EP0581805A1 - Novel pyridazines - Google Patents

Novel pyridazines

Info

Publication number
EP0581805A1
EP0581805A1 EP92908818A EP92908818A EP0581805A1 EP 0581805 A1 EP0581805 A1 EP 0581805A1 EP 92908818 A EP92908818 A EP 92908818A EP 92908818 A EP92908818 A EP 92908818A EP 0581805 A1 EP0581805 A1 EP 0581805A1
Authority
EP
European Patent Office
Prior art keywords
amino
compounds
salts
difluoromethoxy
methoxy
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Withdrawn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
EP92908818A
Other languages
German (de)
French (fr)
Inventor
Hermann Amschler
Christian Schudt
Volker Figala
Dieter Flockerzi
Ulrich Kilian
Rolf Beume
Richard Riedel
Manfrid Eltze
Guido Hanauer
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.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik 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 Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Publication of EP0581805A1 publication Critical patent/EP0581805A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the invention relates to 3-amino-6-aryl-pyridazines, processes for their preparation, their use and medicaments containing them.
  • the compounds according to the invention are used in the pharmaceutical industry for the manufacture of medicaments.
  • the invention relates to 3-amino-6-aryl-pyridazines of the general formula I (see the attached formula sheet), in which one of the substituents R1 and R2 is methoxy, difluoroethoxy or ethoxy, and the other 1-5C-alkoxy, 4-7C -Cycloalkoxy, 3-7C-cycloalkylmethoxy, 3-5C-alkenyloxy or 1-4C-polyfluoroalkoxy means, X means amino, and their salts with acids and their N-oxides.
  • 1-5C-Alkoxy is straight-chain or branched.
  • Exemplary 1-5C-alkoxy radicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, n-pentyloxy and isopentyl - oxy and the 2,2-dimethylpropoxy residue.
  • 3-4C alkoxy is preferred.
  • 4-7C-Cycloalkoxy stands for example for cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopentyloxy is preferred.
  • 3-7C-Cycloalkylmethoxy stands for example for cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy and cyclobutylmethoxy are preferred.
  • j-5C-Alkenyloxy is straight or branched. The double bond of al enyloxy does not start from the carbon atom that binds to the oxygen atom.
  • Examples of 3-5C-alkenyloxy radicals are buten-2-yloxy, the alloxy and the methylyloxy radical.
  • 1-5C-Alkoxy is preferred over 3-5C-alkenyloxy.
  • 1-4C-Polyfluoroalkoxy is understood to mean straight-chain or branched 1-4C-alkoxy in which at least 2 hydrogen atoms have been replaced by fluorine.
  • Straight chain 1-3C-alkoxy in which at least 2 hydrogen atoms are replaced by fluorine is preferred.
  • Preferred 1-4C-polyfluoroalkoxy groups are trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy and in particular difluoromethoxy and 2,2,2-trifluoroethoxy.
  • Amino is understood to mean the NH group.
  • Suitable salts for compounds of the formula I are preferably all acid addition salts. Particular mention should be made of the pharmacologically tolerable salts of the inorganic and organic acids usually used in galenics. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
  • Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, Fe ⁇ dizoat, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate Succinate, oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosilate, 3-hydroxy-2-naphthoate or mesilate.
  • water-soluble and water-insoluble acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, Fe ⁇ dizoat, butyrate, sulfosalicylate, maleate, la
  • N-oxides of the compounds of the formula I can be described by the general formula I * (see formula sheet), in which R1, R2 and X have the meanings indicated above.
  • the N-oxides of the 3-amino-6-aryl-pyridazines according to the invention can exist as tautomeric forms.
  • a proton of the 3-amino group can to migrate this group and the oxygen in the 2-position of the pyridazine ring.
  • the other tautomer is also to be understood.
  • An embodiment (embodiment a) of the invention are 3-amino-6-arylpyridazines of the general formula I, in which
  • R2 is 1-4C-alkoxy, 4-7C-cycloalkoxy, 3-6C-cycloalkylmethoxy, 3-4C-alkenyloxy or 1--2C-polyfluoroalkoxy and X is amino, and their salts with acids and their N-oxides.
  • Another embodiment (embodiment b) of the invention are 3-amino-6-aryl-pyridazines of the general formula I, in which
  • Rl is 3-4C-alkoxy, 4-7C-cycloalkoxy, 3-6C-cycloalkylmethoxy, 3-4C-alkenyloxy or l-2C-polyfluoroalkoxy
  • R2 is methoxy, difluoromethoxy or ethoxy
  • X is amino, and their salts with acids and their N -Oxides.
