Method of preparing salicylanilide derivatives

专利摘要:
Compounds of the class of salicylanilides substituted in the 4-position of the anilino moiety with a -CH(CN)-Ar group wherein Ar is phenyl, substituted phenyl, thienyl, halothienyl or naphthalenyl, said salicylanilides being useful as parasiticides.
公开号:SU728713A3
申请号:SU762338051
申请日:1976-03-18
公开日:1980-04-15
发明作者:А.С.Жансен Марсель；К.Сипидо Виктор
申请人:Жансен Фармасетика Н.В. (Фирма)；
IPC主号:

专利说明:

one
The invention relates to a process for the preparation of new salicylanilide derivatives which possess para-eicidal activity.
The proposed salicylanilides differ from the known ones in that (among other things) they have an oC-cyanoarylmethyl group in position 4 of the aniline moiety of the molecule.
The proposed salicylanilide derivatives are a compound of the general formula (1)
 %
C-NH - / USN-LH
h oh kb
OR its pharmaceutically acceptable
salt,
where Cc is hydrogen, halo, lower alkyl or nitro;
RZ hydrogen or hlsr;
R is hydrogen, halo or nitro; R is hydrogen, hydroxy group or methyl methyl with the proviso that when R is hydroxy or methyl, then R is hydrogen;
Rj - hydrogen, chlorine or lower
alkyl; R is hydrogen, chlorine, cyano or
trifluoromethyl group; Ar is phenyl, substituted phenyl, thienyl, halothienyl or naphthyl, while substituted phenyl means phenyl having 1-3 substituents independently selected from the group,
consisting of a halogen, lower alkyl, lower alkoxyl or trifluoromethyl group.
Lower alkyl may have a straight or branched chain and contain 1-5 carbon atoms, for example methyl, prolyl, isopropyl, butyl, tert-butyl, pentyl, etc .; halogen means bromine, fluorine, chlorine and iodine. Preferred substituted phenyls Ar are halo-phenyl, dihalo-phenyl, trihalo 1-phenyl, lower alkyl-phenyl, lower alkoxy-phenyl, trifluoromethyl-phenyl, and halo-trifluoromethyl-phenyl. The preferred thienyl is vl etc 2-thienyl, and the preferred haloenyl is 5-chloro-2-thienyl,
The invention also relates to pharmacologically acceptable salts for the substitution or addition of an amine of the compounds of the general formula (1). Examples of such salts are metal salts, for example sodium, potassium, calcium, copper or iron, and salts of amines, such as piperidine, piperazine, triethylamine, K-methyl glucose, methylamine, (X.-methy benzylamine or ethanolamine. Compounds of general formula ( I) is obtained using the known method of producing salicylic anilides, by reacting respectively a substituted salicylic acid or its reactive functional derivative with a correspondingly substituted aniline or its reactive derivative (1) The process for preparing compounds of general formula (I) consists in the condensation of a salicylic acid acid halide of general formula (C), preferably RV OH acid chloride with a substituted amine of the general form ;; - L1 1 dK and Ar have the indicated values. The process is carried out in an inert organic solvent medium, from which the target products of the general formula (I) are isolated by conventional methods, for example, by evaporation of the solvent and recrystallization of the residue. In order to increase the reaction rate, the temperature can be raised, preferably the boiling point is reflux. A suitable base can be added to bind the acid which is liberated during the reaction, for example NfN-di-ethylethanamine, pyridine. As an inert organic solvent, you can use any solvent that does not react during the reaction with p agents of the general formulas (P) and (W) f such as ethers, such as dioxane, tetrahydrofuran, diethyl ether, aromatic hydrocarbons, as benzene, toluene, xylene, chlorinated hydrocarbons, such as chloroform, methylene chloride. Rn-cn-Cn + zyl.e / "°" IV} U / TEBM fv) Re Cccicylic acids, as well as their acid halide of the general formula {and) and esters, including the phenyl esters of the general formula, are known and can be obtained by known in ways. Anilines of general formula (m) can be obtained in several ways. For example, they can be obtained: a) by reacting the corresponding ariladetonitrile of general formula (J5) with an appropriately substituted 4-aloidrobrobenzene of general formula (Y) in the presence of a suitable