DE2852945A1 - Benzo:dioxanyl-hydroxyethyl-piperidyl-imidazolidone derivs. - having hypotensive activity, and prepd. by reacting a piperidin-4-yl-imidazolidinone with a halo-hydroxyethyl-benzodioxan - Google Patents
Benzo:dioxanyl-hydroxyethyl-piperidyl-imidazolidone derivs. - having hypotensive activity, and prepd. by reacting a piperidin-4-yl-imidazolidinone with a halo-hydroxyethyl-benzodioxanInfo
- Publication number
- DE2852945A1 DE2852945A1 DE19782852945 DE2852945A DE2852945A1 DE 2852945 A1 DE2852945 A1 DE 2852945A1 DE 19782852945 DE19782852945 DE 19782852945 DE 2852945 A DE2852945 A DE 2852945A DE 2852945 A1 DE2852945 A1 DE 2852945A1
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- Germany
- Prior art keywords
- acid
- hydroxyethyl
- imidazolidinone
- general formula
- compounds according
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- 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.)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (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)
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Abstract
Description
Benzodioxanyl-hydroxyäthylpiperidyl-imidazolidinone, VerfahrenBenzodioxanyl-hydroxyäthylpiperidyl-imidazolidinone, method
zu ihrer Herstellung und diese enthaltende Arzneimittel In der DE-OS 2 400 094 sind Benzodioxanyl-hydroxyäthylpiperidylbenzimidazolidinone beschrieben, die wertvolle therapeutische Eigenschaften besitzen. Nach Arch. int. pharmacodyn. Ther. 215 (1975) 104 - 118 ist insbesondere das 1-t1-[2-(1,4-Benzodioxan-2-yl)-2-hydroxyäthyl)-4-piperidyl -2-benzimidazolinon der Formel als blutdrucksenkender Wirkstoff verwendbar.for their preparation and pharmaceuticals containing them. DE-OS 2 400 094 describes benzodioxanyl-hydroxyethylpiperidylbenzimidazolidinones which have valuable therapeutic properties. According to Arch. Int. Pharmacodyn. Ther. 215 (1975) 104-118 is in particular 1-t1- [2- (1,4-benzodioxan-2-yl) -2-hydroxyethyl) -4-piperidyl -2-benzimidazolinone of the formula usable as an antihypertensive agent.
Es wurde nun gefunden, daß durch Abwandlung der oben gezeigten MolekülstrukturVerbindungen geschaffen werden können, die in ihren pharmakologischen Eigenschaften den vorbekannten Derivaten überlegen sind. Gegenstand der Erfindung sind daher neue Benzodioxanyl-hydroxyäthylpiperidyl-imidazolidinone der allgemeinen Formel und ihre physiologisch verträglichen Säureadditionssalze.It has now been found that, by modifying the molecular structure shown above, compounds can be created which are superior to the previously known derivatives in terms of their pharmacological properties. The invention therefore relates to new benzodioxanyl-hydroxyethylpiperidyl-imidazolidinones of the general formula and their physiologically acceptable acid addition salts.
-In der Formel I bedeutet R Wasserstoff, Niederalkyl mit 1 bis 5 Kohlenstoffatomen, gegebenenfalls substituiertes Phenyl oder Acyl der Teilformel R1-CO-wobei R1 Alkyl mit 1 bis 4 Kohlenstoffatomen oder Phenyl darstellt.-In formula I, R denotes hydrogen, lower alkyl having 1 to 5 carbon atoms, optionally substituted phenyl or acyl of the sub-formula R1-CO-where R1 Represents alkyl of 1 to 4 carbon atoms or phenyl.
Die Erfindung betrifft ferner ein Verfahren zur Herstellung der neuen Verbindungen der Formel I und ihrer Säureadditionssalze.The invention also relates to a method for producing the new Compounds of the formula I and their acid addition salts.
Durch Umsetzung eines Piperidylimidazolidinons der allgemeinen Formel worin R wie oben angegeben definiert ist, mit einem Benzodioxanylderivat der allgemeinen Formel worin Z eine Gruppe der Teilformeln oder bedeutet, wobei Y ein Chlor-, Brom- oder Jodatom oder eine Arylsulfonyloxy-oder Alkylsulfonyloxygruppe darstellt.By implementing a piperidylimidazolidinone of the general formula wherein R is defined as given above, with a benzodioxanyl derivative of the general formula wherein Z is a group of the sub-formulas or denotes where Y represents a chlorine, bromine or iodine atom or an arylsulfonyloxy or alkylsulfonyloxy group.
