DE4309285A1 - Heterocyclic-containing amidine derivatives, their preparation and use - Google Patents

Heterocyclic-containing amidine derivatives, their preparation and use

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Publication number
DE4309285A1
DE4309285A1 DE4309285A DE4309285A DE4309285A1 DE 4309285 A1 DE4309285 A1 DE 4309285A1 DE 4309285 A DE4309285 A DE 4309285A DE 4309285 A DE4309285 A DE 4309285A DE 4309285 A1 DE4309285 A1 DE 4309285A1
Authority
DE
Germany
Prior art keywords
alkyl
formula
compounds
alkoxy
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
DE4309285A
Other languages
German (de)
Inventor
Ernst-Otto Dr Renth
Kurt Dr Schromm
Ralf Dr Anderskewitz
Franz Dr Birke
Armin Dr Fuegner
Hubert Dr Med Heuer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim GmbH
Original Assignee
Boehringer Ingelheim GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim GmbH filed Critical Boehringer Ingelheim GmbH
Priority to DE4309285A priority Critical patent/DE4309285A1/en
Priority to JP6520657A priority patent/JPH08508467A/en
Priority to CN94192207A priority patent/CN1124486A/en
Priority to EP94911191A priority patent/EP0690849A1/en
Priority to CA002158994A priority patent/CA2158994A1/en
Priority to CZ952466A priority patent/CZ246695A3/en
Priority to PL94310806A priority patent/PL310806A1/en
Priority to PCT/EP1994/000856 priority patent/WO1994021616A1/en
Priority to HU9502778A priority patent/HUT73968A/en
Priority to AU63780/94A priority patent/AU6378094A/en
Priority to SK1174-95A priority patent/SK117495A3/en
Priority to ZA941993A priority patent/ZA941993B/en
Priority to IL10907394A priority patent/IL109073A0/en
Publication of DE4309285A1 publication Critical patent/DE4309285A1/en
Priority to KR1019950704014A priority patent/KR960701026A/en
Priority to LVP-95-291A priority patent/LV11465B/en
Priority to FI954491A priority patent/FI954491A/en
Priority to NO953763A priority patent/NO953763L/en
Priority to BG100069A priority patent/BG100069A/en
Withdrawn legal-status Critical Current

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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
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Description

Die Erfindung betrifft neue, Heterocyclen enthaltende Amidinderivate, ihre Herstellung nach konventionellen Methoden und ihre Verwendung als Wirkstoffe in ArzneimittelnThe invention relates to novel, heterocyclic-containing Amidine derivatives, their preparation according to conventional Methods and their use as active ingredients in drugs

Die neuen Amidinderivate entsprechen der FormelThe new amidine derivatives correspond to the formula

in der A für eine der Gruppenin the A for one of the groups

X₁-A₁-X₂ (II)X₁-A₁-X₂ (II)

X₂-A₁-X₁ (III)X₂-A₁-X₁ (III)

wobei
A1 eine geradkettige oder verzweigte zweibindige aliphatische C2-C6-Gruppe bedeutet, die auch eine Doppel- oder Dreifachbindung enthalten kann, oder eine der Gruppen in which
A 1 represents a straight-chain or branched divalent aliphatic C 2 -C 6 group which may also contain a double or triple bond, or one of the groups

bedeutetmeans

Het für einen Heterocyclus oder ein heterocyclisches System aus zwei oder drei kondensierten Ringen, das ein bis drei Substituenten enthalten kann.Het for a heterocycle or a heterocyclic System of two or three condensed rings, the may contain one to three substituents.

Chirale Verbindungen der Formel I können in Form von Racematen, in enantiomerenreiner bzw. angereicherter Form und jeweils als Base oder als Salze mit anorganischen oder organischen, insbesondere physiologisch unbedenklichen Säuren vorliegen. Chiral compounds of the formula I can be in the form of Racemates, in enantiomerically pure or enriched form and in each case as a base or as salts with inorganic or organic, especially physiological harmless acids are present.  

Als Heterocyclen bzw. als kondensierte Systeme im Sinne der obigen Definition kommen vor allem folgende Gruppen in Betracht:As heterocycles or as condensed systems in the sense the above definition comes mainly the following groups in consideration:

Dabei stehen
R1 und R2, die gleich oder verschieden sein können, für CF3, Halogen, R5, OR5, COR6, SR6, SOR6, SO2R6, SO2NR5R7, C(OH)R5R7 oder gemeinsam auch für die mit benachbarten C-Atomen des Benzolrings verknüpften zweibindigen Gruppen -CR8=CR9-CH=CH-, -CH=CR8-C R9=CH-, -CR8=CH-CR9=CH-, -O-CHR10-CH2-, -O-CH2-O-, -O-CH2-CH2-O-, -(CH2)3-4, -NH-CO-O-, -NH-CO-CH2-O-, -CO-CH2-O- oder -CO-CH2CH2-O- stehen, wobei diese Gruppen ihrerseits auch durch C1-C4-Alkyl substituiert sein können,
R3 für Halogen, OH, CF3, R5, OR6, COR6, CONR5R7, CH2OH, CH2-O-(C1-C4-Alkyl), SR6, SOR6, SO2R6, SO2NR5R7, NH-CO-(C1-C4-Alkyl), NH-SO2-(C1-C4-Alkyl), NR5R7 oder C(OH)R5R7 steht (wobei, falls R3 gleich R5 ist, R5 nur dann H sein kann, wenn mindestens einer der Substituenten R1 und R2 nicht H bedeutet), für einen heterocyclischen Fünfring mit 1 bis 3 Heteroatomen und der FormelStanding there
R 1 and R 2 , which can be identical or different, represent CF 3 , halogen, R 5 , OR 5 , COR 6 , SR 6 , SOR 6 , SO 2 R 6 , SO 2 NR 5 R 7 , C (OH) R 5 R 7 or together also for the divalent groups linked to adjacent C atoms of the benzene ring -CR 8 = CR 9 -CH = CH-, -CH = CR 8 -CR 9 = CH-, -CR 8 = CH-CR 9 = CH-, -O-CHR 10 -CH 2 -, -O-CH 2 -O-, -O-CH 2 -CH 2 -O-, - (CH 2 ) 3-4 , -NH-CO- O, -NH-CO-CH 2 -O-, -CO-CH 2 -O- or -CO-CH 2 CH 2 -O- stand, these groups in turn be substituted by C 1 -C 4 alkyl can,
R 3 is halogen, OH, CF 3 , R 5 , OR 6 , COR 6 , CONR 5 R 7 , CH 2 OH, CH 2 -O- (C 1 -C 4 alkyl), SR 6 , SOR 6 , SO 2 R 6 , SO 2 NR 5 R 7 , NH-CO- (C 1 -C 4 -alkyl), NH-SO 2 - (C 1 -C 4 -alkyl), NR 5 R 7 or C (OH) R 5 R 7 (where R 3 is R 5 , R 5 may be H only if at least one of R 1 and R 2 is not H), a heterocyclic five-membered ring having 1 to 3 heteroatoms and the formula

