DE1470261B - Process for the preparation of 3,5-disubstituted isoxazole derivatives - Google Patents
Process for the preparation of 3,5-disubstituted isoxazole derivativesInfo
- Publication number
- DE1470261B DE1470261B DE1470261B DE 1470261 B DE1470261 B DE 1470261B DE 1470261 B DE1470261 B DE 1470261B
- Authority
- DE
- Germany
- Prior art keywords
- general formula
- isoxazole
- phenyl
- nitrile oxide
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 3,5-disubstituted isoxazole Chemical class 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 11
- 150000002825 nitriles Chemical class 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
- IYABWNGZIDDRAK-UHFFFAOYSA-N Propadiene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- YUKUDJRCHPSDGC-UHFFFAOYSA-N 1,2-oxazole;hydrochloride Chemical compound Cl.C=1C=NOC=1 YUKUDJRCHPSDGC-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 4
- 150000002545 isoxazoles Chemical class 0.000 description 4
- 239000001184 potassium carbonate Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 206010011224 Cough Diseases 0.000 description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N Isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 3
- WSCWSMUKWIYUFV-UHFFFAOYSA-N N,N-dimethylbut-3-yn-1-amine Chemical compound CN(C)CCC#C WSCWSMUKWIYUFV-UHFFFAOYSA-N 0.000 description 3
- 231100000403 acute toxicity Toxicity 0.000 description 3
- 230000000202 analgesic Effects 0.000 description 3
- 230000001754 anti-pyretic Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- LYFKKEXEETUKAD-UHFFFAOYSA-N N,N-dimethyl-2-(3-phenyl-1,2-oxazol-5-yl)ethanamine Chemical compound O1C(CCN(C)C)=CC(C=2C=CC=CC=2)=N1 LYFKKEXEETUKAD-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- IDCHQQSVJAAUQQ-UHFFFAOYSA-N Oxolamine Chemical compound O1C(CCN(CC)CC)=NC(C=2C=CC=CC=2)=N1 IDCHQQSVJAAUQQ-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 230000003110 anti-inflammatory Effects 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 230000002757 inflammatory Effects 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 230000000116 mitigating Effects 0.000 description 2
- 229960003625 oxolamine Drugs 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- VTWKXBJHBHYJBI-SOFGYWHQSA-N (NE)-N-benzylidenehydroxylamine Chemical compound O\N=C\C1=CC=CC=C1 VTWKXBJHBHYJBI-SOFGYWHQSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-Methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- UOUVJMKUBQBVKR-UHFFFAOYSA-N 3-phenyl-5-(3-piperidin-1-ylpropyl)-1,2-oxazole Chemical compound C=1C(C=2C=CC=CC=2)=NOC=1CCCN1CCCCC1 UOUVJMKUBQBVKR-UHFFFAOYSA-N 0.000 description 1
- VENMITPILVZPQO-UHFFFAOYSA-N 4-[(3-phenyl-1,2-oxazol-5-yl)methyl]morpholine Chemical compound C=1C(C=2C=CC=CC=2)=NOC=1CN1CCOCC1 VENMITPILVZPQO-UHFFFAOYSA-N 0.000 description 1
- MGTNGJBAIPLUKG-UHFFFAOYSA-N 4-[2-(3-phenyl-1,2-oxazol-5-yl)ethyl]morpholine Chemical compound C1COCCN1CCC(ON=1)=CC=1C1=CC=CC=C1 MGTNGJBAIPLUKG-UHFFFAOYSA-N 0.000 description 1
- 210000001772 Blood Platelets Anatomy 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L Calcium hydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N Dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- RLNDNSDACULHTE-UHFFFAOYSA-N N,N-diethyl-2-(3-phenyl-1,2-oxazol-5-yl)ethanamine Chemical compound O1C(CCN(CC)CC)=CC(C=2C=CC=CC=2)=N1 RLNDNSDACULHTE-UHFFFAOYSA-N 0.000 description 1
- DQMAMIHHNSPITN-UHFFFAOYSA-N N,N-diethyl-2-(3-pyridin-2-yl-1,2-oxazol-5-yl)ethanamine Chemical compound O1C(CCN(CC)CC)=CC(C=2N=CC=CC=2)=N1 DQMAMIHHNSPITN-UHFFFAOYSA-N 0.000 description 1
- WTGOJGJYRSBYQN-UHFFFAOYSA-N N,N-dimethyl-1-(3-phenyl-1,2-oxazol-5-yl)methanamine Chemical compound O1C(CN(C)C)=CC(C=2C=CC=CC=2)=N1 WTGOJGJYRSBYQN-UHFFFAOYSA-N 0.000 description 1
