evaporated under vacuum.
The residual oil was washed with methanol and ethyl ether, and the resulting solid was re-crystallized by methanol so obtaining 3.5 g of a mixture of products A and B in a ratio of about 55:45 (melting point = 134-135C with decomposition).
Preparation of 4-/ (5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-. .
dien-l-yl)-thio /-2-nitro-aniline (A) and of 4-/ (5,6,6,6-tetrafluoro-2-methyl-hexa-2,4-dien-1-yl)-thio /-2-nitro-aniline (~) / Reaction IV and V 7.
A solution of 10.5 g of NaBN4 in 15 ml of dimethyl-3 formamide was added, at room temperature, to a solution of 5 g of 2-nitro-4-thiocyano-aniline (25.6 m.molesl in 15 ml of dimethylformamide.
_ 23 _ ~5~280 The reaction mixture was maintained under stirring at room temperature for 1 hour, whereupon 8.85 g (27 m.moles) of mixture No 2 (see Table 1), were added.
The reaction mixture was heated to 100C for 1 hour.
After cooling 4.9 ml (35 m.moles) of triethylamine were added, then it was heated to 100C for 2 hours.
The mixture was cooled and then diluted with 300 ml of H2O and extracted with chloroform (4 x 100 ml). The organic phase was anhydrified with anhydrous Na2SO4, concentrated under vacuum and was chromatographied on silica gel (eluent: ethyl ether - petroleum ether 1:1).
5.~ g (red oil) of a mixture of compounds A and B
in ratio of about 1:1 (NMR) were obtained.
Preparation of 4-/ (5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-dien-l-yl)-thio 7-1,2-phenylenediamine (A) and of 4-/ (5,6,6,6-tetrafluoro-2-methyl-hexa-2,4-dien-1-yl)-thio 7-1,2-phenylene-diamine (B) ~ Reaction VI ~
Starting from 5.7 g of the mixture of the 2-nitro-anilines obtained as described in Example 12 and operating as described in Example 9, 4.6 g of an intensely coloured oil, consisting of a mixture of compounds A and B in a ratio of about 1:1 (NMR), were obtained.
Preparation of S (6) -/ (5, 6, 5, 6-tetrafluoro-3-methyl-hexa-2,4-dien-l-yl)-thio 7-benzimidazole-2-methylcarbamate (A) and of 5(6)-~ (5,6,6,6-tetrafluoro-2-methyl-hexa-2,4-dien-1-yl)-thio 7-benzimidazole-2-methylcarbamate (B) .
~ Reaction VII 7 .
4.6 g (1.5 m.moles) of the mixture of compounds obtained as described in Example 13 were dissolved in a mixture _ 24 _ ~q3Z80 of 20 ml of H2O, 20 ml of ethanol and 0.5 ml of acetic acid containing 3.1 g (1.5 m.moles) of 1,3-bis-methoxycarbonyl-S-methyl-isothiourea. The reaction mixture was heated at reflux for 2 hours, then it was allowed to cool. A solid formed, which was separated by filtration and crystallized by methano-chloroform (1:1), so obtaining 3.7 g of a mixture of compounds A and B in a ratio of about 1:1 (melting point: 167-170 C).
Preparation of 5~6)-~ (5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-dien-1-yl)-sulphinyl 7-benzimidazole-2-methylcarbamate (A) _ and of 5(6)-~ (5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-dien-l-yl)-sulphinyl ~-benzimidazole-2-methylcarbamate (B) _ _ Reaction VIII_ 7 .
Starting from 1.3 g (3.34 m.moles) of the mixture of benzimidazole carbamates obtained as described in Example 14 and operating as described in Example 11, it was possible to obtain 0.95 g of a mixture of compounds A and B in a ratio of about 1:1 (NMR) (melting point : 147-139C~.
Preparation of 4-/ (5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-oxy 7-2-nitro-aniline (A) and of 4-~ (5,5-dichloro-2-methyl-_ penta-2,4-dien-1-yl)-oxy 7-2-nitro-aniline (B) _ .
/ Reaction III, X = O, R5 = CH3CO /.
A mixture of 10.2 g (52 m.moles) of 3-nitro-4-acetamino-phenol, 20 g of Na2CO3, 11.12 g ~60 m.moles) of the mixture No 18 (see Table 2) and 60 ml of acetone was heated at reflux for 48 hours. The reaction mixture was then allowed to cool, the inorganic salts were filtered and a part of the solvent was removed.