Man verwendet die berechnete Menge des Alkylierungsmittels der Formel III und arbeitet zweckmäßig in Gegenwart eines säurebindenden Stoffes wie Triäthylamin, Dicyclohexylamin, Natriumcarbonat ,Calciumcarbonat, Calciumoxyd oder vorzugsweise NatriumoderKaliumhydrogencarbonat. Obwohl man auf Lösungsmittel verzichten kann, ist die Durchführung in inerten Lösungsmitteln, wie Chloroform, Nitromethan, niederen aliphatischen Alkoholen, z.B. Äthanol, aliphatischen oder cycloaliphatischen Äthern, z.B.The calculated amount of the alkylating agent of the formula is used III and works appropriately in the presence of an acid-binding substance such as triethylamine, Dicyclohexylamine, sodium carbonate, calcium carbonate, calcium oxide or preferably Sodium or potassium hydrogen carbonate. Although you can do without solvents, is to be carried out in inert solvents such as chloroform, nitromethane, lower aliphatic alcohols, e.g. ethanol, aliphatic or cycloaliphatic ethers, e.g.
Tetrahydrofuran, aromatischen-Kohlenwasserstoffen, z .3. Toluol oder Dimethylformamid zweckmäßiger. Die Reaktionstemperatur ist lin weiten Grenzen variabel. Zweckmäßig sind Temperaturen zwischen 50 und 1500C vorzugsweise 1000C. Die Zugabe von katalytischen bis zu molaren Mengen Kaliumjodid oder Natriumjodiderweist sich als günstig.Tetrahydrofuran, aromatic hydrocarbons, e.g. 3. Toluene or Dimethylformamide more appropriate. The reaction temperature can be varied within wide limits. Temperatures between 50 and 1500C are expedient, preferably 1000C. The addition from catalytic to molar amounts of potassium iodide or sodium iodide is found as cheap.
Die erhaltenen Reaktionsprodukte werden aus den Reaktionsansätzen mit Hilfe bekannter Methoden isoliert. Gegebenenfalls können die so erhaltenen Rohprodukte noch unter Anwendung besonderer Verfahren z.B. durch Säulenchromatographie gereinigt werden, ehe man sie in Form der Basen oder geeigneter Säureadditionsverbindungen kristallisiert.The reaction products obtained are made from the reaction mixtures isolated using known methods. The crude products obtained in this way can optionally still purified using special processes, e.g. by column chromatography before they are in the form of bases or suitable acid addition compounds crystallized.
Für die Herstellung der Säureadditionssalze kommen solche Säuren in Frage, die physiologisch unbedenkliche Salze liefern, z.B.Such acids are used for the preparation of the acid addition salts Question that provide physiologically harmless salts, e.g.
Mineralsäuren, wie Halogenwasserstoffsäure, Salpetersäure, |Schwefelsäure, Orthophosphorsäure, Oxalsäure oder organische Carbonsäuren, wie Oxalsäure, Zitronensäure, Weinsäure, Fumarsäure, Maleinsäure, Propionsäure, Buttersäure, Essigsäure, Salicylsäure , Bernsteinsäure oder Sulfonsäuren, wie Methansulfonsäure, Toluolsulfonsäure oder Phosphonsäuren, wie Äthanphosphonsäure und dergleichen.Mineral acids, such as hydrohalic acid, nitric acid, | sulfuric acid, Orthophosphoric acid, oxalic acid or organic carboxylic acids such as oxalic acid, citric acid, Tartaric acid, fumaric acid, maleic acid, propionic acid, butyric acid, acetic acid, salicylic acid , Succinic acid or sulfonic acids, such as methanesulfonic acid, toluenesulfonic acid or Phosphonic acids such as ethanephosphonic acid and the like.
