CH522668A - Verfahren zur Herstellung neuer heterocyclischer Aminoketone - Google Patents
Verfahren zur Herstellung neuer heterocyclischer AminoketoneInfo
- Publication number
- CH522668A CH522668A CH1717968A CH522668DA CH522668A CH 522668 A CH522668 A CH 522668A CH 1717968 A CH1717968 A CH 1717968A CH 522668D A CH522668D A CH 522668DA CH 522668 A CH522668 A CH 522668A
- Authority
- CH
- Switzerland
- Prior art keywords
- mol
- phenyl
- hcl
- paraformaldehyde
- yield
- Prior art date
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Classifications
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
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- C07D217/24—Oxygen atoms
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
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- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
- C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
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- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
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- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
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- C07D307/70—Nitro radicals
- C07D307/71—Nitro radicals attached in position 5
- C07D307/72—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2
- C07D307/73—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2 by amino or imino, or substituted amino or imino radicals
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- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/58—Radicals substituted by nitrogen atoms
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Verfahren zur Herstellung neuer heterocyclischer Aminoketone Die Erfindung betrifft ein Verfahren zur Herstellung von neuen heterocyclischen Aminoketonen der allgemeinen Formel EMI1.1 ihrer Salze und ihrer optisch aktiven Isomeren bzw. Diastereomeren. In dieser Formel bedeuten die Reste R-R4 Wasserstoff, Halogen, niedriges Alkyl, Aralkyl, Phenyl, Hydroxyl, niedriges Alkoxy, Nitro oder niedriges Carbalkoxy, die Reste R5 und R, Wasserstoff oder Methyl, die Reste R7 und R8 Wasserstoff, Halogen oder niedriges Alkoxy und das Symbol X ein heterocyclisches Ringsystem, das monocyclisch oder konden siert bicyclisch ist, 1 Heteroatome aufweist und das auch eine oder mehrere Oxogruppen enthalten kann und dessen Einzelringe vorzugsweise aus 5 oder 6 Gliedern bestehen. Als Heteroatome kommen in Betracht, Sauerstoff, Stickstoff und Schwefel. Als Beispiele für das Symbol X seien folgende heterocyclische Ringsysteme genannt: Furan, Thiophen, Pyrrol, Pyrazol, Thiazol, Pyridin, Pyrimidin, Triazin, Pyrazolon, Benzofuran, Benzthiophen, Indol, Chinolin, Isochinolin, Benzdioxol, Benzdioxan, Dechydroisochinolin, Benzthiazol, Benzimidazol. Es hat sich gezeigt, dass diese Verbindungen wertvolle pharmazeutische Eigenschaften besitzen und sich zur Herstellung von Azzneäniitteln, insbesondere zur Behandlung von Herz- und Kreislaufkrankheiten, eignen. Die Herstellung der heterocyclischen Aminoketone der oben angegebenen allgemeinen Formel erfolgt dadurch, dass man eine Verbindung der allgemeinen Formel EMI1.2 mit einer Verbindung der allgemeinen Formel EMI2.1 in Gegenwart von Formaldehyd oder eines Formaldehyd liefernden Stoffes in einem Lösungsmittel umsetzt. In den erhaltenen Verbindungen kann man in an sich bekannter Weise die Carbonylgruppe zur Hydroxygruppe reduzieren und gegebenenfalls die Basen in ihre