(worin D, E und G, die gleich oder verschieden sein können, CH, N, C-(C1-C4-Alkyl) oder C-Phenyl bedeuten und L O oder S ist),
R4 für Halogen, NH2, NH-(C1C4-Alkyl), N(C1-C4-Alkyl)2, OH, C1-C4-Alkoxy,
R5 für H, C1-C12, Alkyl, Phenyl, gegebenenfalls durch Halogen, C1-C4-Alkyl, C1-C4-Alkoxy oder C2-C5-Acyl substituiertes Phenyl oder Phenyl-(C1-C4-Alkyl),
R6 für C1-C12-Alkyl, Phenyl oder gegebenenfalls durch Halogen, C1-C4-Alkyl, C1-C4-Alkoxy oder C2-C5-Acyl substituiertes Phenyl,
R7 für H oder C1-C12-Alkyl,
R8, R9 (die gleich oder verschieden sein können) für H, OH, C1-C4-Alkyl, C1-C4-Alkoxy oder C 2-C5 -Acyl,
R10 für H oder C1-C4-Alkyl,
R11, R12, die gleich oder verschieden sein können, für H, OH, Halogen, CF3, C1-C4-Alkyl oder C1-C4-Alkoxy,
R13, R14, die gleich oder verschieden sein können, für H, C1-C4 -Alkyl, C1-C4-Alkoxy, Phenyl, Naphthyl, wobei diese Ringsysteme ein- oder mehrfach durch gleiche oder verschiedene Reste aus der Gruppe Fluor, Chlor, Brom, C1-C4-Alkyl, C1-C4-Alkoxy oder Pseudohalogene wie CN, CF3 substituiert sein können, oder für Pyridyl. (wherein D, E and G, which may be the same or different, are CH, N, C- (C 1 -C 4 -alkyl) or C-phenyl and is LO or S),
R 4 is halogen, NH 2, NH- (C 1 C 4 alkyl), N (C 1 -C 4 alkyl) 2, OH, C 1 -C 4 alkoxy,
R 5 is (H, C 1 -C 12 alkyl, phenyl, optionally substituted by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 2 -C 5 acyl-substituted phenyl or phenyl C 1 C 4 alkyl),
R 6 represents C 1 -C 12 -alkyl, phenyl or phenyl optionally substituted by halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or C 2 -C 5 -acyl,
R 7 is H or C 1 -C 12 -alkyl,
R 8 , R 9 (which can be identical or different) represent H, OH, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or C 2 -C 5 -acyl,
R 10 is H or C 1 -C 4 -alkyl,
R 11 , R 12 , which can be identical or different, are H, OH, halogen, CF 3 , C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy,
R 13 , R 14 , which may be identical or different, are H, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, phenyl, naphthyl, where these ring systems are mono- or polysubstituted by identical or different radicals from the group Group fluorine, chlorine, bromine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or pseudohalogens such as CN, CF 3 may be substituted, or pyridyl.

Soweit A1 eine Doppel- oder Dreifachbindung enthält, ist diese im allgemeinen nicht einem Heteroatom benachbart. Dementsprechend bedeutet A1 in diesem Fall vorzugsweise Gruppen wie CH2-CH=CH-CH2 (cis oder trans) oder CH2-C≡C-CH2.As far as A 1 contains a double or triple bond, this is generally not adjacent to a heteroatom. Accordingly, in this case A 1 preferably denotes groups such as CH 2 -CH = CH-CH 2 (cis or trans) or CH 2 -C≡C-CH 2 .

WennIf

steht,
hat X1 diese Bedeutung nicht. Falls A mit einem Stickstoffatom der Gruppe Het verbunden ist (wie z. B. bei den Gruppen j bis o), ist A über ein C-Atom mit diesem Stickstoffatom verknüpft. Im vorliegenden Text ist die Gruppe A jeweils so geschrieben, wie sie in die Formel I einzufügen ist.stands,
X 1 does not have this meaning. If A is linked to a nitrogen atom of the group Het (as in the case of groups j to o), A is linked via a carbon atom to this nitrogen atom. In the present text, the group A is in each case written as it is to be inserted into the formula I.

Bevorzugte Verbindungen im Rahmen der obigen Definitionen umfaßt Formel Ia:Preferred compounds within the scope of the above Definitions includes formula Ia:

worin A′1, X′1, X′2 und Het′ folgendes bedeuten:
A′1: (CH2)2-6, CH2-C6H4-CH2, Z oder E CH2-CH=CH-CH2, CH2-C≡C-CH2;
X′1: O, S;
X′2: O, S;
Het′: eine Gruppe der obigen Formeln a, b, e, f, g, k, n, wobei R1, R2, R3, die gleich oder verschieden sein können, H, R5, OR5 oder COR5 bedeuten und R1 und R2 gemeinsam auch einen ankondensierten Ring bedeuten können. in which A ' 1 , X' 1 , X ' 2 and Het' mean the following:
A ' 1 : (CH 2 ) 2-6 , CH 2 -C 6 H 4 -CH 2 , Z or E CH 2 -CH = CH-CH 2 , CH 2 -C≡C-CH 2 ;
X ' 1 : O, S;
X ' 2 : O, S;
Het ': a group of the above formulas a, b, e, f, g, k, n, where R 1 , R 2 , R 3 , which may be identical or different, denote H, R 5 , OR 5 or COR 5 and R 1 and R 2 together may also signify a fused ring.