The resulting crude product was subjected to chromato-graphied on silica gel (eluent: ethyl ether - petroleum ether 1:1); 7.8 g of a brown crystalline solid consisting of a - ~15~Z80 mixture of compounds A and B in a ratio of about 3:2 (NMR) were obtained.
Preparation of 4-~ (5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-oxy 7-1,2-phenylenediamine (A) and of 4-~ (5,5-dichloro-2-methyl-penta-2,4-dien-1-yl)-oxy 7-1,2-phenylenediamine (B) -Reaction VI~ .
Starting from 7.5 g of the mix~ure of compounds obtained as described in Example 16 and operating as illustrated in Example 9 it was possible to obtain 6.2 g of a thick brown oil consisting of a mixture of compounds A and s in a ratio of about 3:2.
Preparation of 5(6)-~ (5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-oxy /-benzimidazole-2-methylcarbamate (A) and of 5(6)-.
(5,5-dichloro-2-methyl-penta-2,4-dien-1-yl)-oxy_7-benzimidazole-2-methyl-carbamate (B) Reaction VI / .
4.6 g of 1,3-bis-methoxycarbonyl-S-methyl-isothiourea were added to a solution of 6.2 g (22.7 m.moles) of the mixture of products obtained as described in Example 17, in 30 ml of H2O, 30 ml of ethanol and 0.8 ml of acetic acid. The reaction mixture was heated at reflux for 2 hours, whereupon it was allowed to cool. A solid formed, which was filtered and crystal-lized by methanol-chloroform, so obtaining 5.6 9 of a mixture of compounds A and B in a ratio of about 3,2 (NMR) (melting point: 183:185C).
On the following Table 3 benzimidazole-carbamates of general formula I are reported, together with their character-istics and the synthesis procedure.
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C ~ l o l l l lla) o -- 0~ ~ ~ ~D ~
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m u I ~
O ~ O
x æ ~ ~ ,~
U 4~ r~
o ~ ., o u~ .
O ~ ~ In Ln CO OD
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m m ~ _ ~
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~ _ ~ ~ ~ ~ n ~D ~ 00 m ~ ~ ~ ~ ~r ~ ~r ~ _ _. _ ~5~Z80 Notes to Table 3 (a) Mixture of cis and trans isomers (b) Products 1-17 and 18-24 are reported on Table 1 and Table 2 respectively (c) Melting points have not been corrected.
dec. = decomposition, n.d. = not determined (d) Approximative ratio determined by NMR spectroscopy (e) Structures confirmed by the performed analysis NMR = Nuclear Magnetic Resonance spectroscopy IR = Infra-red spectroscopy MS = Mass spectroscopy EA = Elemental analysis (f) Prepared by a procedure analogous to the one described in Example 11, by using two equivalents of 3-chloro-perbenzoic acid.
(g) Mixture 28/3 is described in Example No 21 Compounds of general formula I were tested for anthelmintic activity acc~rding to the procedure described at page 11.
Samples No 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 44, 45 and 47 (see Table 3) tested against Gut-nematodes in infested sheeps, proved to be completely effective (90-100~ reduction of infestation) at the dose of 5 mg/Kg of body weight.
Samples No 28, 29, 35 and 40 tested against Flukes (Fasciola) in infested sheeps, proved to be completely effective (90-100% reduction oE infestation) at the dose of 5 ~g/Kg of body weight.
Samples No 32 and 44 tested against Lungworms (Dictyocaulus) in infested sheeps, proved to be completely effective (90-100% reduction of infestation) at the dose of 31 ~
l~S~Z80 5 and 2.5 mg/Kg of body weight respectively.
Anthelmintic activity of positional isomers mixtures having different isomeric composition.
Sample No 28 (see Table 3) is a mixture of compound A
and compound B in the ratio A/B = 55:45 CC12=CH-C(CH3)=CH-cH2-s ~ NH-coocH3 (A) H
CC12=CH-CH=C(CH3)-CH2-S ~ O X ~ NH-COOCH3 (B) ~, N
Sample No 48 (see Table 3) is compound B (100%).
A mixture consisting of compounds a and b in the ratio a/b = 75:25 (NMR) CC12=CH-C(CH3)=CH-CH2Cl (a) CC12=CH-CH=C(CH3)-CH2Cl (b) was distilled at reduced pressure.
