CH528480A - Alkanolamine derivs. - Google Patents
Alkanolamine derivs.Info
- Publication number
- CH528480A CH528480A CH234772A CH234772A CH528480A CH 528480 A CH528480 A CH 528480A CH 234772 A CH234772 A CH 234772A CH 234772 A CH234772 A CH 234772A CH 528480 A CH528480 A CH 528480A
- Authority
- CH
- Switzerland
- Prior art keywords
- sep
- substd
- isopropyl
- carbon atoms
- phenyl
- Prior art date
Links
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 125000002252 acyl group Chemical group 0.000 claims abstract description 3
- 125000001769 aryl amino group Chemical group 0.000 claims abstract description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- -1 aralkyl radical Chemical class 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 239000003701 inert diluent Substances 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 125000005248 alkyl aryloxy group Chemical group 0.000 abstract description 2
- 125000004104 aryloxy group Chemical group 0.000 abstract description 2
- 238000011282 treatment Methods 0.000 abstract description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 abstract 2
- 125000003342 alkenyl group Chemical group 0.000 abstract 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 abstract 2
- 200000000007 Arterial disease Diseases 0.000 abstract 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- 125000005110 aryl thio group Chemical group 0.000 abstract 1
- 239000002876 beta blocker Substances 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 abstract 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 abstract 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 abstract 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 abstract 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 abstract 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-M oxalate(1-) Chemical compound OC(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-M 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WUPUOUBTQHDBPN-UHFFFAOYSA-N 1-(butan-2-ylamino)-3-(2,3-dichlorophenoxy)propan-2-ol Chemical compound ClC1=C(OCC(CNC(C)CC)O)C=CC=C1Cl WUPUOUBTQHDBPN-UHFFFAOYSA-N 0.000 description 1
- JZEHWMUIAKALDN-UHFFFAOYSA-N 1-amino-3-phenoxypropan-2-ol Chemical class NCC(O)COC1=CC=CC=C1 JZEHWMUIAKALDN-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical class C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- UPMLOUAZCHDJJD-UHFFFAOYSA-N 4,4'-Diphenylmethane Diisocyanate Chemical compound C1=CC(N=C=O)=CC=C1CC1=CC=C(N=C=O)C=C1 UPMLOUAZCHDJJD-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229940035339 tri-chlor Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D207/34—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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
- C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
- C07D207/412—Acyclic radicals containing more than six carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Alkanolamines - (I) where Y = O - R1, R3, R4 = H - (R2 = Et - (B = 4-Cl-3-Me-phenyl; 3,5-Me2-phenyl - (R2 = n-Pr - (B = 3-tolyl; 3,5-Me2-phenyl; 2,5-Cl2-phenyl; 3-MeO-phenyl - or Y = O R1 = H, opt. substd. alkyl, alkenyl, aralkyl - R3, R4 = H, alkyl - R2 = branched alkyl, substd. alkyl, cycloalkyl alkenyl, opt. substd. ( >7C) aralkyl - B = phenyl substd. at 3 or 4 only, or is substd. at 2 only by: iodine, HO, NO2, acyl, aryl, aryloxy, alkylaryloxy, arylthio, arylsulphonyl, arylamino, aralkyl, aralkoxy; or it is substd. by up to 5 substituents, - or Y = S R1 = H R3, R4 = H, alkyl - R2 = H, alkyl, cycloalkyl, alkenyl, aralkyl - B = substd. phenyl - together with their esters and salts, but excluding the following 1-(substd. phenoxy)-3-(substd. amino)-2-propanols:- - 1- 4-Cl3- 1-Me-2-Ph-ethyl; cyclohexyl; - isoamyl - 2,6-Me2 isopropyl - 4-t-amylisobutyl; isoamyl; isopropyl - 4-t-butyl isoamyl - 2-MeO isobutyl; N-isopropyl-N-Me. - beta-Adrenergic blockers, useful in the treatment of coronary arterial disease. - A mixt. of 1-Cl-3-(2,3-Me2-phenoxy)-2-propanol (II) (2.03 pts.) and isopropylamine (15 pts.) is heated at 70-80 deg. for 10 hrs - Working up gives 1-(2,3-Me2-phenoxy)-3-isopropylamino-2-propanol, m.p. 110-2 deg. (petrol).
