IE46102B1 - 5-methylisoxazole-4-carboxylic acid anilides having pharmaceutical activity - Google Patents
5-methylisoxazole-4-carboxylic acid anilides having pharmaceutical activityInfo
- Publication number
- IE46102B1 IE46102B1 IE245177A IE245177A IE46102B1 IE 46102 B1 IE46102 B1 IE 46102B1 IE 245177 A IE245177 A IE 245177A IE 245177 A IE245177 A IE 245177A IE 46102 B1 IE46102 B1 IE 46102B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- group
- radical
- carbon atoms
- salt
- Prior art date
Links
- ZYEWRBNSDKQNSJ-UHFFFAOYSA-N 5-methyl-n-phenyl-1,2-oxazole-4-carboxamide Chemical class O1N=CC(C(=O)NC=2C=CC=CC=2)=C1C ZYEWRBNSDKQNSJ-UHFFFAOYSA-N 0.000 title abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 125000005843 halogen group Chemical group 0.000 claims abstract description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 2
- 239000001257 hydrogen Substances 0.000 claims abstract 2
- -1 alkyl radical Chemical class 0.000 claims description 31
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 16
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- 150000003839 salts Chemical group 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical compound O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 150000003254 radicals Chemical class 0.000 claims description 3
- ZKAQPVQEYCFRTK-UHFFFAOYSA-N 5-methyl-1,2-oxazole-4-carbonyl chloride Chemical compound CC=1ON=CC=1C(Cl)=O ZKAQPVQEYCFRTK-UHFFFAOYSA-N 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- VQBXUKGMJCPBMF-UHFFFAOYSA-N 5-methyl-1,2-oxazole-4-carboxylic acid Chemical class CC=1ON=CC=1C(O)=O VQBXUKGMJCPBMF-UHFFFAOYSA-N 0.000 abstract description 5
- 125000004414 alkyl thio group Chemical group 0.000 abstract description 3
- 230000000202 analgesic effect Effects 0.000 abstract 1
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- 230000001741 anti-phlogistic effect Effects 0.000 abstract 1
- 230000001754 anti-pyretic effect Effects 0.000 abstract 1
- 239000002221 antipyretic Substances 0.000 abstract 1
- 230000002496 gastric effect Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 230000001988 toxicity Effects 0.000 abstract 1
- 231100000419 toxicity Toxicity 0.000 abstract 1
- AGQOIYCTCOEHGR-UHFFFAOYSA-N 5-methyl-1,2-oxazole Chemical compound CC1=CC=NO1 AGQOIYCTCOEHGR-UHFFFAOYSA-N 0.000 description 10
- 238000000354 decomposition reaction Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- IFXKXCLVKQVVDI-UHFFFAOYSA-N 2-amino-5-chlorobenzoic acid Chemical compound NC1=CC=C(Cl)C=C1C(O)=O IFXKXCLVKQVVDI-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SRIPKJKTMUAJMC-UHFFFAOYSA-N 2-chloro-5-[(5-methyl-1,2-oxazole-4-carbonyl)amino]benzoic acid Chemical compound O1N=CC(C(=O)NC=2C=C(C(Cl)=CC=2)C(O)=O)=C1C SRIPKJKTMUAJMC-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- PDEGBONVUJDOFN-UHFFFAOYSA-N 3-(4-fluorophenyl)-5-methyl-1,2-oxazole-4-carboxylic acid Chemical compound OC(=O)C1=C(C)ON=C1C1=CC=C(F)C=C1 PDEGBONVUJDOFN-UHFFFAOYSA-N 0.000 description 1
- YBLSBWHFPXDRHC-UHFFFAOYSA-N 3-methyl-1,2-oxazole-4-carboxylic acid Chemical compound CC1=NOC=C1C(O)=O YBLSBWHFPXDRHC-UHFFFAOYSA-N 0.000 description 1
- PKIJXUFVNGXSEN-UHFFFAOYSA-N 4-bromo-2-[(5-methyl-1,2-oxazole-4-carbonyl)amino]benzoic acid Chemical compound O1N=CC(C(=O)NC=2C(=CC=C(Br)C=2)C(O)=O)=C1C PKIJXUFVNGXSEN-UHFFFAOYSA-N 0.000 description 1