  • Preferred compounds according to the invention are those of the formula I in which one of the substituents R1 and R2 is methoxy, difluoromethoxy or ethoxy and the other is 1-4C-alkoxy, 4-7C-cycloalkoxy, 3-6C-cycloalkylmethoxy or 1-2C-polyfluoroalkoxy and X means amino, and their salts with acids and their N-oxides.
  • Preferred representatives of embodiment a are those in which R2 is 1-4C-A1k-oxy or 1-2C-polyfluoroalkoxy.
  • Preferred representatives of embodiment b are those in which Rl is 3-4C-A1k-oxy, 4-7C-cycloalkoxy, 3-6C-cycloalkylmethoxy or I-2C-polyfluoroalkoxy.
  • the configuration b is preferred over the configuration a.
  • Particularly preferred compounds according to the invention are those of the formula I in which R 1 is 2-4C-alkoxy, cyclopentyloxy, cyclopropyl methoxy, cyclobutyl methoxy, difluoromethoxy or 2,2,2-trifluoroethoxy, R 2 is methoxy, Ethoxy or difluoromethoxy means and X means amino, and their pharmaceutically acceptable salts with acids and their N-oxides.
  • the invention further relates to a process for the preparation of the 3-amino-6-aryl-pyridazines of the general formula I, in which Rl, R2 and X have the meaning given above, and their salts with acids and their N-oxides, which is characterized in that is that one
  • the compounds I obtained according to a), b), c) or d) are subsequently converted into their salts, or if desired the compounds I are subsequently released from the salts of the compounds I obtained or that if desired, the compounds I obtained according to a), b), c) or d) are subsequently converted into their N-oxides.
  • the method according to variant a) is carried out in a manner familiar to the person skilled in the art.
  • Halogen atoms especially chlorine and bromine, are particularly suitable as leaving groups Y which can be displaced nucleophilically.
  • the reaction with ammonia takes place, for example, according to EA Steck et al. , J.Heterocycl .Chem.12, 1009, 1975 in an alcohol such as ethanol, ethylene glycol or polyethylene glycol 400, preferably with excess ammonia at temperatures from 150 to 200 ° C, preferably at 180 to 200 ° C, in one Autoclave is being worked.
  • the 3-hydrazino-pyridazines of formula III are hydrogenated in a manner known per se to the person skilled in the art.
  • the compounds III are hydrogenated in an alcohol, preferably methanol, with the addition of a hydrogenation catalyst such as Raney nickel or palladium / carbon at temperatures between 20 and 65 ° C., preferably at room temperature.
  • a hydrogenation catalyst such as Raney nickel or palladium / carbon at temperatures between 20 and 65 ° C., preferably at room temperature.
  • the compounds III can be subjected to catalytic transfer hydrogenolysis, as described, for example, by G. Brieger and TJNestrick in Chem. Rev. 74, 567 (1974).
  • the compounds III are first converted into their salts with a mineral acid, such as hydrochloric or sulfuric acid, and then in an alcohol, such as, for example, methanol or ethanol, with palladium / carbon and a hydrogen donor, such as cyclohexene, cyclohexadiene, formic acid or hydrogenated ammonium formate at temperatures of 20 to 80 ⁇ C.
  • a mineral acid such as hydrochloric or sulfuric acid
  • an alcohol such as, for example, methanol or ethanol
  • a hydrogen donor such as cyclohexene, cyclohexadiene, formic acid or hydrogenated ammonium formate at temperatures of 20 to 80 ⁇ C.
  • hydrolysis of phosphazenes IV in process variant c) is carried out in a manner known per se, preferably in dilute mineral acids, such as hydrochloric acid or sulfuric acid, or in aqueous organic acids, such as acetic acid or formic acid.
  • the process according to process variant d) is also carried out in a manner known per se, the debenzylation of the benzyl compounds V preferably taking place under the conditions of catalytic transfer hydrogenolysis, for which purpose the compounds V, for example, in a mixture of glacial acetic acid / conc. Hydrochloric acid and cyclohexene can be debenzylated in the presence of palladium / carbon as a catalyst.
  • Acid addition salts are obtained by dissolving the free base in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or to which the desired acid is subsequently added.
  • a chlorinated hydrocarbon such as methylene chloride or chloroform
  • a low molecular weight aliphatic alcohol ethanol, isopropanol
  • the salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent. Salts obtained can by alkalization, for example with aqueous ammonia solution, are converted into the free bases, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically acceptable acid addition salts.