Salze überführen. Das Verfahren wird üblicherweise in einem Temperaturbereich zwischen 20 und 150"C durchgeführt. Als Lösungsmittel kommen hierfür beispielsweise Alkohole, Dioxan, Eisessig usw. in Betracht. Die erhaltenen Verbindungen, die optisch aktive Kohlenwasserstoffatome enthalten und in der Regel als Racemate anfallen, können in an sich bekannter Weise z. B. mittels einer optisch aktiven Säure in die optisch aktiven Isomeren gespalten werden. Es ist aber auch möglich, von vornherein optisch aktive bzw. auch disstereomere Ausgangsstoffe einzusetzen, wobei dann als Endprodukt eine entsprechende reine optisch aktive Form bzw. diastereomere Konfiguration erhalten wird. Die erfindungsgemässen Verbindungen sind zur Herstellung pharmazeutischer Zusalrunensetzungen geeignet. Die pharmazeutischen Zusammensetzungen bzw. Medikamente, die eine oder mehrere der erfindungsgemässen Verbindungen oder auch Mischungen derselben mit anderen pharmazeutisch wirksamen Stoffen enthalten sowie gegebenenfalls Zusätze weiterer pharmazeutischer Trägermittel, können enteral, parenteral, oral oder perlingual angewandt werden. Beispiel I l-(2-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-äthyl } -thienyl-(2)-keton EMI2.2 12,6 g (0,1 Mol) 2-Acetyl-thiophen, 18,7 g (0,1 Mol) l-Norephedrin-HC1 und 4 g (0,13 Mol) Paraformaldehyd werden in 20 ml Isopropanol gelöst und nach Zugabe von 0,2 ml HC1 konz. 2 Stunden unter Rückfluss gekocht. Danach wird die noch warme Lösung mit 100 ml Aceton versetzt. Das beim Erkalten auskristallisierte Hydrochlorid wird durch Umkristallisieren aus Äthanol gereinigt. Fp. 191-192 C, Ausbeute 17 g Beispiel 2 1-(2-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-äthyl)-furyl-(2)-keton EMI2.3 11 g (0,1 Mol) 2-Acetyl-furan, 18,7 g (0,1 Mol) I-Norephedrin-HC1 und 4 g (0,13 Mol) Paraformaldehyd werden in 20 ml Isopropanol unter Zusatz von 5 Tropfen äthanolischer HC1 2 Stunden am Rückfluss erhitzt. Das bereits ausgefallene Hydrochlorid wird mit 50 ml Aceton gut durchgerührt und abgesaugt. Es wird durch Umkristallisieren aus Äthanol gereinigt. Fp. 186-187 C, Ausbeute 10,5 g. Beispiel 3 1- { 2- [3-Phenyl-3-hydroxy-propyl-(2) amino]-äthyl}-[4-methyl-thiazolyl-(2)}-keton EMI2.4 7 g (0,05 Mol) 4-Methyl-2-acetyl-thiazol, 9,4 g (0,5 Mol) l-Norephedrin-HCl, 2 g (0,067 Mol) Paraformaldehyd und 5 Tropfen isopropanolische HC1 werden in 15 ml Isopropanol wie in Beispiel 2 umgesetzt und aufgearbeitet. Das Hydrochlorid wird aus Methanol umkristallisiert. Fp. 197-1990 C. Ausbeute 7 g Beispiel 4 l-{2-[3-Phenyl-3-hydroxy-propyl-(2)- amino] -äthyl} -antipyryl-(4)-keton EMI3.1 11,5 g 4-Acetyl-antipyrin (0,05 Mol), 9,5 g l-Norephedrin-HCl (0,05 Mol) und 2 g Paraformaldehyd (0,67 Mol) werden in 20 ml Isopropanol mit 5 Tropfen isopropanolischer HCI versetzt und insgs samt 5 Stunden unter Rückfluss gekocht, wobei nach 3 Stunden noch 1 g Paraformaldehyd zugesetzt wird. Danach wird das Lösungsmittel abdestilliert und der Rückstand mit Sodalösung behandelt. Die als Öl anfallende Mannichbase wird mit Äther zur Kristallisation gebracht. Mit 2 Mol HC1 bildet sie ein Dihydrochlo- rid, das aus Äthanol umkristallisiert wird. Fp. 206-208 C, Ausbeute 9 g. Beispiel 5 1-(2-[3-Phenyl-3-hydroxy-propyl-(2) amino] -äthyl) -pyridyl-(3)-keton EMI3.2 40 g (0,33 Mol) 3-Acetyl-pyridin, 18,7 g (0,1 Mol) l-Norephedrin-HCI und 3 g (0,1 Mol) Paraforrnalde- hyd werden in 15 ml Isopropanol insgesamt 3 Stunden unter Rückfluss gekocht, wobei nach 1 