- KUYCWPIAKMUDCR-UHFFFAOYSA-N N,N-dimethyl-2-(3-pyridin-2-yl-1,2-oxazol-5-yl)ethanamine Chemical compound O1C(CCN(C)C)=CC(C=2N=CC=CC=2)=N1 KUYCWPIAKMUDCR-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 150000000475 acetylene derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- QUNPTMGXSSDZHZ-UHFFFAOYSA-N benzonitrile oxide Chemical compound O=N#CC1=CC=CC=C1 QUNPTMGXSSDZHZ-UHFFFAOYSA-N 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Description
Die Erfindung betrifft ein Verfahren zur Herstellung von 3,5-disubstituierten Isoxazol-Derivaten der allgemeinen Formel IThe invention relates to a process for the preparation of 3,5-disubstituted isoxazole derivatives of the general Formula I.
R,R,
r/r /
N—AN / A
gemeinen Formel III ist beträchtlich instabil, und es ist deshalb notwendig, dasselbe gleich nach seiner Herstellung zu verwenden. Deshalb kann das Verfahren am besten so durchgeführt werden, daß man die Aminoalkinverbindung der allgemeinen Formel II zum Reaktionsgemisch einer Verbindung der allgemeinen Formel IVCommon Formula III is considerably unstable, and it is therefore necessary to do the same right after his Manufacture to use. Therefore, the procedure can best be carried out in such a way that one the aminoalkyne compound of the general formula II to the reaction mixture of a compound of the general Formula IV
in der R eine Phenylgruppe oder den Pyridylrest, R1 und R2 niedermolekulare Alkylreste bedeuten oder zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Pyrrolidin-, Piperidin- oder Morpholinring bilden und A den Methylen-, Äthylenoder Propylenrest bedeutet, und deren Salzen. Das Verfahren ist dadurch gekennzeichnet, daß man in an sich bekannter Weise eine Aminoalkinverbindung der allgemeinen Formel IIin which R is a phenyl group or the pyridyl radical, R 1 and R 2 are low molecular weight alkyl radicals or, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring and A is the methylene, ethylene or propylene radical, and their Salt. The process is characterized in that an aminoalkyne compound of the general formula II is used in a manner known per se
R-CR-C
NOHNOH
R1 R 1
R,'R, '
N-A-CsCHN-A-CsCH
in der R1, R2 und A oben angegebene Bedeutung besitzen, mit einem Nitriloxyd der allgemeinen Formel IIIin which R 1 , R 2 and A have the meaning given above, with a nitrile oxide of the general formula III
0«-N = C —R III0 "-N = C -R III
in der R die oben angegebene Bedeutung besitzt, in einem inerten Lösungsmittel umsetzt und gewünschtenfalls anschließend die erhaltene Base mit einer Säure in das Salz überfuhrt.in which R has the meaning given above, reacted in an inert solvent and, if desired then the base obtained is converted into the salt with an acid.
Es ist bekannt, daß die Reaktion zwischen einem Acetylenderivat und einem Nitriloxyd ein substituiertes Isoxazol liefert (vgl. zum Beispiel R. C. E 1 d e rfield, Heterocyclic Compounds, Bd. V [ 1957], S. 460; The Chemistry of Heterocyclic Compounds, Bd. 17 [1962], S. 18). Die erfindungsgemäß erhältlichen Isoxazol-Derivate weisen ausgezeichnete, pharmakologische Wirksamkeiten auf und sind bislang noch nicht hergestellt worden.It is known that the reaction between an acetylene derivative and a nitrile oxide is a substituted one Isoxazole provides (cf., for example, R. C. E 1 derfield, Heterocyclic Compounds, Vol. V [1957], p. 460; The Chemistry of Heterocyclic Compounds, Vol. 17 [1962], p. 18). The isoxazole derivatives obtainable according to the invention have excellent pharmacological properties Effects on and have not yet been produced.