  • Suitable oxidants are all reagents commonly used for N-oxidation, in particular hydrogen peroxide or (if necessary prepared in situ) organic and inorganic peroxy compounds, such as e.g. Peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, peroxy alic acid, m-chloroperoxybenzoic acid or potassium per anganate.
  • the compounds of formula II are known or they can be prepared by known processes, e.g. are described in EP-A-393500.
  • the 3-hydrazino-pyridazines of the formula III are obtained, for example, by compounds of the formula II corresponding to CG. Wermuth et al. , J.Med. Chem., Q, 239, 1987, with hydrazine hydrate at 100'C, preferably in an inert solvent, e.g. in an alcohol, such as 1-butanol, or without a solvent.
  • the phosphazenes of the formula IV are also obtained starting from compounds of the formula II, which are initially described in accordance with Th. Cap et al. , Synthesis 1989. 666, converted to tetrazolo [1,5-b] pyridazines by the technique of phase transfer catalysis (see J. Dockx, Synthesis 1973, 441).
  • the compounds II are, for example, in a hydrocarbon, such as toluene or xylene, or in an ether, such as dioxane, or a ketone, such as 2-methyl-4-pentanone (isobutyl methyl ketone), or an N, N- disubstituted acid amide, such as dimethylformamide or N-methylpyrrolidone under anhydrous conditions, preferably in the presence of 0.1 to 1.0 mol of the phase transfer catalyst at temperatures from 50 to ⁇ :..
  • uu "C in particular from 80 to 150 ⁇ C, preferably at the boiling point of the Lö ⁇ sungsmittels, reacted with at least 1 mole of alkali metal azide come ferkatalysatoren
  • Suitable examples are crown ethers , quaternary phosphonium salts and especially quaternary ammonium salts, such as tetrabutylammonium chloride.
  • the tetrazolo [1,5-b] pyridazines obtained are then heated at 80 to 150 ° C., in particular at 80, by heating with at least 1 mol of triphenylphosphine in an inert solvent, such as benzene, toluene, xylene or chlorobenzene to 135 ⁇ C, preferably at the boiling point of the solvent, converted into the phosphazenes IV.
  • an inert solvent such as benzene, toluene, xylene or chlorobenzene
  • the compounds of formula V are prepared from the corresponding compounds II with benzylamine by heating, preferably without a solvent at from 140 to 200 Temperatu ⁇ ren ⁇ C, preferably prepared at 180 to 190 ° C.
  • Mp Means melting point
  • Sdp Means boiling point
  • the 3-amino-6-aryl-pyridazines according to the invention and their salts and N-oxides have valuable pharmacological properties which make them commercially usable. They are characterized above all by those properties that make them appear suitable for the therapy of respiratory diseases of various origins. In particular, inflammatory and allergen-induced bronchial diseases can be treated due to the anti-inflammatory and broncholytic activity of the compounds according to the invention. In addition, the compounds according to the invention are notable for low toxicity, a wide therapeutic range and the absence of significant side effects.
  • broncholytic and anti-inflammatory activity of the compounds according to the invention enables their use in human and veterinary medicine, where they are used for the treatment and prophylaxis of diseases which are based on diseases of the bronchi.
  • diseases which are based on diseases of the bronchi.
  • acute and chronic obstructive respiratory diseases of various origins bronchitis, allergic bronchitis, bronchial asthma
  • Another object of the invention is therefore a method for the treatment of mammals, including humans, who are suffering from one of the above-mentioned diseases.
  • the method is characterized in that the sick mammal is administered a therapeutically effective and pharmacologically compatible amount of one or more of the compounds according to the invention.
  • the invention further relates to the compounds according to the invention for use in the treatment and / or prophylaxis of diseases which are based on diseases of the bronchi.
  • the invention also relates to the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of diseases which are based on diseases of the bronchi.
  • the invention furthermore relates to medicaments for the treatment and / or prophylaxis of diseases which are based on diseases of the bronchi and which contain one or more of the compounds according to the invention and / or their pharmacologically tolerable salts.
  • the medicaments according to the invention are produced by methods known per se, reference being made, for example, to the explanations in European patent 163 965 with regard to the preparations, dosages, dosage forms, etc.
  • 3-amino-6-aryl-pyridazines according to the invention and their salts and N-oxides are furthermore outstandingly suitable for the treatment of dermatoses.
  • proliferative, inflammatory and allergic skin diseases are mentioned as dermatoses.
  • the compounds of the formula I can be used to prevent and treat the following skin diseases: psoriasis vulgaris, toxic and allergic contact dermatitis, atopic dermatitis, seborrheic dermatitis, follicular and areal pyoderma, endogenous and exogenous acne, rosacea and acne other proliferative, inflammatory and allergic skin diseases.