strong base in a suitable inert organic solvent, or b) sequential reduction of the nitro group in the compound (L) thus obtained using standard nitro group reduction techniques, for example, a metallic circus in acetic acid e, metallic iron and ammonium chloride, sodium dithionite or catalytic hydrogenation using, for example, palladium on carbon catalysts. Suitable bases for the reaction of the compound (W) with the compound {N) are, for example, alkali metal hydrates and alkali metal hydride, such as sodium amide and sodium hydride, alkali metal alkoxides, such as sodium ethoxide; alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide. Suitable solvents for this reaction are inert organic solvents, for example aromatic hydrocarbons such as benzene, toluene, xylene, and ethers such as dioxane, tetrahydrofuran, diethyl ether. Good results are obtained when using potassium hydroxide in pyridine. The traditional and most preferred method of carrying out reactions. Compound (W) with Compound () is a known method 2. Typical in reactions of this type is the use of concentrated aqueous alkali, for example 4060% sodium hydroxide, and a suitable inert organic solvent that is not miscible with water, for example benzene , toluene, xylene, tetrahydrofuran, methylene chloride, in the presence of a suitable quaternary ammonium catalyst, preferably N, H, K-triethylbenzenemethanammonium chloride (TABMAX), The above reactions proceed according to the schemes "(-" And Ogi .A Iij: f: f : v L
At the same time, amines of the general formula (§) can be obtained by condensation of arylacetonitrile of the general formula (v) with nitrobenzene of the general formula (YP) to obtain phenylcyanomethylenequinone oxime of the general formula (br). Reduction of the compound (III) to obtain the compound (n}) can be carried out with a suitable reducing agent.
NOj
-f methanol
The starting compounds of the general formulas (| h), (Y) and (VJ)) are known and can be obtained by known methods.
If desired, the compounds of general formula (I) can be converted to a pharmaceutically acceptable salt by reacting with a suitable base, and from these salts, the free salyl yanilides can in turn be isolated by treatment with acid
The proposed compounds of general formula (1) have parasiticidal properties.
They are very potent anthelmintics, very active against hepatic fluke, namely Fasciola hepatica, and against nematodes, such as Halmonchus contortus, in sheep and cattle.
In addition, they have high activity against a number of arthropod parasites, such as Oestrum oriSf Hypoderma bovis, Dermatobia hominis, Lucillia, and the like.
In view of the wide spectrum of antiparasitic activity, the compounds of the invention are valuable agents for the treatment of many warm-blooded animals suffering from such parasites.
A method for controlling parasites is to treat infected objects with an effective antiparasitic amount of the proposed compounds. For this purpose, it is useful to apply 1200 mg / kg of body weight.
The proposed compounds can be used, for example, in the form of pharmaceutical and veterinary formulations containing an anti-parasitic amount of the compound and a suitable organic or inorganic, solid or liquid carrier such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gum polyalkylene glycols and the like.
The formulations may be prepared according to conventional procedures and may be manufactured in any of the conventional pharmaceutical forms, e.g.
72
for example, such as zinc powder in acetic acid, iron powder with ammonium chloride, or catalytic reduction with hydrogen, for example, in the presence of palladium on carbon as a catalyst.
The above reactions proceed according to the scheme;
Wg di
(Iii)
HON
systematic administration by oral or parenteral route or for external application directly to the skin. They can be sterilized, for example, for parenteral
0 introduction and / or contain additives, such as conventional drug carriers, preservatives, stabilizers, wetting. Dispersing, disintegrating or emulsifying agents,
5 fillers, buffering agents, bacteriostats, bactericidal agents, sporicidal agents, sealing agents, colorants, and the like.