Description
verfahren zur Herstellung von Alkanolaminderivaten Die vorliegende Erfindung bezieht sich auf ein Ver fahren zur Herstellung von neuen Alkanolaminderiva- ten, die B-adrenergische Blockierungswirkung besitzen und daher für die Behandlung oder Propylaxe von Herzkrankheiten brauchbar sind.
Es sind bereits bestimmte 1-Amino-3-phenoxy-2-pro- panolderivate bekannt, aber es war bisher nicht bekannt, dass Verbindungen dieses Typs B-adrenergische Blockie rungswirkung besitzen.
Das Verfahren gemäss der Erfindung zur Herstellung von Alkanolaminderivaten der Formel
EMI0001.0004
worin R2 einen in α-Stellung verzweigten Alkylrest mit 3 bis 10 Kohlenstoffatomen oder einen in α-Stellung verzweigten Hydroxyalkylrest mit 4 bis 10 Kohlenstoff atomen oder einen in α
-Stellung verzweigten Aralkyl- rest mit 10 bis 15 Kohlenstoffatomen bedeutet, R3 und R4, die gleich oder verschieden sein können, Wasser stoff oder Alkylreste mit bis zu 5 Kohlenstoffatomen darstellen und 2, 3 oder 4 der Symbole A2, A3, A4 und A5, die gleich oder verschieden sein können, Halogen atome, Hydroxylgruppen, Alkyl-, Alkoxy- oder Halogen alkylreste mit bis zu 4 Kohlenstoffatomen oder Acyl-, Aryl-, Aryloxy-, (z.B.
Alkylaryloxy-), Arylsulfonyl-, Aryl- amino-, Aralkyl- oder Aralkoxyreste mit bis zu 10 Koh lenstoffatomen bedeuten und die übrigen der Symbole A2, A3, A4 und A5 Wasserstoff bedeuten, bzw. von Sal zen davon ist dadurch gekennzeichnet, dass man eine Verbindung der Formel
EMI0001.0015
worin R5 einen hydrogenolysierbaren Rest bedeutet, der Hydrogenolyse unterwirft.
Eine geeignete Bedeutung von R5 ist beispielsweise der Benzylrest. Die Hydrogenolyse kann durch Hydrie rung in Gegenwart eines Palladium-auf-Kohle-Katalysa tors in einem inerten Verdünnungsmittel oder Lösungs mittel, z.B. Äthanol, ausgeführt werden.
Eine geeignete Bedeutung von R2 ist beispielsweise der Isopropyl-, sek.Butyl-, tert.Butyl-, 1-Methyl-octyl-, 2-Hydroxy-1,1-dimethyläthyl- oder 1-Methyl-3-phenyl- propylrest.
Eine geeignete Bedeutung von R3 oder R4, wenn diese einen Alkylrest darstellen, ist beispielsweise der Methylrest.
Eine geeignete Bedeutung von A2, A3, A4 oder A5, wenn diese von Wasserstoff verschieden sind, ist bei spielsweise das Fluor-, Chlor- oder Bromatom oder die Hydroxyl-, Methyl-, Äthyl-, Isopropyl-, tert.Butyl-, Me- thoxy-, Äthoxy-, n-Butoxy-, Acetyl-, Benzoyl-, Tri- fluormethyl-, Phenyl-, Phenoxy-, 4-Tolyloxy-, Phenyl- sulfonyl-, Anilino-, Benzyl- oder α,α-Dimethylbenzyl- gruppe.