Die Reaktion zwischen der Aminoalkinverbindung der allgemeinen Formel II und dem Nitriloxyd der allgemeinen Formel III kann in einem inerten Lösungsmittel innerhalb eines weiten Temperaturbereiches, d. h. bei Zimmertemperatur bis zur Rückflußtemperatur der Lösung, durchgeführt werden. Als Beispiele für ein inertes Lösungsmittel können genannt werden Alkanole, z. B. Methanol, Äthanol; Halogenalkane, ζ. Β. Chloroform, Kohlenstofftetrachlorid, Benzol, Toluol, Xylol, Äther, Tetrahydrofuran und Dioxan. Von diesen Lösungsmitteln werden nicht polare Lösungsmittel, wie Benzol, Äther und Tetrahydrofuran, bevorzugt. Das Nitriloxyd der allworin X ein Halogenatom, z. B. Chlor, Brom, bedeutet und R die eingangs angegebene Bedeutung hat, in dem inerten Lösungsmittel und einer basischen Substanz, in der sich das Nitriloxyd der allgemeinen Formel III bildet, zusetzt. Gemäß einer anderen Alternative kann man mit Vorteil eine basische Substanz zu einem vorher hergestellten Gemisch des Aminoalkins der allgemeinen Formel II und des Hydroxamylhalogenids der allgemeinen Formel IV in einem inerten Lösungsmittel zugeben, wobei sich das gebildete Nitriloxyd der allgemeinen Formel III sofort mit dem Aminoalkinderivat der allgemeinen Formel II umsetzt. Als Beispiele, hier als Säurebindungsmittel verwendete basische Substanzen, sind zu nennen Alkali- oder Erdalkalimetallhydroxyde, z. B. Natriumhydroxyd, Kaliumhydroxyd, Calciumhydroxyd, Alkali- oder Erdalkalimetallsalze anorganischer oder organischer schwacher Säuren, z. B. Natriumcarbonat, Kaliumcarbonat, Natriumbicarbonat, Natriumacetat, ferner Ammoniak und Amine, ζ. B. Dimethylamin, Triäthylamin, Pyridin, Picolin, Dimethylanilin. Statt der genannten basischen Substanzen kann auch das Aminoalkinderivat der allgemeinen Formel II als Säurebindungsmittel verwendet werden.The reaction between the aminoalkyne compound of the general formula II and the nitrile oxide general formula III can be used in an inert solvent within a wide temperature range, d. H. at room temperature to the reflux temperature of the solution. When Examples of an inert solvent can be mentioned alkanols, e.g. B. methanol, ethanol; Haloalkanes, ζ. Β. Chloroform, carbon tetrachloride, benzene, toluene, xylene, ether, tetrahydrofuran and dioxane. Of these solvents are non-polar solvents, such as benzene, ether and Tetrahydrofuran, preferred. The nitrile oxide of the allworin X is a halogen atom, e.g. B. chlorine, bromine, and R is as defined at the beginning has, in the inert solvent and a basic substance in which the nitrile oxide of the general Formula III forms, adds. According to another alternative, a basic one can advantageously be used Substance to a previously prepared mixture of the aminoalkyne of the general formula II and add the hydroxamyl halide of the general formula IV in an inert solvent, wherein the nitrile oxide formed of the general formula III immediately with the aminoalkyne derivative of general formula II implements. As examples, basic substances used here as acid binding agents, are to be mentioned alkali or alkaline earth metal hydroxides, z. B. Sodium Hydroxide, Potassium Hydroxide, Calcium hydroxide, alkali or alkaline earth metal salts of inorganic or organic weak acids, z. B. sodium carbonate, potassium carbonate, sodium bicarbonate, sodium acetate, and ammonia Amines, ζ. B. dimethylamine, triethylamine, pyridine, picoline, dimethylaniline. Instead of the aforementioned basic Substances can also be the aminoalkyne derivative of the general formula II as an acid-binding agent be used.