They may also contain substances that are useful in veterinary medicine or therapy, including, for example, other known anthelminths, such as tetramisole, levamisole, mebendazole, thiabendazole, pyrviniipamoate, pipa5 razintsitrat, 2- (3-methoxyethylpyridine), etc. Suggested compounds; They can also be used as additives and pre-mixes for animal nutrition, drinking water additives, etc.
0
In such formulations and formulations, the concentration of the proposed compound should be at least 0.01%, and preferably at least 0.05% by weight. The concentration of the Compound may vary within very wide limits depending on the form of the composition taken, in some cases it may reach about 95%.
For example, formulations suitable for
0 oral administration may be liquid or solid. Suitable liquid formulations include, for example, aqueous concentrated solutions of the active ingredients, these solutions can
5 contain one or more buffers and / or stabilizing agents, e.g. sodium bisulfite, hydroxylamine or its acid addition salt, e.g. hydrochloric acid salt.
0 Liquid formulations also include solutions in vegetable massou, such as peanut, dimethylacetamide, polyalkylene glycols. Solid formulations include tablets, pills or capsules, which can be made on
basis of conventional drug carriers. Solid formulations can be dispersible formulations containing at least one solid adsorbent, such as fullerosis earth or kieselgur. Solid formulations can be produced in the form of pre-mixes suitable for animal feed additives, or in the form of medical food formulations for animals, for example, formulations contain active ingredients and food for animals. Formulations suitable for parenteral administration include, for example, sterile injectable aqueous solutions and flooding solutions or suspensions.
-In the examples given, if not: others; indications, all parts are by weight.
Example 1. To a stirred and cooled to -5 ° C mixture of 325 parts of nitric acid and 975 hours, concentrated sulfuric acid are added dropwise 220 parts of 1,2-dichloro-4- (1,1-dimethylethyl) benzene . After the addition is complete, stirring is continued for 30 minutes at, the reaction mixture is removed from the feed, the product precipitates, and is formed as an oil. The supernatant is decanted off and the remaining oil is extracted with chloroform. Extraction is washed with water, dried, filtered and evaporated. The residue is crystallized from isopropanol. The product is filtered and recrystallized from isopropanol to give 34.5 parts of 1,2-dichloro-4- {1, 1-dimethylethyl-5-nitrobenzene, m.p. 80 ° C.
Example 2. According to the method of example 1, using an equivalent amount of 1,2-DICHLOR-4- (1-methylethyl) -benzene instead of 1,2-dichloro-4- (1,1-dimethylethyl) -benzene, get 1,2- DICHLOR-4- (1-methylethyl) -5-nitrobenzene, so pl. below.
Example C. To a solution of 39 parts of potassium hydroxide in 39 parts of pyridine was added a solution of 17 parts of 1-chloro-4-nitrobeneol in 46 parts of pyridine. The mixture is cooled to -5 ° C and a solution is added dropwise to it 22 hours. 2,4-dichlorobenzeneacetonitrile in pyridine while cooling to -5 ° C. After completion of the addition, stirring is continued for 10 hours at. After adding 90 hours, the benzene product is o.e. It is filtered off, washed on the filter with benzene and transferred to WATER; Aqueous smelt It is treated with acetic acid, as a result of which the product is separated in the form of an oil. The latter is extracted with toluene. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of methanol, 2,2-oxybispropane, petroleum ether and chloroform. Get 2, 4-dichloro-c (- (4-nitrophenyl) -benzeneacetonitrile, so pl. 81-82,5 ° C
Example 4. To a mixture of 105 parts of a 1-chloro-4-nitro-2- (trifluoromethyl) benzene mixture stirred and heated to 30 ° C, 10 parts of N, N, N-triethylbenzenemethanamine chloride, 900 parts of a 50% solution sodium hydroxide and 135 parts of tetrahydrofuran are added dropwise a mixture of 67.5 hours, 4-fluorobene-acetonitrile and 450 hours, tetrahydrofuran (the reaction is exothermic, the temperature rises to). After the addition is complete, stirring is continued at 5 hours. After cooling, the reaction mixture is poured onto crushed ice and the mixture is acidified with a solution of concentrated hydrochloric acid while cooling. The product is extracted with toluene. The extract is washed with water, dried, filtered and evaporated. The residue is suspended in a mixture of 2,2-hydroxy-propane and petroleum ether. The product is filtered off, semi-chlorine Cl (4-fluorophenyl) -4-nitro-2- (trifluoromethyl) -benzeneacetonitrile, so pl. 68 ° C
Example 5. Work according to the method of example 4, using equivalent amounts of the corresponding starting compounds, get nitriles, are given in table. 1, with the following general formula
110.2
-6 3 70.4 60.2
2.6 - С12 С Нз
122.1
H CF,
2 ,,
107
H CF,
4-YUSN -SN
H CF,
 four
87.4
H CF,
h, 4-c1, 124
H CF,
2 ,. 139.6
5 N CI
Continuation of table 1
Continuation of table 2.