Besonders wertvolle Verbindungen, die erfindungsge- mäss hergestellt werden können, sind z.B. 1-(2,3-Dime- thylphenoxy)-, 1-(2,4-Dimethylphenoxy)-, 1-(3,4-Dime- thylphenoxy)-, 1-(3,5-Dimethylphenoxy)-, 1-(3-Äthyl-5- -methylphenoxy)-, 1-(2,3-Dichlorphenoxy)-, 1-(3,5-Di- chlorphenoxy)-, 1-(2,4,5-Trichlorphenoxy)-, 1-(4-Chlor- -3-methylphenoxy)- und 1-(2-Benzoyl-5-methoxyphen- oxy)-3-isopropylamino-2-propanol sowie 1-(3,
5-Dime thylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propa- nol und 1-(2,3-Dichlorphenoxy)-3-sek.butylamino-2-pro- panol und die Salze derselben.
Geeignete Salze der Alkanolamine sind beispielsweise von anorganischen Säuren abgeleitete Säureadditions salze, wie Hydrochloride,- Hydrobromide, Phosphate oder Sulfate, oder von oganischen Säuren abgeleitete Säureadditionssalze, wie Oxalate, Lactate, Tartrate, Ace tate, Salicylate, Citrate, Benzoate, B-Naphthoate, Adipate oder 1,1'-Methylen-bis-(2-hydroxy-3-naphthoate), oder von sauren synthetischen Harzen, z.B. sulfonierten Poly styrolharzen, wie dem Markenprodukt Zeo-Karb 235, abgeleitete Salze. Verhältnismässig unlösliche Salze, bei spielsweise die 1,1'-Methylen-bis-(2-hydroxy-3-naphthoa- te), haben den Vorteil, dass der Blutspiegel des Medika mentes länger erhalten bleibt.
Das im Verfahren gemäss der Erfindung verwendete Ausgangsmaterial kann durch Umsetzung einer Verbin dung der Formel
EMI0002.0009
EMI0002.0010
EMI0002.0011
Substituenten <SEP> Lösungsmittel <SEP> für <SEP> die
<tb> im <SEP> Ring <SEP> A <SEP> R2 <SEP> Base <SEP> aller <SEP> Salz <SEP> Smp.
<SEP> (00 <SEP> Kristallisation
<tb> 2,4-Dimethyl <SEP> Isopropyl <SEP> Base <SEP> 76-77 <SEP> Petroläther <SEP> (60-80)
<tb> 2,5-Dimethyl <SEP> Isopropyl <SEP> Base <SEP> 68-69 <SEP> Petroläther <SEP> (60-80)
<tb> 3,4-Dimethyl <SEP> Isopropyl <SEP> Hydrochlorid <SEP> 148-149 <SEP> Äthylacetat/Äthanol
<tb> 3,5-Dimethyl <SEP> Isopropyl <SEP> Base <SEP> 108-109 <SEP> Cyclohexan
<tb> 2,4-Di-tert.butyl <SEP> Isopropyl <SEP> Hydrochlorid <SEP> 191-192 <SEP> Äthylacetat
<tb> 2-Isopropyl-5-methyl <SEP> Isopropyl <SEP> Hydrochlorid <SEP> 159-l60 <SEP> Äthylacetat
<tb> 2-tert.Butyl-5-methyl <SEP> Isopropyl <SEP> Hydrochlorid <SEP> 175-176 <SEP> Äthylacetat/Äthanol
<tb> 2-Benzoyl-5-methoxy <SEP> - <SEP> Isopropyl <SEP> Hydrogenoxalat <SEP> 195 <SEP> n-Propanol
<tb> 3,
5-Dimethyl <SEP> 1-Methyl-3-phenyl- <SEP> Hydrochlorid <SEP> 136-137 <SEP> Äthylacetat
<tb> propyl <SEP> (erstes <SEP> Isomer)
<tb> 3,5-Dimethyl <SEP> 1-Methyl-3-phenyl- <SEP> Hydrochlorid <SEP> 149-151 <SEP> Äthylacetat/Äthanol
<tb> propyl <SEP> (zweites <SEP> Isomer)
<tb> 2,3-Dimethoxy <SEP> Isopropyl <SEP> Base <SEP> 77-79 <SEP> Petroläther <SEP> (60-80)
<tb> 2-(α,α-Dimethylben- <SEP> Isopropyl <SEP> Hydrochlorid <SEP> 185-186 <SEP> Äthylacetat/Äthanol
<tb> zyl)-4-methyl worin Z ein Halogenatom bedeutet, mit einem Amin der Formel NHR2R5 erhalten werden.
