DE4244241A1 - Amidine derivs. with LTB4 antagonistic properties - Google Patents
Amidine derivs. with LTB4 antagonistic propertiesInfo
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- DE4244241A1 DE4244241A1 DE4244241A DE4244241A DE4244241A1 DE 4244241 A1 DE4244241 A1 DE 4244241A1 DE 4244241 A DE4244241 A DE 4244241A DE 4244241 A DE4244241 A DE 4244241A DE 4244241 A1 DE4244241 A1 DE 4244241A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
- C07D213/60—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 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Die Erfindung betrifft die neuen Verbindungen der FormelThe invention relates to the novel compounds of the formula
sowie ihre Salze, die Herstellung dieser Verbindungen nach an sich bekannten Methoden und die Verwendung als Wirkstoffe in Arzneimitteln.and their salts, the preparation of these compounds according to known methods and use as Active ingredients in medicines.
In der Formel I bedeutet
a 0 oder 1,
b 1 oder 2,
R C1-C4-Alkyl, im Falle a = 0 oder 1/b = 1 und im
Falle a = 1/b = 2 außerdem Wasserstoff.In the formula I means
a 0 or 1,
b 1 or 2,
RC 1 -C 4 alkyl, in the case of a = 0 or 1 / b = 1 and in the case of a = 1 / b = 2 also hydrogen.
Die neuen Verbindungen können als freie Basen oder als Säureadditionssalze vorliegen.The new compounds can be used as free bases or as Acid addition salts are present.
R bedeutet vorzugsweise CH3, C2H5 oder auch H und wenn a = 1 ist, ist b bevorzugt 1.R is preferably CH 3 , C 2 H 5 or else H and when a = 1, b is preferably 1.
Verfahren zur Herstellung der Verbindungen nach Formel I:Process for the preparation of the compounds according to Formula I:
-
1. Umsetzung von Imidoestern der Formel
(R′ bevorzugt C1-C6-Alkyl oder Benzyl, a, b und R in
der obigen Bedeutung)
mit Ammoniak. Die Umsetzung erfolgt zweckmäßig in einem organischen Lösungsmittel bei Temperaturen zwischen etwa 0°C und der Siedetemperatur des Reaktionsgemischs, vorzugsweise zwischen Raumtemperatur und etwa 100°C bzw. der Siedetemperatur, soweit diese niedriger ist. Geeignete Lösungsmittel sind polare Lösungsmittel wie Methanol, Ethanol, Propanole.
Die Umsetzung kann statt über die Imidoester auch über die entsprechenden Säureimidchloride erfolgen.1. Implementation of imido esters of the formula (R 'is preferably C 1 -C 6 -alkyl or benzyl, a, b and R in the above meaning)
with ammonia. The reaction is conveniently carried out in an organic solvent at temperatures between about 0 ° C and the boiling temperature of the reaction mixture, preferably between room temperature and about 100 ° C or the boiling point, if this is lower. Suitable solvents are polar solvents such as methanol, ethanol, propanols.
The reaction can also take place via the imido esters via the corresponding acid imides. -
2. Umsetzung eines Phenols der Formel
worin R′′ C1-C4-Alkyl bedeutet,
mit einer Verbindung der Formel worin a und b die obige Bedeutung haben und L für eine nucleofuge Abgangsgruppe steht bzw. eines Phenols der Formel worin a die obige Bedeutung hat,
mit einer Verbindung der Formel worin b, L und R′′ die obige Bedeutung haben.
Die Umsetzung der Phenole erfolgt in aprotischen Lösungsmitteln wie Dimethylsulfoxid, Dimethylformamid, Acetonitril oder Alkoholen wie Methanol, Ethanol oder Propanol unter Zusatz einer Base (Metallcarbonate, Metallhydroxide, Metallhydride) bei Temperaturen zwischen etwa 0 und 140°C bzw. der Siedetemperatur des Reaktionsgemischs.
Die Phenole können auch in Form von Salzen, etwa der Alkalisalze, eingesetzt werden. Als nucleofuge Abgangsgruppe eignen sich z. B. Halogene, etwa Br, Cl.2. Reaction of a phenol of the formula in which R "denotes C 1 -C 4 -alkyl,
with a compound of the formula wherein a and b have the above meaning and L is a nucleofugic leaving group or a phenol of the formula where a has the above meaning,
with a compound of the formula wherein b, L and R "have the above meaning.
