DE4244241A1 - Amidine derivs. with LTB4 antagonistic properties - Google Patents

Amidine derivs. with LTB4 antagonistic properties

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Publication number
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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DE
Germany
Prior art keywords
alkyl
formula
compounds
alkoxy
halogen
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.)
Ceased
Application number
DE4244241A
Other languages
German (de)
Inventor
Ralf Anderskewitz
Kurt Schromm
Ernst-Otto Renth
Frank Himmelsbach
Franz Birke
Armin Fuegner
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
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Filing date
Publication date
Application filed by Boehringer Ingelheim GmbH filed Critical Boehringer Ingelheim GmbH
Priority to DE4244241A priority Critical patent/DE4244241A1/en
Priority to SK914-94A priority patent/SK281016B6/en
Priority to PT98121305T priority patent/PT902013E/en
Priority to EP93902195A priority patent/EP0625138B1/en
Priority to EP98121305A priority patent/EP0902013B1/en
Priority to RU94041836A priority patent/RU2124002C1/en
Priority to HU9402291A priority patent/HU216191B/en
Priority to JP51370193A priority patent/JP3487851B2/en
Priority to PCT/EP1993/000070 priority patent/WO1993016036A1/en
Priority to AT93902195T priority patent/ATE180770T1/en
Priority to NZ246593A priority patent/NZ246593A/en
Priority to DK98121305T priority patent/DK0902013T3/en
Priority to KR1019940702669A priority patent/KR0163222B1/en
Priority to PL93304713A priority patent/PL173789B1/en
Priority to CA002427890A priority patent/CA2427890A1/en
Priority to ES93902195T priority patent/ES2132216T3/en
Priority to DE59309630T priority patent/DE59309630D1/en
Priority to UA94095773A priority patent/UA43318C2/en
Priority to AT98121305T priority patent/ATE210634T1/en
Priority to CZ19941886A priority patent/CZ287209B6/en
Priority to PL93316750A priority patent/PL173781B1/en
Priority to ES98121305T priority patent/ES2165122T3/en
Priority to CA002129526A priority patent/CA2129526A1/en
Priority to DK93902195T priority patent/DK0625138T3/en
Priority to AU33497/93A priority patent/AU673343B2/en
Priority to SG1996008431A priority patent/SG44837A1/en
Priority to DE59310252T priority patent/DE59310252D1/en
Priority to TW082100562A priority patent/TW232005B/zh
Priority to IL104589A priority patent/IL104589A0/en
Priority to YU6393A priority patent/YU49038B/en
Priority to HRP4244241.9A priority patent/HRP930102B1/en
Priority to MX9300630A priority patent/MX9300630A/en
Priority to SI9300066A priority patent/SI9300066B/en
Publication of DE4244241A1 publication Critical patent/DE4244241A1/en
Priority to FI943618A priority patent/FI943618A/en
Priority to NO942903A priority patent/NO301540B1/en
Priority to US08/460,961 priority patent/US6037377A/en
Priority to CZ19971203A priority patent/CZ287173B6/en
Priority to GR990401541T priority patent/GR3030468T3/en
Priority to US09/484,073 priority patent/US6489365B1/en
Priority to FI20002501A priority patent/FI20002501A/en
Priority to JP2002073593A priority patent/JP2002322143A/en
Priority to US10/252,976 priority patent/US20030130232A1/en
Ceased legal-status Critical Current

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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