Die in den folgenden Beispielen angegebenen Teile bedeuten Gewichtsteile. <I>Beispiel 1</I> Eine Lösung von 1 Teil 1-(N-Benzyl-N-isopropyl- amino)-3-(2,3-dimethylphenoxy)-2-propanol in 10 Teilen Äther wird mit einer ätherischen Chlorwasserstofflösung versetzt, bis die Ausfällung beendet ist. Das Gemisch wird zur Trockene eingedampft und der Rückstand in 15 Teilen Äthanol gelöst. Die Lösung wird mit 10 Teilen Palladium-auf-Kohle-Katalysator versetzt, worauf das Gemisch bei Umgebungstemperatur und Atmosphären druck 6 Stunden lang in einer Wasserstoffatmosphäre geschüttelt wird.
Das Gemisch wird filtriert und das Lösungsmittel aus dem Filtrat durch Destillation unter vermindertem Druck entfernt. Der feste Rückstand wird in Wasser gelöst und die Lösung mit 50 Teilen Äther gewaschen und dann mit 2n Natriumhydroxydlösung al kalisch gemacht, worauf das resultierende Gemisch fil triert wird. Der feste Rückstand wird mit Wasser ge waschen, getrocknet und aus Petroläther (Siedebereich 60 bis 80 C), der eine kleine Menge Petroläther vom Siedebereich 10 bis 120 C enthält, kristallisiert.
Auf diese Weise erhält man 1-(2,3-Dimethylphenoxy)-3-isopropyl- amino-2-propanol vom Smp. 110 bis 112 C.
<I>Beispiel 2</I> Das in Beispiel 1 beschriebene Verfahren wird unter Verwendung des entsprechenden Ausgangsmaterials wie derholt, wobei die in der folgenden Tabelle angegebenen Verbindungen erhalten werden:
EMI0003.0000
Substituenten <SEP> R3 <SEP> Base <SEP> oder <SEP> Salz <SEP> Smp.
<SEP> ( C) <SEP> Lösungsmittel <SEP> für <SEP> die
<tb> <I>im <SEP> Ring <SEP> A <SEP> Kristallisation</I>
<tb> 3-Äthyl-5-methyl <SEP> Isopropyl <SEP> Base <SEP> 86-87 <SEP> Petroläther <SEP> (60-80)
<tb> 2,3-Dichlor <SEP> Isopropyl <SEP> Base <SEP> 96-97 <SEP> Cyclohexan
<tb> 2,4-Dichlor <SEP> Isopropyl <SEP> Base <SEP> 90-91 <SEP> Cyclohexan
<tb> 2,5-Dichlor <SEP> Isopropyl <SEP> Base <SEP> 83 <SEP> Cyclohexan
<tb> 3,4-Dichlor <SEP> Isopropyl <SEP> Base <SEP> 124-125 <SEP> Cyclohexan
<tb> 3,5-Dichlor <SEP> Isopropyl <SEP> Base <SEP> 117-118 <SEP> Cyclohexan
<tb> 2,4,5-Trichlor <SEP> Isopropyl <SEP> Base <SEP> 114-1l5 <SEP> Cyclohexan
<tb> 4-Chlor-3-methyl <SEP> Isopropyl <SEP> Base <SEP> 119 <SEP> Cyclohexan
<tb> 3-Chlor-4-methyl <SEP> Isopropyl <SEP> Base <SEP> 128-129 <SEP> Petroläther <SEP> (80-100)
<tb> 4-Chlor-3,
5-dimethyl <SEP> Isopropyl <SEP> Base <SEP> 142 <SEP> Cyclohexan
<tb> 4-Methoxy-2-methyl <SEP> Isopropyl <SEP> Hydrogenoxalat <SEP> 162-163 <SEP> Äthylacetat/Äthanol
<tb> 3-tert.Butyl-4-methoxy <SEP> Isopropyl <SEP> Base <SEP> 95 <SEP> Petroläther <SEP> (100-120)
<tb> 2-Chlor-4-methyl <SEP> Isopropyl <SEP> Hydrochlorid <SEP> 165-166 <SEP> Äthylacetat/Äthanol
<tb> 2,3-Dichlor <SEP> sek.Butyl <SEP> Hydrochlorid <SEP> 159-l60 <SEP> Äthylacetat/Äthanol
<tb> 4-Chlor-3-methyl <SEP> 2-Hydroxy-1,1-di- <SEP> Hydrogenoxalat <SEP> 192 <SEP> wässriges <SEP> Äthanol
<tb> methyläthyl
<tb> 3,5-Dimethoxy <SEP> Isopropyl <SEP> Hydrogenoxalat <SEP> 149-150 <SEP> Äthylacetat/Äthanol
Process for the production of alkanolamine derivatives The present invention relates to a process for the production of new alkanolamine derivatives which have B-adrenergic blocking action and are therefore useful for the treatment or prophylaxis of heart diseases.