The reaction of the phenols takes place in aprotic solvents such as dimethyl sulfoxide, dimethylformamide, acetonitrile or alcohols such as methanol, ethanol or propanol with the addition of a base (metal carbonates, metal hydroxides, metal hydrides) at temperatures between about 0 and 140 ° C or the boiling temperature of the reaction mixture.
The phenols can also be used in the form of salts, such as the alkali metal salts. As nucleofugic leaving group are z. B. halogens, such as Br, Cl. -
3. Reduktion der Amidoxime der Formel
worin R, a und b die obige Bedeutung haben.
Für die Reduktion der Amidoxime eignet sich die katalytische Hydrierung, insbesondere mit Raney-Nickel in einem niederen Alkohol, z. B. Methanol.
Zweckmäßig werden die Amidoxime unter Zugabe der berechneten Menge derjenigen Säure, deren Salz als Endprodukt gewünscht wird, in Methanol gelöst und bei Raumtemperatur unter leichtem Druck, z. B. bei 5 bar, bis zur beendeten Wasserstoffaufnahme hydriert.3. Reduction of amidoximes of the formula wherein R, a and b are as defined above.
For the reduction of the amidoximes, the catalytic hydrogenation, in particular with Raney nickel in a lower alcohol, for. For example methanol.
The amidoximes are expediently dissolved in methanol with the addition of the calculated amount of that acid whose salt is desired as the end product, and at room temperature under slight pressure, eg. B. at 5 bar, hydrogenated to completion of hydrogen uptake.
Die Ausgangsstoffe können nach üblichen Methoden aus bekannten Verbindungen erhalten werden. Die Amidoxime werden z. B. aus den entsprechenden Nitrilen mit Hydroxylamin erhalten.The starting materials can be prepared by customary methods known compounds are obtained. The amidoximes be z. B. from the corresponding nitriles with Hydroxylamine obtained.
Die erfindungsgemäßen Verbindungen sind therapeutisch verwendbar, insbesondere aufgrund ihrer LTB4-antagonistischen Wirkung. Sie eignen sich daher für die Anwendung vor allem bei solchen Krankheiten, bei denen entzündliche und/oder allergische Vorgänge eine Rolle spielen, beispielsweise, Asthma, Colitisulcerosa, Psoriasis, ferner zur Behandlung einer durch nichtsteroidale Antiphlogistika induzierten Gastropathie. Die neuen Verbindungen können auch in Kombination mit anderen Wirkstoffen angewendet werden, z. B. mit Antiallergika, Sekretolytika, β2-Mimetika, inhalativ anwendbaren Steroiden, Antihistaminika und/oder PAF-Antagonisten. Die Verabreichung kann topisch, oral, transdermal, nasal, parenteral oder inhalativ erfolgen.The compounds of the invention are therapeutically useful, especially because of their LTB 4 antagonist activity. They are therefore suitable for use in particular in those diseases in which inflammatory and / or allergic processes play a role, for example, asthma, ulcerative colitis, psoriasis, and also for the treatment of nonsteroidal anti-inflammatory gastropathy. The new compounds may also be used in combination with other agents, e.g. As with antiallergics, secretolytics, β 2 -mimetics, inhaled steroids, antihistamines and / or PAF antagonists. Administration may be topical, oral, transdermal, nasal, parenteral or inhalative.
Die therapeutische oder prophylaktische Dosis ist - außer von der Wirkungsstärke der einzelnen Verbindungen und dem Körpergewicht des Patienten - abhängig von der Beschaffenheit und Ernsthaftigkeit des Krankheitszustandes. Bei oraler Anwendung liegt die Dosis zwischen 10 und 250 mg, vorzugsweise zwischen 20 und 200 mg. Bei inhalativer Anwendung werden dem Patienten zwischen etwa 2 und 20 mg Wirkstoff zugeführt. Die neuen Verbindungen können in üblichen Zubereitungen verabreicht werden, etwa als Tabletten, Drag´es, Kapseln, Oblaten, Pulver, Granulate, Lösungen, Emulsionen, Sirupe, Inhalationsaerosole, Salben, Suppositorien.The therapeutic or prophylactic dose is - except for the potency of each compound and the body weight of the patient - depending on the Nature and seriousness of the Disease state. For oral use is the Dose between 10 and 250 mg, preferably between 20 and 200 mg. When inhaled, the Patients are fed between about 2 and 20 mg of active ingredient. The new compounds can be prepared in conventional formulations be administered, such as tablets, Drag'es, Capsules, wafers, powders, granules, solutions, Emulsions, syrups, inhalation aerosols, ointments, Suppositories.
