IL31399A - 3-nitro-gamma-resorcylic acid anilides and process for preparing them - Google Patents
3-nitro-gamma-resorcylic acid anilides and process for preparing themInfo
- Publication number
- IL31399A IL31399A IL31399A IL3139969A IL31399A IL 31399 A IL31399 A IL 31399A IL 31399 A IL31399 A IL 31399A IL 3139969 A IL3139969 A IL 3139969A IL 31399 A IL31399 A IL 31399A
- Authority
- IL
- Israel
- Prior art keywords
- nitro
- acid
- general formula
- methyl
- resorcylic acid
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- XBVDFJKAEFEIFI-UHFFFAOYSA-N 2,6-dihydroxy-3-nitro-N-phenylbenzamide Chemical class [N+](=O)([O-])C=1C(=C(C(=O)NC2=CC=CC=C2)C(=CC=1)O)O XBVDFJKAEFEIFI-UHFFFAOYSA-N 0.000 title 1
- 229940051881 anilide analgesics and antipyretics Drugs 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 150000002431 hydrogen Chemical group 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- -1 Resorcylic acid anilides Chemical class 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- UIAFKZKHHVMJGS-UHFFFAOYSA-N beta-resorcylic acid Natural products OC(=O)C1=CC=C(O)C=C1O UIAFKZKHHVMJGS-UHFFFAOYSA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- PBKONEOXTCPAFI-UHFFFAOYSA-N 1,2,4-trichlorobenzene Chemical compound ClC1=CC=C(Cl)C(Cl)=C1 PBKONEOXTCPAFI-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 150000003931 anilides Chemical class 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 241000242711 Fasciola hepatica Species 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 150000001448 anilines Chemical class 0.000 description 5
- 208000006275 fascioliasis Diseases 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241001494479 Pecora Species 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 206010061217 Infestation Diseases 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 230000000507 anthelmentic effect Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 244000045947 parasite Species 0.000 description 3
- ZTMOBDRDEWHDKN-UHFFFAOYSA-N phenyl 2,6-dihydroxy-3-nitrobenzoate Chemical compound OC1=CC=C([N+]([O-])=O)C(O)=C1C(=O)OC1=CC=CC=C1 ZTMOBDRDEWHDKN-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- ALIBUAQOBPFPFJ-UHFFFAOYSA-N 2,6-dihydroxy-3-nitrobenzoic acid Chemical compound OC(=O)C1=C(O)C=CC([N+]([O-])=O)=C1O ALIBUAQOBPFPFJ-UHFFFAOYSA-N 0.000 description 2
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 description 2
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000001424 substituent group Chemical class 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- BHMLFPOTZYRDKA-IRXDYDNUSA-N (2s)-2-[(s)-(2-iodophenoxy)-phenylmethyl]morpholine Chemical compound IC1=CC=CC=C1O[C@@H](C=1C=CC=CC=1)[C@H]1OCCNC1 BHMLFPOTZYRDKA-IRXDYDNUSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- 125000005274 4-hydroxybenzoic acid group Chemical group 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000415078 Anemone hepatica Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- SYKNUAWMBRIEKB-UHFFFAOYSA-N [Cl].[Br] Chemical compound [Cl].[Br] SYKNUAWMBRIEKB-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002012 dioxanes Chemical class 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- AKEUNCKRJATALU-UHFFFAOYSA-N gamma-resorcylic acid Natural products OC(=O)C1=C(O)C=CC=C1O AKEUNCKRJATALU-UHFFFAOYSA-N 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- IMKMXSNXUMMLGW-UHFFFAOYSA-N phenyl 3-chloro-2,6-dihydroxy-5-nitrobenzoate Chemical compound OC1=C(Cl)C=C([N+]([O-])=O)C(O)=C1C(=O)OC1=CC=CC=C1 IMKMXSNXUMMLGW-UHFFFAOYSA-N 0.000 description 1
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
-NITR0-y-RES0RCYLI0 ACID ANILIDES AND PROCESS FOR PREPARING THEM j5-Nitro~ -resorcylic acid anilides and process for prep ring them (Fw 5 12) -Resorcyl-anilides (- 2,6-dihydroxybenzoic acid anilides) are already known; 2-nitro- T-resorcylic acid and their simple derivatives, however, have not been known as yet.