  • the invention thus furthermore relates to the use of compounds of the formula I and their pharmacologically tolerable salts and N-oxides for the treatment of such individuals who are suffering from dermatoses.
  • the compounds of the formula I are used in particular in the form of those medicaments which are suitable for topical application.
  • suitable pharmaceutical formulations include, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions in which the active substance content is advantageously between 0.1 and 99%.
  • the person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • active substance carriers for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters can be used.
  • 3-amino-6-aryl-pyridazines to the invention are as well as their salts and N-oxides, 'the released (in particular by interleukins and mainly by tumor necrosis factor) as well as leukotrienes by certain cytokines for the prevention and treatment of theimiszustän- , where the treatment of the septic shock or the toxic shock syndrome should be particularly emphasized.
  • 3-amino-6-aryl-pyridazines according to the invention and their salts and N-oxides for the prevention and treatment of allergic and / or chronic incorrect reactions in the area of the upper respiratory tract (throat, nose) and the adjacent regions (paranasal sinuses, eye) , such as allergic rhinitis / sinusitis, chronic rhinitis / sinusitis, allergic conjunctivitis and nasal polyps.
  • the guinea pig chain was tested in vitro as follows:
  • test substance in a cumulative semi-logarithmic increase
  • Concentration for example 1x10 + 2x10 + 7x10 + 2x10 etc. mol / 1:
  • Table 1 shows the values -lg [EC 5Q ] and the quotients from the EC ⁇ o values for theophylline and the substance investigated. The values found show a great superiority of the compounds according to the invention over theophylline in terms of bronchospasmolytic activity.
  • bronchospasmolytic effect was also determined using the model "Hista-induced bronchospasm in anesthetized guinea pigs":
  • test substances were administered intravenously (IV) and / or intrajejunal (IV).
  • Guinea pigs 250 - 350 g are sealed in a sealed plexiglass cylinder (volume 5 l) twice before the administration of the substance with an acetylcholine mist (0.06% in 0.9% sodium chloride solution; ultrasonic nebulizer Heyer Use 77) at intervals of 20 minutes after the administration of the substance. set out.
  • the time from the beginning of the nebulization until the onset of significant breathing efforts is measured and referred to as latency.
  • test substances are administered orally by means of a pharyngeal tube (dose 100 ⁇ mol / kg, volume 1 ml / kg, suspension medium 4% methocel suspension in 0.9% sodium chloride solution).
  • the latency is 2 minutes.
  • the test substance is administered orally using a pharyngeal tube (standard dose 100 ⁇ ol, volume 1 ml of 4% methocel suspension in 0.9% sodium chloride solution / kg).
  • a pharyngeal tube standard dose 100 ⁇ ol, volume 1 ml of 4% methocel suspension in 0.9% sodium chloride solution / kg.
  • the animals are again exposed to the acetylcholine mist and the latency times are measured.
  • An extension of the latency to at least three times the length is regarded as a protective effect.
  • PDE IV high affinity cAMP-PDE cannot be inhibited by cGMP, Rolipra-sensitive
  • PDE III high affinity cAMP-PDE inhibitable by cGMP
  • the PDE inhibition of the compounds according to the invention was therefore determined on a PDE III isolated from human thrombocytes or from human neutrophilic polymorphonuclear cells (PMN's) and from PDE IV isolated from the dog trachea.
  • the phosphodiesterases III and IV are according to Polson et al., Bioche. Phar acol .21, 3403-3406 (1982) chromatographically isolated.
  • the substances are dissolved in DMSO and further diluted. 2.1 .mu.l of each are introduced from a series of solutions diluted up to 100 times and 212 .mu.l of reaction mixture are added.
  • the reaction mixture contains Hepes (100 mmol / 1), DTE (5 mmol / 1), MgCl 2 (5 mmol / 1), CaCl 2 (10 ⁇ mol / 1), BSA fraction V 0.5 mg / ml, cAMP 0, 5 mol / 1, 2.8 to 3 H-cAMP 250,000 cpm / ml (0.3 uCi / ml, SA 33.5 Ci / mmol), SV (snake venom) 25 ug / 212 ul Testan ⁇ set).
  • Table 4 shows the negative logarithms of the IC ⁇ Q values found and the quotients from the IC 50 values of the substances according to the invention determined for PDE III and PDE IV inhibition.
  • the substances according to the invention inhibit PDE IV significantly more specifically and more strongly than theophylline.