Die nachstehenden Beispiele zeigen einige Möglichkeiten für die Formulierung der Darreichungsformen. The examples below show some possibilities for the formulation of the dosage forms.
Die Bestandteile werden in üblicher Weise zu Tabletten von 500 mg Gewicht verarbeitet. Gewünschtenfalls kann der Wirkstoffgehalt erhöht oder vermindert und die Traubenzuckermenge entsprechend vermindert oder erhöht werden.The ingredients are added in the usual way Tablets of 500 mg weight processed. If desired, the active ingredient content can be increased or diminished and the amount of glucose be reduced or increased accordingly.
Die Bestandteile werden in üblicher Weise zu Suppositorien von 1,7 g Gewicht verarbeitet.The ingredients are added in the usual way Suppositories of 1.7 g weight processed.
Mikronisiertes Wirkstoffpulver (Verbindung der Formel 1; Teilchengröße ca. 0,5 bis 7 µm) werden in einer Menge von 5 mg gegebenenfalls unter Zusatz mikronisierter Lactose in Hartgelatinekapseln abgefüllt. Das Pulver wird aus üblichen Inhalationsgeräten, z. B. gemäß DE-A 33 45 722, inhaliert. Micronised active ingredient powder (compound of Formula 1; Particle size about 0.5 to 7 microns) in an amount of 5 mg optionally below Addition of micronized lactose in Bottled hard gelatine capsules. The powder will from conventional inhalers, z. B. according to DE-A 33 45 722, inhaled.
Die Bindung von 3H-LTB4 (3nM) auf vitalen U937-Zellen (differenzierte, humane monozytäre Zellinie mit natürlich exprimierten LTB4-Rezeptoren) wird durch steigende Konzentration der Testsubstanz dosisabhängig inhibiert (Inkubation 2h bei 0°C). Nach Abtrennung des ungebundenen 3H-LTB4 durch Membranfiltration wird die Radioaktivität des gebundenen LTB4-Rezeptor/3H-LTB4-Komplexes durch Szintilationsmessung quantifiziert. Die Bestimmung der Affinität (Inhibitionskonstante Ki) erfolgte durch iterative Anpassung einer Verdrängungskurve an die Meßwerte (Programm: "gekoppelte Massengleichgewichte" auf Wang-Computer).The binding of 3 H-LTB 4 (3 nM) to vital U937 cells (differentiated, human monocytic cell line with naturally expressed LTB 4 receptors) is inhibited by increasing concentration of the test substance in a dose-dependent manner (incubation for 2 h at 0 ° C.). After separation of the unbound 3 H-LTB 4 by membrane filtration, the radioactivity of the bound LTB 4 receptor / 3 H-LTB 4 complex is quantified by scintillation measurement. The determination of the affinity (inhibition constant K i ) was carried out by iterative adaptation of a displacement curve to the measured values (program: "coupled mass equilibria" on Wang computer).
Indiziert durch LTB4 in vitro (Zunahme der Lichttransmission im Aggregometer, aufgezeichnet in mm; je Experiment Doppelbestimmung): Hemmung 2 min nach Inkubation mit Prüfsubstanz in Polydiol/DMSO.Indicated by LTB 4 in vitro (increase in light transmission in the aggregometer, recorded in mm, double determination per experiment): Inhibition 2 min after incubation with test substance in polydiol / DMSO.
Bewertung des neutrophilen Einstroms durch fotometrische Messung (mOD/min) der Myeloperoxidaseaktivität (Bradley et al.: J. Invest. Dermatol. 78, 206, 1982) in der Ohrhaut. Zunahme 6 h nach topischer Behandlung des linken Ohres mit LTB4 (beidseitig je 250 ng) gegenüber dem rechten Ohr (2 × 5 µl Aceton als Lösungsmittel). Substanzgabe per os in 1%iger Tylose 300, 30 min vor LTB4-Reiz.Evaluation of neutrophil influx by photometric measurement (mOD / min) of myeloperoxidase activity (Bradley et al .: J. Invest. Dermatol., 78, 206, 1982) in the ear skin. Increase 6 h after topical treatment of the left ear with LTB 4 (bilaterally 250 ng each) to the right ear (2 × 5 μl acetone as solvent). Substance per os in 1% Tylose 300, 30 min before LTB 4 -reiz.