Certain 1-amino-3-phenoxy-2-propanol derivatives are already known, but it was not previously known that compounds of this type have B-adrenergic blocking action.
The process according to the invention for the preparation of alkanolamine derivatives of the formula
EMI0001.0004
wherein R2 is an α-branched alkyl radical having 3 to 10 carbon atoms or an α-branched hydroxyalkyl radical having 4 to 10 carbon atoms or an α-branched hydroxyalkyl radical.
-Position branched aralkyl radical with 10 to 15 carbon atoms means, R3 and R4, which can be the same or different, represent hydrogen or alkyl radicals with up to 5 carbon atoms and 2, 3 or 4 of the symbols A2, A3, A4 and A5, which can be the same or different, halogen atoms, hydroxyl groups, alkyl, alkoxy or haloalkyl radicals with up to 4 carbon atoms or acyl, aryl, aryloxy, (e.g.
Alkylaryloxy), arylsulfonyl, arylamino, aralkyl or aralkoxy radicals with up to 10 carbon atoms mean and the rest of the symbols A2, A3, A4 and A5 mean hydrogen, or salts thereof is characterized in that one a compound of the formula
EMI0001.0015
wherein R5 is a hydrogenolysable radical which is subjected to hydrogenolysis.
A suitable meaning of R5 is, for example, the benzyl radical. The hydrogenolysis can be carried out by hydrogenation in the presence of a palladium-on-carbon catalyst in an inert diluent or solvent, e.g. Ethanol.
A suitable meaning of R2 is, for example, the isopropyl, sec-butyl, tert-butyl, 1-methyl-octyl, 2-hydroxy-1,1-dimethylethyl or 1-methyl-3-phenylpropyl radical.
A suitable meaning of R3 or R4 when these represent an alkyl radical is, for example, the methyl radical.
A suitable meaning of A2, A3, A4 or A5, if these are different from hydrogen, is for example the fluorine, chlorine or bromine atom or the hydroxyl, methyl, ethyl, isopropyl, tert-butyl, Me - thoxy, ethoxy, n-butoxy, acetyl, benzoyl, trifluoromethyl, phenyl, phenoxy, 4-tolyloxy, phenylsulfonyl, anilino, benzyl or?,? -Dimethylbenzyl- group.
Particularly valuable compounds that can be prepared according to the invention are e.g. 1- (2,3-dimethylphenoxy) -, 1- (2,4-dimethylphenoxy) -, 1- (3,4-dimethylphenoxy) -, 1- (3,5-dimethylphenoxy) -, 1- (3-ethyl-5-methylphenoxy) -, 1- (2,3-dichlorophenoxy) -, 1- (3,5-dichlorophenoxy) -, 1- (2,4,5-trichlorophenoxy) -, 1 - (4-chloro- -3-methylphenoxy) - and 1- (2-benzoyl-5-methoxyphenoxy) -3-isopropylamino-2-propanol and 1- (3,
5-Dimethylphenoxy) -3- (1-methyl-3-phenylpropylamino) -2-propanol and 1- (2,3-dichlorophenoxy) -3-sec-butylamino-2-propanol and the salts thereof.