Amidine derivs. of formula (I), in the form of their racemates, enantiomer pure or enriched forms, diastereomer pairs, cis- and trans-isomers, free bases or salts (pref. with physiologically acceptable acids) are new. In (I), R1 and R2 are each CF3, halogen, R5, OR5, COR6, SR6, SOR6, SO2R6, SO2NR5R7, C(OH)R5R7, or R1 and R2 connect neighbouring C atoms on the benzene ring to which they are attached with -CR8=CR9CH=CH-, -CH=CR8CR9=CH-, -CR8=CHCR9=CH-, -OCHR10CH2-, -OCH2O-, -OCH2CH2O-, -(CH2)3-4-, -NHCOO-, -NHCOCH2O-, -COCH2O- or -COCH2CH2O-, each of these gps. being opt. substd. with 1-4C alkyl; R3 is H, OH, CF3, R5, OR6, COR6, CONR5R7, CH2OH, CH2O(1-4C alkyl), SR6, SOR6, SO2R6, SO2NR5R7, NHCO(1-4C alkyl), NHSO2(1-4C alkyl), NR5R7 or C(OH)R5R7 or a heterocyclic 5-ring contg. 1-3 heteroatoms and of formulae (a), (b) or (c); provided that if R3 is R5, R5 can only be H if at least one of R1 and R2 is not H; D, E and G are each CH, N, C(1-4C alkyl) or C-Ph; L is O or S; R4 is halogen, NH2, NH(1-4C alkyl), N(1-4C alkyl)2, OH, 1-4C alkoxy; R5 is H, 1-12C alkyl, phenyl(1-4C)alkyl or Ph (opt. substd. with halogen, 1-4C alkyl, 1-4C alkoxy or 2-5C acyl); R6 is 1-12C alkyl, Ph (opt. substd. with halogen, 1-4C alkyl, 1-4C alkoxy or 2-5C acyl); R7 is H or 1-12C alkyl; R8 and R9 are each H, OH, 1-4C alkyl, 1-4C alkoxy or 2-5C acyl; R10 is H or 1-4C alkyl; R11 and R12 are each H, OH, halogen, CF3, 1-4C alkyl or 1-4C alkoxy; A is (d), (e), X1A1X2, X2A2X3, X4A2X2, (CH2)1-2NHCO(CH2)1-3X2, -CH=CHA2X2; B is CH=CH, CH=N, S or (f); A1 is 2-4C alkylene, cis- or trans-CH2CH=CHCH2, CH2CCCH2, etc.; A2 is 1-5C alkylene; X1 is O, NH, S, SO, SO2, CO, CH2 or a gp. of formula (d); X2 is O, NH, S or a gp. of formula (e); X3 is NHCO, CONH, SO2NH or a gp. of formula (d); X4 is NHCO, CONH, NHSO2, SO2NH or NHCONH.

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.  

Formulierungsbeispieleformulation Examples 1. Tabletten1. tablets

Zusammensetzungcomposition 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

Zusammensetzungcomposition 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. Inhalation powder

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.  

Ergebnisse Results

a) U937 - Rezeptorverbindunqstest/LTB4 a) U937 receptor compound test / LTB 4

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).

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

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.

c) Leukotrien-B4-indizierte 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.

Beispiel 1example 1

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.  

Verbindungen der Formel I Compounds of the formula I

Claims (11)

1. Verbindungen der Formel in der
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. 2. Verbindungen der Formel I, worin a = 0 oder 1/b = 1 oder a = 0/b = 2 ist, als freie Basen oder als Säureadditionssalze.2. Compounds of the formula I in which a = 0 or 1 / b = 1 or a = 0 / b = 2, as free bases or as Acid addition salts. 3. Verbindungen nach Anspruch 2, wobei R H, CH3 oder C2H5, a 0 oder 1 und b1 bedeutet, als freie Basen oder als Säureadditionssalze.3. Compounds according to claim 2, wherein R is H, CH 3 or C 2 H 5 , a is 0 or 1 and b1, as free bases or as acid addition salts. 4. Verbindungen nach Anspruch 2, wobei a 0, b2 und R CH3 bedeutet, als freie Basen oder als Säureadditionssalze. 4. Compounds according to claim 2, wherein a 0, b2 and R are CH 3 , as free bases or as acid addition salts. 5. Pharmazeutische Zubereitungen, gekennzeichnet durch einen Gehalt an einer Verbindung nach Anspruch 1 bis 4 in Verbindung mit üblichen Hilfs- und/oder Trägerstoffen.5. Pharmaceutical preparations, characterized by A content of a compound according to claim 1 to 4 in conjunction with usual auxiliary and / or Excipients. 6. Verwendung von Verbindungen nach Anspruch 1 bis 4 zur Herstellung von Arzneimitteln für die Behandlung von Krankheiten, bei denen LTB4- antagonistische Verbindungen eingesetzt werden können.6. Use of compounds according to claim 1 to 4 for the preparation of medicaments for the treatment of diseases in which LTB 4 - antagonistic compounds can be used. 7. 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.7. 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. 8. Verwendung einer wirksamen Dosis einer Verindung nach Anspruch 1 bis 4 zur Behandlung von Krankheiten, bei denen LTB4-antagonistische Verbindungen eingesetzt werden können.8. Use of an effective dose of a compound according to claim 1 to 4 for the treatment of diseases in which LTB 4 -antagonistic compounds can be used. 9. 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. 9. 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.   10. Verfahren zur Herstellung von Verbindungen nach Anspruch 1 bis 4, dadurch gekennzeichnet, daß man
  • 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
10. A process for the preparation of compounds according to claim 1 to 4, characterized in that
  • 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
und gewünschtenfalls an erhaltenen Basen Säureadditionssalze aus erhaltenen Säureadditionssalzen die freien Basen herstellt.and, if desired, acid bases obtained from bases obtained from obtained acid addition salts produces the free bases.
DE4244241A 1992-02-05 1992-12-24 Amidine derivs. with LTB4 antagonistic properties Ceased DE4244241A1 (en)