Neither a mixture of acetic acid and BO, CI (1: 1 by volume) oil is precipitated. The supernatant water layer is decanted and the oil is transferred to toluene. The solution is evaporated. The oily residue is triturated with a mixture of 2, 2-hydroxy-propane and petroleum ether to give 2, 4-dichloro-o-2-chloro-4- (oxyimino) -5-methyl-2,5-cyclohexadiene-1-ylidene - benzeneacetonitrile.
Stir and heat to boil at 370 parts. 0.78 n. ammonium chloride solution. Then 37 parts of iron powder are added, after which a solution of 37 hours, 2,4-dichloro with (, 2-chloro-4- (oxyimino) -5-methyl-2, 5-cyclohexadien-1- 333 parts of toluene ylidene-benzene-acetonitrile After the addition is complete, stir the mixture overnight at reflux. The reaction mixture is cooled to 60 ° C, filtered and the residue is washed on the filter with tetrahydrofuran, filtered, filtered, and evaporated. The residue is taken up in tetraphydrofuran. in 2,2-oxybispropane and isopropanol, 4-amino-2-chloro-oC- (2, 4-dichlorophenyl-5-methyl is obtained benzeneacetonitrile in the form of a hydrochloric acid salt.
Example 9. A mixture of 40 parts of 4-chloro-d-2-HLOR-4- (hydroxymino) -5 - methyl-2, 5-cyclohexadien-1-ylidene 1 -benzeneacetonitrile, 50 parts of iron powder, 1500 hours 0.78 and. ammonium chloride solution and 270 parts of toluene are stirred and refluxed overnight. The reaction mixture is filtered and washed; the filter cake is washed with 4-methyl-2-pentanone. The filtrate is dried, filtered and evaporated. The solid residue is crystallized from toluene. The product is filtered and recrystallized from toluene to give 4-amino-2-chloro-oC- (4-chlorophenyl) -5-methylbenzeneacetonitrile, m.p. 152.6 ° C.
Example 10, A mixture of 4 parts of 2-hydroxy-3, 5-diiodobenzoyl chloride, 2.9 parts of 4-amino-2-chloro-o- (4-chlorophenyl) 5-methylbenzeneacetonitrile and 75 hours ,. The 1,4-dioxane is stirred and refluxed for 10 minutes. The reaction mixture is evaporated and the oily residue is crystallized from methanol. The product is filtered off and dried, yielding 5.3 h. K- {5-chloro 4- (i- (4-chlorophenyl) -cL-cyanomethyl -2-methylphenyl} -2-hydroxy-3, 5-diiodbenzamide, m.p. . 217.8 p.
Winner 11. Working according to the procedure of Example 10, using equivalent amounts of appropriately substituted chlorohydrin1:) Salicylic acid and correspondingly substituted 4-amino-cC arylbenzenecetonitriles or their hydrochloride salts, are obtained.