The present invention provides 2-nitro- "y-resorcylic acid anilides having an anthelmintic action and corresponding to the general formula I in which R represents hydrogen, chlorine, bromine or iodine, X represents a halogen atom, a nitro group or a trifluoro-methyl group, and Y represents hydrogen, a methyl, trifluoro-methyl or methoxy group or a halogen atom, and Z represents hydrogen or, if. Y stands for methoxy or halogen, Z may have the same meaning as Y.
The present invention also provides a process for preparing the above-identi ied compounds of the general formula I, wherein a) a 5-nitro- -resorcylic acid ester of the general formula II in which R has the meaning given above and R1 stands for a phenyl group which may be substituted, is reacted with an aniline of the general formula III (III) Y z in which R, X^ Y and Z have the meanings given above, is nitrated or c) compounds of the general formula V in which R, X, Y and Z have the meanings given above, and R 2 and R stand for low molecular weight alkyl, aralkyl or acyl groups, are treated with ether-splitting agents and/or hydro-lyzed, and, if desired^ the compounds of the formula I thu~ obtained, in which R stands for hydrogen, are halogenated.
According to method of operation a), the 3-nitro- resorcyllc acid anilides are obtained by reaction of J-nitro-TF-resorcylic acid phenyl esters of the formula II with anilines. For this reaction, there may be used, besides unsubstituted phenyl esters, also enters which are derived from substituted phenols. As examples, there may be mentioned the esters of -nitro- ¾*-resorcylic acid with flresols, anisoi^ phenetol* 4-nitrophenol, 2-chlorophenol, 2-chlorophenol, -chlorophenol or -bromophenol. These esters can be easily prepared from the corresponding ¾"-resorcylic acid esters by nitration, for example with 65^ nitric acid in glacial acetic acid at 5 » 15° C0 If in the esters of the formula II R respresents halogen, the starting materials may also be obtained by halogenation of the nitro-resorcylic acid phenyl esters (II, R = H).
As starting substances of formula III to be used in method a), there are used, according to the present invention, anilines whose benzene nucleus is substituted by at least one halogen atom, one nitro group or one trifluoromethyl group. As halogen atomy's, any of the halogens may be used, chlorine and bromine being especially preferred. In addition to the mentioned sub-stituents, the anilines may be substituted in all free positions by further halogen atoms, methoxy, methyl or trifluoromethyl groups.
The reaction of the j5-nitro- '-resorcylic acid esters with substituted anilines mentioned under a) is effected by heating a mixture of the reaction components to temperatures in the range of from 150 to 200° C. The reaction is advantageously effected in the presence of an iner ^ solvent having a high boiling point. Especially suitable arc, for example, l,≥-di-chlorobenzene, 1,2, -trichlorobenzene or ..-methylnaphth lene.
The reaction is in general completed after 10 to J>0 minutes.
After cooling of the reaction mixture, the anilides crystallize in most cases and they can be isolated by suction-filtration.
According to the method of operation b), the -nitro- Y-resorcylic acid anilides can be prepared by nitration of corresponding y-resorcylic acid anilides. This is carried out, for . acid example by allowing nitric/having a density of 1.4 to react with the T-resorcylic- acid anilides at a temperature "in the range of from 0 to 40° C. Advantageously, the temperature is maintained between 20 et >0° C. It is also possible to carry out the reaction in the presence of diluents such as sulfuric acid or glacial acetic acid*. This method of operation, however, does not bring any advantages. After completion of the reaction, the reaction mixture is diluted with water. The anilides can then be isolated as usual. The T"-resorcylic acid- anilides used as starting material can be prepared, for example according to the method described in French Fatent 1 507 38, According to the present invention, the anilides of the 3-nitro- IT -resorcylic acid can also be prepared according to the method of operation c), by splitting off the protective groups from anilides in which the hydroxyl groups of .nitro- 3* -resorcylic acid are protected by lower nlkyl, arnlkyl or acyl groups, by treatment with ether-splitting agents and/or by hydrolysis. These protected 2-nitro- T-resorcylic acid anilides can be prepared, for example, by treatment of substituted anilines with reactive acid derivatives of a j5-nitro- 2 -resor-cyclic acid whose hydroxyl groups are protected. It is also possible to nitrate T-resorcylic acid anilides carrying pro-* tective groups by reaction with nitric acid.