The following fractions were collected:
Fraction B.p. Composition No (C/mmHg) a/b (NMR) , 1 50-54/0.5 90:10 2 54-57/0.5 80:20 3 5?/0.5 70:30 From fractions 1 and 3 independently and by operating as described in Examples 8-10, the corresponding benzimidazole-carbamate derivatives (Samples 28/1 and 28/3) were prepared.
Sample 28/1 A/B = 90:10 (NMR) m.p. = 163-5 C
Sample 28/3 AJB = 70:30 (NMR) m.p. = 160-5 C
Samples 28, 28/1, 28/3 and 48 were separately tested for anthelmintic activity against Gut-nematodes in infested sheeps.
The obtained activity data are reported on tne following Table 4 and are expressed according to the following scale of values:
O O-10~ reduction o infestation 1 Il-25% reduction 2 26-60~ reduction 3 61-90% reduction 4 91-100% reduction Sample Compositions dose Activity No of Sample (~) (mg/Kg) l 28 A=55, B=45 5 4 28/1 A=90, B=10 5 4 - 28/3 A=70, B=30 5 4 48 A=0 , B=100 3 SUPPL~;M~;~TARY DISCLOSVRE
Example 22 Activity against ~rugia pahangi (Filarioidea) n vivo Brugia pahangi adult worm transplant screen.
Young male adult birds were infested with large numbers of larvae by the intraperitoneal route. 60 days later adult worm were rec~vered, washed, sexed and counted into groups of 10 female and 5 male. These were then transplanted into the peritoneal cavities of naive (normal) birds. Following a recovery period, the compound to be tested was administered at 100 mg/kg for 5 consecutiye days by subcutaneous injection.
The compound was formulated in 1~ Tween 80 (trademark).
Each compound was tested in two animals. If the compound was inactive a worm recovery of 85-90% was expected;
this was then considered to be a pseudo-control. In this way control~> groups of 20 or more animals can be used, against which active compounds were compared. The selection of pseudo-controls is thus subjective but the hypothesis tha~t a compound i8 inactive was tested by the <sF test. If the variances of the pseudo-con-trols were homogeneous, then the active compounds were tested against thi~group by the <~student t test.
At autopsy (32 days after administration of the final dose of compound), the peritoneal fluid was also examined for the presence of microfilariae.
When these were absent, present in only small numbers, or abnorma~, the adult worms were examlned to determine if the compound has effected em~ryogenesis and/or spermetogenesis.
Reference to the F test and <~student t test maybefound in Snedecor and Cochran, Statistical Methods, published by Iowa State University Press at pages 258-268.
- _ 34 _ llSV~30 The following scores were allocated according to the pe~ce~tage worm reduc~ion observed.
Percentage worm reduction . Score 0 - 10% 0 11 - 25%
26 - 60% 2 61- 90% 3 91 -100% 4 ^ Samples n~ 25, 29, 35, 44 and 45 (see Table 3' reported ~ereinafter) tested against Brugia ~ahangi according to the above reported procedure proved to be completely effective (91-100~ reduct~on o~ infes~ion, score 4). - -z80 ~: I
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Claims (39)
1. Benzimidazole-carbamates substituted in position 5 of general formula:
(I) wherein:
R = C1-C4 alkyl, R1 and R2 (like or unlike each other) = H, halogen, methyl optionally substituted by one or more halogen atoms, R3 and R4 (like or unlike each other) = H, Cl, CH3, X = O, S, SO, SO2.
(I) wherein:
R = C1-C4 alkyl, R1 and R2 (like or unlike each other) = H, halogen, methyl optionally substituted by one or more halogen atoms, R3 and R4 (like or unlike each other) = H, Cl, CH3, X = O, S, SO, SO2.
2. Benzimidazole-carbamates according to claim 1 in which R1 is halogen, CH3, CF3 and R is H, halogen, CH3; R3 and R4 = H, CH3, in which at least one is H; R and X have the meanings specified in claim 1.
3. Benzimidazole-carbamates according to claim 2, in which R = CH3 and R1, R2, R3, R4 and X have the meanings specified in claim 2.