- YQNGTNOFBNZADU-UHFFFAOYSA-N 5-chloro-2-[(5-methyl-1,2-oxazole-4-carbonyl)amino]benzoic acid Chemical compound O1N=CC(C(=O)NC=2C(=CC(Cl)=CC=2)C(O)=O)=C1C YQNGTNOFBNZADU-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- LITCYFDFTKSNSK-UHFFFAOYSA-N O1N=CC(C(=O)NC=2C(=CC=C(Cl)C=2)O)=C1C Chemical compound O1N=CC(C(=O)NC=2C(=CC=C(Cl)C=2)O)=C1C LITCYFDFTKSNSK-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000003931 anilides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Novel 5-methyl-isoxazole-4-carboxylic acid anilides of the formula I wherein one, two or three of the radicals R1, R2 and R3 denote a carboxyl group and/or a hydroxyl group and the remaining radicals R1, R2 and R3, which may be identical or different, denote alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1, 2 and 3 carbon atoms or alkylthio having 1, 2 or 3 carbon atoms, which groups may each be completely or partially substituted by identical or different halogen atoms, or denote hydrogen, halogen, nitro, cyano or carbalkoxy having 1, 2 or 3 carbon atoms in the alkyl group, are prepared by reacting a 5-methyl-isoxazole-4-carboxylic acid derivative with an appropriately substituted aniline. The compounds of the formula I are pharmacologically active. They exhibit a powerful antiphlogistic, antipyretic and analgesic action. Their toxicity is low and their gastric toleration is good.
Description
PATENT APPLICATION BY (71) HOECHST AKTIENGESELLSCHAFT, A JOINT STOCK COMPANY ORGANISED AND EXISTING UNDER THE LAWS OF THE FEDERAL REPUBLIC OF GERMANY, OF 8230 FRANKFURT/MAIN 80, FEDERAL REPUBLIC OF GERMANY.
Price 90p
This invention relates to isoxazole derivatives and is an improvement in, or modification of, the invention of our Patent Specification No. 43136.
Patent Specification No. 43136 describes and 5 claims 5 - methyl - isoxazole - 4 - carboxylic acid anilides of the general formula
represents a hydrogen atom; an alkyl group of 1, 2 or 3 carbon atoms, an alkoxy group of 1, 2 or 3 carbon atoms, an alkylthio group of 1, 2 or 3 carbon atoms, the alkyl groups of which may be substituted partly or totally by identical or different halogen atoms, for example, fluorine, chlorine, bromine or iodine atoms, or represents a halogen atom, for example, a fluorine, chlorine, bromine or iodine atom, or represents a nitro or cyano group or an alkoxycarbonyl group having 1, 2 or 3 carbon atoms in the alkyl moiety,
R represents an alkyl group of 1, 2 or 3 carbon atoms, an alkoxy group of 1, 2 or 3 carbon atoms, an alkylthio group of 1, 2 or 3 carbon atoms, the alkyl groups of which
- 3 may be substituted partly or totally by identical or different halogen atoms, for example fluorine, chlorine, bromine or iodine atoms, or represents a halogen atom, for example, a fluorine, chlorine, bromine or iodine atom, or represents a nitro or cyano group or an alkoxycarbonyl group having 1, 2 or 3 carbon atoms in the alkyl moiety; or represents a phenyl group which may carry one or two substituents selected from fluorine, chlorine, bromine and iodine atoms, alkyl groups of 1, 2 or 3 carbon atoms and alkoxy groups of 1, 2 or 3 carbon atoms, or a phenoxy group which may carry one or two substituents selected from fluorine, chlorine, bromine and iodine atoms, alkyl groups of 1, 2 or 3 carbon atoms and alkoxy groups of 1, 2 or 3 carbon atoms; or
2 3 in which R stands for a hydrogen atom, and R and R together represent a methylenedioxy group or, together with the phenyl ring, to which they are linked, represents a naphthalene ring;
with the proviso that R3 does not represent a methyl 1 2 group when R and R both represent hydrogen atoms.
We have now found that pharmacological properties are also shown by compounds of the above general formula in which at least one of the radicals R1 to R3 represents a carboxy or hydroxy group and the remaining group or groups, if any, have the meanings given above.