The protective groups are split off depending on their nature, using the usual methods. Acyl groups can be removed, for example by hydrolysis, for example bY treatment with dilute alkalies; alkyl or aralkyl groups can be split off, for example, by heating with hydrobromic or hydrolodic acid.
If the 5-nitro- Γ -resorcylic acid anilides prepared according to the present invention do not carry a halogen atom as substituent in the 5-position (R = H), it may be introduced subsequently, if desired. For this purpose, the anilides are-dissolved in suitable solvents such^as glacial acetic acid, aliphatic chlorohydrocarbons or cyclic ethers, and then chlorine bromine,, iodine or another halogenating agent, for example this reaction is effected at elevated temperatures. After completion of the reaction, the reaction products in many cases crystallize directly and can be isolated and purified in the usual manner.
The 3-nitro» -resorcylic acid anilides prepared according to the present invention constitute crystalline, light yellow colored substances which are sparingly soluble in water. They can in general be easily purified by recrystalli-zation from suitable solvents.
The novel anilides of J-nltro- -resorcylic acid are distinguished by a marked anthelmintic activity. This activity is especially directed against liver flukes, in particular against the great liver fluke PiPbiola hepatica. This anthelmintic activity can be demonstrated when using rats and rabbits as test animals. In practice, however, the infestation of sheep with liver flukes has considerable , importance. In combatting these infestations, the products of the present invention have proved to be valuable chemotherapeutic agents. They can be applied perorally or subcutaneously; the mode of administration depends on the individual case. The following table lists the doses of some products of the invention whose single, administration to naturally strongly infested sheep resulted in complete cessation of the excretion of eggs and in a complete liberation from liver flukes.
T a b l e Chemotherapeutic tests Host: sheep Parasite: Fasciola hepatica Substance Mode of Therapeutic dose administration (mgAg of body weight) Nitro-2,6-dihydroxy- perora1 < 50 Substance Mode of Therapeutic dose administration (m^/lcr; of body weight) -Chloro-3-nitro-2,6-di- peroral 4 hydroxybenzoic acid-4'- chloroanilide -Nitro-2,6-dihydroxy- peroral < ≥5 benzoic acid-21 ,4' ,6'-tribromoanilide 2-Nitro-2,6-dihydroxy- subcutaneous < 5 benzoic acid-J' ,5?-bis- (trifluoronethyl )-nnilide The indicated doses were tolerated by the animals without side effects.
Hence, the products of the present invention are valuable medicaments in veterinary medicine for combat ing liver fluke infestations.
The following Examples illustrate the invention but they are not intended to limit it thereto: Example 1; 3-Nitro-2,6-dlhydr0xybenzoic acld-4' -chloroanilidc 26 g of' 4-chloroaniline, 55 g of 3-nitro-2,6-dihydroxy-benzoic acid phenyl ester and 120 ml of 1,2,4-trichlorobenzene were heated together for 30 minutes to l80e C. After cooling, the crystals were separated by filtration with suction, washed with 80 ml of benzene and recrystallized from dioxane. 51 g of 3-nitrc~2,6-dihydroxybenzoic acid-41 -chloroanilide were obtained. Melting point 198 - 200° C.
Preparation of the f-resoroylic acid phenyl ester used as the starting substances 6 ml of HNO, having a strength of 65 % were added drop- .5 wise, within one hour, while stirring and cooling, to 46 g of 2,6-dihydroxybenzoic add phenyl ester dissolved in ¾60 ml of glacial acetic acid in such a manner that the internal temperature was maintained below + 10° C. The whole was fur the crystals that had precipitated were filtered off with suction, washed with 50 ml of glacial acetic acid, 180 ml of water and dried at room temperature. Yield: 40 g. Melting point: 119 - 121 * C. After recrys.tallization from CCl^, the pure 3-nitro-2,6-dihydroxybenzoic acid phenyl ester melts at 121 - 123° C.
Example 2i 3-Nitro-2, 6-dihydroxy-benzoic acld-4 ' -bromoanilide 26 g of 4-bromoaniline, l g of 3-nitro-2, 6-dihydroxy-benzoic acid phenyl e3ter and 120 ml of 1 , 2, 4-trichlorobenzene were heated together for 5 minutes to l85° C. After cooling, the (crystals were filtered off with suction, washed with 50 ml of benzene and recrystallized twice from dioxane. 1 g of 3-nitro-2, 6-dihydroxybenzoic acid-41 -bromoanilide were obtained. Melting point 201 - 203° C.