Abstract

Des composés de formule (I) dans laquelle R1, R2 et X ont les significations données dans la description, ainsi que leurs sels et leurs oxydes de N, sont de nouvelles substances actives pour le traitement d'affections bronchitiques et de dermites.Compounds of formula (I) in which R1, R2 and X have the meanings given in the description, as well as their salts and their oxides of N, are new active substances for the treatment of bronchitic affections and dermatitis.

Description

Neue Pyridazine New pyridazines
Technisches GebietTechnical field
Die Erfindung betrifft 3-Amino-6-aryl-pyridazine, Verfahren zu ihrer Her¬ stellung, ihre Anwendung und sie enthaltende Arzneimittel. Die erfindungs¬ gemäßen Verbindungen werden in der pharmazeutischen Industrie zur Herstel¬ lung von Medikamenten verwendet.The invention relates to 3-amino-6-aryl-pyridazines, processes for their preparation, their use and medicaments containing them. The compounds according to the invention are used in the pharmaceutical industry for the manufacture of medicaments.
Stand der TechnikState of the art
Die beschriebenen 3-Amino-6-aryl-pyridazine sind neu.The 3-amino-6-aryl-pyridazines described are new.
Beschreibung der ErfindungDescription of the invention
Es wurde gefunden, daß die unten näher beschriebenen neuen Verbindungen vorteilhafte phar akologische Eigenschaften aufweisen, durch die sie sich von bekannten Verbindungen in überraschender und besonders vorteilhafter Weise unterscheiden.It has been found that the new compounds described in more detail below have advantageous pharmaceutical properties, by which they differ from known compounds in a surprising and particularly advantageous manner.
Gegenstand der Erfindung sind 3-Amino-6-aryl-pyridazine der allgemeinen Formel I (siehe das beigefügte Formelblatt), worin einer der Substituenten Rl und R2 Methoxy, Difluor ethoxy oder Ethoxy, und der andere l-5C-Alkoxy, 4-7C-Cycloalkoxy, 3-7C-Cycloalkylmethoxy, 3-5C-Alkenyloxy oder l-4C-Poly- fluoralkoxy bedeutet, X Amino bedeutet, und ihre Salze mit Säuren und ihre N-Oxide.The invention relates to 3-amino-6-aryl-pyridazines of the general formula I (see the attached formula sheet), in which one of the substituents R1 and R2 is methoxy, difluoroethoxy or ethoxy, and the other 1-5C-alkoxy, 4-7C -Cycloalkoxy, 3-7C-cycloalkylmethoxy, 3-5C-alkenyloxy or 1-4C-polyfluoroalkoxy means, X means amino, and their salts with acids and their N-oxides.
l-5C-Alkoxy ist geradkettig oder verzweigt. Als beispielhafte l-5C-Alkoxy- reste seien genannt der Methoxy-, Ethoxy-, n-Propoxy-, Isopropoxy-, n-Butoxy-, Isobutoxy-, sec.-Butoxy, tert.-Butoxy-, n-Pentyloxy, Isopentyl- oxy- und der 2,2-Dimethylpropoxyrest. 3-4C-Alkoxy ist bevorzugt.1-5C-Alkoxy is straight-chain or branched. Exemplary 1-5C-alkoxy radicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, n-pentyloxy and isopentyl - oxy and the 2,2-dimethylpropoxy residue. 3-4C alkoxy is preferred.
4-7C-Cycloalkoxy steht beispielsweise für Cyclobutyloxy, Cyclopentyloxy, Cyclohexyloxy und Cycloheptyloxy, wovon Cyclopentyloxy bevorzugt ist.4-7C-Cycloalkoxy stands for example for cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopentyloxy is preferred.
3-7C-Cycloalkylmethoxy steht beispielsweise für Cyclopropylmethoxy, Cyclo- butylmethoxy, Cyclopentylmethoxy, Cyclohexylmethoxy und Cycloheptylmethoxy, wovon Cyclopropylmethoxy und Cyclobutylmethoxy bevorzugt sind. j-5C-Alkenyloxy ist geradkettig oder verzweigt. Die Doppelbindung von Al enyloxy geht nicht von dem Kohlenstoffatom aus, das an das Sauerstoff- atom bindet. Als beispielhafte 3-5C-Alkenyloxyreste seien genannt der Buten-2-yloxy, der All loxy- und der Methailyloxyrest.3-7C-Cycloalkylmethoxy stands for example for cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy and cyclobutylmethoxy are preferred. j-5C-Alkenyloxy is straight or branched. The double bond of al enyloxy does not start from the carbon atom that binds to the oxygen atom. Examples of 3-5C-alkenyloxy radicals are buten-2-yloxy, the alloxy and the methylyloxy radical.
l-5C-Alkoxy ist gegenüber 3-5C-Alkenyloxy bevorzugt.1-5C-Alkoxy is preferred over 3-5C-alkenyloxy.