In eine Lösung von 2,5 g 4-[4-(2-propyl-3-methoxy- phenoxy)-butyloxyl]-benzonitril, hergestellt aus 2-Propyl-3-methoxy-phenol und 4-Brombutoxybenzonitril, in 40 ml Ethanol leitet man bei -20°C unter Rühren 1 Stunde Chlorwasserstoff ein und läßt das Gemisch 16 Stunden bei Raumtemperatur stehen.In a solution of 2.5 g of 4- [4- (2-propyl-3-methoxy- phenoxy) -butyloxyl] -benzonitrile, prepared from 2-propyl-3-methoxy-phenol and 4-bromobutoxybenzonitrile, in 40 ml of ethanol is passed at -20 ° C with stirring. 1 Hour of hydrogen chloride and leaves the mixture 16 Hours at room temperature.
Man destilliert das Lösungsmittel im Vakuum ab und
nimmt den Rückstand in 50 ml Ethanol auf. Dazu tropft
man ein Gemisch aus 14 ml ethanolischer Ammoniaklösung
und 50 ml Ethanol und läßt das Gemisch 24 Stunden bei
Raumtemperatur stehen. Das Lösungsmittel dampft man ab
und chromatographiert den Rückstand
(Chloroform/Methanol 8 : 2; Kieselgel 60).
Man erhält 1,8 g 4-[4-(2-propyl-3-methoxy-phenoxy)-
butyloxy]-benzamidin-hydrochlorid-hemihydrat.
(Fp. 117-121°C).The solvent is distilled off in vacuo and the residue is taken up in 50 ml of ethanol. To this is added dropwise a mixture of 14 ml of ethanolic ammonia solution and 50 ml of ethanol and the mixture is allowed to stand at room temperature for 24 hours. The solvent is evaporated off and the residue is chromatographed (chloroform / methanol 8: 2, silica gel 60). 1.8 g of 4- [4- (2-propyl-3-methoxy-phenoxy) -butyloxy] -benzamidine hydrochloride hemihydrate are obtained.
(Mp 117-121 ° C).
In der nachstehenden Tabelle sind weitere erfindungsgemäß herstellbare Verbindungen aufgeführt. In the table below are more Listed according to the invention compounds.
Claims (11)
a 0 oder 1,
b 1 oder 2,
R C1-C4-Alkyl, im Falle a = 0 oder 1/b = 1 und im Falle a = 1/b = 2 außerdem Wasserstoff,
als freie Basen oder als Säureadditionssalze.1. Compounds of the formula in the
a 0 or 1,
b 1 or 2,
RC 1 -C 4 -alkyl, in the case of a = 0 or 1 / b = 1 and in the case of a = 1 / b = 2 also hydrogen,
as free bases or as acid addition salts.