Accordingly, the present invention provides a compound of the general formula
eoiua
- 4 1 2 3 in which any two or more of R , S and R may be the same or different and each represents an alkyl radical having 1, 2 or 3 carbon atoms, an alkoxy radical having 1, 2 or 3 carbon atoms, or an alkylthio radical having 1, 2 or 3 carbon atoms, each of which radicals may be unsubstituted or completely or partially substituted by one or more of the same or different halogen atoms;
a halogen atom; a nitro group; a cyano group?
an alkoxycarbonyl radical having 1, 2 or 3 carbon atoms in the alkyl moiety;
a hydroxy group; a carboxy group; or a hydrogen atom;
3 and in which R and R together may represent a methylenedioxy group or, together with the phenyl ring carrying them, a naphthalene ring;
3 and in which if one of R to R represents a hydrogen atom one other may represent a phenyl radical which may be unsubstituted or substituted in each case once or twice by fluorine, chlorine, bromine or iodine or by alkyl having 1, or 3 carbon atoms or alkoxy having 1, 2 or 3 carbon atoms, or may represent a phenoxy radical which may be unsubstituted or substituted in each case once or twice by fluorine, chlorine, bromine or iodine or by alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1, 2 or 3 carbon atoms; and 1 3 wherein at least one of R to R represents a carboxy or hydroxy group.
610 2
2
One or both of R and R may represent a hydrogen 3 atom and if one represents a hydrogen atom, R additionally may represent a phenyl radical which may be unsubstituted or substituted in each case once or twice by a fluorine, chlorine, bromine or iodine atom, by an alkyl radical having 1, 2 or 3 carbon atoms, or by an alkoxy radical having 1, or 3 carbon atoms, or may represent a phenoxy radical which may be unsubstituted or substituted in each case once or twice by a fluorine, chlorine, bromine or iodine atom, by an alkyl radical having 1, 2 or 3 carbon atoms or by an alkoxy radical having 1, 2 or 3 carbon atoms.
The present invention also provides a salt, especially a physiologically tolerable salt, of such a compound.
Preferred compounds of the invention are those of the general formula I in which either represents a hydrogen atom or a halogen atom, e.g. a fluorine, chlorine, bromine 2 or iodine atom, or a trifluoromethyl group, and R represents
2 a carboxy group; or R represents a hydroxy group and R a halogen atom, e.g. a fluorine, chlorine, bromine or iodine 3 atom, a trifluoromethyl or carboxy group; and R in each case represents a hydrogen atom.
The present invention also provides a process for the preparation of a compound of the invention of the general formula I or a salt thereof, which comprises reacting a 5methylisoxazole - 4 - carboxylic acid derivative of the general formula
X
IX
CH.
- 6 4610 a in which X represents
a) a halogen atom, preferably a chlorine or bromine atom?
b) a Y0— group in which Y represents (i) a phenyl radical which is unsubstituted or substituted by one, two or three substituents selected from fluorine, chlorine, bromine and iodine atoms, and methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro and cyano groups, or (ii) the acyl radical corresponding to the formula II, that is, /°
or
c) a group in which Z represents a '1 “4 an aniline of the general formula
with a salt thereof.
Preferably, a substituted phenyl radical Y contains
- 7 one substituent or two or three identical substituents.
The reaction is advantageously carried out in a dispersing agent or solvent that is inert towards the reactants, for example in a nitrile, e.g. acetonitrile; an ether, e.g. diethyl ether, tetrahydrofuran or dioxan; or an alcohol, e.g. methanol, ethanol, propanol or isopropanol.
Preferably the compound of the general formula II is the carboxylic acid chloride. It has proved advantageous in this case for the reaction to be carried out in the presence of an acid-binding agent, e.g. potassium or sodium carbonate, an alkali metal hydroxide or alcoholate, an alkaline earth metal hydroxide or alcoholate, an organic base, for example triethylamine, pyridine, picoline or quinoline, or the aniline reactant used in excess at temperatures of from 0 to 150°C, preferably from 20 to 80°C. The reaction time may be from a few minutes to two hours.
If desired, a compound of the general formula I obtained may be converted into a salt thereof.