Unter l-4C-Polyfluoralkoxy wird geradkettiges oder verzweigtes l-4C-Alkoxy verstanden, bei dem mindestens 2 Wasserstoffatome durch Fluor ersetzt sind. Geradkettiges l-3C-Alkoxy, bei dem mindestens 2 Wasserstoffatome durch Fluor ersetzt sind, ist bevorzugt. Bevorzugte l-4C-Polyfluoralkoxygruppen sind Trifluormethoxy, 1,1,2,2-Tetrafluorethoxy und insbesondere Difluor- methoxy und 2,2,2-Trifluorethoxy.1-4C-Polyfluoroalkoxy is understood to mean straight-chain or branched 1-4C-alkoxy in which at least 2 hydrogen atoms have been replaced by fluorine. Straight chain 1-3C-alkoxy in which at least 2 hydrogen atoms are replaced by fluorine is preferred. Preferred 1-4C-polyfluoroalkoxy groups are trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy and in particular difluoromethoxy and 2,2,2-trifluoroethoxy.
Unter Amino wird die Gruppe NH« verstanden.Amino is understood to mean the NH group.
Als Salze kommen für Verbindungen der Formel I bevorzugt alle Säureaddi¬ tionssalze in Betracht. Besonders erwähnt seien die pharmakologisch ver¬ träglichen Salze der in der Galenik üblicherweise verwendeten anorganischen und organischen Säuren. Pharmakologisch unverträgliche Salze, die bei¬ spielsweise bei der Herstellung der erfindungsgemäßen Verbindungen im in¬ dustriellen Maßstab als Verfahrensprodukte zunächst anfallen können, werden durch dem Fachmann bekannte Verfahren in pharmakologisch verträgliche Salze übergeführt. Als solche eignen sich beispielsweise wasserlösliche und was¬ serunlösliche Säureadditionssalze, wie das Hydrochlorid, Hydrobromid, Hydroiodid, Phosphat, Nitrat, Sulfat, Acetat, Citrat, Gluconat, Benzoat, Hibenzat, Feπdizoat, Butyrat, Sulfosalicylat, Maleat, Laurat, Malat, Fumarat, Succinat, Oxalat, Tartrat, Amsonat, Embonat, Metembonat, Stearat, Tosilat, 3-Hydroxy-2-naphthoat oder Mesilat.Suitable salts for compounds of the formula I are preferably all acid addition salts. Particular mention should be made of the pharmacologically tolerable salts of the inorganic and organic acids usually used in galenics. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art. Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, Feπdizoat, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate Succinate, oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosilate, 3-hydroxy-2-naphthoate or mesilate.
Die N-Oxide der Verbindungen der Formel I lassen sich durch die allgemeine Formel I* (siehe Formelblatt) beschreiben, in der Rl, R2 und X die oben angegebenen Bedeutungen haben.The N-oxides of the compounds of the formula I can be described by the general formula I * (see formula sheet), in which R1, R2 and X have the meanings indicated above.
Die N-Oxide der erfindungsgemäßen 3-Amino-6-aryl-pyridazine können als tau- tomere Formen vorliegen. Ein Proton der 3-Aminogruppe vermag zwischen die- ser Gruppe und dem Sauerstoff in 2-Stellung des Pyridazinrings zu wandern. Erfindungsgemäß ist bei Angabe oder Darstellung nur eines Tautomeren je¬ weils auch das andere Tauto ere zu verstehen.The N-oxides of the 3-amino-6-aryl-pyridazines according to the invention can exist as tautomeric forms. A proton of the 3-amino group can to migrate this group and the oxygen in the 2-position of the pyridazine ring. According to the invention, when only one tautomer is specified or shown, the other tautomer is also to be understood.
Eine Ausgestaltung (Ausgestaltung a) der Erfindung sind 3-Amino-6-aryl- pyridazine der allgemeinen Formel I, worinAn embodiment (embodiment a) of the invention are 3-amino-6-arylpyridazines of the general formula I, in which
Rl Methoxy, Difluor ethoxy oder Ethoxy,Rl methoxy, difluoro ethoxy or ethoxy,
R2 l-4C-Alkoxy, 4-7C-Cycloalkoxy, 3-6C-Cycloalkylmethoxy, 3-4C-Alkenyloxy oder l-2C-Polyfluoralkoxy und X Amino bedeutet, und ihre Salze mit Säuren und ihre N-Oxide.R2 is 1-4C-alkoxy, 4-7C-cycloalkoxy, 3-6C-cycloalkylmethoxy, 3-4C-alkenyloxy or 1--2C-polyfluoroalkoxy and X is amino, and their salts with acids and their N-oxides.