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
ES98121305T ES2165122T3 (en) 1992-02-05 1993-01-14 NEW DERIVATIVES OF AMIDINA, ITS PREPARATION AND USE AS MEDICATIONS WITH ANTAGONIST EFFECT OF LTB4.
CA002129526A CA2129526A1 (en) 1992-02-05 1993-01-14 Novel amidine derivatives, their preparation and their use as medicaments 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
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
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
HU9402291A HU216191B (en) 1992-02-05 1993-01-14 Process for preparing novel amidine derivs. pharmaceutical compns. containing them
JP51370193A JP3487851B2 (en) 1992-02-05 1993-01-14 Novel amidine derivatives, their preparation and use as LTB4 antagonists
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
AT93902195T ATE180770T1 (en) 1992-02-05 1993-01-14 NEW AMIDENE DERIVATIVES, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCTS WITH LTB4 ANTAGONISTIC EFFECT
NZ246593A NZ246593A (en) 1992-02-05 1993-01-14 Amidine derivatives; their preparation and medicaments containing them
DK98121305T DK0902013T3 (en) 1992-02-05 1993-01-14 Novel amidine derivatives, their preparation and use as drugs with LTB4 antagonistic effect
KR1019940702669A KR0163222B1 (en) 1992-02-05 1993-01-14 New amidine derivatives, their preparation and their use as medicaments with ltb-4 antagonistic effect
PL93304713A PL173789B1 (en) 1992-02-05 1993-01-14 Method of obtaining novel derivatives of amidine
CA002427890A CA2427890A1 (en) 1992-02-05 1993-01-14 New amidine derivatives, the preparation and use thereof
ES93902195T ES2132216T3 (en) 1992-02-05 1993-01-14 NEW AMIDINE DERIVATIVES, THEIR PREPARATION AND USE AS AN ANTAGONIST EFFECT OF LTB4.
DK93902195T DK0625138T3 (en) 1992-02-05 1993-01-14 Novel amidine derivatives, their preparation and use as a drug with LTB-4 antagonist activity
UA94095773A UA43318C2 (en) 1992-02-05 1993-01-14 Amidine derivatives, pharmaceutical composition with ltb-4 antagonistic effect
AT98121305T ATE210634T1 (en) 1992-02-05 1993-01-14 NEW AMIDERIVATES, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCTS WITH LTB4 ANTAGONISTIC EFFECT
CZ19941886A CZ287209B6 (en) 1992-02-05 1993-01-14 Amidine derivatives, process of their preparation and pharmaceutical preparations containing thereof
PL93316750A PL173781B1 (en) 1992-02-05 1993-01-14 Method of obtaining novel derivatives of amidine
SK914-94A SK281016B6 (en) 1992-02-05 1993-01-14 Amidine derivatives, method of their preparation, their use and pharmaceuticals them containing
EP98121305A EP0902013B1 (en) 1992-02-05 1993-01-14 Novel amidine derivatives, their preparation and their use as medicaments 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
AU33497/93A AU673343B2 (en) 1992-02-05 1993-01-14 Novel amidine derivatives, their preparation and their use as mediaments with LTB4 antagonistic effect
SG1996008431A SG44837A1 (en) 1992-02-05 1993-01-14 New amidine derivatives the preparation and use thereof as pharmaceutical compositions with ltb4-antagonistic activity
DE59310252T DE59310252D1 (en) 1992-02-05 1993-01-14 New amide derivatives, their production and use as medicinal products with an LTB4-antagonistic effect
TW082100562A TW232005B (en) 1992-02-05 1993-01-29
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
HRP4244241.9A HRP930102B1 (en) 1992-02-05 1993-02-03 Novel amidine derivatives, their preparation and their use
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
FI943618A FI943618A (en) 1992-02-05 1994-08-04 New amidine derivatives, their preparation and use as drugs with LTB4 antagonistic action
NO942903A NO301540B1 (en) 1992-02-05 1994-08-04 New amidine derivatives, their use in the preparation of drug with LTB4 antagonistic effect
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

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