Die Verbindungen der Formel 1 werden nach an sich bekannten Verfahren erhalten, insbesondere wie folgt:The compounds of formula 1 are per se obtained, in particular as follows:

  • 1. Umsetzung einer Verbindung der Formel (worin Het, R4, A und B die obige Bedeutung haben und R bevorzugt für einen C1-C4-Alkylrest oder für Benzyl steht) mit Ammoniak in einem Alkohol, wie Methanol, Ethanol, n-Propanol, i-Propanol, oder in einem inerten Lösungsmittel, etwa Dichlormethan, Tetrahydrofuran, Dioxan, bei Temperaturen zwischen etwa 0 und 50°C, vorzugsweise bei etwa 20°C.1. Reaction of a compound of the formula (in which Het, R 4 , A and B have the above meaning and R preferably represents a C 1 -C 4 -alkyl radical or benzyl) with ammonia in an alcohol, such as methanol, ethanol, n-propanol, i-propanol, or in an inert solvent, such as dichloromethane, tetrahydrofuran, dioxane, at temperatures between about 0 and 50 ° C, preferably at about 20 ° C.
  • 2. Reduktion eines Amidoxims der Formel (worin Het, R4, A und B die obige Bedeutung haben) durch Einwirkung von Wasserstoff in Gegenwart eines Katalysators wie Raney-Nickel, Palladium oder Platin.2. Reduction of an amidoxime of the formula (wherein Het, R 4 , A and B have the above meaning) by the action of hydrogen in the presence of a catalyst such as Raney nickel, palladium or platinum.
  • 3. Verbindungen der Formel I, in der X1 bzw. X2 O oder S bedeuten, können auch gemäß dem Schema bzw. (wobei A, B, Het, X1, X2 und R4 die obige Bedeutung haben und L eine nucleofuge Abgangsgruppe, Z OH oder SH ist) erhalten werden.3. Compounds of formula I where X 1 and X 2 is O or S, can also according to the scheme or. (wherein A, B, Het, X 1 , X 2 and R 4 are as defined above and L is a nucleofugic leaving group, Z is OH or SH).

Die Umsetzung erfolgt in 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.The reaction takes place in solvents such as Dimethylsulfoxide, 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 point of the reaction mixture.

Die Phenole oder Thiophenole können auch in Form von Salzen, etwa der Alkalisalze, eingesetzt werden. Als nucleofuge Abgangsgruppe eignen sich z. B. Halogene, etwa Br, Cl oder Reste von Sulfonsäuren wie Methansulfonsäure, Benzolsulfonsäure. The phenols or thiophenols may also be in the form of salts, such as the alkali metal salts used become. As nucleofugic leaving group are suitable z. As halogens, such as Br, Cl or residues of Sulfonic acids such as methanesulfonic acid, Benzene sulfonic acid.  

Die Ausgangsstoffe V und VI werden vorzugsweise aus den entsprechenden Nitrilen der FormelThe starting materials V and VI are preferably from the corresponding nitriles of the formula

(worin A, B, Het und R4 die obige Bedeutung haben) hergestellt, die ihrerseits beispielsweise analog der Umsetzung gemäß Verfahren 3 erhalten werden können. Der weitere Syntheseweg besteht in der Umsetzung der entsprechenden Nitrilen mit HCl über die Stufe der Imidchloride bzw. der direkten Umsetzung mit z. B. C1-C6-Alkoholen bzw. Benzylalkohol in Gegenwart einer Säure wie HCl. Auch die Umsetzung der Nitrile mit H2S in Lösungsmitteln wie Pyridin oder Dimethylformamid in Gegenwart einer Base wie Triethylamin und anschließende Alkylierung bzw. Benzylierung führen zu Verbindungen der Formel V. Ausgehend von Carbonsäureamiden, die im übrigen den Verbindungen der Formel V entsprechen, gelangt man auch durch Umsetzung mit einem Trialkyloxoniumsalz wie Triethyloxoniumtetrafluoroborat in einem Lösungsmittel wie Dichlormethan, Tetrahydrofuran oder Dioxan bei Temperaturen zwischen 0 und 50°C, vorzugsweise bei Raumtemperatur zu Verbindungen der Formel V.(wherein A, B, Het and R 4 have the above meaning) prepared, which in turn can be obtained, for example, analogously to the reaction according to method 3. The further synthetic route consists in the implementation of the corresponding nitriles with HCl over the stage of the imide chlorides or the direct reaction with z. B. C 1 -C 6 alcohols or benzyl alcohol in the presence of an acid such as HCl. The reaction of the nitriles with H 2 S in solvents such as pyridine or dimethylformamide in the presence of a base such as triethylamine and subsequent alkylation or benzylation lead to compounds of the formula V. Starting from carboxylic acid amides, which otherwise correspond to the compounds of formula V, one arrives also by reaction with a Trialkyloxoniumsalz such as Triethyloxoniumtetrafluoroborat in a solvent such as dichloromethane, tetrahydrofuran or dioxane at temperatures between 0 and 50 ° C, preferably at room temperature to compounds of the formula V.

Aus den Nitrilen XI lassen sich durch Umsetzung mit Hydroxylamin in Alkoholen, z. B. Methanol, Ethanol, Propanol, Isopropanol, die entsprechenden Amidoxime der Formel VI erhalten.From the nitriles XI can be by reaction with Hydroxylamine in alcohols, eg. Methanol, ethanol, Propanol, isopropanol, the corresponding amidoximes of Obtained formula VI.

Auch die Ausgangsstoffe der Formeln VII, VIII, IX und X sind nach konventionellen Verfahren herstellbar. Also, the starting materials of the formulas VII, VIII, IX and X. can be produced by conventional methods.  