Formula (I)
melt temperature in the table. 3 which are given
a b and c a 3
T
Continuation of table 3
Continuation of table 3
Note, in this and subsequent tables, the Roman numerals correspond to the number of the example description.
Example 12. A mixture of 12 parts of the acid chloride 3,5-diiodosalicylic acid, 8.3 parts of 2- (4-amino-2-chloro) -2- (p-chlorophenyl) -acetonitrile and
5 to 150 parts of dioxane are stirred and boiled for 15 minutes under reflux. The solvent is concentrated to about 50 parts of its volume. 160 parts of methanol and 5 parts of water are added and after completion of crystallization the solid product is filtered off. It is washed with methanol and dried under vacuum at 100 ° C., to obtain 3-chloro-in (- {p-chlorophenyl) -c1. Cyano-3,5-diiodo-p-salicylotoluidide, mp. 229 C.
five
Example 13. A mixture of 3.1 parts of 2-hydroxybenzoyl chloride, 4.2 parts of 4-amig10-o (.-Phenylbenzeneacetonitrile and 100 parts of dioxane is stirred and boiled for 2 hours under reflux. Then
0 0.7 p. N, K-diethylethanolamine is added thereto and the mixture is evaporated. The oily residue is triturated with toluene. The product is filtered off and crystallized from toluene, get 2.3 hours (o6-cyano-bS-phenylmethyl) -phenyl -2-oxyben8amide, so pl. 176, “C,
Example 14. A mixture of 3.1 parts of 2-hydroxybenzoyl chloride, 4.4 parts of 4-amino-cC- (4-methylphenyl) benzeneacetonitrile and 100 parts of 1,4-dioxane is stirred and refluxed 1 during this boiling, 0.7 hours of H, N-diethylethanamine was added. The reaction mixture is evaporated.
C The residue is stirred in ethanol. The product is filtered and crystallized from ethyl acetate. It is filtered and dissolved in isopropanol. The solution is filtered and the filtrate is evaporated; 0.9 parts are obtained. N- {4-cC-cyano-cL- (4-methylphenyl) methyl phenyl J-2-hydroxybenzamide, m.p. 157.4С.
EXAMPLE 15 A mixture of 6.5 parts of 3,5-diiodo-2-hydroxybenzoyl chloride, 5.3 parts of 4-amino-2 chloro-c (, - (4-chlorophenyl) -5- (1 , 1-dimethylethyl) -benzeneacetonitrile and 60 parts of 1,4-dioxane are stirred and refluxed for 30 minutes, the reaction mixture is evaporated. The residue is purified by chromatography on a silica gel column using chloroform as a solvent. Clean fractions are collected and the eluent is evaporated. The product is filtered off and dried, yielding 2.2 hours, N- {5-chloro-4-c - (4-chlorophenyl) -sb-tscanomethyl -2- (1,1-dimethylethyl) -phenyl} -2 -oxy-3, 5-diiodbenzamide, t, pl. 149 ,,