Eine weitere Ausgestaltung (Ausgestaltung b) der Erfindung sind 3-Amino-6- aryl-pyridazine der allgemeinen Formel I, worinAnother embodiment (embodiment b) of the invention are 3-amino-6-aryl-pyridazines of the general formula I, in which
Rl 3-4C-Alkoxy, 4-7C-Cycloalkoxy, 3-6C-Cycloalkylmethoxy, 3-4C-Alkenyloxy oder l-2C-Polyfluoralkoxy, R2 Methoxy, Difluormethoxy oder Ethoxy und X Amino bedeutet, und ihre Salze mit Säuren und ihre N-Oxide. •Rl is 3-4C-alkoxy, 4-7C-cycloalkoxy, 3-6C-cycloalkylmethoxy, 3-4C-alkenyloxy or l-2C-polyfluoroalkoxy, R2 is methoxy, difluoromethoxy or ethoxy and X is amino, and their salts with acids and their N -Oxides. •
Bevorzugte erfindungsgemäße Verbindungen sind solche der Formel I, worin einer der Substituenten Rl und R2 Methoxy, Difluormethoxy oder Ethoxy, und der andere l-4C-Alkoxy, 4-7C-Cycloalkoxy, 3-6C-Cycloalkylmethoxy oder 1-2C- Polyfluoralkoxy bedeutet und X Amino bedeutet, und ihre Salze mit Säuren und ihre N-Oxide.Preferred compounds according to the invention are those of the formula I in which one of the substituents R1 and R2 is methoxy, difluoromethoxy or ethoxy and the other is 1-4C-alkoxy, 4-7C-cycloalkoxy, 3-6C-cycloalkylmethoxy or 1-2C-polyfluoroalkoxy and X means amino, and their salts with acids and their N-oxides.
Bevorzugte Vertreter der Ausgestaltung a sind solche, in denen R2 1-4C-A1k- oxy oder l-2C-Polyfluoralkoxy bedeutet.Preferred representatives of embodiment a are those in which R2 is 1-4C-A1k-oxy or 1-2C-polyfluoroalkoxy.
Bevorzugte Vertreter der Ausgestaltung b sind solche, in denen Rl 3-4C-A1k- oxy, 4-7C-Cycloalkoxy, 3-6C-Cycloalkylmethoxy oder l-2C-Polyfluoralkoxy be¬ deutet.Preferred representatives of embodiment b are those in which Rl is 3-4C-A1k-oxy, 4-7C-cycloalkoxy, 3-6C-cycloalkylmethoxy or I-2C-polyfluoroalkoxy.
Die Ausgestaltung b ist gegenüber der Ausgestaltung a bevorzugt.The configuration b is preferred over the configuration a.
Besonders bevorzugte erfindungsgemäße Verbindungen sind solche der Formel I, worin Rl 2-4C-Alkoxy, Cyclopentyloxy, Cyclopropylmethoxy, Cyclobutyl- methoxy, Difluormethoxy oder 2,2,2-Trifluorethoxy bedeutet, R2 Methoxy, Ethoxy oder Difluormethoxy bedeutet und X Amino bedeutet, und ihre pharma¬ kologisch verträglichen Salze mit Säuren und ihre N-Oxide.Particularly preferred compounds according to the invention are those of the formula I in which R 1 is 2-4C-alkoxy, cyclopentyloxy, cyclopropyl methoxy, cyclobutyl methoxy, difluoromethoxy or 2,2,2-trifluoroethoxy, R 2 is methoxy, Ethoxy or difluoromethoxy means and X means amino, and their pharmaceutically acceptable salts with acids and their N-oxides.