A 5 - methylisoxazole - 4 - carboxylic acid derivative of the general formula II required as starting material may be obtained in accordance with the method described in German Patent 634,286. In this method ethoxymethylideneacetoacetic ester is reacted with hydroxylamine to form the 5 - methyl - isoxazole - 4 - carboxylic acid ester, the ester is hydrolysed under acid conditions, preferably with a mixture of glacial acetic acid and concentrated hydrochloric acid in the ratio 1:1, and the 5 - methylisoxazole - 4 - carboxylic acid formed is converted according to a customary method into a carboxylic acid halide, ester or mixed anhydride.
The following are examples of carboxylic acid derivatives of the general formula II:
- methylisoxazole - 4 - carboxylic acid phenyl esters, especially the 2,4 - dichlorophenyl ester or the 2,4,6 - trichlorophenyl ester; and
- methylisoxazole - 4 - carboxylic acid anhydrides, especially those in which X represents the methoxycarbonyloxy radical, the ethoxycarbonyloxy radical, the phenoxycarbonyloxy radical or the benzyloxycarbonyloxy radical.
Compounds of the invention of the general formula I and their physiologically tolerable salts may be used for combating inflammations, fevers and pain.
Accordingly, the present invention provides a pharmaceutical preparation, which comprises a compound of the general formula I of the invention or a physiologically tolerable salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier. Preferably the preparation is in dosage unit form.
The following Examples illustrate the invention:
1. 5-methylisoxazole-4-carboxylic acid 2-carboxy-4-chloroanilide of the general formula I
a) A solution of 0.05 mole of 5 - methylisoxazole - 4carboxylic acid chloride of the formula II (7.3 g) in 20 ml of tetrahydrofuran is added dropwise at room temperature, while stirring, to 0.1 mole of 2 - amino - 5 - chlorobenzoic acid of the formula III (17.2 g) dissolved in 200 ml of tetrahydrofuran. After stirring for a further 20 minutes the precipitate that has formed is suction-filtered off and extracted by boiling with 200 ml of 2N hydrochloric acid.
The remaining precipitate is suction-filtered off, washed with water until neutral, and dried. In this manner 13.1 g
- 9 οι u a (93% of the theoretical yield) of a colorless crystalline powder are obtained? melting point after recrystallization from ethanol: 240 to 243°C (with decomposition).
b) 0.1 mole of 2 - amino - 5 - chlorobenzoic acid of the formula III (17.2 g) and 0.1 mole of 4 - fluorophenyl5 - methylisoxazole - 4 - carboxylate of the formula II (22.1 g) dissolved in 100 ml of tetrahydrofuran are refluxed for 80 minutes. Subsequently the precipitate is suction-filtered off and extracted by boiling with 200 ml of 2N hydrochloric acid. The remaining precipitate is suction-filtered off, washed with water until neutral and dried. In this manner 19.4 g (69% of the theoretical yield) of crystalline powder having a melting point (after recrystallization from ethanol) of 240 to 243°C (with decomposition) are obtained.
c) 0.1 mole of 2 - amino - 5 - chlorobenzoic acid of the formula III (17.2 g) and 0.1 mole of methoxycarbonyl 5methylisoxazole - 4 - carboxylate of the formula II (18.5 g) dissolved in 150 ml of tetrahydofuran are refluxed for 70 minutes. Subsequently the precipitate that has formed is suction-filtered off and extracted by boiling with 200 ml of 2N hydrochloric acid. The remaining precipitate is suction-filtered off, washed with water until neutral and dried. In this manner 20.2 g (72% of the theoretical yield) of a crystalline powder having a melting point (after recrystallization from ethanol) of 240 to 243°C (with decomposition) are obtained.
The compounds listed in Table 1 were prepared in accordance with the process described above.