Die verwendeten Ausgangsmaterialien, das Aminoalkinderivat der allgemeinen Formel II, das Nitriloxyd der allgemeinen Formel III bzw. Hydroxamylhalogenid können mit Hilfe üblicher Verfahren erhalten werden.The starting materials used, the aminoalkyne derivative of the general formula II, the nitrile oxide of the general formula III or hydroxamyl halide can with the help of customary processes can be obtained.
Die so erhältlichen Isoxazolverbindungen der allgemeinen Formel I sind im freien Zustand flüssig
oder fest. Die Verbindungen können mit Hilfe üblicher Verfahren in ihre Salze umgewandelt werden.
Die erfindungsgemäß erhältlichen Isoxazolverbindüngen der allgemeinen Formel I und ihre nicht
toxischen Salze weisen stärkere antipyretische, analgetische, entzündungshemmende und/oder hustenreizmildernde
Wirksamkeiten als die des Oxolamins, eines im Handel erhältlichen Medikamentes, auf,
wie dies aus der Tabelle ersichtlich ist.The isoxazole compounds of the general formula I obtainable in this way are liquid or solid in the free state. The compounds can be converted into their salts using conventional methods.
The isoxazole compounds of the general formula I obtainable according to the invention and their non-toxic salts have stronger antipyretic, analgesic, anti-inflammatory and / or anti-coughing effects than those of oxolamine, a commercially available drug, as can be seen from the table.
Wirksamkeiteffectiveness
hemmendeinhibiting
mildernde Wirkmitigating effect
Wirksamkeit2)Effectiveness 2 )
CC.
Wirksamkeiteffectiveness
.ED30 J).ED 30 J )
mg/ kg .mg / kg.
mildernde Wirkmitigating effect
samkeit Ep5O9)sameness Ep 5 O 9 )
mg/kgmg / kg
LD511')LD 511 ')
m&kgm & kg
hemmendeinhibiting
Wirksamkeit4)Effectiveness 4 )
%%
3-Phenyl-5-pyrrolidinomethyI-3-phenyl-5-pyrrolidinomethyl
isoxazol-hydrochlorid isoxazole hydrochloride
3-Phenyl-5-(2-dimethylaminoäthyI)-3-phenyl-5- (2-dimethylaminoethyI) -
isoxazol-hydrochlorid isoxazole hydrochloride
3- Phenyl-5-(2-piperidinoäthyl)-3- phenyl-5- (2-piperidinoethyl) -
isoxazol-citrat isoxazole citrate
3-PhenyI-5-(2-morpholinoäthy!)-3-PhenyI-5- (2-morpholinoethy!) -
isoxazol-hydrochlorid isoxazole hydrochloride
3-Phenyl-5-(2-pyrrolidinoäthyI)-3-phenyl-5- (2-pyrrolidinoethyI) -
isoxazol-hydrochlorid isoxazole hydrochloride
3-PhenyI-5-(3-piperidinopropyl)-3-PhenyI-5- (3-piperidinopropyl) -
isoxazol-hydrochlorid isoxazole hydrochloride
3-(2-Pyridyl)-5-(2-diäthyiamino-3- (2-pyridyl) -5- (2-diethyiamino-
äthylisoxazol-citrat ethyl isoxazole citrate
3-(2-Pyridyl)-6-(2-piperidinoäthyI)-3- (2-pyridyl) -6- (2-piperidinoethyI) -
isoxazol-hydrochlorid isoxazole hydrochloride
3-(3-Pyridyl)-5-(2-diäthylamino-3- (3-pyridyl) -5- (2-diethylamino-
äthyl)-isoxazol-citrat ethyl) isoxazole citrate
') Akute Toxizität: Die Testverbindungen wurden subkutan un Mäusen verabreicht.Acute toxicity: the test compounds were administered subcutaneously to mice.
') Antipyretische Wirksamkeit: Die Testverbindungen wurden subkutan an Mäusen mit einer Dosis von KX)mg kg Körpergewicht ver abreicht, und die Depression der Körpertemperatur wurde gemessen.') Antipyretic activity: the test compounds were administered subcutaneously to mice at a dose of KX) mg kg body weight, and the depression of body temperature was measured.