Example 16, Mixture of 2.9 h, 3,4,5-trichloro-2-hydroxybenzoyl chloride, 3.3 h, 4-amino-2-chloro-c (, - (4-chlorophenyl-5- (1,1- dimethylethyl) -benzene-acetonitrile and 60 parts of 1,4-dioxane are stirred and refluxed for 20 minutes, the reaction mixture is evaporated and the residue is purified by chromatography on a column of silica gel using chloroform as the solvent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2-oxybispropane, the Product is filtered and dried in vacuum at 100 ° C / 10 mm Hg, cent. Receive 3.5 h, 3, 4, 5-trichloro-M - {5-HLOR-4- ° C- (4-chlorophenyl) -c (-cyanometes l -2- (1,1-dimethylethyl) -2-hydroxybenzamide, t, pl, 231 ,,
Example 17, A mixture of 4.8 hours, 2-hydroxy-3, 5-diiodobenzoyl chloride, 6.5 parts of 4-amino-2-chloro-c - (4-chlorophenyl) -5- (1-methylethyl) -benzeneacetonitrile, hydrochloric acid salt and 60 hours, 1,4-dioxane is stirred and refluxed for 30 minutes. The reaction mixture is evaporated and the residue is purified by silica gel column chromatography using a mixture of chloroform, hexane and methanol (50: 50: 5) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile, get 4.2 h, N-5-chloro-4-to - (4-chlorophenyl) -sHg cyanomethyl -2- (1-methylethyl) -phenyl} -2-hydroxy-3, 5-diiodobenzamide, t, pl, 200 ,,
Example 18, Warm solution for 1 h, Y | 5-chloro-4-ct- (4-chlorophenyl) -oL-cyanomethyl -2-methylphenyl j-2-hydroxy-3, 5-diiodo-enzamide, 0.3 h, 10 n. a solution of sodium hydroxide, .8 hours, methanol and 10 parts of water are left; l; crystallization. The product is filtered BcUOT, pack with water and dry, get 0.7 h, (67.5%) NJ B-chloro-- - with - (4-chlorophenyl) -d-cyanomethyl -2-methylphenyl} -2-hydroxy-3, 5-diiodobenzamide in the form of sodium salt hydrate, t, pl, 270-300s,
Example 19. 0,65 h. N- | 5-chloro-4-aL (4-chlorofekyl) -l-cyacomethyl -2-methylphenyl} -2-hydroxy-3, 5-diiodbenzamide and 0.1 h, piperidine solution in 4 parts of methanol and in 5 parts of 1,4-dioxane. The solvent is distilled off in vacuo. The residue is solidified, ground to powder with 2,2-oxybispropane. The product is filtered and washed with 2,2.2-hydroxybispropane. After drying, the compound N- | 5-chloro-4-cC- (4-chlorophenyl) -ct-cyanomethyl -2-methylphenyl} -2-hydroxy-3, 5-diiodbenzamide with piperidine is obtained, mp. I40.3 ° C (decomposition).
Example 20, 0.494 parts N- / 5-chloro-4-d. (4-chlorophenyl) -c.-cyanomethyl -2-methylphenyl j-2-hydroxy-3, 5-diyodamideamide and 0.1 h, sat-methylbenzenemethanamine is dissolved in 4 parts of methanol and 5 hours. 1,4- dioxaca. The solvent is distilled off in vacuo. The residue is cured by rubbing into powder with 2,2-oxybispropane. The product is filtered off and washed with 2,2-hydroxy-propane drying to give the compound N- {5-chloro-4-oC- (4-chlorophenyl) -oC-cyanomethyl -2-methylphenyl) -2-hydroxy-3,5-benzamide with sC- methylbenzenemethane.min, so pl. 116.7 ° C (with decomposition).
Similarly, compounds are obtained whose melting points are listed in Table. four.