- 10 Table 1: 5 - methylisoxazole - 4 - carboxylic acid anilides of the general formula I
Mo. 1 R1 H R2 H R3 4 5 * 7 8 9 10 4-0H Melting point °C 160—163 5 2 H H 4-C00H 128—130 3 H 3-0H 4-C00H 228—231 4 H 3-COOH H 242—245 5 H 2-COOH H 208—211 δ H 2-OH 5-COOH 231—234 (with decomposition) 10 7 H 2-OH 3-C00H 198—201 (with decomposition) 8 H 3-C00H 4-OH 247—251 (with decomposition) 9 H 2-C00H 4-OH 228—231 (with decomposition) 10 H 2-C00H 4-C1 240—243 (with decomposition) 11 H 2-OH 4-C1 186—188 15 12 H 2-C00H 5-Br >300 (with decomposition) 13 H 2-OH 5-Cl 84—86 14 H 3-C00H 4-Cl 244—250 (with decomposition)
1. 5 - Methylisoxazole - 4
2. 5 - Methylisoxazole - 4
3. 5 - Methylisoxazole - 4 hydroxyanilide
4. 5 - Methylisoxazole - 4 anilide
. 5 - Methylisoxazole - 4
6. 5 - Methylisoxazole - 4 hydroxyanilide
7. 5 - Methylisoxazole - 4 hydroxyanilide
8. 5 - Methylisoxazole - 4 hydroxyanilide
9. 5 - Methylisoxazole - 4 hydroxyanilide
. 5 - Methylisoxazole 4 - chloroanilide
- carboxylic acid 4 - hydroxyanilide
- carboxylic acid 4 - carboxyanilide
- carboxylic acid 4 - carboxy - 3- carboxylic acid 3 - carboxy- carboxylic acid 2 - carboxyanilide
- carboxylic acid 5 - carboxy - 2- carboxylic acid 3 - carboxy - 2- carboxylic acid 3 - carboxy - 4- carboxylic acid 2 - carboxy - 4i - carboxylic acid 2 - carboxy46102
- 11 11. 5 ~ Methylisoxazole - 4 - carboxylic acid 4 - ehloro2 - hydroxyanilide
12. 5 - Methylisoxazole - 4 - carboxylic acid 5 - bromo2 - carboxyanilide
13. 5 - Methylisoxazole - 4 - carboxylic acid 5 - chloro2 - hydroxyanilide
14. 5 - Methylisoxazole - 4 - carboxylic acid 3 - carboxy4 - chloroanilide
Claims (15)
1. CIAIMS:1. A compound of the general formula 5 or different and each represents an alkyl radical having 1, 2 or 3 carbon atoms,an alkoxy radical having 1, 2 or 3 carbon atoms, or an alkylthio radical having 1, 2 or 3 carbon atoms, each of which radicals may be unsubstituted or completely or partially 10 substituted by one or more of the same or different halogen atoms; a halogen atom; a nitro group; a cyano group; 15 an alkoxycarbonyl radical having 1, 2 or 3 carbon atoms in the alkyl moiety; a hydroxy group; a carboxy group; or a hydrogen atom; 2. 3 20 and in which R and R together may represent a methylenedioxy group or, together with the phenyl ring carrying them 1 3 a naphthalene ring and in which if one of R to R represents a hydrogen atom, one other may represent a phenyl radical which may be unsubstitued or substituted in each 4 610 2 - 13 case once or twice by fluorine, chlorine, bromine or iodine or by (C^—c^) alkyl or (C^—c^) alkoxy, or may represent a phenoxy radical which may be unsubstituted or substituted in each case once or twice by fluorine, chlorine, bromine 5 or iodine or by (C—Cl) alkyl or (C—C,) alkoxy; and 1 3 1 3 I J wherein at least one of R to R represents a carboxy or hydroxy group, or a salt of such a compound.
2. A compound as claimed in claim 1, wherein Ζ represents a hydrogen or halogen atom or a trifluoromethyl 2 , 1 10 group and R represents a carboxy group; or R represents a 2 hydroxy group and R a halogen atom or a trifluoromethyl or carboxy group; whilst R 3 in each case represents a hydrogen atom.
3. A compound as claimed in claim 1 which is shown 15 in Example 1 or Table I herein.
4. A salt of a compound claimed in any one of claims 1 to 3.
5. A physiologically tolerable salt of a compound claimed in any one of claims 1 to 3. 20
6. A process for the preparation of a compound claimed in claim 1 or a salt thereof, which comprises reacting a compound of the general formula II in which X represents 4 6 & 0 2 - 14 a) a halogen atom, b) a YO—group in which Y represents (i) a phenyl radical which isunsubstituted or substituted by one, two or three of the same or different substituents selected from fluorine, chlorine, bromine and iodine atoms and methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro and cyano groups, or (ii) the acyl radical corresponding to the formula II? or c) a JaO—CO—0— group in which Z represents a (C^—c^) alkyl radical or a phenyl or benzyl radical; with an aniline of the general formula or with a salt thereof.