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 IBD (inflammatory bowel diseases), allergische Rhinitis; ARDS (adult respiratory distress syndron), Asthma, Colitis ulcerosa, Psoriasis, ferner zur Behandlung einer durch nichtsteroidale Antiphlogistika (NSAID) induzierten Gastropathie. Die neuen Verbindungen können auch in Kombination mit anderen Wirkstoffen angewendet werden, z. B. mit Antiallergika, Sekretolytika, β2-Adrenergika, 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 above all in those diseases in which inflammatory and / or allergic processes play a role, for example IBD (inflammatory bowel diseases), allergic rhinitis; Adult respiratory distress syndrome (ARDS), asthma, ulcerative colitis, psoriasis, and treatment of non-steroidal anti-inflammatory drug (NSAID) induced gastropathy. The new compounds may also be used in combination with other agents, e.g. As antiallergic drugs, secretolytics, β 2 -adrenergics, 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.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.

Die neuen Verbindungen können topisch, oral, transdermal, parenteral oder durch Inhalation verabreicht werden. Die Verbindungen liegen hierbei als aktive Bestandteile in üblichen Darreichungsformen vor, z. B. in Zusammensetzungen, die im wesentlichen aus einem inerten pharmazeutischen Träger und einer effektiven Dosis des Wirkstoffes bestehen, wie z. B. Tabletten, Drag´es, Kapseln, Oblaten, Pulver, Lösungen, Suspensionen, Inhalationsaerosole, Salben, Emulsionen, Sirupe, Suppositorien usw. Eine wirksame Dosis der erfindungsgemäßen Verbindungen liegt bei oraler Anwendung zwischen 20 und 200 mg/Dosis. Für die Inhalation sollen Pulver oder Lösungen, die 0,5% bis 5 % Wirkstoff enthalten, eingesetzt werden, wobei die Dosis jeweils ca. 2 bis 20 mg Wirkstoff enthält.The new compounds can be topically, orally, transdermally, parenterally or by inhalation be administered. The compounds are here as active ingredients in conventional dosage forms, z. B. in compositions consisting essentially of an inert pharmaceutical carrier and a consist effective dose of the drug, such as. B. Tablets, Drag'es, Capsules, Wafers, Powders, Solutions, Suspensions, inhalation aerosols, ointments, emulsions, Syrups, suppositories, etc. An effective dose of  Compounds of the invention is oral Application between 20 and 200 mg / dose. For the Inhalation should be powders or solutions containing 0.5% to 5 % Active ingredient, are used, the Each dose contains about 2 to 20 mg of active ingredient.

Die neuen Verbindungen sind u. a. mit Antiallergika, Sekretolytika, β2-Adrenergika, inhalativ anwendbaren Steroiden oder Antihistaminika kombinierbar.The new compounds can be combined, inter alia, with antiallergics, secretolytics, β 2 -adrenergics, inhaled steroids or antihistamines.

Die nachstehenden Beispiele zeigen einige Möglichkeiten für die Formulierung der Darreichungsformen. The examples below show some possibilities for the formulation of the dosage forms.  

Formulierungsbeispieleformulation Examples 1. Tabletten1. tablets

Zusammensetzung:Composition: Wirkstoff gemäß der ErfindungActive ingredient according to the invention 20 Gew.-Teile20 parts by weight Stearinsäurestearic acid 6 Gew.-Teile6 parts by weight Traubenzuckerglucose 474 Gew.-Teile474 parts by weight

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.

2. Suppositorien2. suppositories

Zusammensetzung:Composition: Wirkstoff gemäß der ErfindungActive ingredient according to the invention 100 Gew.-Teile100 parts by weight Laktose, gepulvertLactose, powdered 45 Gew.-Teile45 parts by weight Kakao-ButterCocoa butter 1555 Gew.-Teile1555 parts by weight

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.

3. Inhalationspulver3. inhalable powder

Mikronisiertes Wirkstoffpulver (Verbindung der Formel I; 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 I; 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 erfindungsgemäßen Verbindungen wurden u. a. auf ihre Wirkung in den nachstehenden Testen untersucht.The compounds of the invention were u. a. on their Effect tested in the following tests.

a) LTB4-Rezeptorverbindungstesta) LTB 4 receptor compound test

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 2 h 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).

b) Aggregation von neutrophilen Granulozyten des Meerschweinchensb) aggregation of neutrophilic granulocytes of the guinea pig

Induziert 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.Induced 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.

c) Leukotrien-B4-induzierte Neutrophilen- Akkumulation am Mäuseohrc) Leukotriene B 4 -induced neutrophil accumulation on the mouse ear

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.

Die Ki-Werte aus Test a) liegen für die erfindungsgemäßen Verbindungen zwischen etwa 1 und 20 nmol/l, vorzugsweise unter 10 nmol/l. Hervorzuheben ist die günstige orale Wirkung der neuen Verbindungen.The K i values from test a) are between about 1 and 20 nmol / l, preferably less than 10 nmol / l, for the compounds according to the invention. To emphasize is the favorable oral effect of the new connections.

Die nachstehenden Beispiele verdeutlichen die Herstellmöglichkeiten der erfindungsgemäßen Verbindungen. In den Tabellen bedeutet BS Base, MS Methansulfonat. The following examples illustrate the Production possibilities of the invention Links. In the tables, BS Base means MS Methanesulfonate.  

Verfahren 1process 1 Beispiel 1Example 1

9,6 g 4-[2-(2-Benzthiazolyloxy)-ethoxy]-benzonitril werden in 100 ml absolutem Dichlormethan und 100 ml absolutem Ethanol gelöst. Bei ca. -15°C wird 4 Stunden HCl-Gas eingeleitet. Man läßt über Nacht bei Raumtemperatur stehen, fügt ca. 800 ml Äther zu und dekantiert das Lösungsmittel von den angefallenen Kristallen ab. Der Rückstand wird in 50 ml Ethanol gelöst und nach Zugabe von 50 ml mit Ammoniak gesättigtem Ethanol 1,5 Stunden unter Rückfluß gekocht. Das Lösungsmittel wird im Vakuum abdestilliert und der Rückstand aus Ethanol/Diethylether umkristallisiert. Man erhält 2.5 g 4-[2-(2-Benzthiazolyloxy)-ethoxy]- benzamidin Hydrochlorid mit einem Schmelzpunkt von 205-207°C. 9.6 g of 4- [2- (2-benzthiazolyloxy) -ethoxy] -benzonitrile are dissolved in 100 ml of absolute dichloromethane and 100 ml dissolved absolute ethanol. At about -15 ° C is 4 hours HCl gas introduced. One lets in overnight Room temperature, adds about 800 ml of ether and decant the solvent from the incurred Crystals off. The residue is dissolved in 50 ml of ethanol dissolved and after adding 50 ml with ammonia saturated ethanol for 1.5 hours under reflux. The solvent is distilled off in vacuo and the Residue recrystallized from ethanol / diethyl ether. 2.5 g of 4- [2- (2-benzthiazolyloxy) -ethoxy] are obtained. benzamidine hydrochloride having a melting point of 205-207 ° C.  