Stunde 1 g Paraformaldehyd zugegeben wird. Anschliessend wird mit 300 ml Aceton verdünnt. Das ausfallende Hydrochlorid wird aus Methanol/Äthanol (1:2) umkristallisiert. Fp. 187-189 C, Ausbeute 7 g. Beispiel 6 1-(2- [3-Phenyl-3-hydroxy-propyl(2)-amino]- äthyl}-[2,4-dimethyl-thiazolyl-(5)]-keton EMI3.3 25 g (0,16 Mol) 2,4-Dimethyl-5-acetyl-thiazol, 30 g (0,16 Mol) l-Norephedrin-HCl und 5 g (0,16 Mol) Paraformaldehyd werden in 50 ml Isopropanol mit 15 Tropfen isopropanolischer HCI versetzt und insgesamt 1 Stunde am Wasserbad gekocht. Nach t/2 Stunde werden weitere 1,5 g Paraformaldehyd zugegeben. Die noch warme Lösung wird mit 100 ml Aceton verdünnt. Das ausfallende Hydrochlorid wird aus 80 proz. Athanol umkristallisiert. Fp. 208-2100 C. Ausbeute 6,6 g. Beispiel 7 l-(2-[3-Phenyl-3-hydroxy-propyl-(2)-aminoj- äthyl)-[4-methyl-2 -hydroxy-thiazolyl -(5)1-keton EMI4.1 5 g (0,035 Mol) 4-Methyl-2-hydroxy-5-acetyl-thia- zol, 6,6 g (0,035) Mol) l-Norephedrin-HCI und 1,5 g (0,05 Mol) Paraformaldehyd werden 2 Stunden in 20 ml Eisessig am Rüclcfluss gekocht. Das beim Erkalten ausfallende Hydrochlorid wird aus Methanol/Ätha- nol (1:1) umkristallisiert. Fp. 209-2100 C. Ausbeute 4,5 g. Beispiel 8 l-{ 2- [3-Phenyl-3 -hydroxy-propyl-(2)- amino]-äthyl)-cumaronyl-keton EMI4.2 40g (0,25 Mol) 2-Acetyl-cumaron, 46,5 g (0,25 Mol) l-Norephedrin-HCI und 7,5 g (0,25 Mol) Paraformaldehyd werden in 200 ml Isoamylalkohol gelöst und nach Zugabe von 10 Tropfen äthanolischer HCl 1/2 Stunde am Rückfluss gekocht. Dann werden weitere 2,5 g (0,083 Mol) Paraformaldehyd zugesetzt und noch 1/4 Stunde erhitzt. Die noch warme Lösung wird mit 100 ml Aceton verdünnt. Beim Erkalten kristallisiert das Hydrochlorid aus, das aus Äthanol umgelöst wird. Fp. 199-200 C, Ausbeute 31,5 g. Beispiel 9 1-3-( 3-[3-Phenyl-3-hydroxy-propylg2)- amino]-propionyl) -thionaphthen EMI4.3 17,6 g (0,1 Mol) 3-Acetyl-thionaphthen, 18,7 g (0,1 Mol) l-Norephedrin-HCl und 4,5 g (0,15 Mol) Paraformaldehyd werden 2 Stunden in 50 ml Isopropanol am Rückfluss gekocht. Die noch warme Lösung wird mit 100 ml Aceton verdünnt. Beim Erkalten fällt das Hydrochlorid aus, das aus Methanol umkristallisiert wird. Fp. 220-2210 C, Ausbeute 18,5 g. Beispiel 10 1-3- { 3- [3-Phenyl-3-hydroxy-propyl-(2) amino] -p ropionyl) -l-m ethyli ndol EMI4.4 25 g (0,13 Mol) 1-Methyl-3-acetyl-indol, 24,3 g (0,13 Mol) I-Norephedrin-HCI und 5 g (0,17 Mol) Paraformaldehyd werden in 100 ml Isopropanol gelöst und insgesamt 6 Stunden am Wasserbad erhitzt. Nach jeweils 2 Stunden werden noch 2,5 g Paraformaldehyd zugegeben. Danach wird das Lösungsmittel abdestilliert und der Rückstand in warmem Aceton gelöst. Das beim Erkalten ausfallende Hydrochlorid wird aus Äthanol umkristallisiert. Fp. 194-195 C, Ausbeute 22 g. Beispiel 11 l-5-( 3-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-propionyl) -benzdioxol-(1,3) EMI5.1 8 g (0,048 Mol) 5-Acetyl-benzdioxol-(1,3), 9,1 g (0,048 Mol) l-Norephedrin-HCl und 2,9 g (0,097 Mol) Paraformaldehyd werden in 30 ml Isopropanol unter Zusatz von 5 Tropfen isopropanolischer HCt 2 Stunden auf dem Wasserbad gekocht. Nach Zugabe von 100 ml Aceton zur warmen Reaktionslösung fällt das Hydrochlorid aus, das aus Äthanol umkristallisiert wird. Fp. 195-1970 C, Ausbeute 9 g. Beispiel 12 1-4-(3-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-propionyl)-l,3-dimethylpyrazol und -1,5-dimethyl-pyrazol (Gemisch). EMI5.2 26 g (0,19 Mol) des bei der Synthese anfallenden Isomerengemisches von 1,3- und 