7. A process as claimed in claim 6, wherein the compound of the general formula II is 5 - methylisoxazole - 4carboxylic acid chloride, and the reaction is carried out in the presence of an acid-binding agent.
8. A process as claimed in claim 7, wherein the reaction is carried out at a temperature in the range of from 20 to 80°C.
9. A process as claimed in claim 6, wherein the compound of the general formula II is the 2,4 - dichlorophenyl - 15 ester, the 2,4,6 - trichlorophenyl ester, or the anhydride in which X represents the methoxycarbonyloxy, ethoxycarbonyloxy, phenoxycarbonyloxy or benzyloxycarbonyloxy radical.
10. A process as claimed in claim 6, carried out 5 substantially as described in the Example herein.
11. A compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 6 to 10.
12. A salt of a compound claimed in claim 1, whenever prepared by a process as claimed in any one of claims 6 to 10. 10
13. A physiologically tolerable salt of a compound claimed in claim 1, whenever prepared by a process as claimed in any one of claims 6 to 10.
14. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 1 to 3, 5, 11 and 15. 13, in admixture or conjunction with a pharmaceutically suitable carrier.
15. A pharmaceutical preparation as claimed in claim 14, which is in dosage unit form.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762655094 DE2655094A1 (en) | 1976-12-04 | 1976-12-04 | ISOXAZOLE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THE PRODUCTS CONTAINING THE SAME |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE46102L IE46102L (en) | 1978-06-04 |
| IE46102B1 true IE46102B1 (en) | 1983-02-23 |
Family
ID=5994722
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE245177A IE46102B1 (en) | 1976-12-04 | 1977-12-02 | 5-methylisoxazole-4-carboxylic acid anilides having pharmaceutical activity |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS5371069A (en) |
| AT (1) | AT362788B (en) |
| BE (1) | BE861502R (en) |
| CA (1) | CA1094564A (en) |
| CH (1) | CH614945A5 (en) |
| DE (1) | DE2655094A1 (en) |
| DK (1) | DK538577A (en) |
| ES (1) | ES464553A2 (en) |
| FR (1) | FR2372813A2 (en) |
| GB (1) | GB1595467A (en) |
| IE (1) | IE46102B1 (en) |
| IT (1) | IT1113801B (en) |
| LU (1) | LU78626A1 (en) |
| NL (1) | NL7713148A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1980000964A1 (en) * | 1978-11-03 | 1980-05-15 | American Cyanamid Co | Anti-inflammatory agents including 2-carbonyl-3-hydroxy-2-alkenonitriles |
| EP0035285A3 (en) * | 1979-08-17 | 1981-10-14 | American Cyanamid Company | Novel isoxazole carboxylic acid phenyl esters, pharmaceutical compositions containing certain of said esters, and process for preparing said esters |
| DE3247454A1 (en) * | 1982-12-22 | 1984-06-28 | Laboratorios Bago S.A., Buenos Aires | Substituted 3-phenyl-5-methylisoxazole-4-carboxanilides, process for their preparation and pharmaceutical compositions containing these compounds |
| FR2538806B1 (en) * | 1982-12-30 | 1986-02-21 | Bago Sa Labor | PHENYL-3 METHYL ISOXAZOLE-5 CARBOXY-4 COMPOUNDS SUBSTITUTED ANILIDES, THERAPEUTICALLY ACTIVE INFLAMMATION AND PAIN |
| US20040110802A1 (en) * | 2002-08-23 | 2004-06-10 | Atli Thorarensen | Antibacterial benzoic acid derivatives |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2126329A (en) * | 1936-03-20 | 1938-08-09 | Hoffmann La Roche | Amide derivatives of isoxazole carboxylic acids |
| US2288863A (en) * | 1940-02-27 | 1942-07-07 | Hoffmann La Roche | Process for the manufacture of substituted amides of 3,5-dimethylisoxazole-4-carboxylic acid |
-
1976
- 1976-12-04 DE DE19762655094 patent/DE2655094A1/en not_active Withdrawn
