DE1470258C - - Google Patents
Info
- Publication number
- DE1470258C DE1470258C DE1470258C DE 1470258 C DE1470258 C DE 1470258C DE 1470258 C DE1470258 C DE 1470258C
- Authority
- DE
- Germany
- Prior art keywords
- hydrochloride
- isoxazole
- phenyl
- phenylisoxazole
- general formula
- 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.)
- Active
Links
- -1 haloalkyl compound Chemical class 0.000 claims description 17
- 150000002545 isoxazoles Chemical class 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000011780 sodium chloride Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- IYABWNGZIDDRAK-UHFFFAOYSA-N Propadiene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 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
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- 239000012530 fluid Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 7
- KKUDUDGVXMDUAH-UHFFFAOYSA-N 5-phenyl-1,2-oxazole;hydrochloride Chemical compound Cl.O1N=CC=C1C1=CC=CC=C1 KKUDUDGVXMDUAH-UHFFFAOYSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000000202 analgesic Effects 0.000 description 4
- 230000003110 anti-inflammatory Effects 0.000 description 4
- 230000001754 anti-pyretic Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 206010011224 Cough Diseases 0.000 description 3
- 231100000403 acute toxicity Toxicity 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000001772 Blood Platelets Anatomy 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N Isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N Nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 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
- 230000000954 anitussive Effects 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 229960003625 oxolamine Drugs 0.000 description 2
- 239000001184 potassium carbonate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-Methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- HAARZQOXENAXOY-UHFFFAOYSA-N 3-phenyl-5-(2-piperidin-1-ylethyl)-1,2-oxazole Chemical compound C1CCCCN1CCC(ON=1)=CC=1C1=CC=CC=C1 HAARZQOXENAXOY-UHFFFAOYSA-N 0.000 description 1
- IVDLMJVLIPZPJC-UHFFFAOYSA-N 3-phenyl-5-(2-pyrrolidin-1-ylethyl)-1,2-oxazole Chemical compound C1CCCN1CCC(ON=1)=CC=1C1=CC=CC=C1 IVDLMJVLIPZPJC-UHFFFAOYSA-N 0.000 description 1
- IDNKMEIJFTWUEG-UHFFFAOYSA-N 3-phenyl-5-(piperidin-1-ylmethyl)-1,2-oxazole Chemical compound C=1C(C=2C=CC=CC=2)=NOC=1CN1CCCCC1 IDNKMEIJFTWUEG-UHFFFAOYSA-N 0.000 description 1
- IEFFAOXMKNLERG-UHFFFAOYSA-N 3-phenyl-5-(pyrrolidin-1-ylmethyl)-1,2-oxazole Chemical compound C=1C(C=2C=CC=CC=2)=NOC=1CN1CCCC1 IEFFAOXMKNLERG-UHFFFAOYSA-N 0.000 description 1
- AYTLPTRYSGTHNV-UHFFFAOYSA-N 3-propyl-1,2-oxazole Chemical compound CCCC=1C=CON=1 AYTLPTRYSGTHNV-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 description 1
- WFNHAQXQKOMQJD-UHFFFAOYSA-N 5-(2-piperidin-1-ylethyl)-3-pyridin-2-yl-1,2-oxazole Chemical compound C1CCCCN1CCC(ON=1)=CC=1C1=CC=CC=N1 WFNHAQXQKOMQJD-UHFFFAOYSA-N 0.000 description 1
- WKLODVHSLLFKMY-UHFFFAOYSA-N 5-(chloromethyl)-3-phenyl-1,2-oxazole Chemical compound O1C(CCl)=CC(C=2C=CC=CC=2)=N1 WKLODVHSLLFKMY-UHFFFAOYSA-N 0.000 description 1
- BXQDLEHCXQQSCH-UHFFFAOYSA-N 5-phenyl-1,2-oxazole Chemical compound O1N=CC=C1C1=CC=CC=C1 BXQDLEHCXQQSCH-UHFFFAOYSA-N 0.000 description 1
- FMKRVPJPFOGYQU-UHFFFAOYSA-N 5-phenyl-3-(2-piperidin-1-ylethyl)-1,2-oxazole Chemical compound C1CCCCN1CCC(=NO1)C=C1C1=CC=CC=C1 FMKRVPJPFOGYQU-UHFFFAOYSA-N 0.000 description 1
- 229960003563 Calcium Carbonate Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- NSVPXSQGKZPPQO-UHFFFAOYSA-N Cl.NCCC1=NOC(=C1)C1=CC=CC=C1 Chemical compound Cl.NCCC1=NOC(=C1)C1=CC=CC=C1 NSVPXSQGKZPPQO-UHFFFAOYSA-N 0.000 description 1
- FXBAOPOSLKKSMZ-UHFFFAOYSA-N ClCCC1=NOC(=C1)C1=CC=CC=C1 Chemical compound ClCCC1=NOC(=C1)C1=CC=CC=C1 FXBAOPOSLKKSMZ-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001072332 Monia Species 0.000 description 1