') Analgetische Wirksamkeit: Die Testverbindungen wurden subkutan Mäusen verabreicht, und die Wirksamkeit wurde gemäß der Haffner-Methode (Deuische Med. Wochenschrift. 55 [1929], S. 731 bis 733) bestimmt.') Analgesic activity: the test compounds were administered subcutaneously to mice, and the activity was determined according to the Haffner method (Deuische Med. Wochenschrift. 55 [1929], pp. 731 to 733).
4) Entzündungshemmende Wirksamkeit: Die Testverbindungen wurden subkutan an Ratten mit einer Dosis von 100 mg,Tier verabreicht, wobei die genannten Ratten vorher mit 0.05 ml 3.7"„iger Formalinlösung behandelt wurden. Die Inhibition des Oedems in Prozenten wurde dann gemessen.' 4 ) Anti-inflammatory activity: the test compounds were administered subcutaneously to rats at a dose of 100 mg, animal, the said rats having previously been treated with 0.05 ml 3.7% formalin solution . The percentage of inhibition of the edema was then measured.
5) Hustenreizmildernde Wirksamkeit: Die Testverbindungen wurden subkutan an Meerschweinchen verabreicht, und dann wurden diese Tiere mit 12,5",>igem Ammoniak besprüht. Aus der prozentualen Anzahl der nicht hustenden Meerschweinchen wurde dann die wirk same Dosis 50 errechnet. · 5 ) Cough-reducing activity: the test compounds were administered subcutaneously to guinea pigs, and these animals were then sprayed with 12.5 "ammonia. The effective dose 50 was then calculated from the percentage number of non-coughing guinea pigs.
Das erfindungsgemäße Verfahren wird im nachfolgenden durch einige Beispiele näher erläutert.The process according to the invention is explained in more detail below by means of a few examples.
Zu einer Lösung von 0,97 g 4-Dimethylamino-1-butin (J. Org. Chem., Bd. 17 [1952], S. 1141 bis 1148) in 3,4 g Triäthylamin wird eine Lösung von 1,6 g Benzohydroxamylchlorid, F. = 480C, in 10 ml Benzol bei 5° C unter Rühren zugegeben und das erhaltene Gemisch allmählich auf 60 bis 70° C erhitzt und 1 Stunde gerührt. Nach Kühlen wird das Reaktionsgemisch mit verdünnter Chlorwasserstoffsäure geschüttelt. Die wäßrige Phase wird mit Benzol gewaschen, mit 20%iger Natriumhydroxydlösung alkalisch gemacht und mit Äther geschüttelt. Die Ätherschicht wird mit Wasser gewaschen, über wasserfreiem Kaliumcarbonat getrocknet und das Lösungsmittel durch Destillieren entfernt. Die erhaltene Flüssigkeit wird unter reduziertem Druck destilliert. Man erhält 0,83 g 3-Phenyl-5-(2-dimethylaminoäthyl)-isoxazol als hellgelbes öl, Kp.4 = 151°C. Das Hydrochlorid besteht aus farblosen Nadeln, F. = 187 bis 188° C, nach Kristallisieren aus Äthanol.A solution of 1.6 g is added to a solution of 0.97 g of 4-dimethylamino-1-butyne (J. Org. Chem., Vol. 17 [1952], pp. 1141 to 1148) in 3.4 g of triethylamine heated Benzohydroxamylchlorid, F. = 48 0 C, added in 10 ml benzene at 5 ° C with stirring and the resulting mixture gradually to 60 to 70 ° C and stirred for 1 hour. After cooling, the reaction mixture is shaken with dilute hydrochloric acid. The aqueous phase is washed with benzene, made alkaline with 20% sodium hydroxide solution and shaken with ether. The ether layer is washed with water, dried over anhydrous potassium carbonate and the solvent is removed by distillation. The liquid obtained is distilled under reduced pressure. 0.83 g of 3-phenyl-5- (2-dimethylaminoethyl) isoxazole is obtained as a pale yellow oil, boiling point 4 = 151.degree. The hydrochloride consists of colorless needles, mp = 187 to 188 ° C, after crystallization from ethanol.