Die für das Herstellungsverfahren eingesetzten Piperidylimidazolidinone der allgemeinen Formel II sind in den deutschen Offenlegungsschriften DE-OS 2 701 794 und 2 341 229 beschrieben. Die Benzodioxanyl-Ausgangsverbindungen sind aus J. Med. Chem. Jl, (1970) 169 bekannt.The piperidylimidazolidinones used for the manufacturing process the general formula II are in the German Offenlegungsschrift DE-OS 2 701 794 and 2,341,229. The benzodioxanyl starting compounds are from J. Med. Chem. Jl, (1970) 169 known.
Da der Benzodioxanyl-hydroxyäthyl-Rest der Verbindungen der Formel I zwei chirale Zentren enthält, treten die Verbindungen als Diastereomere auf, die durch Kristallisation aus geeigneten Lösungsmitteln gewonnen werden können. Die Erfindung umfaßt sowohl die Diastereomeren als auch die Racemate und die dazugehörigen optisch aktiven Formen. Die Verbindungen der Formel I und deren Säureadditionssalze zeigen im Tierversuch an der Ratte eine ausgeprägte und langanhaltende blutdrucksenkende Wirkung, wobei die gute orale Wirksamkeit auffällt. Im Vergleich zu strukturähnlichen bekannten Derivaten ist die a-adrenolytische Wirkung geringer ausgeprägt. Die blutdrucksenkende Wirkung wird von einer herzfrequenzsenkenden Wirkung (Bradycardie) begleitet, was als günstig zu beurteilen ist.Since the benzodioxanyl-hydroxyethyl radical of the compounds of the formula I contains two chiral centers, the compounds occur as diastereomers, the can be obtained by crystallization from suitable solvents. the Invention includes both the diastereomers and the racemates and their associated optically active forms. The compounds of the formula I and their acid addition salts show in animal experiments on rats a pronounced and long-lasting antihypertensive effect Effect, whereby the good oral effectiveness is noticeable. Compared to structurally similar known derivatives, the α-adrenolytic effect is less pronounced. The antihypertensive Effect is accompanied by a heart rate lowering effect (bradycardia) what is to be judged as favorable.
Die neuen Verbindungen der allgemeinen Formel I können enteral oder parenteral angewandt werden. Die Dosierung bei oraler Verabreichung liegt bei 0,5 bis 10, vorzugsweise 1 bis 5 mg.The new compounds of general formula I can enteral or can be used parenterally. The dosage for oral administration is 0.5 to 10, preferably 1 to 5 mg.
Die erfindungsgemäß erhältlichen Verbindungen können allein oder in Kombination mit anderen erfindungsgemäßen Wirkstoffen zur Anwendung gelangen. Geeignete Anwendungsformen sind beispielsweise Tabletten, Kapseln, Zäpfchen, Lösungen, Säfte, Emulsionen oder dispersible Pulver. Entsprechende Tabletten können beispielsweise durch Mischen des oder der Wirkstoffe mit-bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln, wie Calciumcarbonat, Calciumphosphat oder Milchzucker, Sprengmitteln, wie Maisstärke oder Alginsäure, Bindemitteln, wie Stärke oder Gelatine,~Schmiermitteln, wie Magnesiumstearat oder Talk und/oder Mitteln zur Erzielung eines Depoteffektes, wie Carboxypolymethylen, Carboxymethylcellulose, Celluloseacetatphthalat oder Polyvinylacetat erhalten werden.The compounds obtainable according to the invention can be used alone or in Combination with other active ingredients according to the invention are used. Suitable Application forms are, for example, tablets, capsules, suppositories, solutions, juices, Emulsions or dispersible powders. Corresponding tablets can, for example by mixing the active ingredient (s) with known auxiliaries, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, Disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, ~ lubricants, such as magnesium stearate or talc and / or agents to achieve a depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained.