- a) einen Imidoester der Formel
(R′ bevorzugt C1-C6-Alkyl oder Benzyl, a, b und R in
der obigen Bedeutung) oder das entsprechende
Säureimidchlorid mit Ammoniak umsetzt
oder daß man - b1) ein Phenol der Formel
worin R′′ C1-C4-Alkyl bedeutet,
mit einer Verbindung der Formel worin a und b die obige Bedeutung haben und L für eine nucleofuge Abgangsgruppe steht bzw. - b2) ein Phenol der Formel
worin a die obige Bedeutung hat,
mit einer Verbindung der Formel worin b, L und R′′ die obige Bedeutung haben,
umsetzt oder daß man - c) ein Amidoxim der Formel
worin R, a und b die obige Bedeutung haben,
zum entsprechenden Amidin reduziert
- a) an imidoester of the formula (R 'preferably C 1 -C 6 alkyl or benzyl, a, b and R in the above meaning) or the corresponding acid imide chloride with ammonia
or that one - b1) a phenol of the formula in which R "denotes C 1 -C 4 -alkyl,
with a compound of the formula in which a and b have the above meaning and L stands for a nucleofugic leaving group or - b2) a phenol of the formula where a has the above meaning,
with a compound of the formula wherein b, L and R '' have the above meaning,
implements or that one - c) an amidoxime of the formula wherein R, a and b are as defined above,
reduced to the corresponding amidine
Priority Applications (42)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4244241A DE4244241A1 (en) | 1992-12-24 | 1992-12-24 | Amidine derivs. with LTB4 antagonistic properties |
EP98121305A EP0902013B1 (en) | 1992-02-05 | 1993-01-14 | Novel amidine derivatives, their preparation and their use as medicaments with LTB-4 antagonistic effect |
PCT/EP1993/000070 WO1993016036A1 (en) | 1992-02-05 | 1993-01-14 | Novel amidine derivatives, their preparation and their use as mediaments with ltb-4 antagonistic effect |
PL93316750A PL173781B1 (en) | 1992-02-05 | 1993-01-14 | Method of obtaining novel derivatives of amidine |
KR1019940702669A KR0163222B1 (en) | 1992-02-05 | 1993-01-14 | New amidine derivatives, their preparation and their use as medicaments with ltb-4 antagonistic effect |
CZ19941886A CZ287209B6 (en) | 1992-02-05 | 1993-01-14 | Amidine derivatives, process of their preparation and pharmaceutical preparations containing thereof |
PT98121305T PT902013E (en) | 1992-02-05 | 1993-01-14 | NEW DERIVATIVES AMIDINATE ITS PREPARATION AND USE AS A MEDICINAL PRODUCT WITH ANTAGONIST ACTIVITY OF LTB4 |
HU9402291A HU216191B (en) | 1992-02-05 | 1993-01-14 | Process for preparing novel amidine derivs. pharmaceutical compns. containing them |
ES93902195T ES2132216T3 (en) | 1992-02-05 | 1993-01-14 | NEW AMIDINE DERIVATIVES, THEIR PREPARATION AND USE AS AN ANTAGONIST EFFECT OF LTB4. |
AU33497/93A AU673343B2 (en) | 1992-02-05 | 1993-01-14 | Novel amidine derivatives, their preparation and their use as mediaments with LTB4 antagonistic effect |
EP93902195A EP0625138B1 (en) | 1992-02-05 | 1993-01-14 | Novel amidine derivatives, their preparation and their use as medicaments with ltb4 antagonistic effect |
UA94095773A UA43318C2 (en) | 1992-02-05 | 1993-01-14 | Amidine derivatives, pharmaceutical composition with ltb-4 antagonistic effect |
DE59309630T DE59309630D1 (en) | 1992-02-05 | 1993-01-14 | NEW AMIDINE DERIVATIVES, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCTS WITH LTB4 ANTAGONISTIC EFFECT |
DK98121305T DK0902013T3 (en) | 1992-02-05 | 1993-01-14 | Novel amidine derivatives, their preparation and use as drugs with LTB4 antagonistic effect |
DE59310252T DE59310252D1 (en) | 1992-02-05 | 1993-01-14 | New amide derivatives, their production and use as medicinal products with an LTB4-antagonistic effect |
NZ246593A NZ246593A (en) | 1992-02-05 | 1993-01-14 | Amidine derivatives; their preparation and medicaments containing them |
DK93902195T DK0625138T3 (en) | 1992-02-05 | 1993-01-14 | Novel amidine derivatives, their preparation and use as a drug with LTB-4 antagonist activity |
CA002427890A CA2427890A1 (en) | 1992-02-05 | 1993-01-14 | New amidine derivatives, the preparation and use thereof |
AT98121305T ATE210634T1 (en) | 1992-02-05 | 1993-01-14 | NEW AMIDERIVATES, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCTS WITH LTB4 ANTAGONISTIC EFFECT |