Eine Benzollösung von Benzonitriloxyd, hergestellt durch Reaktion von 1,6 g Benzohydroxamylchlorid mit 3,4 g Triäthylamin in 10 ml Benzol bei 5° C, wird mit 0,97 g 4-Dimethylamino-l-butin versetzt. Das erhaltene Gemisch wird allmählich auf 60 bis 70° C erhitzt und anschließend noch 1 Stunde gerührt.A benzene solution of benzonitrile oxide made by reacting 1.6 g of benzohydroxamyl chloride with 3.4 g of triethylamine in 10 ml of benzene at 5 ° C., 0.97 g of 4-dimethylamino-l-butyne are added. The mixture obtained is gradually heated to 60 to 70 ° C. and then stirred for a further 1 hour.
Das Reaktionsgemisch wird gemäß Beispiel 1 behandelt. Man erhält 0,79 g 3-Phenyl-5-(2-dimethyIaminoäthyl)-isoxazol als hellgelbes öl, Kp4 = 15PC.The reaction mixture is treated as in Example 1. 0.79 g of 3-phenyl-5- (2-dimethylaminoethyl) isoxazole is obtained as a pale yellow oil, b.p. 4 = 15PC.
B e i s ρ i e 1 3B e i s ρ i e 1 3
Zu einer Lösung von 3,0 g 5-Piperidino-l-pentin, Kp.7 = 72 bis 74 C, und 11,1g Triäthylamin in 40 ml Benzol läßt man eine Lösung von Benzohydroxamylchlorid, hergestellt aus 12,1 g Benzaldehydoxim in 30 ml Benzol bei 10 bis 15° C, unter Rühren zutropfen und rührt das erhaltene Gemisch 1 Stunde bei 60 bis 700C. Nach Kühlen wird das Reaktionsgemisch filtriert und das Filtrat mit 5%'ger Chlorwasserst offsäure geschüttelt. Die wäßrige Schicht wird mit 20%'ger Natriumhydroxydlösung alkalisch gemacht und mit Äther geschüttelt. Die Ätherschicht wird mit Wasser gewaschen, über wasserfreiem Kaliumcarbonat getrocknet und eingeengt, wobei 3,6 g rohes 3-Phenyl-5-(3-piperidinopropyl)-isoxazol in Form eines gelblichen Öls erhalten werden. Das Hydrochlorid besteht aus farblosen Plättchen, welche nach Umkristallisieren aus Aceton einen Schmelzpunkt von 166 bis 167° C haben.A solution of benzohydroxamyl chloride, prepared from 12.1 g of benzaldehyde oxime in 30 °, is added to a solution of 3.0 g of 5-piperidino-1-pentine, b.p. 7 = 72 to 74 ° C., and 11.1 g of triethylamine in 40 ml of benzene ml of benzene at 10 to 15 ° C, is added dropwise with stirring and stirring the resulting mixture for 1 hour at 60 to 70 0 C. After cooling, the reaction mixture is filtered and the filtrate washed with 5% 'ger Chlorwasserst offsäure shaken. The aqueous layer is made alkaline with 20% sodium hydroxide solution and shaken with ether. The ether layer is washed with water, dried over anhydrous potassium carbonate and concentrated to give 3.6 g of crude 3-phenyl-5- (3-piperidinopropyl) isoxazole in the form of a yellowish oil. The hydrochloride consists of colorless platelets which, after recrystallization from acetone, have a melting point of 166 to 167 ° C.