Die folgenden Beispiele erläutern die Erfindung in nicht beschränkender Weise: A. Herstellungsbespiele Beispiel 1 1-{1-[2-(1,4-Benzodioxanyl-2)-2-hydroxyäthyl]-4-piperidyl}-imidazolidin-2-on 1,7 g (10 mMol) Piperidylimidazolidinon 3,0 g (11 mMol) 2-(2-Benzodioxanyl)-2-hydroxyäthylbromid und 1,8 g (20 mMol) NaHC03 wurden in 50 ml Dimethylformamid 2 Stunden bei 100°C geriihrt, Anschließend wurde bei 70°C am Rotationsverdampfer eingeengt und der Rückstand in 250 ml Methylenchlorid gelöst und 3 mal mit je 250 ml Wasser kräftig geschüttelt. Nach dem Abtrennen und Trocknen über Natriumsulfat wurde die organische Phase eingeengt. Der Rückstand wurde in Äthanol gelöst. mit einer äquivalenten Menge äthanolischer Salzsäure versetzt und mit Äther solange, bis die Trübung gerade verschwand. Es kristallisierte das Hydrochlorid obiger Verbindung. Dieses wurde abgesaugt und aus Isopropanol nochmals umkristallisiert. Man erhielt auf diese Weise 3 g entsprechend 78,1 fi der Theorie mit einem Schmelzpunkt von 227 - 229°C.The following examples illustrate the invention in a non-limiting manner Method: A. Preparation examples Example 1 1- {1- [2- (1,4-Benzodioxanyl-2) -2-hydroxyethyl] -4-piperidyl} -imidazolidin-2-one 1.7 g (10 mmoles) of piperidylimidazolidinone 3.0 g (11 mmoles) of 2- (2-benzodioxanyl) -2-hydroxyethyl bromide and 1.8 g (20 mmol) of NaHCO 3 were in 50 ml of dimethylformamide for 2 hours at 100 ° C The mixture was then concentrated on a rotary evaporator at 70.degree. C. and the residue dissolved in 250 ml of methylene chloride and shaken vigorously 3 times with 250 ml of water each time. After separation and drying over sodium sulfate, the organic phase was concentrated. The residue was dissolved in ethanol. with an equivalent amount of ethanol Hydrochloric acid was added and ether was added until the cloudiness just disappeared. It the hydrochloride of the above compound crystallized. This was sucked off and off Isopropanol recrystallized again. In this way, 3 g were obtained accordingly 78.1 fi of theory with a melting point of 227-229 ° C.
Auf diese Weise wurden die in der Tabelle 1 aufgeführten Verbindungen hergestellt.Thus, the compounds listed in Table 1 became manufactured.
Tabelle 1 Verbindungen der allgemeinen Formel I als Hydrochloride
Beispiel Nr. R Ausbeute Fp.: (°C) (% der Theorie) 2 CH3 - 51,5 237
Dragée-Endgewicht: 100 mg.Final dragée weight: 100 mg.
b) Tabletten Wirkstoff gemäß vorliegender Erfindung 2,0 mg Milchzucker 55,0 mg Maisstärke 38,0 mg lösliche Stärke 4,0 mg Magnesiumstearat 1,0 mg 100,0 mg Herstellunz: Wirkstoff und Magnesiumstearat werden mit einer wässerigen Lösung der löslichen Stärke granuliert, das Granulat getrocknet und innig mit Milchzucker und Maisstärke vermischt. Das Gemisch wird sodann zu Tabletten von 100 mg Gewicht verpreßt, die 2 mg Wirkstoff enthalten.b) tablets active ingredient according to the present invention 2.0 mg lactose 55.0 mg corn starch 38.0 mg soluble starch 4.0 mg magnesium stearate 1.0 mg 100.0 mg Manufacture: Active ingredient and magnesium stearate are mixed with an aqueous solution the soluble starch granulated, the granules dried and intimately mixed with lactose and cornstarch mixed together. The mixture then becomes tablets of 100 mg in weight compressed, the 2 mg Contain active ingredient.
c) Suppositorien 1 Zäpfchen enthält: Wirkstoff gemäß vorliegender Erfindung 1,0 mg Zäpfchenmasse 1699,0 mg Herstellung: Die feingepulverte Substanz wird mit Hilfe eines Eintauch-Homogenisators in die geschmolzene und auf 400C abgekühlte Zäpfchenmasse eingerührt. Die Masse wird bei 35 0C in leicht vorgekühlte Formen gegossen.c) Suppositories 1 suppository contains: active ingredient according to the present Invention 1.0 mg suppository mass 1699.0 mg Production: The finely powdered substance is melted and cooled to 400C with the help of an immersion homogenizer Stir in suppository mass. The mass is at 35 0C in slightly pre-cooled molds poured.