- TZURGBMKPQSCEX-UHFFFAOYSA-N N,N-diethyl-2-(1,2-oxazol-3-yl)ethanamine Chemical compound CCN(CC)CCC=1C=CON=1 TZURGBMKPQSCEX-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
- CRRDAMTVJKZOCP-UHFFFAOYSA-N N,N-dimethyl-1-(3-phenyl-1,2-oxazol-5-yl)ethanamine Chemical compound O1C(C(N(C)C)C)=CC(C=2C=CC=CC=2)=N1 CRRDAMTVJKZOCP-UHFFFAOYSA-N 0.000 description 1
- UWMXSCVXWHUWDH-UHFFFAOYSA-N N,N-dimethyl-1-(5-phenyl-1,2-oxazol-3-yl)methanamine Chemical compound O1N=C(CN(C)C)C=C1C1=CC=CC=C1 UWMXSCVXWHUWDH-UHFFFAOYSA-N 0.000 description 1
- IWFDFAVUKYJQTM-UHFFFAOYSA-N O1CCN(CC1)CCC1=NOC(=C1)C1=CC=CC=C1 Chemical compound O1CCN(CC1)CCC1=NOC(=C1)C1=CC=CC=C1 IWFDFAVUKYJQTM-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 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
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 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
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Description
Die Erfindung betrifft disubstituierte Isoxazol-Derivate und deren pharmazeutisch verträgliche Salze und ein Verfahren zur Herstellung dieser Derivate, denen eine der allgemeinen Formeln I und IIThe invention relates to disubstituted isoxazole derivatives and their pharmaceutically acceptable salts and a process for the preparation of these derivatives, which one of the general formulas I and II
-N-N
N-AN / A
R,'R, '
IIII
zukommt, in denen R eine Phenylgruppe oder den Pyridylrest und R1 und R2 Alkylreste mit höchstens 3 Kohlenstoffatomen bedeuten oder zusammen mit dem Stickstoffatom einen Pyrrolidin-, Piperidin- oder Morpholinring bilden und A eine Methylen-, Äthylenoder Propylengruppe darstellt.in which R is a phenyl group or the pyridyl radical and R 1 and R 2 are alkyl radicals with a maximum of 3 carbon atoms or together with the nitrogen atom form a pyrrolidine, piperidine or morpholine ring and A represents a methylene, ethylene or propylene group.
Das Verfahren zur Herstellung obengenannter disubstituierter Isoxazol-Derivate der allgemeinen Formeln I und II und von deren pharmazeutisch verträglichen Salzen ist dadurch gekennzeichnet, daß man entweder eine Halogenalkylverbindung der allgemeinen Formel III ■The process for the preparation of the above-mentioned disubstituted isoxazole derivatives of the general formulas I and II and their pharmaceutically acceptable salts is characterized in that one either a haloalkyl compound of the general formula III ■
A-XA-X
IIIIII
oder der allgemeinen Formel IVor the general formula IV
X-AX-A
IVIV
in denen X ein Halogenatom darstellt und R und A die oben angegebene Bedeutung haben, in an sich bekannter Weise mit einem Amin der allgemeinen Formel Vin which X represents a halogen atom and R and A have the meanings given above, in per se known manner with an amine of the general formula V
Λ .'■-.■ Λ . '■ -. ■
Η —Ν V-Η —Ν V-
in der R1 und R2 die oben angegebene Bedeutungin which R 1 and R 2 have the meaning given above
haben, umsetzt und gewürischtenfalls die erhaltene Base mit einer Säure in ihr Salz überführt.have reacted and if necessary converted the base obtained into its salt with an acid.
Bisher waren keine Isoxazol-Derivate mit einer substituierten oder unsubstituierten Alkylaminogrüppe am Isoxazolring bekannt. Es wurde festgestellt, daß die erfindungsgemäß erhältlichen Isoxazol-Derivate verschiedene pharmakologische Wirksamkeiten aufweisen. . . . ■So far there have been no isoxazole derivatives with a substituted or unsubstituted alkylamino group known on the isoxazole ring. It was found that the isoxazole derivatives obtainable according to the invention have different pharmacological activities. . . . ■
Die Halogenalkylisoxazolausgangsverbindungen der allgemeinen Formel III oder IV können mit Hilfe üblicher Verfahren erhalten werden.The haloalkylisoxazole starting compounds of the general formula III or IV can be prepared with the aid conventional procedures can be obtained.