Example 3¾ 3-Nitro-2, 6-dihydroxybenzoic acid-4 ' -chloroanillde 13.1 g of 2, 6-dihydroxybenzoic acid-4 ' -chloroanillde were introduced within minutes, while stirring, into 120 ml of HNO^ (d = 1.40) in such a manner that the internal temperature did not exceed 30° C. The whole was stirred for 2 hours at - 30° C, diluted with 120 ml of water while cooling, the crystals were filtered off with suction and washed with 80 ml of water. After recrystallization from dioxane, 8.0 g of 3-nitro-2, 6-dihydroxybenzoic acid-4 '-chloroanillde were obtained. Melting point 198 - 200° C.
Example 4 : 3-Nitro-2, 6-dihydroxybenzolc acid-4 '-bromoanilide .4 g of 2, 6-dihydroxybenzoic acid-4 ' -bromoanilide were introduced, while stirring, within 5 minutes into 125 ml of did not exdeed 30 ° C. The whole was stirred for 2 hours at - 30° C, diluted with 125 ml of water while cooling, the crystals were filtered off with suction, washed with 130 ml of water and' recrystalllsed from dioxnne. 10.2 g of 3-nitro-2, 6-dihydroxybenzoic acid-4' -bromoanilide wore obtained. Melting point 201 ° C.
In a manner analogous to tho methods described in the Example 1 to 4, the following compounds were obtained: 3-nitro-2, (5-dihydroxybenzoic ncid-3' ,4'-dichloroanilide m.p. = 205 - 206° C 3-nitro-2, 6-dihydroxybenzoic acid-2 * ,4' , 6' -trichloroanilide m.p. = 206 - 207° C 3-nitro-2,6-dihj'droxybenzolc ricld-2 ' ,4' , 6 ' -tribromoanilide m.p. « 212 - 213° C 3-nitro-2, 6-dihydroxybenzoic acid-2 * -methoxy-4'-chloroanilide m.p. = 225 - 226° C 3-nitro-2,6-dihydroxybenzoic acid-4' -nitroanilide m.p. = 240° C(deoi) 3-nitro-2, 6-dihydroxybenzoio acid-2 ' , 5 ' -dimethoxy-4*-chloroahilide m.p. = \200° C 3-nitro-2,6-dihydroxybenzoic acid-3' , 51 - bis-trifluoromethylanilide m.p. «= 1?8 - 179° C Example v -Chloro-3-nitro-2, 6-dihydroxybenzoic acid-4' -chloroanllide .5 g of 5-chloro-3-nitro-2,6-dihydroxybenzoic acid phenyl ester, 5.0 g of 4-chloroaniline and 25 ml of 1, 2,4-trichloro-benzene were heated together, for 10 minutes, to l80° C. After cooling, the crystals that had formed were filtered off with suction, washed with 30 ml of ethanol and recrystallized from dioxane. 8.6 g of 5-chloro-3-nitro-2,6-dihydroxybenzoic acid- -chloroanllide were obtained. Melting point 210° C (decomposition).
Preparation of the ^'-resorcylic acid ester used as the starting substance ι 1 g of 3-nitro-2,6-dihydroxybenzoic acid phenyl ester in ml of glacial acetic acid were heated for 5 minutes with 7.5 ml of sulfuryl chloride to 70° C. The whole was then allowed to stand for 15 hours at room temperature, the crystals were filtered off with suction and washed with 15 ml of benzene.
Upon recrystallization from benzene, 10.7 g of 5-chloro-3-nitro-2,6-dihydroxybenzoio acid phenyl ester were obtained.
Melting point 1 5° C.