d) Ampullen Wirkstoff gemäß vorliegender Erfindung 2,0 mg Natriumchlorid 18,0 mg destilliertes Wasser ad 2,0 ml Herstelluna: Wirkstoff und Natriumchlorid werden in Wasser gelöst, die Lösung frei von suspendierten Partikeln filtriert und in 2 ccm-Ampullen unter aseptischen Bedingungen abgefüllt. Zuletzt werden die Ampullen sterilisiert und verschlossen. Jede Ampulle enthält 2 mg Wirkstoff.d) Ampoules of active ingredient according to the present invention 2.0 mg of sodium chloride 18.0 mg distilled water to 2.0 ml Manufacture: active ingredient and sodium chloride are dissolved in water, the solution is filtered free of suspended particles and Filled in 2 cc ampoules under aseptic conditions. Last are the ampoules sterilized and sealed. Each ampoule contains 2 mg of active ingredient.
Claims (10)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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DE19782852945 DE2852945A1 (en) | 1978-12-07 | 1978-12-07 | Benzo:dioxanyl-hydroxyethyl-piperidyl-imidazolidone derivs. - having hypotensive activity, and prepd. by reacting a piperidin-4-yl-imidazolidinone with a halo-hydroxyethyl-benzodioxan |
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DE19782852945 DE2852945A1 (en) | 1978-12-07 | 1978-12-07 | Benzo:dioxanyl-hydroxyethyl-piperidyl-imidazolidone derivs. - having hypotensive activity, and prepd. by reacting a piperidin-4-yl-imidazolidinone with a halo-hydroxyethyl-benzodioxan |
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DE2852945A1 true DE2852945A1 (en) | 1980-06-26 |
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DE19782852945 Withdrawn DE2852945A1 (en) | 1978-12-07 | 1978-12-07 | Benzo:dioxanyl-hydroxyethyl-piperidyl-imidazolidone derivs. - having hypotensive activity, and prepd. by reacting a piperidin-4-yl-imidazolidinone with a halo-hydroxyethyl-benzodioxan |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2433526A1 (en) * | 1978-07-28 | 1980-03-14 | Chimosa Chimica Organica Spa | NOVEL PIPERIDINE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THEIR USE AS STABILIZERS FOR SYNTHETIC POLYMERS |
US4329348A (en) | 1979-02-26 | 1982-05-11 | Ciba-Geigy Corporation | N-Oxacyclic-alkylpiperidines as psychostimulants |
US5232931A (en) * | 1990-05-29 | 1993-08-03 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Oxazolidinones |
WO1997028157A1 (en) * | 1996-02-01 | 1997-08-07 | Pierre Fabre Medicament | NOVEL PIPERIDINE DERIVATIVES 4-SUBSTITUTED BY AN IMIDAZOLIDIN-2-ON-1-YL-ETHYL, TETRAHYDROPYRIMIDIN-2-ON-1-YL-ETHYL AND 1,3-DIAZEPIN-2-ON-1-YL-ETHYL GROUP, AND USE THEREOF AS α2-ADRENERGIC RECEPTOR ANTAGONISTS |
WO1999029687A1 (en) * | 1997-12-05 | 1999-06-17 | Janssen Pharmaceutica N.V. | (benzodioxan, benzofuran or benzopyran) derivatives having fundic relaxation properties |
WO2000075137A1 (en) * | 1999-06-02 | 2000-12-14 | Janssen Pharmaceutica N.V. | Pyrrolidinyl, piperidinyl or homopiperidinyl substituted (benzodioxan, benzofuran or benzopyran) derivatives |
US6864273B1 (en) | 1999-06-02 | 2005-03-08 | Janssen Pharmaceutica N.V. | Aminoalkyl substituted (benzodioxan, benzofuran or benzopyran) derivatives |
-
1978
- 1978-12-07 DE DE19782852945 patent/DE2852945A1/en not_active Withdrawn
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2433526A1 (en) * | 1978-07-28 | 1980-03-14 | Chimosa Chimica Organica Spa | NOVEL PIPERIDINE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THEIR USE AS STABILIZERS FOR SYNTHETIC POLYMERS |