Gemäß dem erfindungsgemäßen Verfahren kann die Reaktion so durchgeführt werden, daß man die Halogenalkylisoxazolverbindung der allgemeinen Formel III oder IV mit dem Amin der allgemeinen Formel. V in einem inerten Lösungsmittel innerhalb eines weiten Temperaturbereiches und, falls notwendig, in Gegenwart einer basischen Substanz zur Säurebindung umsetzt.According to the process of the invention, the reaction can be carried out so that the Haloalkylisoxazole compound of the general formula III or IV with the amine of the general formula. V in an inert solvent within a wide temperature range and, if necessary, in Reacts the presence of a basic substance for acid binding.
Als Reaktionsmedium verwendbare inerte Lösungsmittel kommen in Betracht: Wasser, wäßrige Alkanole, Alkanole, Benzol, Toluol, Xylol, Phenol und Nitrobenzol. Als Beispiele basischer Substanzen können erwähnt werden: organische Basen, wie Pyridinbasen, z. B. Pyridin, Picolin, Butidin, Collidin, und aliphatische Amine, z. B. Dimethylamin. Diethylamin, Triäthylamin, und anorganische Basen, z.B. Alkalimetallcarbonate, z. B. Natriumcarbonat, Kaliumcarbonat, Alkalimetallbicarbonate, z. B. Natriumbicarbonat, Kaliumbicarbonat, und Erdalkalimetallcarbonate, z. B. Calciumcarbonat, Bäriumcarbonat. Die basische Substanz kann in Form eines Gemisches, ■ einer Suspension oder Lösung im genannten inerten organischen Lösungsmittel oder im Falle einer Flüssigkeit allein verwendet werden. Falls das Ausgangsamin . der allgemeinen Formel V flüssig ist, wird ein Überschuß desselben bevorzugt, da es nicht nur als Reaktionsmittel, sondern auch als Reaktionslösungsmittel und als Mittel zur Säurebindung dienen kann.Inert solvents which can be used as the reaction medium are: water, aqueous alkanols, Alkanols, benzene, toluene, xylene, phenol and nitrobenzene. As examples of basic substances can mentioned are: organic bases, such as pyridine bases, e.g. B. pyridine, picoline, butidine, collidine, and aliphatic Amines, e.g. B. dimethylamine. Diethylamine, triethylamine, and inorganic bases, e.g. alkali metal carbonates, z. B. sodium carbonate, potassium carbonate, alkali metal bicarbonates, e.g. B. Sodium bicarbonate, Potassium bicarbonate, and alkaline earth metal carbonates, e.g. B. calcium carbonate, bearium carbonate. the basic substance can be in the form of a mixture, ■ a suspension or solution in said inert organic solvents or, in the case of a liquid, alone can be used. If the starting amine . of the general formula V is liquid, an excess of the same is preferred, since it is not only used as a reactant, but can also serve as a reaction solvent and as an acid binding agent.
Die so erhaltenen Isoxazolverbindungen der allgemeinen Formel I und II sind im freien Zustand flüssig oder fest. Zweckmäßigkeitshalber können sie bei der Herstellung in ihre Salze mit. Hilfe üblicher Verfahren umgewandelt werden. - .The isoxazole compounds of the general formulas I and II obtained in this way are in the free state liquid or solid. For convenience, they can be added to their salts during manufacture. Help usual Procedure to be converted. -.
Die so erhaltenen disubstituierten Isoxazolverbindungen der allgemeinen Formeini und II und ihre nicht toxischen Salze weisen im allgemeinen stärkere antipyretische, analgetische, entzündungshemmende und/oder hustenreizmildernde Wirksamkeiten auf als jene des Oxolamins, eines im Handel erhältlichen Medikamentes (vgl. Tabelle I).The disubstituted isoxazole compounds of the general formeini and II obtained in this way and their Non-toxic salts generally have more potent antipyretic, analgesic, anti-inflammatory and / or antitussive activities than that of oxolamine, one of the commercially available ones Drug (see Table I).