Verfahren 2process 2 Beispiel 2example 2

3,85 g 4-[5-(5-Methyl-2-benzoxyzolyl)-mercapto]- pentyloxy-benzamidoxim Methansulfonat werden in 200 ml Methanol gelöst. Nach Zugabe von Raney-Nickel wird bei 50°C unter Normalbedingungen so lange hydriert, bis die berechnete Menge Wasserstoff aufgenommen wurde (ca. 5 Stunden). Es wird vom Katalysator abgesaugt, das Lösungsmittel abdestilliert und der Rückstand aus Isopropylalkohol umkristallisiert. Das Methansulfonat des 4-[5-(5-Methyl-2-benzoxyzolyl)-mercapto]-pentyloxy- benzamidin schmilzt bei 129-130°C. 3.85 g of 4- [5- (5-methyl-2-benzoxy-zolyl) -mercapto] - pentyloxy-benzamidoxime methanesulfonate are dissolved in 200 ml Dissolved methanol. After adding Raney nickel is added at 50 ° C under normal conditions until the hydrogenated calculated amount of hydrogen was recorded (about 5 Hours). It is sucked off by the catalyst, the Solvent distilled off and the residue Isopropyl alcohol recrystallized. The methanesulfonate of 4- [5- (5-methyl-2-benzoxyzolyl) -mercapto] -pentyloxy- Benzamidine melts at 129-130 ° C.  

Verfahren 3process 3 Beispiel 3example 3

1,6 g 2-Mercapto-5-phenyl-1,2,4-oxadiazol werden in 40 ml absolutem Dimethylformamid gelöst. Nach Zugabe von 270 mg Natriumhydrid-Dispersion (80%ig) wird zunächst eine halbe Stunde bei Raumtemperatur gerührt. Man erwärmt dann auf 50°C und tropft langsam eine Lösung 2 g 4-Bromethoxy-benzamidin, gelöst in 40 ml absolutem Dimethylformamid zu. Man läßt noch 2 Stunden bei 50°C nachreagieren, kühlt ab und gießt auf Eiswasser. Man saugt ab, suspendiert in Ethanol und gibt etherische Salzsäure bis zur sauren Reaktion zu. Die zwischenzeitlich gelöste Verbindung fällt als Hydrochlorid aus. Man saugt ab und kristallisiert aus Wasser um. Nach dem Trocknen erhält man 0,6 g 2-[2-(4-amidino-phenoxy)-ethylmercapto]-5-phenyl-1,3,4- oxadiazol als Hydrochlorid (Fp: 237-8°C).1.6 g of 2-mercapto-5-phenyl-1,2,4-oxadiazole are dissolved in Dissolved 40 ml of absolute dimethylformamide. After adding of 270 mg sodium hydride dispersion (80%) initially stirred for half an hour at room temperature. It is then heated to 50 ° C and slowly dripping one Solution 2 g of 4-bromoethoxy-benzamidine dissolved in 40 ml absolute dimethylformamide too. It is left for 2 hours After-reacting at 50 ° C, cooled and poured Ice water. It sucks, suspended in ethanol and Add ethereal hydrochloric acid to the acidic reaction. The temporarily dissolved compound falls as Hydrochloride. It sucks and crystallizes out Water around. After drying, 0.6 g 2- [2- (4-amidino-phenoxy) -ethylmercapto] -5-phenyl-1,3,4- oxadiazole as hydrochloride (mp: 237-8 ° C).

Analog diesen Beispielen können folgende Verbindungen hergestellt werden: Analogous to these examples, the following compounds getting produced:  

Tabelle I Table I

Tabelle II Table II

Tabelle III Table III

Tabelle IV Table IV

Tabelle V Table V

Tabelle VI Table VI

Tabelle VII Table VII

Tabelle VIII Table VIII

Tabelle IX Table IX

Claims (11)