US4329348A (en) | 1979-02-26 | 1982-05-11 | Ciba-Geigy Corporation | N-Oxacyclic-alkylpiperidines as psychostimulants |
US5232931A (en) * | 1990-05-29 | 1993-08-03 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Oxazolidinones |
WO1997028157A1 (en) * | 1996-02-01 | 1997-08-07 | Pierre Fabre Medicament | NOVEL PIPERIDINE DERIVATIVES 4-SUBSTITUTED BY AN IMIDAZOLIDIN-2-ON-1-YL-ETHYL, TETRAHYDROPYRIMIDIN-2-ON-1-YL-ETHYL AND 1,3-DIAZEPIN-2-ON-1-YL-ETHYL GROUP, AND USE THEREOF AS α2-ADRENERGIC RECEPTOR ANTAGONISTS |
FR2744451A1 (en) * | 1996-02-01 | 1997-08-08 | Pf Medicament | NOVEL IMIDAZOLIDINONES, PYRIMIDINONES, AND 1,3-DIAZEPIN-2-ONES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATIONS |
AU748669B2 (en) * | 1997-12-05 | 2002-06-06 | Janssen Pharmaceutica N.V. | (Benzodioxan, benzofuran or benzopyran) derivatives having fundic relaxation properties |
US6133277A (en) * | 1997-12-05 | 2000-10-17 | Janssen Pharmaceutica N.V. | (Benzodioxan, benzofuran or benzopyran) derivatives having fundic relaxation properties |
CZ297895B6 (en) * | 1997-12-05 | 2007-04-25 | Janssen Pharmaceutica N. V. | Benzodioxane, benzofuran or benzopyran derivative, process for its preparation, use, and pharmaceutical composition in which the derivative is comprised |
WO1999029687A1 (en) * | 1997-12-05 | 1999-06-17 | Janssen Pharmaceutica N.V. | (benzodioxan, benzofuran or benzopyran) derivatives having fundic relaxation properties |
EA003365B1 (en) * | 1997-12-05 | 2003-04-24 | Янссен Фармацевтика Н.В. | (benzodioxan, benzofuran or benzopyran) derivatives having fundic relaxation properties |
US6852714B2 (en) | 1997-12-05 | 2005-02-08 | Janssen Pharmaceutica N.V. | (Benzodioxan, benzofuran or benzopyran) derivatives having fundic relaxation properties |
US6900222B1 (en) | 1999-06-02 | 2005-05-31 | Janssen Pharmaceutica N.V. | Pyrrolidinyl, piperdinyl or homopiperidinyl substituted (benzodioxan, benzofuran or benzopyran) derivatives |
US6864273B1 (en) | 1999-06-02 | 2005-03-08 | Janssen Pharmaceutica N.V. | Aminoalkyl substituted (benzodioxan, benzofuran or benzopyran) derivatives |
MY120617A (en) * | 1999-06-02 | 2005-11-30 | Janssen Pharmaceutica Nv | Pyrrolidinyl, piperidinyl or homopiperidinyl substituted (benzodioxan, benzofuran or benzopyran) derivatives. |
WO2000075137A1 (en) * | 1999-06-02 | 2000-12-14 | Janssen Pharmaceutica N.V. | Pyrrolidinyl, piperidinyl or homopiperidinyl substituted (benzodioxan, benzofuran or benzopyran) derivatives |
US7273862B2 (en) | 1999-06-02 | 2007-09-25 | Janssen Pharmaceutica N.V. | Aminoalkyl substituted (benzodioxan, benzofuran or benzopyran) derivatives |
BG65269B1 (en) * | 1999-06-02 | 2007-11-30 | Janssen Pharmaceutica N.V. | Aminoalkyl substituted (benzodioxan, benzofuran or benzopyran) derivatives |
BG65278B1 (en) * | 1999-06-02 | 2007-11-30 | Janssen Pharmaceutica N.V. | Pyrrolidinyl, piperidinyl or homopiperidinyl substituted (benzodioxan, benzofuran or benzopyran) derivatives and method for obtaining them |
US7358239B2 (en) | 1999-06-02 | 2008-04-15 | Janssen Pharmaceutica, N.V. | Pyrrolidinyl, piperidinyl or homopiperidinyl substituted (benzodioxan, benzofuran or benzopyran) derivatives |
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