4040
4545
Verbindungconnection
3-Phehyl-5-(2-diäthylaminoäthyl)-1,2,4-oxadiazöl (Oxolamin) 3-Phehyl-5- (2-diethylaminoethyl) -1,2,4-oxadiazole (Oxolamine)
S-Dimethylaminomethyl-S-phenylisoxazolhydrochlorid S-dimethylaminomethyl-S-phenylisoxazole hydrochloride
3-Diäthylaminomethy!-5-phenylisoxazolhydrochlorid 3-diethylaminomethyl! -5-phenylisoxazole hydrochloride
^-Pyrrolidinomethyl-S-phenylisoxazol- .
hydrochlorid ^ -Pyrrolidinomethyl-S-phenylisoxazole-.
hydrochloride
Akute Toxizität1) LD50 Acute toxicity 1 ) LD 50
(mg/kg)(mg / kg)
500 bis 212 Antipyretische Wirksamkeit2) 500 to 212 antipyretic effectiveness 2 )
(C)(C)
-0,46-0.46
-2,5-2.5
-1,38-1.38
-4,67-4.67
AnalgetischeAnalgesic
Wirksamkeit3)
ED50 Effectiveness 3 )
ED 50
(mg/kg)(mg / kg)
131
113131
113
55
6055
60
Entzündungshemmende Anti-inflammatory
Wirksamkeit4) Effectiveness 4 )
l"' 1l "'1
6,8
30,5
22.4
28,06.8
30.5
22.4
28.0
Hustenreizmildernde
. Wirksamkeit5)
ED50 -Cough reliever
. Effectiveness 5 )
ED 50 -
(in g/kg)(in g / kg)
43,2
11043.2
110
Fortsetzungcontinuation
Verbindungconnection
Akute Toxizität1)" LD,„ Acute toxicity 1 ) "LD,"
(mg/kg) Antipyretische Wirksamkeit2) (mg / kg) Antipyretic efficacy 2 )
(0C)( 0 C)
Wirksamkeit3) ED50 Effectiveness 3 ) ED 50
(mg/kg)(mg / kg)
Entzündungs hemmendeAnti-inflammatory
Wirksamkeit4)Effectiveness 4 )
HustenreizmilderndeCough reliever
Wirksamkeit5) ED50.Effectiveness 5 ) ED 50 .
(mg/kg)(mg / kg)
.VPiperidinoniethyl-S-phenylisoxazol-.VPiperidinoniethyl-S-phenylisoxazole-
hydrochlorid : hydrochloride:
3-^lorpllolinomethyl-5-phcnylisόxa/.ol- .3- ^ lorpllolinomethyl-5-phcnylisόxa / .ol-.
. hydiochlorid . hydrochloride
3-(2-Piperidinoäthyl)-5-phenylisoxazol-3- (2-piperidinoethyl) -5-phenylisoxazole-
hydrochlorid hydrochloride
3-(2-Pyrrolidinoäthyl)-5-phenylisoxazoI-3- (2-pyrrolidinoethyl) -5-phenylisoxazoI-
hydrochlorid · hydrochloride
3-(2-Morpholinoäthyl)-5-phenylisoxazol-3- (2-morpholinoethyl) -5-phenylisoxazole-
hydrochlorid hydrochloride
3-PhenyI-5-dimethylamino-methylisoxazol-3-PhenyI-5-dimethylamino-methylisoxazole-
hydrochlorid hydrochloride
3-Phenyl-5-piperidino-methylisoxazol-3-phenyl-5-piperidino-methylisoxazole-
hydrochlorid . ..hydrochloride. ..
3-PhenyI-5-pyrroliclino-methylisoxazol-3-PhenyI-5-pyrroliclino-methylisoxazole-
hydrochlorid ...·.;.. hydrochloride ... ·.; ..
3-Phenyl-5-(2-dimethylaminoätliyl)-isüXiizol-3-phenyl-5- (2-dimethylaminoätliyl) -isüXiizol-
hydrochlörid hydrochloride
3-Phenyl-5-(2-pyrrolidinoäthyl)-isoxazol-3-phenyl-5- (2-pyrrolidinoethyl) -isoxazole-
hydrochlorjd .:... hydrochloride.: ...
3-Phenyl-5-(2-piperidinoäthyl)-isoxazol-3-phenyl-5- (2-piperidinoethyl) -isoxazole-
citrat ..· citrate ..