4. Benzimidazole-carbamates according to claim 3 in which R1 and R2 = halogen and X = O, S, SO, SO2.
5. Benzimidazole-carbamates according to claim 4 in which R1=R2=Cl, R3=R4=H and X=S.
6. Benzimidazole-carbamates according to claim 4 in which R1=R2=Cl, R3=R4 = H and X = SO.
7. Benzimidazole-carbamates according to claim 4 in which R1=R2=Cl, R3=R4=H and X = SO2.
8. Benzimidazole-carbamates according to claim 4 in which R1=R2=Cl, R3 and R4 (different from each other) = H, CH3 and X = O.
9. Benzimidazole-carbamates according to claim 4 in which R1=R2=Cl, R3 and R4 (different from each other) = H, CH3 and X = S.
10. Benzimidazole-carbamates according to claim 4 in which R1=R2=Cl, R3 and R4 (different from each other) = H, CH3, and X = SO.
11. Benzimidazole-carbamates according to claim 4 in which R1=R2=Cl, R3 and R4 (different from each other) = H, CH3 and X = SO2.
12. Benzimidazole-carbamates according to claim 4 in which R1=R2=Br, R3 and R4 (different from each other) = H, CH3 and X = S.
13. Benzimidazole-carbamates according to claim 4 in which R1=R2=Br, R3 and R4 (different from each other) = H, CH3 and X = SO.
14. Benzimidazole-carbamates according to claim 4 in which R1=R2=F, R3 and R4 (different from each other) = H, CH3 and X = S.
15. Benzimidazole-carbamates according to claim 4 in which R1=R2=F, R3 and R4 (different from each other) = H, CH3 and X = SO.
16. Benzimidazole-carbamates according to claim 3 in which R1 = CF3, R2 = H, halogen and X= O, S, SO, SO2.
17. Benzimidazole-carbamates according to claim 16 in which R1 = CF3, R2 = H, R3 and R4 (different from each other) = H, CH3 and X= S.
18. Benzimidazole-carbamates according to claim 16 in which R1 = CF3, R2 = H, R3 and R4 (different from each other) =
H, CH3 and X = SO.
H, CH3 and X = SO.
19. Benzimidazole-carbamates according to claim 15 in which R1 = CF3, R2 = F, R3 and R4 (different from each other) =
H, CH3 and X = S.
H, CH3 and X = S.
20. Benzimidazole-carbamates according to claim 16 in which R1 = CF3, R2 = F, R3 and R4 (different from each other) = H, CH3 and X = SO.
21. Benzimidazole-carbamates according to claim 3 in which R1 = CH3, R = H, halogen and X = O, S, SO, SO2.
22. Benzimidazole-carbamates according to claim 21 in which R1 = CH3, R2 = Cl, R3=R4=H and X = S.
23. Benzimidazole-carbamates according to claim 21 in which R1=CH3, R2=Cl, R3=R4=H and X = SO.
24. Benzimidazole-carbamates according to claim 21 in which R1 = CH3, R2 = Cl, R3=R4= H and X = SO2.
25. Benzimidazole-carbamates according to claim 21 in which R1 = CH3, R2 = Cl, R3 and R4 (different from each other) = H, CH3 and X = S.
26. Benzimidazole-carbamates according to claim 21 in which R1 = CH3, R2 = C1, R3 and R4 (different from each other) = H, CH3 and X = SO.
27. Benzimidazole-carbamates according to claim 21 in which R1 = CH3, R2 = Cl, R3 and R4 (different from each other) = H, CH3 and X = SO2.