Suitable salts of the alkanolamines are, for example, acid addition salts derived from inorganic acids, such as hydrochlorides, hydrobromides, phosphates or sulfates, or acid addition salts derived from organic acids, such as oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, B-naphthoates, Adipates or 1,1'-methylene-bis- (2-hydroxy-3-naphthoate), or from acidic synthetic resins, e.g. sulfonated polystyrene resins, such as the branded product Zeo-Karb 235, derived salts. Relatively insoluble salts, for example the 1,1'-methylene-bis (2-hydroxy-3-naphthoates), have the advantage that the blood level of the medicament is maintained for longer.
The starting material used in the process according to the invention can be prepared by reacting a compound of the formula
EMI0002.0009
EMI0002.0010
EMI0002.0011
Substituents <SEP> Solvent <SEP> for <SEP> die
<tb> in the <SEP> ring <SEP> A <SEP> R2 <SEP> Base <SEP> of all <SEP> salt <SEP> Smp.
<SEP> (00 <SEP> crystallization
<tb> 2,4-dimethyl <SEP> isopropyl <SEP> base <SEP> 76-77 <SEP> petroleum ether <SEP> (60-80)
<tb> 2,5-dimethyl <SEP> isopropyl <SEP> base <SEP> 68-69 <SEP> petroleum ether <SEP> (60-80)
<tb> 3,4-Dimethyl <SEP> isopropyl <SEP> hydrochloride <SEP> 148-149 <SEP> ethyl acetate / ethanol
<tb> 3,5-Dimethyl <SEP> Isopropyl <SEP> Base <SEP> 108-109 <SEP> Cyclohexane
<tb> 2,4-Di-tert.butyl <SEP> isopropyl <SEP> hydrochloride <SEP> 191-192 <SEP> ethyl acetate
<tb> 2-isopropyl-5-methyl <SEP> isopropyl <SEP> hydrochloride <SEP> 159-160 <SEP> ethyl acetate
<tb> 2-tert-butyl-5-methyl <SEP> isopropyl <SEP> hydrochloride <SEP> 175-176 <SEP> ethyl acetate / ethanol
<tb> 2-Benzoyl-5-methoxy <SEP> - <SEP> isopropyl <SEP> hydrogen oxalate <SEP> 195 <SEP> n-propanol
<tb> 3,
5-dimethyl <SEP> 1-methyl-3-phenyl- <SEP> hydrochloride <SEP> 136-137 <SEP> ethyl acetate
<tb> propyl <SEP> (first <SEP> isomer)
<tb> 3,5-Dimethyl <SEP> 1-methyl-3-phenyl- <SEP> hydrochloride <SEP> 149-151 <SEP> ethyl acetate / ethanol
<tb> propyl <SEP> (second <SEP> isomer)
<tb> 2,3-dimethoxy <SEP> isopropyl <SEP> base <SEP> 77-79 <SEP> petroleum ether <SEP> (60-80)
<tb> 2 - (α, α-dimethylben- <SEP> isopropyl <SEP> hydrochloride <SEP> 185-186 <SEP> ethyl acetate / ethanol
<tb> zyl) -4-methyl in which Z is a halogen atom, can be obtained with an amine of the formula NHR2R5.
The parts given in the following examples are parts by weight. <I> Example 1 </I> A solution of 1 part 1- (N-benzyl-N-isopropyl-amino) -3- (2,3-dimethylphenoxy) -2-propanol in 10 parts of ether is mixed with an ethereal solution of hydrogen chloride added until the precipitation has ended. The mixture is evaporated to dryness and the residue is dissolved in 15 parts of ethanol. 10 parts of palladium on carbon catalyst are added to the solution and the mixture is shaken in an atmosphere of hydrogen at ambient temperature and pressure for 6 hours.
The mixture is filtered and the solvent is removed from the filtrate by distillation under reduced pressure. The solid residue is dissolved in water and the solution washed with 50 parts of ether and then made alkaline with 2N sodium hydroxide solution, whereupon the resulting mixture is filtered. The solid residue is washed with water, dried and crystallized from petroleum ether (boiling range 60 to 80 C), which contains a small amount of petroleum ether with a boiling range of 10 to 120 C.