3-Phenyl-5-(2-morpholinoäthyI.)-isoxazol-3-phenyl-5- (2-morpholinoethyI.) - isoxazole-
hydrochlorid hydrochloride
3-Phenyl-5-(3-pipendinopropyJ)-isoxazol-3-phenyl-5- (3-pipendinopropyJ) -isoxazole-
hydrochlörid hydrochloride
3-Phenyl-5-(l-dimethylaminoäthyl)-isoxazol-3-phenyl-5- (l-dimethylaminoethyl) -isoxazole-
hydrochlorid hydrochloride
3-Phenyl-5-(l-piperidinoäthyI)-isoxazol- ,3-phenyl-5- (l-piperidinoethyI) -isoxazole-,
hydrochlorid '.....· hydrochloride '..... ·
3-{2-PyridyI)-5-(2-dimethylaminoäthyl)-3- {2-pyridyl) -5- (2-dimethylaminoethyl) -
isoxazol-citrat isoxazole citrate
3-(2-Pyridyl)-5-(2-piperidinoäthyl)-isoxazol-3- (2-pyridyl) -5- (2-piperidinoethyl) -isoxazole-
hydrochlorid hydrochloride
> > 1000>> 1000
455 '; 500 bis , >800 >800 600 bis ■ 455 '; 500 to,>800> 800 600 to ■
6X26X2
41Ί41Ί
398 700 bis 156.82398 700 to 156.82
231231
800 bis 1000 800 bis 1000 200 bis -4.81800 to 1000 800 to 1000 200 to -4.81
- 3.48
-3.68
·- 3.02
-3,5
■-1,68- 3.48
-3.68
- 3.02
-3.5
■ -1.68
- 4 2
-4.3 ■
-1.Ϊ8- 4 2
-4.3 ■
-1.Ϊ8
- 2,42
-4.3'
-3,8
-3.58
-3.4
-1,65
-1.12
-4,46- 2.42
-4.3 '
-3.8
-3.58
-3.4
-1.65
-1.12
-4.46
.39 * 138.39 * 138
93
10693
106
102 .'102. '
72
> 40072
> 400
57.2457.24
32
143
290
10032
143
290
100
19.619.6
6.86.8
39.839.8
35.435.4
37.637.6
7.77.7
4.34.3
18.918.9
23.523.5
37.837.8
33.633.6
.27.1.27.1
.32,5 4.2 3,7.32.5 4.2 3.7
26,926.9
16,4 28,9 68,216.4 28.9 68.2
71.571.5
54 11054 110
■ 65.0 38,3■ 65.0 38.3
') Akute Toxizität: Die Testverbindungen wurden subkutan an Mäusen verabreicht. . .') Acute toxicity: the test compounds were administered subcutaneously to mice. . .
2) Antipyretische Wirksamkeit: Die Testverbindungen wurden subkutan an Mäusen mit einer Dosis vori 100 mg/kg Körpergewicht verabreicht, und die Depression der Körpertemperatur wurde gemessen. 2 ) Antipyretic activity: The test compounds were subcutaneously administered to mice at a dose of 100 mg / kg of body weight and the depression of body temperature was measured.
3) Analgetische Wirksamkeit: Die Testverbindungen wurden subkutan Mäusen verabreicht. Die Wirksamkeit wurde gemäß der Haffner-Methode (Deutsche Med. Woch., 55 [1929], 731 bis 733) bestimmt. 3 ) Analgesic efficacy: The test compounds were administered subcutaneously to mice. The effectiveness was determined according to the Haffner method (Deutsche Med. Woch., 55 [1929], 731 to 733).
■4) Entzündungshemmende Wirksamkeit: Die Testverbindungen wurden subkutan Ratten mit einer Dosis von 100 mg/Tier verabreicht, die genannten Ratten wurden vorher mit 0;05 ml 3.7"oiger Formalihlösung behandelt. Die prozentuale Inhibition des Ddems wurde gemessen.■ 4) Anti-inflammatory activity: The test compounds were subcutaneously administered rats at a dose of 100 mg / animal, the rats were referred to previously with 0; treated 05 ml 3.7 "o acetic Formalihlösung The percent inhibition of Ddems was measured..
5) Hustenreizmildernde Wirksamkeit: Die Testverbindungen wurden subkutan Meerschweinchen verabreicht, und dann wurden die Tiere mit 12,5%igem Ammoniak besprüht. Aus der prozentualen Anzahl der nicht hustenden Meerschweinchen wurde die wirksame Dosis 50 berechnet. ' . .' • " 5 ) Antitussive activity: The test compounds were subcutaneously administered to guinea pigs, and then the animals were sprayed with 12.5% ammonia. The effective dose 50 was calculated from the percentage number of non-coughing guinea pigs. '. . ' • "
Das erfindungsgemäße Verfahren wird im einzelnen an Hand nachfolgender Beispiele näher erläutert.The method according to the invention is explained in more detail using the following examples.