28. Benzimidazole-carbamates according to claim 3 in which R1 = R2 = CH3 and X - O, S, SO, SO2.
29. Benzimidazole-carbamates according to claim 28 in which R1 = R2 = R4 = CH3, R3 = H, and X = S.
30. Benzimidazole-carbamates according to claim 28 in which R1 = R2 = R4 = CH3, R3 = H, and X = SO.
31. A process for preparing the compounds of claim 1, characterized in that a compound of formula:
(D) (in which X = O,S) is either reacted with a compound of formula:
(C) (in which R1, R2, R3 and R4 have the meanings specified in claim 1 and Z = Cl, Br), or reacted with a compound of formula:
(C') [in which R1, R2, R3 and R4 have the meanings specified in claim 1 and Z and Z' (equal to or different from each other) = Cl,Br]
and the product thus obtained is dehydrohalogenated in the presence of a base, to prepare a 2-nitroanaline of formula:
(E) (in which R1, R2, R3 and R4 have the same meanings as specified in claim 1, and X = O, S) which is thereafter reacted with re-ducers, so providing the corresponding 1,2-phenylenediamine, which by reaction with 1,3-bis-alkoxycarbonyl-S-methyl-isothiou-rea, provides the compounds of claim 1, in which X = O or X = S, and from these latter, by treatment with peracids, the compounds of claim 1, wherein X = SO, SO2, are obtained, accord-ing to the following reaction scheme:
(F)
(D) (in which X = O,S) is either reacted with a compound of formula:
(C) (in which R1, R2, R3 and R4 have the meanings specified in claim 1 and Z = Cl, Br), or reacted with a compound of formula:
(C') [in which R1, R2, R3 and R4 have the meanings specified in claim 1 and Z and Z' (equal to or different from each other) = Cl,Br]
and the product thus obtained is dehydrohalogenated in the presence of a base, to prepare a 2-nitroanaline of formula:
(E) (in which R1, R2, R3 and R4 have the same meanings as specified in claim 1, and X = O, S) which is thereafter reacted with re-ducers, so providing the corresponding 1,2-phenylenediamine, which by reaction with 1,3-bis-alkoxycarbonyl-S-methyl-isothiou-rea, provides the compounds of claim 1, in which X = O or X = S, and from these latter, by treatment with peracids, the compounds of claim 1, wherein X = SO, SO2, are obtained, accord-ing to the following reaction scheme:
(F)
32. Method for fighting infestations due to helmin-thes in domestic and breeding animals, characterized in that an effective amount of one or more of the compounds of claim 1, either as such or in form of suitable composition, is given to the animals to be treated.
33. A method according to claim 32, characterized in that one or more of the compounds of claim 1 are administered orally to the infested animals in form of a suitable composi-tion or admixed with the food.
34. A method according to claim 32, characterized in that one or more of the compounds of claim 1 are administered by injection to the infested animals in form of suitable liquid injectable compositions.
35. A method according to claim 32, characterized in that one or more of the compounds of claim 1 are administered to the infested animals by absorption through the skin, in form of suitable compositions.
36. A method according to claim 32, characterized in that the anthelmintic agent is one or more of the compounds of claim 4.
37. A method according to claim 32, characterized in that the anthelmintic agent is one or more of the compounds of claim 16.
38. A method according to claim 32, characterized in that the anthelmintic agent is one or more of the compounds of claim 21.
39. A method according to claim 32, characterized in that the anthelmintic agent is one or more of the compounds of claim 28.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT30618/78A IT1100788B (en) | 1978-12-06 | 1978-12-06 | Benzimidazole-carbamates |
| IT30618A/78 | 1978-12-06 | ||
| IT26734A/79 | 1979-10-24 | ||
| IT26734/79A IT1125577B (en) | 1979-10-24 | 1979-10-24 | 5(6)-Substd. benzimidazole-2-carbamate ester(s) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1150280A true CA1150280A (en) | 1983-07-19 |
Family