In this way, 1- (2,3-dimethylphenoxy) -3-isopropyl-amino-2-propanol of melting point 110 to 112 ° C. is obtained.
<I> Example 2 </I> The procedure described in Example 1 is repeated using the appropriate starting material, the compounds indicated in the following table being obtained:
EMI0003.0000
Substituents <SEP> R3 <SEP> Base <SEP> or <SEP> Salt <SEP> m.p.
<SEP> (C) <SEP> Solvent <SEP> for <SEP> die
<tb> <I> in the <SEP> ring <SEP> A <SEP> Crystallization </I>
<tb> 3-Ethyl-5-methyl <SEP> Isopropyl <SEP> Base <SEP> 86-87 <SEP> Petroleum ether <SEP> (60-80)
<tb> 2,3-dichloro <SEP> isopropyl <SEP> base <SEP> 96-97 <SEP> cyclohexane
<tb> 2,4-dichloro <SEP> isopropyl <SEP> base <SEP> 90-91 <SEP> cyclohexane
<tb> 2,5-dichloro <SEP> isopropyl <SEP> base <SEP> 83 <SEP> cyclohexane
<tb> 3,4-dichloro <SEP> isopropyl <SEP> base <SEP> 124-125 <SEP> cyclohexane
<tb> 3,5-dichloro <SEP> isopropyl <SEP> base <SEP> 117-118 <SEP> cyclohexane
<tb> 2,4,5-trichlor <SEP> isopropyl <SEP> base <SEP> 114-1l5 <SEP> cyclohexane
<tb> 4-chloro-3-methyl <SEP> isopropyl <SEP> base <SEP> 119 <SEP> cyclohexane
<tb> 3-chloro-4-methyl <SEP> isopropyl <SEP> base <SEP> 128-129 <SEP> petroleum ether <SEP> (80-100)
<tb> 4-chloro-3,
5-dimethyl <SEP> isopropyl <SEP> base <SEP> 142 <SEP> cyclohexane
<tb> 4-methoxy-2-methyl <SEP> isopropyl <SEP> hydrogen oxalate <SEP> 162-163 <SEP> ethyl acetate / ethanol
<tb> 3-tert-butyl-4-methoxy <SEP> isopropyl <SEP> base <SEP> 95 <SEP> petroleum ether <SEP> (100-120)
<tb> 2-chloro-4-methyl <SEP> isopropyl <SEP> hydrochloride <SEP> 165-166 <SEP> ethyl acetate / ethanol
<tb> 2,3-dichloro <SEP> sec-butyl <SEP> hydrochloride <SEP> 159-160 <SEP> ethyl acetate / ethanol
<tb> 4-chloro-3-methyl <SEP> 2-hydroxy-1,1-di- <SEP> hydrogen oxalate <SEP> 192 <SEP> aqueous <SEP> ethanol
<tb> methylethyl
<tb> 3,5-dimethoxy <SEP> isopropyl <SEP> hydrogen oxalate <SEP> 149-150 <SEP> ethyl acetate / ethanol
Claims (1)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2871763 | 1963-07-19 | ||
| GB4674063 | 1963-11-13 | ||
| CH506967A CH521945A (en) | 1962-12-11 | 1963-12-10 | Process for the preparation of alkanolamine derivatives |
| CH1509363A CH515212A (en) | 1962-12-11 | 1963-12-10 | Alkanolamine derivs. - beta-adrenergic blockers |
| GB3934465A GB1123258A (en) | 1965-09-15 | 1965-09-15 | Alkanolamine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH528480A true CH528480A (en) | 1972-09-30 |
Family
ID=27509229
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH234772A CH528480A (en) | 1963-07-19 | 1963-12-10 | Alkanolamine derivs. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH528480A (en) |
-
1963
- 1963-12-10 CH CH234772A patent/CH528480A/en not_active IP Right Cessation
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|---|---|---|---|
| PL | Patent ceased |