Example 6 -Chloro-3-nltro~2J6-dlhydroxy-benzoio acid- -chloroanllide 21 g of 2-nitro-2,6-dihydroxybenzolc aoid- -chloroanllide, 105 ml of glacial acetic acid and 12 g of sulfurylchloride were heated together, while stirring, for 90 minutes to 80° C. After cooling, the orystals were filtered off with suction, washed with 40 ml of ethanol and recrystalllzed from dioxane. 18 g of 5-chloro-2-nitro-2,6-dihydroxybenzoic acid- -chloroanllide were obtained. Melting point 209 - 210° C (decomposition). Example 7* -Bromo-^-nitro-2<6-dlhydroxy-benzolc acid- -chloroanllide .8 g of 3-nitro-2,6-dihydroxybenzoic acid- '-chloroanllide were heated in 100 ml of dioxane to 95° C. Then, a suspension of the bromo-dloxane complex (from 17 g of bromine and 55 ml of dioxane) was added in one portion, the whole was heated for 2 minutes to the boiling temperature, during whioh with time a solution was formed uratecevolution of HBr. After cooling, of dioxanes 32 g of S-bromo-^nitro-S^-dihydroxybenzoio acid- V=chloroanilide were thus obtained 0 Melting point SOI ® C (decomposition) ,, In the following Table a comparison is given between compounds according to the present invention and compotmds of Branch patent UTo0 lc5079958o Table Chemotherapeutic comparison tests; Hosts sheep Parasite; Fasciola hepatica Substance Administration Dose Parasites Killed According to invention; 3-Nitro- 2 j, 6-dihydroxy-benzoic acid- * -nitro-anilide peroral k mg/kg 1 00 s -bis-trifluoro-methyl-anilide subcutaneous < mg/kg 1 00 a 3-Nitro- 2 „ 6-dihydroxy-benzoic acid- * , '-f■* , 1 -tribrorao-anilide ral < 25 mg/kg According to French Patent o o 1 507958 2 „ 6-Dihydroxy-benzoic acid- '* -chloro-anilide peroral 200 mg/kg none 2 , 6-Dihydroxy-benzoic acid- J -bromo-anilide peroral 200 mg/kg 1 00 o 2 j 6-Dihydroxy-benzoic acid-3 ' -chloro-anilide subcutaneous 50 mg/kg about 2 , 6-Dihydroxy-benzoic acid-2 > -chloro-^ * -n tro-anilide salt with diethanolamine peroral 1 50 mg/kg 1 00 <*°' The above given test results reveal the superiority of
Claims (2)
1. We claim: Resorcylic acid anilides of the general formula wherein R represents hydrogen, chlorine, bromine or iodine, X represents a halogen atom, a nitro group or a trifluoro-methyl group, and Y represents hydrogen, a methyl, trifluoro-methyl or methoxy group or a halogen atom, and Z represents hydrogen, or, if Y stands for methoxy or halogen, Z may have the same meaning as Y.
2. ) Process for preparing 3-nitro- Ί -resorcylic acid anilides of the general formula I wherein R represents hydrogen, chlorine, bromine or iodine, X represents a halogen atom, a nitro group or a trifluoro-methyl group, and Y represents hydrogen, a methyl, trifluoro-methyl or methoxy group or a halogen atom, and Z represents hydrogen, or, if Y stands for methoxy or halogen, Z may have the same meaning as Y, wherein a) a 3-nitro- 7Γ -resorcylic acid ester of the general formula II in which R has the meaning given above and R' stands for a phenyl group which may be substituted, is reaoted with an aniline of the general formula III in which X, Y and Z have the meanings given above, or b) a Τ-resorcylic acid anilide of the general formula in which R, X, Y and Z have the meanings given above, nitrated, or c) compounds of the general formula V in which R, X, Y and Z. have the meanings given above, and R and R stand for low molecular weight alkyl, aralkyl or apyl groups, are treated with ether-splitting agents and/or hydro-lyzed, and, if desired, the compounds of the formula I thus obtained, in which R stands for hydrogen, are halogenated.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEF0054570 | 1968-01-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL31399A0 IL31399A0 (en) | 1969-03-27 |
| IL31399A true IL31399A (en) | 1972-12-29 |
Family
ID=7107178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL31399A IL31399A (en) | 1968-01-18 | 1969-01-10 | 3-nitro-gamma-resorcylic acid anilides and process for preparing them |
Country Status (2)
| Country | Link |
|---|---|
| IL (1) | IL31399A (en) |
| NO (1) | NO126684B (en) |
-
1969
- 1969-01-10 IL IL31399A patent/IL31399A/en unknown
- 1969-01-13 NO NO12369A patent/NO126684B/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL31399A0 (en) | 1969-03-27 |
| NO126684B (en) | 1973-03-12 |
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