CA002129526A CA2129526A1 (en) | 1992-02-05 | 1993-01-14 | Novel amidine derivatives, their preparation and their use as medicaments with ltb4 antagonistic effect |
SK914-94A SK281016B6 (en) | 1992-02-05 | 1993-01-14 | Amidine derivatives, method of their preparation, their use and pharmaceuticals them containing |
ES98121305T ES2165122T3 (en) | 1992-02-05 | 1993-01-14 | NEW DERIVATIVES OF AMIDINA, ITS PREPARATION AND USE AS MEDICATIONS WITH ANTAGONIST EFFECT OF LTB4. |
RU94041836A RU2124002C1 (en) | 1992-02-05 | 1993-01-14 | Amidine derivatives, mixture of their isomers or separate isomers and salts, pharmaceutical composition showing antagonistic effect with respect to leukotriene-b4 |
AT93902195T ATE180770T1 (en) | 1992-02-05 | 1993-01-14 | NEW AMIDENE DERIVATIVES, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCTS WITH LTB4 ANTAGONISTIC EFFECT |
PL93304713A PL173789B1 (en) | 1992-02-05 | 1993-01-14 | Method of obtaining novel derivatives of amidine |
SG1996008431A SG44837A1 (en) | 1992-02-05 | 1993-01-14 | New amidine derivatives the preparation and use thereof as pharmaceutical compositions with ltb4-antagonistic activity |
JP51370193A JP3487851B2 (en) | 1992-02-05 | 1993-01-14 | Novel amidine derivatives, their preparation and use as LTB4 antagonists |
TW082100562A TW232005B (en) | 1992-02-05 | 1993-01-29 | |
HRP4244241.9A HRP930102B1 (en) | 1992-02-05 | 1993-02-03 | Novel amidine derivatives, their preparation and their use |
YU6393A YU49038B (en) | 1992-02-05 | 1993-02-03 | New derivatives of amidine and their usage thereof |
IL104589A IL104589A0 (en) | 1992-02-05 | 1993-02-03 | Amidine derivatives,their preparation and pharmaceutical compositions containing them |
MX9300630A MX9300630A (en) | 1992-02-05 | 1993-02-04 | DERIVATIVES OF AMIDINE, PROCEDURE FOR ITS PREPARATION AND MEDICINES THAT CONTAIN THEM. |
SI9300066A SI9300066B (en) | 1992-02-05 | 1993-02-05 | Novel amidine derivatives, their preparation and use |
NO942903A NO301540B1 (en) | 1992-02-05 | 1994-08-04 | New amidine derivatives, their use in the preparation of drug with LTB4 antagonistic effect |
FI943618A FI943618A0 (en) | 1992-02-05 | 1994-08-04 | Novel amidine derivatives, their preparation and use as drugs with LTB4 antagonistic activity |
US08/460,961 US6037377A (en) | 1992-02-05 | 1995-06-05 | Amidine derivatives, the preparation and use thereof as medicaments with LTB4 antagonistic effect |
CZ19971203A CZ287173B6 (en) | 1992-02-05 | 1997-04-18 | Amidine derivatives, process of their preparation and pharmaceutical preparations containing thereof |
GR990401541T GR3030468T3 (en) | 1992-02-05 | 1999-06-09 | Novel amidine derivatives, their preparation and their use as mediaments with ltb-4 antagonistic effect. |
US09/484,073 US6489365B1 (en) | 1992-02-05 | 2000-01-18 | Amidine derivatives, the preparation and use thereof as medicaments with Itb4 antagonistic effect |
FI20002501A FI20002501A (en) | 1992-12-24 | 2000-11-15 | Novel amidine derivatives, their preparation and their use as a drug having LTB4 antagonistic activity |
JP2002073593A JP2002322143A (en) | 1992-02-05 | 2002-03-18 | Amidine derivative, preparing method used for the same, and pharmaceutical composition containing the same |
US10/252,976 US20030130232A1 (en) | 1992-02-05 | 2002-09-23 | Amidine derivatives, the preparation and use thereof as medicaments with LTB4 antagonistic effect |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4244241A DE4244241A1 (en) | 1992-12-24 | 1992-12-24 | Amidine derivs. with LTB4 antagonistic properties |
Publications (1)
Publication Number | Publication Date |
---|---|
DE4244241A1 true DE4244241A1 (en) | 1994-06-30 |
Family
ID=6476648
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE4244241A Ceased DE4244241A1 (en) | 1992-02-05 | 1992-12-24 | Amidine derivs. with LTB4 antagonistic properties |
Country Status (2)
Country | Link |
---|---|
DE (1) | DE4244241A1 (en) |
FI (1) | FI20002501A (en) |
-
1992
- 1992-12-24 DE DE4244241A patent/DE4244241A1/en not_active Ceased
-
2000
- 2000-11-15 FI FI20002501A patent/FI20002501A/en unknown
Also Published As
Publication number | Publication date |
---|---|
FI20002501A (en) | 2000-11-15 |
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