1,5-Dimethyl-4-acetylpyrazol, 37,4 g (0,2 Mol) l-Norephedrin-HCl und 9 g (0,3 Mol) Paraformaldehyd werden in 150 ml Isopropanol 3 Stunden unter N,-Atmosphäre gekocht. Beim Erkalten kristallisiert das Hydrochlorid, das aus Isopropanol und anschliessend 2mal aus Äthanol umkristallisiert wird. Fp. 196 C, Ausbeute 11 g. Beispiel 13 1-(2-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-äthyl)-chinolyl-(3)-keton EMI5.3 10 g (0,058 Mol) 3-Acetylchinolin, 11,2 g (0,058 Mol) l-Norephedrin-HCl und 1,6 g (0,058 Mol) Paraformaldehyd werden 2,5 Stunden in 75 ml Isopropanol auf dem Wasserbad gekocht, wobei nach 1 Stunde weitere 0,8 g (0,026 Mol) Paraformaldehyd zugegeben werden. Beim Versetzen mit 150 ml Aceton fällt das Hydrochlorid aus, das aus 800/oigem Methanol umkristallisiert wird. Fp. 205-2060 C, Ausbeute 5 g. Beispiel 14 1-(2-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-äthyl) -isochinolyl-(4)-keton EMI6.1 S g (0,024 Mol) 4-AcetylisochinoJin-HCI, 4,6 g (0,024 Mol) l-Norephedrin-HCl und 0,7 g (0,024 Mol) Paraformaldehyd werden in 50 ml Äthanol-Iso propanol-Gemisch (1:1) 2,5 Stunden auf dem Wasserbad gekocht, wobei nach 1 Stunde weitere 0,4 g (0,012 Mol) Paraformaldehyd zugegeben werden. Beim Erkalten fällt das Dihydrochlorid aus, das aus Äthanol umkristallisiert wird. Fp. 208O C, Ausbeute 3 g. Beispiel 15 1-{2-[3-Phenyl-3-hydroxy-propyl- (2)-amino]-äthyl)-[ 1,2,4-trimethyl- 5 -carbäthoxypyrrolyl-(3)] -keton EMI6.2 18 g (0,081 Mol) 1,2,4-Trimethyl-3-acetyl-5 carb- äthoxypyrrol, 15,2 g (0,081 Mol) l-Norephedrin HC1 und 2,4 g (0,081 Mol) Paraforma1:1ehyd werden in 50 ml Isopropanol 1,5 Stunden auf dem Wasserbad gekocht, wobei nach 0,5 Stunden weitere 1,2 g (0,04 Mol) Paraformaldehyd zugegeben werden. Beim Versetzen mit 100 ml Aceton fällt das Hydrochlorid aus, das aus Äthanol umkristallisiert wird. Fp. 179-1800 C, Ausbeute 10 g. Beispiel 16 1-6-(3-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-propionyl}-benzdioxan-(1 ,4) EMI6.3 11,7 g (0,066 Mol) 6-Acetyl-1,4-benzdioxan, 12,3 g (0,066 Mol) I-Norephedrin-HCI und 2g (0,067 Mol) Paraformaldehyd werden in 33 ml Isopropanol 2 Stunden auf dem Wasserbad gekocht, wobei nach 1 Stunde weitere 2 g (0,067 Mol) Paraformaldehyd zugegeben werden. Das Lösungsmittel wird abdestilliert und der Rückstand mit Aceton behandelt. Das anfallende Hydrochlorid wird aus Äthanol umkristallisiert. Fp. 201O C, Ausbeute 7,5 g. Beispiel 17 1-2-(3-[3-Phenyl-3-hydroxy-propyl-(2)- aminol-propionyl) -benzdioxan-(1,4) EMI7.1 11 g (0,061 Mol) 2-Acetyl-1,4-benzdioxan, 11,6 g (0,062 Mol) l-Norephedrin-HCl und 1,85 g (0,062 Mol) und 1,85 g Paraformaldehyd werden in 30 ml Isopropanol wie in Beispiel 16 umgesetzt und aufgearbeitet. Fp. 1780 C, Ausbeute 8 g. Beispiel 18 1-(2-[3-PhenyI-3-hydroxy-propyl- (2)-amino]-äthyi)-[2-benzyl-lO-hydroxy- decahydroisochinolyl-(4)] -keton. EMI7.2 11 g (0,0339 Mol) 2-Benzyl-4-acetyl10-hydroxy-decahydroisochinolin. HC1, 6,5 g (0,035 Mol) l-Norephedrin.HCl und 1,4 g (0,047 Mol) Paraformaldehyd werden 2 Stunden in 35 ml Isopropanol auf dem Wasserbad gekocht, wobei nach 1 Stunde weitere 1,4 g Paraformaldehyd zugegeben werden. Anschliessend wird das Lösungsmittel abdestilliert und der Rückstand mit Aceton und Essigester versetzt. Das anfallende Dihydrochlorid wird aus Athanol umkristallisiert. Fp. 182-183 C, Ausbeute 7 g. Beispiel 19 l-f2-[3-Phenyl-3-hydroxy-propyl-(2). amrno]-äthyl}-5-nitrofuryl.