1. Amidinderivate der Formel in der
A für eine der GruppenX₁-A₁-X₂ (II)X₂-A₁-X₁ (III) wobei
A1 eine geradkettige oder verzweigte zweibindige aliphatische C2-C6-Gruppe bedeutet, die auch eine Doppel- oder Dreifachbindung enthalten kann, oder eine der Gruppen bedeutet, Het für einen Heterocyclus oder ein heterocyclisches System aus zwei oder drei kondensierten Ringen, das ein bis drei Substituenten enthalten kann,
R4 für F, Cl, Br, J, NH2, NH-(C1-C4-Alkyl), N(C1-C4-Alkyl)2, OH, C1-C4-Alkoxy, C1-C4-Alkyl,
R11, R12, die gleich oder verschieden sein können,
für H, OH, F, Cl, Br, J, CF3, C1-C4-Alkyl oder -Alkoxy,
stehen,
(wobei chirale Verbindungen in Form von Racematen, enantiomerenreiner bzw. angereicherter Form vorliegen können), jeweils als Base oder als Salze mit anorganischen oder organischen Säuren.1. Amidine derivatives of the formula in the
A is one of the groups X₁-A₁-X₂ (II) X₂-A₁-X₁ (III) in which
A 1 represents a straight-chain or branched divalent aliphatic C 2 -C 6 group which may also contain a double or triple bond, or one of the groups means Het for a heterocycle or a heterocyclic system of two or three fused rings, which may contain one to three substituents,
R 4 is F, Cl, Br, J, NH 2 , NH- (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 , OH, C 1 -C 4 -alkoxy, C 1 C 4 alkyl,
R 11 , R 12 , which may be the same or different,
for H, OH, F, Cl, Br, J, CF 3 , C 1 -C 4 -alkyl or -alkoxy,
stand,
(where chiral compounds may be in the form of racemates, enantiomerically pure or enriched form), in each case as a base or as salts with inorganic or organic acids. 2. Verbindungen nach Anspruch 1, worin Het für die Gruppen (a) bis (z): und
R1 und R2, die gleich oder verschieden sein können, für CF3, Halogen, R5, OR5, COR6, SR6, SOR6, SO2R6, SO2NR5R7, C(OH)R5R7 oder gemeinsam auch für die mit benachbarten C-Atomen des Benzolrings verknüpften zweibindigen Gruppen -CR8=CR9-CH=CH-, -CH=CR8-C R9=CH-, -CR8=CH-CR9=CH-, -O-CHR10-CH2-, -O-CH2-O-, -O-CH2-CH2-O-, -(CH2)3-4-, -NH-CO-O-, -NH-CO-CH2-O-, -CO-CH2-O- oder -CO-CH2CH2-O- stehen, ,wobei diese Gruppen ihrerseits auch durch C1-C4-Alkyl substituiert sein können,
R3 für Halogen, OH, CF3, R5, OR6, COR6, CONR5R7, CH2OH, CH2-O-(C1-C4-Alkyl), SR6, SOR6, SO2R6, SO2NR5R7, NH-CO-(C1-C4-Alkyl), NH-SO2-(C1-C4-Alkyl), NR5R7 oder C(OH)R5R7 steht (wobei, falls R3 gleich R5 ist, R5 nur dann H sein kann, wenn mindestens einer der Substituenten R1 und R2 nicht H bedeutet), für einen heterocyclischen Fünfring mit 1 bis 3 Heteroatomen und der Formel (worin D, E und G, die gleich oder verschieden sein können, CH, N, C-(C1-C4-Alkyl) oder C-Phenyl bedeuten und L O oder S ist),
R4 für Halogen, NH2, NH-(C1-C4-Alkyl), N(C1-C4-Alkyl)2, OH, C1-C4-Alkoxy oder -Alkyl,
R5 für H, C1-C12, Alkyl, Phenyl, gegebenenfalls durch Halogen, C1-C4-Alkyl, C1-C4-Alkoxy oder C2-C5-Acyl substituiertes Phenyl oder Phenyl-(C1-C4-Alkyl),
R6 für C1-C12-Alkyl, Phenyl oder gegebenenfalls durch Halogen, C1-C4-Alkyl, C1-C4-Alkoxy oder C2-C5-Acyl substituiertes Phenyl,
R7 für H oder C1-C12-Alkyl,
R8, R9 (die gleich oder verschieden sein können) für H, OH, C1-C4-Alkyl, C1-C4-Alkoxy oder C2-C5-Acyl,
R10 für H oder C1-C4-Alkyl,
R11, R12, die gleich oder verschieden sein können, für H, OH, Halogen, CF3, C1-C4-Alkyl oder C1-C4 -Alkoxy,
R13, R14, die gleich oder verschieden sein können, für H, C1-C4-Alkyl, C1-C4-Alkoxy, Phenyl, Naphthyl, wobei diese Ringsysteme ein- oder mehrfach durch gleiche oder verschiedene Reste aus der Gruppe Fluor, Chlor, Brom, C1-C4-Alkyl, C1-C4-Alkoxy oder Pseudohalogene wie CN, CF3 substituiert sein können, oder für Pyridyl.2. Compounds according to claim 1, wherein Het for the groups (a) to (z): and
R 1 and R 2 , which can be identical or different, represent CF 3 , halogen, R 5 , OR 5 , COR 6 , SR 6 , SOR 6 , SO 2 R 6 , SO 2 NR 5 R 7 , C (OH) R 5 R 7 or together also for the divalent groups linked to adjacent C atoms of the benzene ring -CR 8 = CR 9 -CH = CH-, -CH = CR 8 -CR 9 = CH-, -CR 8 = CH-CR 9 = CH-, -O-CHR 10 -CH 2 -, -O-CH 2 -O-, -O-CH 2 -CH 2 -O-, - (CH 2 ) 3-4 -, -NH-CO -O-, -NH-CO-CH 2 -O-, -CO-CH 2 -O- or -CO-CH 2 CH 2 -O- stand, wherein these groups in turn by C 1 -C 4 alkyl can be substituted
R 3 is halogen, OH, CF 3 , R 5 , OR 6 , COR 6 , CONR 5 R 7 , CH 2 OH, CH 2 -O- (C 1 -C 4 alkyl), SR 6 , SOR 6 , SO 2 R 6 , SO 2 NR 5 R 7 , NH-CO- (C 1 -C 4 -alkyl), NH-SO 2 - (C 1 -C 4 -alkyl), NR 5 R 7 or C (OH) R 5 R 7 (where R 3 is R 5 , R 5 may be H only if at least one of R 1 and R 2 is not H), a heterocyclic five-membered ring having 1 to 3 heteroatoms and the formula (wherein D, E and G, which may be the same or different, are CH, N, C- (C 1 -C 4 -alkyl) or C-phenyl and is LO or S),
R 4 is halogen, NH 2 , NH- (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 , OH, C 1 -C 4 -alkoxy or -alkyl,
R 5 is (H, C 1 -C 12 alkyl, phenyl, optionally substituted by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 2 -C 5 acyl-substituted phenyl or phenyl C 1 C 4 alkyl),
R 6 represents C 1 -C 12 -alkyl, phenyl or phenyl optionally substituted by halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or C 2 -C 5 -acyl,
R 7 is H or C 1 -C 12 -alkyl,
R 8 , R 9 (which can be identical or different) represent H, OH, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or C 2 -C 5 -acyl,
R 10 is H or C 1 -C 4 -alkyl,
R 11 , R 12 , which can be identical or different, are H, OH, halogen, CF 3 , C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy,
R 13 , R 14 , which may be identical or different, are H, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, phenyl, naphthyl, where these ring systems are mono- or polysubstituted by identical or different radicals from the group Group fluorine, chlorine, bromine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or pseudohalogens such as CN, CF 3 may be substituted, or pyridyl. 3. Verbindungen nach Anspruch 1 oder 2 mit der Formel worin A′1, X′1, X′2 und Het′ folgendes bedeuten:
A′1: (CH2)2-6, CH2-C6H4-CH2, Z oder E CH2-CH=CH-CH2, CH2-C≡C-CH2;
X′1: O, S;
X′2: O, S;
Het′: eine Gruppe der obigen Formeln a, b, e, f, g, k, n, wobei R1, R2, R3, die gleich oder verschieden sein können, H, R5, OR5 oder COR5 bedeuten und R1 und R2 gemeinsam auch einen ankondensierten Ring bedeuten können.3. Compounds according to claim 1 or 2 with the formula in which A ' 1 , X' 1 , X ' 2 and Het' mean the following:
A ' 1 : (CH 2 ) 2-6 , CH 2 -C 6 H 4 -CH 2 , Z or E CH 2 -CH = CH-CH 2 , CH 2 -C≡C-CH 2 ;
X ' 1 : O, S;
X ' 2 : O, S;
Het ': a group of the above formulas a, b, e, f, g, k, n, where R 1 , R 2 , R 3 , which may be identical or different, denote H, R 5 , OR 5 or COR 5 and R 1 and R 2 together may also signify a fused ring. 4. Die Verbindungen der Formel worin Rx bedeutet, und ihre Säureadditionssalze.4. The compounds of the formula where R x means, and their acid addition salts. 5. Arzneimittel, gekennzeichnet durch einen Gehalt an einer Verbindung nach Anspruch 1 bis 4.5. Medicines characterized by a content A compound according to claims 1 to 4. 6. Verwendung von Verbindungen nach Anspruch 1 bis 4 bei der Herstellung von Arzneimitteln für die Behandlung von Krankheiten, bei denen entzündliche und/oder allergische Vorgänge eine Rolle spielen, insbesondere Asthma, Colitis ulcerosa, Psoriasis und zur Behandlung einer durch nichtsteroidale Antiphlogistika induzierten Gastropathie.6. Use of compounds according to claim 1 to 4 in the manufacture of medicines for the Treatment of diseases in which inflammatory and / or allergic processes play a role, especially asthma, ulcerative colitis, psoriasis and to treat one by non-steroidal Antiphlogistics induced gastropathy. 7. Verwendung einer wirksamen Dosis einer Verbindung nach Anspruch 1-4 zur Behandlung von Krankheiten, bei denen LTB4-antagonistische Verbindungen eingesetzt werden können.7. Use of an effective dose of a compound according to claims 1-4 for the treatment of diseases in which LTB 4 -antagonistische compounds can be used. 8. Verwendung einer wirksamen Dosis einer Verbindung nach Anspruch 1 bis 4 für die Behandlung von Krankheiten, bei denen entzündliche und/oder allergische Vorgänge eine Rolle spielen, insbesondere Asthma, Colitis ulcerosa, Psoriasis, sowie zur Behandlung einer durch nichtsteroidale Antiphlogistika induzierten Gastropathie. 8. Use of an effective dose of a compound according to claim 1 to 4 for the treatment of Diseases in which inflammatory and / or allergic processes play a role, especially asthma, ulcerative colitis, psoriasis, as well as for treatment of non-steroidal Antiphlogistics induced gastropathy.   9. Verfahren zur Herstellung der Verbindungen nach Anspruch 1 bis 4 in an sich bekannter Weise, dadurch gekennzeichnet, daß man
  • a) eine Verbindung der Formel (worin Het, R4, A und B die obige Bedeutung haben und R bevorzugt für einen C1-C4-Alkylrest oder für Benzyl steht) mit Ammoniak in einem inerten Lösungsmittel umsetzt
9. A process for the preparation of the compounds according to claim 1 to 4 in a conventional manner, characterized in that
  • a) a compound of the formula (wherein Het, R 4 , A and B have the above meaning and R is preferably a C 1 -C 4 alkyl radical or benzyl) with ammonia in an inert solvent
oder daß man
  • b) ein Amidoxim der Formel (worin Het, R4 A und B,die obige Bedeutung haben) mit Wasserstoff in Gegenwart eines Katalysators reduziert
or that one
  • b) an amidoxime of the formula (wherein Het, R 4 A and B, as defined above) with hydrogen in the presence of a catalyst reduced
oder daß man
  • c) Verbindungen der Formel VII mit Verbindungen der Formel VIII bzw. Verbindungen der Formel IX mit Verbindungen der Formel X umsetzt.
or that one
  • c) reacting compounds of the formula VII with compounds of the formula VIII or compounds of the formula IX with compounds of the formula X.
DE4309285A 1993-03-23 1993-03-23 Heterocyclic-containing amidine derivatives, their preparation and use Withdrawn DE4309285A1 (en)