-
1977
- 1977-11-15 CH CH1393377A patent/CH614945A5/en not_active IP Right Cessation
- 1977-11-29 ES ES464553A patent/ES464553A2/en not_active Expired
- 1977-11-29 NL NL7713148A patent/NL7713148A/en not_active Application Discontinuation
- 1977-12-02 DK DK538577A patent/DK538577A/en unknown
- 1977-12-02 GB GB5034677A patent/GB1595467A/en not_active Expired
- 1977-12-02 LU LU78626A patent/LU78626A1/xx unknown
- 1977-12-02 IE IE245177A patent/IE46102B1/en unknown
- 1977-12-02 CA CA292,276A patent/CA1094564A/en not_active Expired
- 1977-12-02 AT AT0866277A patent/AT362788B/en not_active IP Right Cessation
- 1977-12-02 IT IT3035177A patent/IT1113801B/en active
- 1977-12-03 JP JP14562177A patent/JPS5371069A/en active Pending
- 1977-12-05 BE BE183169A patent/BE861502R/en not_active IP Right Cessation
- 1977-12-05 FR FR7736546A patent/FR2372813A2/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| CH614945A5 (en) | 1979-12-28 |
| DE2655094A1 (en) | 1978-06-15 |
| IE46102L (en) | 1978-06-04 |
| CA1094564A (en) | 1981-01-27 |
| AT362788B (en) | 1981-06-10 |
| DK538577A (en) | 1978-06-05 |
| FR2372813A2 (en) | 1978-06-30 |
| ES464553A2 (en) | 1979-08-01 |
| NL7713148A (en) | 1978-06-06 |
| ATA866277A (en) | 1980-11-15 |
| LU78626A1 (en) | 1978-07-11 |
| IT1113801B (en) | 1986-01-27 |
| BE861502R (en) | 1978-06-05 |
| FR2372813B2 (en) | 1980-06-20 |
| GB1595467A (en) | 1981-08-12 |
| JPS5371069A (en) | 1978-06-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| PL164432B1 (en) | Method for the production of new aminophenol derivatives PL | |
| NO811730L (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF PHYSIOLOGICALLY ACTIVE N-ACYLANILINES. | |
| CS208112B2 (en) | Method of making the new fluoralcylsubstituted derivatives of theacylanilides | |
| PL84493B1 (en) | ||
| IE46269B1 (en) | Isoxazole derivatives,process for their manufacture and preparations containing these compounds | |
| IE46102B1 (en) | 5-methylisoxazole-4-carboxylic acid anilides having pharmaceutical activity | |
| US3324121A (en) | Alpha-(secondary aminomethyl)acylphenoxy (and phenylmercapto) monocarboxylic acids | |
| IE46001B1 (en) | Process for the manufacture of 5-methyl isoxazole-4-carboxylic acid anilide derivatives | |
| US3900486A (en) | 3-methyl-2-phenyl-5-benzothiazoline acetic acid compounds and process for producing the same | |
| GB2146983A (en) | Preparation of substituted benzamides | |
| HU199800B (en) | Process for producing substituted pyridylalkylketone derivatives | |
| US4895950A (en) | 5-halogeno-6-amino-nicotinic acid halides | |
| IL149063A0 (en) | Process to prepare aryltriazolinones and novel intermediates thereto | |
| CN116947837B (en) | Topramezone intermediate and preparation method thereof | |
| US5952494A (en) | Method for the preparation of pyrido benzoxazine derivatives | |
| JPS5927343B2 (en) | Synthesis method of 3-aminoisoxazoles | |
| US3703513A (en) | Novel 3,5-dioxopyrazolidine derivatives | |
| KR800001145B1 (en) | Process for isoxazole derivatives | |
| JPS63280084A (en) | Manufacture of 1-alkyl-3-carboxy-4-cinnolones | |
| US5071994A (en) | 2-aryl-4-halomethyl-4-isoxazolin-3-one derivatives | |
| JP2538335B2 (en) | Process for producing aromatic amines | |
| CN120987772A (en) | Benzotril intermediate and its preparation method | |
| PL192002B1 (en) | Method of obtaining derivatives of propionic acid | |
| EP0036684A1 (en) | Derivatives of 4-methyl-5-(2-aminoethyl)-thiomethyl-imidazole having therapeutic activity | |
| SU1325052A1 (en) | Method of producing 5-5-bis(2-methyl-5-nitro-1,3-dioxanyl) |