(2)j-keton EMI7.3 11,6 g (0,075 Mol) 2-Acetyl-5-nitro-furan, 14 g (0,075 Mol) l-Norephedrin.HC1 und 3 g (0,1 Mol) Paraformaldehyd werden in 50 ml Isopropanol 3 Stunden auf dem Wasserbad erhitzt. Das beim Erkalten ausfallende Hydrochlorid wird aus 800/oigem Äthanol umkristallisiert. Fp. 210 C unter Zersetzung. Ausbeute 3 g. Beispiel 20 1-4-(3-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-propionyl}-1 ,3,5-trimethyl-pyrazol EMI8.1 27 g (0,178 Mol) 1 ,3,5-Trimethyl-4-acetyl-pyrazol, 33 g (0,177 Mol) l-Norephedrin.HCl und 10,8 g (0,36 Mol) Paraformaldehyd werden in 150 ml Isopropanol 2 Stunden auf dem Wasserbad erhitzt. Danach wird das Lösungsmittel abdestilliert und der Rückstand mit 100 ml Aceton versetzt. Das ausgefallene Hydrochlorid wird aus Isopropanol umkristallisiert. Fp. 1910 C; Ausbeute 14,5 g. Beispiel 21 l-4-3-[3-Phenyl-3-hydroxy-propyl-(2)- amino] -propionyl)-l -benzyl3 ,5 -dimethyl-pyrazol EMI8.2 13,5 g (0,0624 Mol) 3,5-Dimethyl-1-benzyl-4-acetyl-pyrazol, 11,1 g (0,0593 Mol l-Norephedrin-HCl und 3,6 g (0,12 Mol) Paraformaldehyd werden 2 Stunden auf dem Wasserbad erhitzt. Beim Versetzen der Reaktionslösung mit 100 ml Aceton fällt das Hydrochlorid aus, das aus Äthanol umkristallisiert wird. Fp. 2000 C; Ausbeute 11 g. Beispiel 22 d,l- { 2-[3-(3-Fluor-4-methoxy-phenyl) 3-hydroxy-propyl-(2)-amino] äthyl } -thienyl{2)-keton EMI8.3 28 g (0,119 Mol) d,l-3-(3-Fluor-4-methoxy-phenyl)3-hydroxy-propyl-(2)-amin.HC1, 15 g (0,119 Mol) 2-Acetylthiophen und 7,2 g (0,24 Mol) Paraformaldehyd werden in 200 ml Isopropanol wie in Beispiel 21 umgesetzt und aufgearbeitet. Das Hydrochlorid wird aus Äthanol umkristallisiert. Fp. 2080 C; Ausbeute 10 g. Beispiel 23 I-(l-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-propyl-(2))-thienyl-(2)-keton EMI9.1 43g (0,307 Mol) 2-Propionylthiophen, 57,7 g (0,308 Mol) l-Norealiedrin.HCl und 18,4 g (0,614 Mol) Paraformaldehyd werden in 60 ml Isopropanol 1 Stunde wie in Beispiel 21 umgesetzt und aufgearbeitet. Das Hydrochlorid wird aus Äthanol umkristallisiert. Fp. 208 C; Ausbeute 16,5 g. Beispiel 24 1-(2-[3-Phenyl-3-hydroxy-propyl-(2)- aminoj-äthyl }-[5-chlor-thienyl-(2)] -keton EMI9.2 30 g (0,187 Mol) 2-Acetyl-5-chlor-thiophen, 35 g (0,187 Mol) l-Norephedrin.HCI und 5,6 g (0,187 Mol) Paraformaldehyd werden in 50 ml Isopropanol 1 Stunde wie in Beispiel 21 umgesetzt und auf gearbeitet. Das Hydrochlorid wird aus Äthanol umkristallisiert. Fp. 198 C; Ausbeute 16 g. Beispiel 25 d,l-(2-[2-(2-Chlor-phenyl)-2-hydroxy- äthylamino]-äthyl)-thienyl-(2)-keton EMI9.3 12,6 g (0,1 Mol) 2-Acetyl-thiophen, 20,8 g (0,1 Mol) d,l-2-(2-Chlor-phenyl)- 2-hydroxy-äthylamin.HCl und 4,5 g (0,15 Mol) Paraformaldehyd werden in 100 ml Isopropanol 2 Stunden auf dem Wasserbad erhitzt. Danach wird das Lösungsmittel abdestilliert und der Rückstand mit Essigester zur Kristallisation gebracht. Das Hydrochlorid wird aus Athanol umkristallisiert. Fp. 158-160 C; Ausbeute 4 g. Beispiel 26 [3-Phenyl-3-hydroxy-propyl-(2)]-{3-[4-phenyl thiazolyl-(2)]-3-hydroxypropyl(1)y amin EMI9.4 6 g (0,015 Mol) 1-(2-[3-Phenyl-3-hydroxypropyl-(2)-amino äthyl}-[4-phenyl-thiazolyl-(2)-]keton.HCl werden in 60 ml Methanol aufgeschlämmt und durch Zugabe von 0,6 g (0,016 Mol) Natriumborhydrid reduziert. Nach 1 Stunde wird das Lösungsmittel abdestilliert und der Rückstand in Aceton gelöst. Aus dieser Lösung wird mit Fumarsäure das Fumarat gefällt und anschliessend mit Natronlauge wieder die Base freigesetzt. Die ölige Base wird in Äther aufgenommen, mit isopropanolischer Salzsäure in das