B ei spiel ΐFor example game ΐ
A. Zu einer Lösung von 2,9 e 3-Ohlormethyl-5-phenylisoxazol, F. = 49 bis 500C, in 20 ml Toluol werden 1,5 g Dimethylamin zugegeben, und die erhaltene Lösung wird, dann bei ΓΙΟ C 8 Stunden erhitzt. Nach Kühlung, wird das Reaktionsgemisch mit verdünnter Chlorwasserstoffsäurc geschüttelt und die wäßrige Phase mit Benzol gewaschen, mit 2%iger Natriumhydroxydlösung alkalisiert und dann mit Äther geschüttelt. Die Ätherschicht wird mit Wasser gewaschen, über wasserfreiem 'Kaliumcarbonat getrocknet und das Lösungsmittel entfernt..TDie erhaltene Flüssigkeit wird unter reduziertem ;Druck destilliert und liefert 2,1 g 3 - Dimethylaminomethyl - 5 - phenylisoxazol, in Form von hellgelblichem öl, Kp. = 132'C bei 2 mm Hg. Das Hydrochlorid besteht aus farblosen Plättchen mit F. = 223 bis 225 C, nach Kristallisie-A. To a solution of 2.9 e-3 Ohlormethyl-5-phenylisoxazole, mp = 49-50 0 C, in 20 ml of toluene, 1.5 g of dimethylamine are added and the resulting solution is then at ΓΙΟ C 8 Heated for hours. After cooling, the reaction mixture is shaken with dilute hydrochloric acid and the aqueous phase is washed with benzene, made alkaline with 2% sodium hydroxide solution and then shaken with ether. The ether layer is washed with water, dried over anhydrous potassium carbonate and the solvent is removed. The liquid obtained is distilled under reduced pressure and yields 2.1 g of 3 - dimethylaminomethyl - 5 - phenylisoxazole, in the form of a pale yellowish oil, b.p. 132'C at 2 mm Hg. The hydrochloride consists of colorless platelets with a F. = 223 to 225 C, after crystallization
ί>5 rung aus Äthanol.ί> 5 tion from ethanol.
B. In einem verschlossenen Rohr wird ein Gemisch von 3,1 g 3-(2-Chloräthyl)-5-phenylisoxazol. F. = bis 62JC, lind 20 ml gesättigtem äthanolischem Am-B. A mixture of 3.1 g of 3- (2-chloroethyl) -5-phenylisoxazole is placed in a sealed tube. F. = up to 62 J C, and 20 ml of saturated ethanol
moniak bei 140 C 10 Stunden erhitzt. Nach Kühlen wird das Reaktionsgemisch filtriert. Das Filtrat wird unter reduziertem Druck konzentriert, mit Äther vereinigt und die unlösliche Substanz abfiltriert. Die so erhaltene Substanz wird dann in heißem Äthanol gelöst, und es wird filtriert. Das Filtrat wird unter reduziertem Druck eingeengt und der Rückstand ausmonia heated at 140 C for 10 hours. After cooling the reaction mixture is filtered. The filtrate is concentrated under reduced pressure with ether combined and the insoluble substance filtered off. The substance thus obtained is then poured into hot ethanol dissolved and it is filtered. The filtrate is concentrated under reduced pressure and the residue is eliminated
Aceton kristallisiert und aus Äthanol umkristallisiert, wobei 1,5 g3-(2-Aminoäthyl)-5-phenylisoxazol-hydrochlorid, in Form farbloser Prismen mit F. = 197 bis 198° C erhalten werden.Acetone crystallized and recrystallized from ethanol, 1.5 g of 3- (2-aminoethyl) -5-phenylisoxazole hydrochloride, can be obtained in the form of colorless prisms with a temperature of 197 to 198 ° C.
5 Weitere Isoxazolverbindungen, die in oben angeführter Weise hergestellt wurden, sind in der nachstehenden Tabelle!! zusammengestellt.5 Additional isoxazole compounds prepared in the above manner are shown below Table!! compiled.
. N XR2 —R A \
. N X R 2
(F. oder Kp.)(F. or Kp.)