Zu einer Lösung von 1,9 g 4-Dimethylamino-l-butin und 3,0 g Triäthylamin in 15 ml Äthanol werden 1,95 g 2-Pyridylhydroxamylchlorid (Bull. Soc. Chim. France [1962], S. 2215 bis 2221) bei 10 bis 12°C unter Rühren zugegeben, und das erhaltene Gemisch wird 2 Stunden bei 60 bis 65° C gerührt. Das Reak-To a solution of 1.9 g of 4-dimethylamino-l-butyne and 3.0 g of triethylamine in 15 ml of ethanol, 1.95 g of 2-pyridylhydroxamyl chloride (Bull. Soc. Chim. France [1962], pp. 2215 to 2221) was added at 10 to 12 ° C. with stirring, and the mixture obtained is stirred at 60 to 65 ° C for 2 hours. The Rea-
tionsgemisch wird dann unter vermindertem Druck eingeengt, mit einer kleinen Wassermenge vermischt und mit Chloroform geschüttelt. Die Chloroformschicht wird über wasserfreiem Kaliumcarbonat getrocknet, mit Aktivkohle behandelt und das Lösungsmittel durch Destillieren unter vermindertem Druck entfernt. Die erhaltene Flüssigkeit wird mit Petroläther vermengt und stehengelassen, wobei sich Kristalle abscheiden. Die Kristalle werden filtriert, und das Filtrat wird eingeengt. Der Rückstand wird unter vermindertem Druck destilliert, wobei man 1.8 g 3-(2-Pyridyl)-5-(2-dimethylaminoäthyl)-isoxazol als hellgelbes öl. Kp.2 =127 C. erhält. Das Citrat besteht aus farblosen Prismen, F. = 110 bis 111 C. nach Umkristallisieren aus Äthanol.tion mixture is then concentrated under reduced pressure, mixed with a small amount of water and shaken with chloroform. The chloroform layer is dried over anhydrous potassium carbonate, treated with activated charcoal, and the solvent is removed by distillation under reduced pressure. The liquid obtained is mixed with petroleum ether and left to stand, whereupon crystals separate out. The crystals are filtered and the filtrate is concentrated. The residue is distilled under reduced pressure, 1.8 g of 3- (2-pyridyl) -5- (2-dimethylaminoethyl) isoxazole being obtained as a pale yellow oil. Kp. 2 = 127 C. obtained. The citrate consists of colorless prisms, F. = 110 to 111 C. after recrystallization from ethanol.
In entsprechender Weise sind folgende Isoxazolderivate erhältlich:The following isoxazole derivatives are analogous available:
3-Phenyl-5-dimethylaminomcthylisoxazol (Hydrochlorid, F. = 207 bis 208 C),3-phenyl-5-dimethylaminomethylisoxazole (hydrochloride, F. = 207 to 208 C),
3-Phcnyl-5-diäthylaminomethy!isoxazol (Hydro-3-Phcnyl-5-diethylaminomethyl! Isoxazole (Hydro-
chlorid, F. = 145 bis 146 C), S-Phcnyl-S-piperidinomcthylisoxazol (Hydro-chloride, F. = 145 to 146 C), S-Phcnyl-S-piperidinomcthylisoxazole (Hydro-
chlorid, F. = 225 bis 226 C), 3-Phenyl-5-morpholinomcthylisoxazolchloride, m.p. = 225 to 226 C), 3-phenyl-5-morpholinomethylisoxazole
(F. = 44 bis 46 C),
S-Phenyl-S-pyrrolidinomcthylisoxazol (I lydro-(F. = 44 to 46 C),
S-phenyl-S-pyrrolidinomethylisoxazole (I lydro-
chlorid. F. = 189 bis 190 C). 3-Phcnyl-5-(2-diäthyIaminoäthyl)-isoxazol (Hydrochlorid, F. = 162 bis 163 C).chloride. F. = 189 to 190 C). 3-Phenyl-5- (2-diethylaminoethyl) isoxazole (Hydrochloride, m.p. = 162 to 163 ° C).
3-Phenyl-5-(2-pipcridinoüthyi)-isoxazol3-phenyl-5- (2-pipcridinoüthyi) -isoxazole
(F. = 55 bis 56 C).
3-Phenyl-5-(2-morpholinöäthyl)-isoxazol(F. = 55 to 56 C).
3-phenyl-5- (2-morpholinoethyl) isoxazole
(F. = 70 bis 71 C).
3-Phenyl-5-(2-pyrrolidinoäthyI)-isoxazol(F. = 70 to 71 C).
3-phenyl-5- (2-pyrrolidinoethyI) isoxazole
(F. = 43 bis 44 C).
3-(2-Pyridyl)-5-(2-diäthylaminoäthyl)-isoxazol(F. = 43 to 44 C).