Hydrochlorid übergeführt und das Salz aus Äthanol umkristallisiert. Fp. 178-181 C, Ausbeute 2,5 g. Beispiel 27 [1 -Phenyl-1-hydroxy-propyl-(2)] - ( 1-[4-methyl thiazolyl- < 2) ]-1-hydroxy-propyl-(3)}-amin EMI10.1 15 g (0,044 Mol) {2-[1-Phenyl-1-hydroxy-propyl-(2)-amino]- äthyl}-[4-methyl-thiazolyl-(2)]-keton.HCl werden in 150 ml Methanol mit 1 g Natriumboranat bei Raumtemperatur reduziert. Nach Stehenlassen über Nacht wird mit konz. HCI angesäuert, das Lösungsmittel abdestilliert und der Rückstand mit kochendem Äthanol extrahiert. Beim Abkühlen kristallisiert das HCl-Salz aus. Fp. 201-202 C; Ausbeute 5,5 g. Beispiel 28 [l-Phenyl-l-hydroxy-propyl-(2)1-( 1-[2,4-dime- thyl-thiazolyl-(5)].1-hydroxy-propyl-(3)}-amin EMI10.2 10,7 g (0,03 Mol) (2-[1-Phenyl-1-hydroxy-propyl-(2)-amino]- äthyl }-[2,4dimethyl-thiazolyl-(5)]-keton.llCl werden in 100 ml Methanol mit 1 g Natriumboranat wie in Beispiel 5 reduziert und aufgearbeitet. HCl-Salz. F. 217-218 , Ausbeute 5 g. Beispiel 29 [3-Phenyl-3-hydroxy-propyl-(2)]-{2-[thienyl- (2)]-3-hydroxypropyl-(1)}-amin EMI10.3 63 g (0,2 Mol) 1-(2-[3-Phenyl-3-hydroxy-propyl- (2)-amiao]-äthyl) -thienyl < 2)-keton-HCI und 300 g Aluminiumisopropylat werden in 21 Isopropanol auf 1300 erhitzt und das bei der Reduktion entstehende Aceton über eine Kolonne abdestilliert. Nach 7 Stunden wird die erkaltete Lösung mit Zitronensäure (100 g in 200 ml Wasser) zersetzt und anschliessend mit 30prozentiger Natronlauge stark alkalisch gemacht. Die organische Phase wird über Calciumoxyd getrocknet, das Lösungsmittel im Vakuum abdestilliert und der Rückstand mit Äther zur Kristallisation gebracht. Der Aminoalkohol schmilzt bei 123-125 , nachdem er aus 50prozentigem Alkohol umkristallisiert wurde. Mit 1 Mol HC1 entsteht ein Hydrochlorid, das aus Dioxan umkristallisiert, bei 152-155 schmilzt. Ausbeute 13 g. Beispiel 30 [3-Phenyl-3-hydroxy-propyl-(2)] - { 3-[comaronyl (2)]-3-hydroxy-propyl-(1)}-amin EMI11.1 18 g (0,05 Mol) 1-(2-[3-Phenyl-3-hydroxy-propyl (2)-aminoj-äthyl Ycumaronyl-keton-HCl werden in 100 ml Äthanol aufgeschlämmt und mit 2 g Natriumborhydrid, gelöst in 50 mal äthanol, bei Zimmertemperatur reduziert. Nach 1 Stunde wird mit 5 ml HCl (konzentriert) zersetzt, vom NaCI abfiltriert, das Lösungsmittel i.v. abdestilliert und der Rückstand aus Isopropanol/Essigester (1:1) umkristallisiert. Das Hydrochlorid schmilzt bei 210-2150 unter Zersetzung, Ausbeute 11 g. Beispiel 31 [3-Phenyl-3-hydroxy-propyl-(2)]-{[3-thionaphthenyl-(3)]-3-hydroxypropyl-(1)}-amin EMI11.2 19 g (0,05 Mol) 1-3 - { 3 -[phenyl-3-hydroxy-propyl- (2)-am ino] -prop ionyl) -thionaphthen-HC1 werden in 100 ml Äthanol aufgeschlämmt und mit 2 g Natriumborhydrid, gelöst in 50 mal Äthanol, bei Zim- mertemperatur reduziert. Nach 1 Stunde wird filtriert, das Lösungsmittel abdestilliert und der Rückstand in Äther gelöst. Aus der ätherischen Lösung wird das Hydrochlorid mit äthanolischen HC1 gefällt. Es wird aus Isopropanol umkristallisiert. Fp. 167-1700, Ausbeute 12 g. Beispiel 32 1-4-{3-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-propionyl}-1-phenyl-5-methyl-pyrazol EMI11.3 4,5 g (0,0225 Mol) 4-Acetyl-5-methyl-1-phenyl-pyrazol, 2 mal 0,75 g Paraformaldehyd und 4,5 g (0,0248 Mol) l-Norephedrin.HCl werden in 40 mg Isopropanol 2 Stunden unter Rückfluss gekocht, wobei die 2. Portion Paraformaldehyd nach 1 Stunde zugegeben wird. Das HCl-Salz, das aus der Reaktionslösung ausfällt, wird aus Athanol umkristallisiert. F. 221 C. Ausbeute 2,5 g.