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SK1174-95A SK117495A3 (en) 1993-03-23 1994-03-18 Heterocycle containing amidine derivatives, their preparation and use
EP94911191A EP0690849A1 (en) 1993-03-23 1994-03-18 Heterocycle-containing amidine derivatives, their preparation and use
CA002158994A CA2158994A1 (en) 1993-03-23 1994-03-18 Heterocycle-containing amidine derivatives, their preparation and use
CZ952466A CZ246695A3 (en) 1993-03-23 1994-03-18 Amidine derivatives, their use, process for preparing such derivatives and pharmaceutical composition containing thereof
PL94310806A PL310806A1 (en) 1993-03-23 1994-03-18 Amidine derivatives containing heterocyclic groups, their production and application of such derivatives
PCT/EP1994/000856 WO1994021616A1 (en) 1993-03-23 1994-03-18 Heterocycle-containing amidine derivatives, their preparation and use
HU9502778A HUT73968A (en) 1993-03-23 1994-03-18 Heterocycle-containing amidine derivatives, process for preparing them and pharmaceutical compositions containing them
JP6520657A JPH08508467A (en) 1993-03-23 1994-03-18 Amidine derivative containing heterocyclic group, method for producing the same and use thereof
CN94192207A CN1124486A (en) 1993-03-23 1994-03-18 Heterocycle-containing amidine derivatives, their preparation and use
ZA941993A ZA941993B (en) 1993-03-23 1994-03-22 Amidine derivatives containing heterocyclic groups the preparation and use thereof
IL10907394A IL109073A0 (en) 1993-03-23 1994-03-22 Amidine derivatives, their preparation and pharmaceutical compositions containing them
KR1019950704014A KR960701026A (en) 1993-03-23 1995-09-21 Heterocycle-containing amidine derivatives, their preparation and use
LVP-95-291A LV11465B (en) 1993-03-23 1995-09-22 Heterocycle-containing amidine derivatives, their preparation and use
FI954491A FI954491A (en) 1993-03-23 1995-09-22 Heterocycles containing imidine derivatives, their preparation and use
NO953763A NO953763L (en) 1993-03-23 1995-09-22 Heterocycle-containing amidine derivatives, their preparation and use
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997021670A1 (en) * 1995-12-13 1997-06-19 Boehringer Ingelheim Kg New phenylamidine derivatives, a process for preparing the same and their use as medicaments
EP1773333A1 (en) * 2004-07-05 2007-04-18 Dong Wha Pharmaceutical Industrial Co. Ltd. Composition for the prevention and treatment of allergic inflammatory disease
US8030305B2 (en) 2005-12-21 2011-10-04 Janssen Pharmaceutica N.V. Triazolopyridazines as kinase modulators
WO2023144450A1 (en) * 2022-01-28 2023-08-03 Oulun Yliopisto Compounds for use in the treatment of cancer and inflammatory conditions