ID=26328693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000341291A Expired CA1150280A (en) | 1978-12-06 | 1979-12-05 | Benzimidazole-carbamates |
Country Status (22)
| Country | Link |
|---|---|
| AR (1) | AR222847A1 (en) |
| AT (1) | AT364832B (en) |
| AU (1) | AU536133B2 (en) |
| BR (1) | BR7907892A (en) |
| CA (1) | CA1150280A (en) |
| CS (1) | CS242859B2 (en) |
| DD (1) | DD147539A5 (en) |
| DE (1) | DE2948885A1 (en) |
| DK (1) | DK157547C (en) |
| ES (1) | ES8101560A1 (en) |
| FR (2) | FR2443461A1 (en) |
| GB (1) | GB2037758B (en) |
| HU (1) | HU183093B (en) |
| IE (1) | IE49976B1 (en) |
| IL (1) | IL58885A (en) |
| KE (1) | KE3326A (en) |
| MX (1) | MX6197E (en) |
| NL (1) | NL7908719A (en) |
| NZ (1) | NZ192311A (en) |
| PL (1) | PL126932B1 (en) |
| SE (1) | SE445641B (en) |
| SU (1) | SU1169532A3 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU628671B2 (en) * | 1989-10-12 | 1992-09-17 | Michael John Crooks | Non-aqueous micellar solutions of various drugs |
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 |
| IT1076022B (en) * | 1977-04-20 | 1985-04-22 | Montedison Spa | ANTIELMINTIC BENZIMIDAZOLCARBAMMATES |
| HU177182B (en) * | 1977-05-10 | 1981-08-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing tetraamino-diphenyl-disulfide derivatives |
| AU4185678A (en) * | 1978-01-09 | 1979-07-19 | Squibb & Sons Inc | Derivatives of benzimidazoles |
-
1979
- 1979-12-03 DD DD79217331A patent/DD147539A5/en not_active IP Right Cessation
- 1979-12-03 SE SE7909932A patent/SE445641B/en not_active IP Right Cessation
- 1979-12-03 NL NL7908719A patent/NL7908719A/en not_active Application Discontinuation
- 1979-12-03 DK DK512179A patent/DK157547C/en not_active IP Right Cessation
- 1979-12-04 CS CS798397A patent/CS242859B2/en unknown
- 1979-12-04 MX MX798521U patent/MX6197E/en unknown
- 1979-12-04 BR BR7907892A patent/BR7907892A/en unknown
- 1979-12-04 NZ NZ192311A patent/NZ192311A/en unknown
- 1979-12-04 AU AU53417/79A patent/AU536133B2/en not_active Ceased
- 1979-12-05 SU SU792847574A patent/SU1169532A3/en active
- 1979-12-05 FR FR7929894A patent/FR2443461A1/en active Granted
- 1979-12-05 CA CA000341291A patent/CA1150280A/en not_active Expired
- 1979-12-05 HU HU79MO1070A patent/HU183093B/en not_active IP Right Cessation
- 1979-12-05 IL IL58885A patent/IL58885A/en unknown
- 1979-12-05 DE DE19792948885 patent/DE2948885A1/en active Granted
- 1979-12-05 AT AT0770279A patent/AT364832B/en not_active IP Right Cessation
- 1979-12-05 ES ES486612A patent/ES8101560A1/en not_active Expired
- 1979-12-05 IE IE2347/79A patent/IE49976B1/en unknown
- 1979-12-05 GB GB7941960A patent/GB2037758B/en not_active Expired
- 1979-12-06 AR AR279174A patent/AR222847A1/en active
- 1979-12-06 PL PL1979220185A patent/PL126932B1/en unknown
-
1980
- 1980-03-21 FR FR8006331A patent/FR2445306A1/en active Granted
-
1983
- 1983-09-01 KE KE3326A patent/KE3326A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU536133B2 (en) | 1984-04-19 |
| IE49976B1 (en) | 1986-01-22 |
| DE2948885C2 (en) | 1990-05-23 |
| FR2445306A1 (en) | 1980-07-25 |
| PL126932B1 (en) | 1983-09-30 |
| MX6197E (en) | 1984-12-13 |
| IL58885A0 (en) | 1980-03-31 |
| ATA770279A (en) | 1981-04-15 |
| FR2443461B1 (en) | 1983-05-13 |
| BR7907892A (en) | 1980-07-22 |
| NZ192311A (en) | 1982-12-21 |
| ES486612A0 (en) | 1980-12-16 |
| DD147539A5 (en) | 1981-04-08 |
| CS839779A2 (en) | 1985-08-15 |
| SE7909932L (en) | 1980-06-07 |
| DK157547C (en) | 1990-06-25 |
| PL220185A1 (en) | 1980-12-01 |
| AR222847A1 (en) | 1981-06-30 |
| CS242859B2 (en) | 1986-05-15 |
| AU5341779A (en) | 1980-06-12 |
| HU183093B (en) | 1984-04-28 |
| DE2948885A1 (en) | 1980-06-19 |
| IE792347L (en) | 1980-06-06 |
| GB2037758A (en) | 1980-07-16 |
| KE3326A (en) | 1983-09-16 |
| AT364832B (en) | 1981-11-25 |
| DK157547B (en) | 1990-01-22 |
| DK512179A (en) | 1980-06-07 |
| FR2445306B1 (en) | 1982-12-10 |
| SE445641B (en) | 1986-07-07 |
| NL7908719A (en) | 1980-06-10 |
| SU1169532A3 (en) | 1985-07-23 |
| IL58885A (en) | 1985-01-31 |
| FR2443461A1 (en) | 1980-07-04 |
| ES8101560A1 (en) | 1980-12-16 |
| GB2037758B (en) | 1983-05-05 |
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