Claims (1)
- PATENTANSPRUCH 1 Verfahren zur Herstellung von neuen heterocyclischen Aminoketonen der allgemeinen Fonnel EMI12.1 worin die Reste Rt - R4 gleich oder verschieden sind und Wasserstoff, Halogen, niedriges Alkyl, Aralkyl, Phenyl, Hydroxyl, niedriges Alkoxy, Nitro oder niedriges Carbalkoxy bedeuten, die Reste R5 und R;gleich oder verschieden sind und Wasserstoff oder Methyl darstellen, die Reste R7 und R8 gleich oder verschieden sind und Wasserstoff, Halogen oder niedriges Alkoxy sind und das Symbol X ein heterocyclisches Ringsystem ist, das monocyciisch oder kondensiert bicyclisch ist, 14 Heteroatome aufweist und das als weitere Substituenten auch eine oder mehrere Oxogruppen enthalten kann, dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel EMI12.2 mit einer Verbindung der allgemeinen Formel EMI12.3 in Gegenwart von Formaldehyd oder eines Formaldehyd liefernden Stoffes in einem Lösungsmittel umsetzt.PATENTANSPRUCH II Verwendung der gemäss Patentanspruch I erhaltenen Verbindungen oder deren Salze zur Herstellung von Verbindungen der allgemeinen Formel EMI12.4 durch Reduktion der Carbonylgruppe zur Hydroxygruppe.UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass man die erhaltenen Basen in ihre Säuradditionssalze überführt.2. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass man die erhaltenen racemischen Verbindungen in ihre optisch aktiven Isomeren auftrennt.3. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass man optisch aktive Isomere bzw.Diastereomere als Ausgangsstoffe verwendet.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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DE1966D0051910 DE1543538A1 (de) | 1966-12-30 | 1966-12-30 | Verfahren zur herstellung neuer heterocyclischer aminoalkohole |
DED0051911 | 1966-12-30 | ||
CH1717968 | 1968-11-18 | ||
US1827970A | 1970-03-10 | 1970-03-10 |
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Publication Number | Publication Date |
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CH522668A true CH522668A (de) | 1972-05-15 |
Family
ID=27429664
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH1717968A CH522668A (de) | 1966-12-30 | 1968-11-18 | Verfahren zur Herstellung neuer heterocyclischer Aminoketone |
Country Status (5)
Country | Link |
---|---|
US (5) | US3514465A (de) |
AT (1) | AT286978B (de) |
CH (1) | CH522668A (de) |
FR (1) | FR8021M (de) |
GB (1) | GB1203810A (de) |
Families Citing this family (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3897441A (en) * | 1971-10-27 | 1975-07-29 | Syntex Inc | Certain thiazole-carboxamides and acylamino-thiazoles |
US3982010A (en) * | 1971-10-27 | 1976-09-21 | Syntex (U.S.A.) Inc. | Thiazole cardiovascular agents |
US4001421A (en) * | 1971-10-27 | 1977-01-04 | Syntex (U.S.A.) Inc. | Thiazole cardiovascular agents |
US3935231A (en) * | 1972-10-17 | 1976-01-27 | Sandoz Ltd., (Sandoz Ag) | Novel benzothiophene derivatives as stabilizers for organic compounds |
DE2300018C2 (de) * | 1973-01-02 | 1983-01-20 | Knoll Ag, 6700 Ludwigshafen | 1-[N-Methyl-N-(β-phenyläthyl)-3-aminopropyl]- benzimidazol-Abkömmlinge |
US4020071A (en) * | 1973-12-20 | 1977-04-26 | Cassella Farbwerke Mainkur Aktiengesellschaft | Derivatives of 1-phenoxy-3-amino-propan-2-ol |
US4088764A (en) * | 1973-12-27 | 1978-05-09 | Cassella Farbwerke Mainkur Aktiengesellschaft | Pharmaceutically active derivatives of 1-phenoxy-3-amino-propan-2-ol |
US3897442A (en) * | 1974-03-14 | 1975-07-29 | Syntex Inc | Thiazole cardiovascular agents |
GB1456323A (en) * | 1974-06-06 | 1976-11-24 | Labaz | Benzothiophenes process for preparing them and pharmaceutical compositions containing the same |
US4024273A (en) * | 1974-06-20 | 1977-05-17 | Smithkline Corporation | Coronary vasodilator and anti-anginal compositions comprising substituted benzofurans and benzothiophenes and methods of producing coronary vasodilation and anti-anginal activity |
US3947470A (en) * | 1974-06-20 | 1976-03-30 | Smithkline Corporation | Substituted benzofurans and benzothiophenes |
US4203899A (en) * | 1974-12-19 | 1980-05-20 | Takeda Chemical Industries, Ltd. | Thiazolylacetamido compounds |