Table 4
Continuation of Table 4 Example 21. To a stirred mixture of 4 parts of 3- (I, 1-dimethylethyl) -2 -oxy-6-methyl-5-nitrobenzoic acid, 6.9 parts of 4-amino-2-chloro-c1. - (4-chlorophenyl) -5-methylbenzetonitrile and 55 parts of chlorobenzene are added dropwise a solution of 1.5 parts of phosphorus oxychloride in 11 parts of chlorobenzene at. After completion of the addition, it is stirred for another 3 hours. The reaction mixture is cooled and poured into 450 parts of petroleum ether. The latter is decanted and (The remaining precipitate is boiled for 350 hours, 1,1-oxybisethane. The solution is saturated with gaseous hydrogen chloride and filtered. The filtrate is washed twice with water, dried, filtered and evaporated. The residue is crystallized from toluene, obtained 4 hours. (471) N- | 5-chloro-4-c (g (4-chlorophenyl) -c, cyano methyl -2-methylphenyl} -3- {1,1-dimethyl ethyl) -2-oxy b-methyl- 5-nitro benzenes T. S1. 133, f C. Example 22. Work according to the method of Example 23, using equimolar amounts of the corresponding starting materials, Table 5 shows the melting points of the compounds obtained , Table 5
Continuation of Table 5 Example 23, K is switchable to a solution of b h, 3- (1,1-dimethylethyl) -2-hydroxy-5-iodo-b-methylbenzoic acid and 5 parts 4-aMKHo-cf, - (4-chlorophenyl) -2- (trifluoromethyl) -benzeneacetonitrile in 5h of chlorobenzene solution is added dropwise 1.2b of phosphorus oxychloride in 11 parts of chlorobenzene, heating at. After the addition is complete, stirring is continued for 2 hours at. After cooling, a second portion of 2.5 hours, 4-akshn-oC- {4-chlorophenyl) -2- (trifluoromethyl) -benzeneacetonitrile is added and the mixture is stirred for 2 hours at 120 ° C. The reaction mixture is cooled and 300 parts of chloroform are added. The solution is filtered and 1) the filtrate is washed with sodium carbonate solution, with chpiat, filtered and evaporated. The residue was purified by chromatography on a column of silica gel using a mixture of chloroform, L0% hexane, and 5% L5 ethanol as eluent. Collect the pure fractions and evaporate the eluent. The residue is crystallized from cyclohexane to give 2.5 parts of N-J4-oC- (4-hl-esphenyl) -ti-cyanomethyl-3- (trifluoromethyl) -phenyl) -3- (1, 1-dimethylethyl) -2-ocoes -5-iodo-b-methylben 3amide, so pl. 154.3 C. Example 24. The procedure is as in Example 10 and equivalent amounts of the corresponding starting materials are used, and the following compounds of general formula (I) are obtained: 3,5-dibromo-K-5-chloro-4-o (g ( -chlorfekyl) -oC-cyanomethyl -2-methylphenyl} -2-oxybenzamide; 3,5 Dibrom-N-15-HLOR-4-- OL- (4-hpriphenyl) -sb-cyanomethyl-phenyl) -2-hydroxy ben 3 aot d; N-52-chloro-4- oL- (4-chlorophenyl) -oC-cyanomethyl-phenyl 2-hydroxy-3,5-diiodobenzate 1 id; 19 3,4, 5-trichloro-K-2-chloro-4-aC- (4-chlorophenyl) -oC-cyanomethyl-phenyl 5-2-hydroxybenzamide; 4-chloro-H- | 5-chloro-4-oC- (4-chlorophenyl) -CC-cyanomethyl) -2-methylphenyl-2-hydroxy-3, 5-diiodobene-amide; 4-chloro-H- 5 5-ChLOR-4- with (- (4-chlorophenyl) -c6-cyanomethyl-phenyl -2-hydroxy-3, 5-diiodbenzamide; 3-bromo-4,5-dichloro-I- 5-chloro-4-cC- (4-chlorophenyl) -ct-cyanomethyl -2-methylphenyl} -2-hydroxybenzamide and 3-bromo-4, 5-dichloro-M-5-chloro-4-cL- (4- chlorophenyl) cc-cyanomethyl-phenyl -2-hydroxybenzamide. Example 25. A mixture of 8.75 parts of 4-amino-2-chloro-c3- (4-chlorophenyl) -5-methylbenzeneacetonitrile, 2.10 parts of phosphorus trichloride and 176 hours 3 chlorobenzene is stirred and boiled under reflux for 2 hours. After cooling to 60 ° C, 11.7 hours of 2-hydroxy-3, 5-diiodobenzoic acid are added and the whole mixture is heated to 115 C. Continue mixing for 2 hours at 115 ° C. The reaction mixture is filtered hot. The product crystallizes from the filtrate at room temperature. It is filtered and dried, yielding 10.5 hours (52.8%) of N-5-chloro-4-cC - (4:; chlorophenyl) -t -iianomethyl -2-methylphenyl j-2-hydroxy-3,5-diiodobenzamide, mp 217 ° C. The data of analysis of the compounds obtained according to examples 10-25 are presented in table. 6,
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have the same composition as described in example 27.