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ID24720A (en) 1997-12-12 2000-08-03 Novartis Ag COMPOUNDED AMIDINO COMPOUNDS IN TREATMENT OF CHRONIC LUNGS DISEASE
KR20060017929A (en) * 2004-08-04 2006-02-28 동화약품공업주식회사 Novel benzamidine derivatives substituted by thiazole derivatives, a process for the preparation thereof and pharmaceutical composition comprising the same
US7683060B2 (en) 2006-08-07 2010-03-23 Incyte Corporation Triazolotriazines as kinase inhibitors
WO2008064157A1 (en) 2006-11-22 2008-05-29 Incyte Corporation Imidazotriazines and imidazopyrimidines as kinase inhibitors
EP3287449A3 (en) 2008-05-21 2018-05-30 Incyte Holdings Corporation Salts of 2-fluoro-n-methyl-4-[7-(quinolin-6-yl-methyl)- imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same
EP2531509B1 (en) 2010-02-03 2016-10-05 Incyte Holdings Corporation Imidazo[1,2-b][1,2,4]triazines as c-met inhibitors
KR101216274B1 (en) * 2011-06-17 2012-12-28 이화여자대학교 산학협력단 New compounds for alleviation, prevention or treatment of osteoporosis, the preparation thereof and pharmaceutical composition comprising the same
EP2758403B1 (en) 2011-09-21 2016-04-27 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents
CN102993109A (en) * 2012-12-03 2013-03-27 浙江工业大学 Preparation method of amidine compound
US11919872B1 (en) 2023-10-11 2024-03-05 King Faisal University N′-(2-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthio)acetoxy)benzimidamide as an antimicrobial compound
US11897850B1 (en) 2023-10-11 2024-02-13 King Faisal University N′-(2-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthio)acetoxy)-4-methoxybenzimidamide as an antimicrobial compound
US11912675B1 (en) 2023-10-11 2024-02-27 King Faisal University N'-(2-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthio)acetoxy)-3,4-dimethoxybenzimidamide as an antimicrobial compound
US11891366B1 (en) 2023-10-12 2024-02-06 King Faisal University 4-methoxy-n′-(2-(5-phenyl-1,3,4-oxadiazol-2-ylthio)acetoxy)benzimidamide as an antimicrobial compound
US11932632B1 (en) 2023-10-13 2024-03-19 King Faisal University N'-(2-(5-phenyl-1,3,4-oxadiazol-2-ylthio)acetoxy)benzo[d][1,3]dioxole-5 carboximidamide as an antimicrobial compound
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Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB868552A (en) * 1957-12-03 1961-05-17 Wellcome Found Improvements in or relating to novel amidines and the preparation thereof
JPS60130561A (en) * 1983-12-16 1985-07-12 Torii Yakuhin Kk Amidine derivative and cardiotonic agent containing the same
US4889871A (en) * 1987-05-29 1989-12-26 G. D. Searle & Co. Alkoxy-substituted dihydrobenzopyran-2-carboxylate derivatives
EP0518818A3 (en) * 1991-06-11 1993-04-28 Ciba-Geigy Ag Arylethers, their manufacture and use as medicament
ATE125791T1 (en) * 1991-06-11 1995-08-15 Ciba Geigy Ag AMIDINO COMPOUNDS, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCTS.
WO1993010091A2 (en) * 1991-11-14 1993-05-27 Glaxo Group Limited Piperidine acetic acid derivatives as inhibitors of fibrinogen-dependent blood platelet aggregation
AU673343B2 (en) * 1992-02-05 1996-11-07 Boehringer Ingelheim International Gmbh Novel amidine derivatives, their preparation and their use as mediaments with LTB4 antagonistic effect

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997021670A1 (en) * 1995-12-13 1997-06-19 Boehringer Ingelheim Kg New phenylamidine derivatives, a process for preparing the same and their use as medicaments
US6127423A (en) * 1995-12-13 2000-10-03 Boehringer Ingelheim Kg Phenylamidine derivatives, a process for preparing the same and their use as medicaments
MY120683A (en) * 1995-12-13 2005-11-30 Boehringer Ingelheim Kg New phenylamidine derivatives, processes for their preparation and their use as pharmaceuticals.
EP1773333A1 (en) * 2004-07-05 2007-04-18 Dong Wha Pharmaceutical Industrial Co. Ltd. Composition for the prevention and treatment of allergic inflammatory disease
EP1773333A4 (en) * 2004-07-05 2010-04-21 Dong Wha Pharm Co Ltd Composition for the prevention and treatment of allergic inflammatory disease
US8030305B2 (en) 2005-12-21 2011-10-04 Janssen Pharmaceutica N.V. Triazolopyridazines as kinase modulators
US8173654B2 (en) 2005-12-21 2012-05-08 Janssen Pharmaceutica N.V. Triazolopyridazine compounds
WO2023144450A1 (en) * 2022-01-28 2023-08-03 Oulun Yliopisto Compounds for use in the treatment of cancer and inflammatory conditions

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