FR2305981A1 (fr) * | 1975-04-03 | 1976-10-29 | Innothera Lab Sa | Nouvelles benzothienyl aminoethyl cetones, leur procede de preparation et leur application en therapeutique |
US4206125A (en) * | 1979-05-04 | 1980-06-03 | Richardson-Merrell Inc. | 5-[2-[(2,3-Dihydro-1,4-benzodioxan-2-ylmethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoic acid derivatives |
US4644008A (en) * | 1979-12-07 | 1987-02-17 | Adir | Perhydroindole-2-carboxylic acids as antihypertensives |
US4616031A (en) * | 1979-12-07 | 1986-10-07 | Adir | Perhydroindole-2-carboxylic acids as antihypertensives |
US4508729A (en) * | 1979-12-07 | 1985-04-02 | Adir | Substituted iminodiacids, their preparation and pharmaceutical compositions containing them |
US4616030A (en) * | 1979-12-07 | 1986-10-07 | Adir | Perhydroindole-2-carboxylic acids as antihypertensives |
US4616029A (en) * | 1979-12-07 | 1986-10-07 | Adir | Perhydromdole-2-carboxylic acids as antihypertensives |
US4374246A (en) * | 1981-06-18 | 1983-02-15 | Norwich Eaton Pharmaceuticals, Inc. | 1-N-[(1-Carboxy-3-phenylpropyl)glycyl]-1,2,3,4-tetrahydroquinoline-2-carboxylic acid compounds |
IE54220B1 (en) * | 1981-12-23 | 1989-07-19 | Ici Plc | Phenol esters |
CA1219865A (en) * | 1982-05-14 | 1987-03-31 | Leo Alig | Aziridine phenethanolamine derivatives |
US4599333A (en) * | 1982-06-14 | 1986-07-08 | Teikoku Hormone Mfg. Co., Ltd. | Hydrazinopyridazine compound, process for production thereof, and use thereof as medicament |
DK169672B1 (da) * | 1985-05-20 | 1995-01-09 | Mitsubishi Chem Ind | Farmaceutiske præparater indeholdende pyrazolonderivater som aktiv bestanddel og anvendelsen af pyrazolonderivater til fremstilling af farmaceutiske præparater |
USRE35801E (en) * | 1985-05-20 | 1998-05-19 | Mitsubishi Chemical Corporation | Prophylactic and therapeutic composition for circulatory disorders and method of treatment |
US4927939A (en) * | 1985-10-15 | 1990-05-22 | Merrell Dow Pharmaceuticals | Cardiotonic aroylthiazolones |
US4762849A (en) * | 1985-10-15 | 1988-08-09 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic alkanoylthiazolones |
US4623651A (en) * | 1985-10-15 | 1986-11-18 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic heterocyclocarbonyl- and acetyl-thiazolones |
DE3621775A1 (de) * | 1986-03-13 | 1988-01-07 | Thomae Gmbh Dr K | Neue substituierte thiazole und oxazole, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
US4866182A (en) * | 1988-02-18 | 1989-09-12 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic alkanoyl and aroyl oxazolones |
ZA889405B (en) * | 1987-12-18 | 1989-12-27 | Glaxo Group Ltd | Ethanolamine derivatives |
DE3884363T2 (de) * | 1987-12-18 | 1994-01-20 | Glaxo Group Ltd | Ethanolaminderivate. |
AU613687B2 (en) * | 1987-12-18 | 1991-08-08 | Glaxo Group Limited | Ethanolamine derivatives |
US5321036A (en) * | 1993-02-10 | 1994-06-14 | Bristol-Myers Squibb Company | Thiazole and oxazole-based β3 adrenergic receptor agonists |
CN109810040B (zh) * | 2018-11-07 | 2020-02-18 | 西南石油大学 | 一种曼尼希碱季铵盐耐高温酸化缓蚀剂的制备方法及应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2556636A (en) * | 1948-06-23 | 1951-06-12 | Schering Corp | gamma-substituted propylamine type antihistamines |
-
1967
- 1967-12-26 US US693138A patent/US3514465A/en not_active Expired - Lifetime
- 1967-12-29 GB GB59037/67A patent/GB1203810A/en not_active Expired
- 1967-12-29 AT AT11809/67A patent/AT286978B/de not_active IP Right Cessation
- 1967-12-29 FR FR134364A patent/FR8021M/fr not_active Expired
-
1968
- 1968-11-18 CH CH1717968A patent/CH522668A/de not_active IP Right Cessation
-
1970
- 1970-03-10 US US18300A patent/US3658845A/en not_active Expired - Lifetime
- 1970-03-10 US US18279A patent/US3631055A/en not_active Expired - Lifetime
- 1970-03-13 US US19511A patent/US3686206A/en not_active Expired - Lifetime
- 1970-03-27 US US00023455A patent/US3715369A/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
US3514465A (en) | 1970-05-26 |
US3686206A (en) | 1972-08-22 |
US3658845A (en) | 1972-04-25 |
AT286978B (de) | 1971-01-11 |
FR8021M (de) | 1970-08-03 |
GB1203810A (en) | 1970-09-03 |
US3631055A (en) | 1971-12-28 |
US3715369A (en) | 1973-02-06 |
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