— N/ R, ·
- N
Picrat(F. = 139 to 140 C)
Picrat
Zu einer Lösung von 2.9 g 3-Phenyl-5-chlormethylisoxazol. F. = 70 bis 71 C, in 20 ml Toluol werden 1,5 g Dimethylamin zugegeben, worauf die erhaltene Lösung bei 120 C 8 Stunden erhitzt wird. Das Reaktionsgemisch wird dann gemäß Beispiel 1, A, behandelt und ergibt 2.5 g 3-Phenyl-5-dimethylaminomethylisoxazol als hellgelbliches öl, Kp. = 120 bis 123°C/2 mm Hg. Das Hydrochlorid besteht aus farblosen Plättchen, F. = 207 bis 2080C nach Umkristallisieren aus Äthanol.To a solution of 2.9 g of 3-phenyl-5-chloromethylisoxazole. F. = 70 to 71 ° C., 1.5 g of dimethylamine in 20 ml of toluene are added, whereupon the resulting solution is heated at 120 ° C. for 8 hours. The reaction mixture is then treated as in Example 1, A, and gives 2.5 g of 3-phenyl-5-dimethylaminomethylisoxazole as a pale yellowish oil, b.p. = 120 to 123 ° C./2 mm Hg. The hydrochloride consists of colorless platelets, m.p. = 207 to 208 0 C after recrystallization from ethanol.
In analoger Weise werden folgende Isoxazolverbindungen hergestellt, die in der Tabelle III angeführt werden.The following isoxazole compounds, which are listed in Table III, are prepared in an analogous manner will.
Verbindungconnection
Aussehen
(F. oder Kp.)Look
(F. or Kp.)
Salze
(F.)Salts
(F.)
,CH3 , CH 3
3-Phenyl-5-dimethylaminomethylisoxazol 3-phenyl-5-dimethylaminomethylisoxazole
3-Phenyl-5-diäthyIaminomethylisdxazor 3-phenyl-5-diethyIaminomethylisdxazor
3-PhenyI-5-piperidinomcthylisoxazol 3-Phenyl-5-piperidinomethylisoxazole
■3-Phenyi-5-morpholinomethylisoxazol ■ 3-Phenyi-5-morpholinomethylisoxazole
3-Phenyl-5-pyrrolidinomethylisoxazol 3-phenyl-5-pyrrolidinomethylisoxazole
3-Phenyl-5-(2-dimethyIaminoäthyD-isoxazol 3-phenyl-5- (2-dimethylaminoethyD-isoxazole
3-Phcnyl-5-(2-diäthylaminoäthvlj-isoxazol 3-Phcnyl-5- (2-diethylaminoethyl-isoxazole
3-Phenyl-5-(2-piperidinoäthyl)-isoxazof ,3-phenyl-5- (2-piperidinoethyl) isoxazof,
3-Phenyl-5-(2-morpholinoäthyD-isoxazol 3-phenyl-5- (2-morpholinoethyD-isoxazole
3-Phenyl-5-(2-pyrrolidinoäthvD-isoxazol 3-phenyl-5- (2-pyrrolidinoethvD-isoxazole
-CH2-Cn2 -CH 2 -Cn 2
-CH2--CH 2 -
CH2 -CH2-CH 2 -CH 2 -
-(CH2)2- -(CH2J2-- (CH 2 ) 2 - - (CH 2 J 2 -
-(CHj)2- -(CH2J2- -(CHj)2-- (CHj) 2 - - (CH 2 J 2 - - (CHj) 2 -
— Ν- Ν
— Ν —Ν- Ν —Ν
— Ν- Ν
— Ν- Ν
—ν"—Ν "
— Ν- Ν
— Ν- Ν
— Ν- Ν
— Ν- Ν
'C2H5 'C 2 H 5
-2 "5 flüssig, Kp. = 120 ·
bis 123°C/2mmHg -2 "5 liquid, bp = 120 ·
up to 123 ° C / 2mmHg
flüssig. .Kp. = 128
bis 130 C/2 mm Hgfluid. .Kp. = 128
up to 130 C / 2 mm Hg
/CH3 kristallin,/ CH 3 crystalline,
F. = 44 bis 46 CF. = 44 to 46 C.
flüssig.fluid.
Kp.= 160 C 2 mm HgBp = 160 C 2 mm Hg
flüssig.fluid.