3- (2-pyridyl) -5- (2-diethylaminoethyl) isoxazole
(Citrat. F. = 150 bis 151 C). 3-(2-PyridyI)-5-(2-pipcridinoäthyD-isoxazol (Hydrochlorid, F. = 218 bis 219 C).(Citrate. F. = 150 to 151 C). 3- (2-pyridyl) -5- (2-pipcridinoethyD-isoxazole (Hydrochloride, m.p. = 218 to 219 C).
3-(3-Pyridyl)-5-(2-diäthylaminoäthyl)-isoxa/ol (Citrat. F. = 151 bis 152 C).3- (3-pyridyl) -5- (2-diethylaminoethyl) -isoxa / ol (citrate. F. = 151 to 152 ° C).
Claims (2)
Family
ID=
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2909025A1 (en) * | 1978-03-09 | 1979-09-13 | Taiho Pharmaceutical Co Ltd | GLYOXAL-2-OXIME DERIVATIVES, METHOD FOR THEIR PRODUCTION AND PHARMACEUTICAL AGENT |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2909025A1 (en) * | 1978-03-09 | 1979-09-13 | Taiho Pharmaceutical Co Ltd | GLYOXAL-2-OXIME DERIVATIVES, METHOD FOR THEIR PRODUCTION AND PHARMACEUTICAL AGENT |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE2658544C2 (en) | Carbostyril derivatives, processes for their preparation and pharmaceuticals containing these compounds | |
| DE2503815C2 (en) | Indazole derivatives, processes for their preparation and pharmaceuticals | |
| DE69212870T2 (en) | 4-aryl-thiazoles or imidazole derivatives | |
| DE69023928T2 (en) | DIAMINE COMPOUNDS AND DRUGS AGAINST CEREBRAL DISORDERS THAT CONTAIN THEM. | |
| DE1445603A1 (en) | Process for the preparation of new oxadiazole derivatives | |
| DE2532742A1 (en) | (1,2,4-OXADIAZOL-3-YL) -PHENYL DERIVATES, METHOD FOR THEIR MANUFACTURING, AND MEDICINAL PRODUCTS | |
| EP0089028A1 (en) | Theophyllin derivatives, and process for their preparation | |
| DE2533821A1 (en) | THIAZOLIDE DERIVATIVES AND METHOD FOR THEIR PRODUCTION | |
| EP0018360B1 (en) | N-(5-methoxybenzofuran-2-ylcarbonyl)-n'-benzylpiperazine and process for its preparation | |
| CH615151A5 (en) | ||
| DE1470261C (en) | Process for the preparation of 3.5 "disubstituted isoxazole derivatives | |
| DE1470261B (en) | Process for the preparation of 3,5-disubstituted isoxazole derivatives | |
| CH638525A5 (en) | 3- (TETRAZOL-5-YL) -1-AZAXANTHONE AND METHOD FOR THE PRODUCTION THEREOF. | |
| DE1470257C (en) | Process for the preparation of disubstituted1 isoxazole derivatives and their pharmaceutically acceptable salts | |
| CH634828A5 (en) | METHOD FOR PRODUCING NEW OXIMETHER COMPOUNDS. | |
| DE1470258C (en) | ||
| DE1287582B (en) | Process for the preparation of disubstituted isoxazole compounds and their non-toxic salts | |
| DE1470258A1 (en) | Disubstituted isoxazole compounds and processes for their preparation | |
| AT223196B (en) | Process for the preparation of new, 2-araliphatic 3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxydes | |
| DE1470258B (en) | Di "substituted isoxazole derivatives and processes for their preparation | |
| DE2500840A1 (en) | PROCESS FOR THE PREPARATION OF 1H-TETRAZOLE-1-ACETIC ACID | |
| DE1235922B (en) | Process for the preparation of new N-substituted 4-phenyl-piperidine-4-carbon-acidic ethyl ester compounds | |
| DE1445800C (en) | Process for the preparation of diben zoazepines | |
| DE1695707C3 (en) | Benzimidazole derivatives and processes for their preparation | |
| EP2563762B1 (en) | Method for producing substituted pyridin-2-one |