In tab. 9 shows the structure of a number of proposed compounds and their effs
) -, CN
OH OH

权利要求:
Claims (3)
[1]
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Efficiency with one intrageneous dose: 2.5 mg / kg of live weight. Efficiency is expressed as a percentage reduction in trematodes compared to controls.
T a
faces
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2.4- (C1) .- SbND
42 72 71 83 75 71
4-C1-C H 4- (SND). 4- (OCH.j) 4-P-CbH 2.4- (C1) 2.4- (C1) 45 79 57 96 85 60 75 73
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4- (SNZ)
Hf,
4- (COHj) 71 3- {CFj)
100 69 99 99 84 61
4- (CHj) 2-Naphthyl --5-: e-2-thienyl 62 87
-Ch- ™
4-CI-C H 91 4-CI-C4H4
100 Example 29. Shows the efficacy of the compounds of the invention against Hypoderma bovis in cattle. The test is carried out with livestock with natural infection, which has visible larvae of each gadfly caused by Hypoderma bovis. Animals are shaved back to make visible marble spots (for counting). The drug is administered by intramuscular injection of a 5% aqueous solution for injecting N-5-chloro-4-d- (4-chloro-phenyl) -C6-cyanomethyl -2-methylphenyl} -2-hydroxy-3, 5-diiodbenzamide, having the same composition as in Example 28. 10 days after the administration of the drug, the larvae were squeezed out of the jelly and checked if they were alive or dead. Such a study makes it possible to directly observe the further development of the larvae in the artificial environment from the pupa stage to the final species. The obtained experimental data are given in Table. 10. Table. Abdomen. Activity control 10 days after treatment, dead larvae (recovered larvae). Compound dose 2.5 mg / kg 1285 12/15 21915/6
Continued table. 9 Continuation of Table 10 Compound 5 mg / kg 44 of the formula of the invention compilation of ylide derivatives of the general formula of BC O V-L SL -NH- / V JH-Ar OHB6 are pharmaceutically acceptable hydrogen, halide, lower alkyl or nitro group; hydrogen or chlorine; hydrogen, halo, or nitro; hydrogen, hydroxy or methyl with the proviso that when R4 is hydroxy or methyl, then R is hydrogen;
Rj. - hydrogen,
chlorine, or lower alkyl;
6 hydrogen, chlorine, cyashe- or trifluoromethyl rpynnai; phenyl, substituted phenyl, Ag thienyl, halothienyl or naphthyl, wherein substituted phenyl means phenyl having 1–3 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, and a trifluoromethyl group,
distinguished by the fact that common salt of salicylic acid
.
- yalad
AT.
K / OH
subjected to interaction with aniline of the General formula
NHj.
in which the substituents have the indicated meanings,
in an inert organic solvent.
[2]
2. A method according to claim 1, characterized in that 1,4-dioxane is used as an inert organic solvent.
[3]
3. Method POP.1, characterized in that the process is carried out at the boiling point of the reaction mass with reflux condenser.
The priority on the basis of signs is 13.01.76 for all values of radicals, except RJ - halogen.
R 5 is halogen, Ed is hydrogen, Ar is phenyl or substituted phenyl.
03.18.75 - with the above values of the radicals.
Sources of information 0 taken into account in the examination
1.Patent of England No. 1183641,
cl. C 2 C, pub. 1970 (prototype).
2.Mokosza M. et al., Reactions 5 of organic anions Tetrahedron, 1974,
V. 30, 20, p. 3723-3735.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US55961675A| true| 1975-03-18|1975-03-18|

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US05/648,681|US4005218A|1975-03-18|1976-01-13|Antiparasitic salicylanilide derivatives|

---