Kp.= 151 C 4 mm HgBp = 151 C 4 mm Hg
3-Phenyl-5-(.3-piperidiiuv
propyll-isoxazol '3-phenyl-5 - (. 3-piperidiiuv
propyl isoxazole
Zu einer Lösung von 2.1 g 3-(2-Pyridyl)-5-(2-chloräthyD-isoxazol in 20 ml Toluol werden 1.4 g Dilnethylamin /ugeücben. und die erhaltene Lösung wird1'«. Stunden· unter Rückfluß erhitzt. Dann wird lias Reiiklions'gemisch gemäß Beispiel L A, behanHydrochlorid To a solution of 2.1 g of 3- (2-pyridyl) -5- (2-chloräthyD-isoxazole in 20 ml of toluene 1.4 g Dilnethylamin / ugeücben. And the resulting solution is heated for 1 '. "· Hours under reflux. Then As a Reiiklions' mixture according to Example LA, treated hydrochloride
(F. = 207 bis 208 C)(F. = 207 to 208 C)
HydrochloridHydrochloride
(F. = 145 bis 146 C)(F. = 145 to 146 C)
CitratCitrate
(F. = 117 bis 118 C)(F. = 117 to 118 C)
HydrochloridHydrochloride
(F. = 225 bis 226 C)(F. = 225 to 226 C)
HydrochloridHydrochloride
(F. = 205 bis 207 C)(F. = 205 to 207 C)
HydrochloridHydrochloride
(F. = 189 bis 190 C)(F. = 189 to 190 C)
HydrochloridHydrochloride
(F'. = 187 bis 188 C)(F '. = 187 to 188 C)
HydrochloridHydrochloride
(F. = 162 bis 163 C)(F. = 162 to 163 C)
PicratPicrat
(F. = 175 bis 176 C)(F. = 175 to 176 C)
HydrochloridHydrochloride
(F. = 223 bis 225 C)(F. = 223 to 225 C)
HydrochloridHydrochloride
(F. = 253 bis 255 C)(F. = 253 to 255 C)
HydrochloridHydrochloride
(F. - 205 bis 206 C)(F. - 205 to 206 C)
HydrochloridHydrochloride
(F". = 166 bis 167 C)(F ". = 166 to 167 C)
delt, und man erhält 1.8 g 3-(2-Pyridyl)-6-(2-dimethylaminoäthylj-isoxazol als hellgelbes öl. Kp. = 127 C ds bei 2 mm Hg. Das Citrat besteht aus farblosen Prismen, welche nach Kristallisieren aus einem Gemisch von Aceton und Methanol einen Schmelzpunkt von IK) bis 111 C haben.delt, and 1.8 g of 3- (2-pyridyl) -6- (2-dimethylaminoethyl isoxazole are obtained as a light yellow oil. Bp = 127 C ds at 2 mm Hg. The citrate consists of colorless Prisms which, after crystallization from a mixture of acetone and methanol, have a melting point from IK) to 111 C.
,C2H5 , C 2 H 5
Kp.= 161 C 5 mm HgBp = 161 C 5 mm Hg
kristallin,crystalline,
F. = 55 bis 56 CF. = 55 to 56 C.
kristallin,crystalline,
F. = 70 bis 71 CF. = 70 to 71 C.
kristallin,crystalline,
F. = 43 bis 44 CF. = 43 to 44 C.
•OS? 645M5• OS? 645M5
9 109 10
In ähnlicher Weise erhält man die Isoxazolverbindungen in der folgenden Tabelle IV.The isoxazole compounds in Table IV below are obtained in a similar manner.
R1.R 1 .
R2'R 2 '
Ν —ΑΝ —Α
— N
\/
- N
\
(Roder Kp.)Look
(Roder Kp.)
(F.)Salts
(F.)
methylaminoäthy 1)
isoxazol3- (2-pyridyl) -5- (2-di-
methylaminoethy 1)
isoxazole
— N
\/
- N
\
CH3 CH 3
CH 3
Kp. = 127° C/ ·
2 mm Hgfluid
Bp = 127 ° C / ·
2 mm Hg
F. = UO bisCitrate
F. = UO to
äthylaminoäthyl)-
isoxazol3- (2- pyridyl) -5- (2-di-
ethylaminoethyl) -
isoxazole
\- N
\
Kp. = 127° C/
1 mm Hgfluid
Bp = 127 ° C /
1 mm Hg
F. = 150 bisCitrate
F. = 150 to
peridinoäthyl)-
isoxazol3- (2-pyridyl) -5- (2-pi-
peridinoethyl) -
isoxazole
\_- N
\ _
Kp. = 1530C/
1 mm Hgfluid
Bp = 153 0 C /
1 mm Hg
F. = 218 bisHydrochloride
F. = 218 to
aminoäthyl)-isoxazol3- (3-pyridyl) -5- (2-diethyl-
aminoethyl) isoxazole
\- N
\
Kp. = 159'C/
3 mm Hgfluid
Bp = 159'C /
3 mm Hg
F.·= 151 bisCitrate
F. = 151 to
Claims (2)
Family
ID=
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