Gegenstand der Erfindung ist ferner ein Verfahren zur Herstellung der 3-Amino-6-aryl-pyridazine der allgemeinen Formel I, worin Rl, R2 und X die oben angegebene Bedeutung haben, und ihrer Salze mit Säuren und ihrer N-Oxide, das dadurch gekennzeichnet ist, daß manThe invention further relates to a process for the preparation of the 3-amino-6-aryl-pyridazines of the general formula I, in which Rl, R2 and X have the meaning given above, and their salts with acids and their N-oxides, which is characterized in that is that one
a) Verbindungen der Formel II (siehe beigefügtes Formelblatt ), worin Rl und R2 die oben angegebene Bedeutung besitzen und Y eine nucleophil ver¬ drängbare Abgangsgruppe bedeutet, mit Ammoniak umsetzt, oder daß mana) compounds of the formula II (see attached formula sheet), in which Rl and R2 have the meaning given above and Y is a nucleophilically displaceable leaving group, reacted with ammonia, or in that
b) 3-Hydrazino-pyridazin der Formel III (siehe beigefügtes Formelblatt), worin Rl und R2 die oben angegebene Bedeutung haben, katalytisch hy¬ driert, oder daß manb) 3-hydrazino-pyridazine of the formula III (see attached formula sheet), in which Rl and R2 have the meaning given above, catalytically hydride, or that
c) Phosphazene der Formel IV (siehe beigefügtes Formelblatt), worin Rl und R2 die oben angegebene Bedeutung haben, hydrolysiert, oder daß manc) phosphazenes of the formula IV (see attached formula sheet), in which Rl and R2 have the meaning given above, hydrolyzed, or that one
d) BenzylVerbindungen der Formel V (siehe beigefügtes Formelblatt), worin Rl und R2 die oben angegebene Bedeutung haben, katalytisch hydriert,d) catylated benzyl compounds of the formula V (see attached formula sheet), in which Rl and R2 have the meaning given above,
und daß man gewünschtenfalls anschließend die nach a), b), c) oder d) er¬ haltenen Verbindungen I in ihre Salze überführt, oder daß man gewünschten¬ falls anschließend aus erhaltenen Salzen der Verbindungen I die Verbin¬ dungen I freisetzt oder daß man gewünschtenfalls anschließend die nach a), b), c) oder d) erhaltenen Verbindungen I in ihre N-Oxide überführt.and that, if desired, the compounds I obtained according to a), b), c) or d) are subsequently converted into their salts, or if desired the compounds I are subsequently released from the salts of the compounds I obtained or that if desired, the compounds I obtained according to a), b), c) or d) are subsequently converted into their N-oxides.
Das Verfahren gemäß Variante a) wird auf eine dem Fachmann an sich vertrau¬ te Weise durchgeführt. Als nucleophil verdrängbare Abgangsgruppen Y kommen insbesondere Halogenatome, vor allem Chlor und Brom in Betracht. Die Um¬ setzung mit Ammoniak erfolgt beispielsweise entsprechend E.A. Steck et al . , J.Heterocycl .Chem.12, 1009, 1975 in einem Alkohol, wie Ethanol , Ethylen- glykol oder Polyethylenglykol 400, wobei vorzugsweise mit überschüssigem Ammoniak bei Temperaturen von 150 bis 200°C, bevorzugt bei 180 bis 200°C, in einem Autoklaven gearbeitet wird. Beim Verfahren gemäß Variante b) werden die 3-Hydrazino-pyridazine der For¬ mel III auf eine dem Fachmann an sich bekannte Weise hydriert. Beispiels¬ weise werden die Verbindungen III in einem Alkohol, bevorzugt Methanol, mit einem Zusatz eines Hydrierungskatalysators, wie Raney-Nickel oder Palla¬ dium/Kohle bei Temperaturen zwischen 20 und 65°C, bevorzugt bei Raumtempe¬ ratur hydriert. Alternativ können die Verbindungen III der katalytischen Transfer-Hydrogenolyse unterworfen werden, wie sie z.B. bei G. Brieger und T.J.Nestrick in Chem.Rev. 74, 567 (1974) beschrieben wird. Demgemäß werden die Verbindungen III zunächst mit einer Mineralsäure, wie Salz- oder Schwe¬ felsäure, in ihre Salze überführt und anschließend in einem Alkohol, wie z.B. Methanol oder Ethanol, mit Palladium/Kohle und einem Wasserstoff- Donor, wie Cyclohexen, Cyclohexadien, Ameisensäure oder Ammoniumformiat bei Temperaturen von 20 bis 80βC hydriert.The method according to variant a) is carried out in a manner familiar to the person skilled in the art. Halogen atoms, especially chlorine and bromine, are particularly suitable as leaving groups Y which can be displaced nucleophilically. The reaction with ammonia takes place, for example, according to EA Steck et al. , J.Heterocycl .Chem.12, 1009, 1975 in an alcohol such as ethanol, ethylene glycol or polyethylene glycol 400, preferably with excess ammonia at temperatures from 150 to 200 ° C, preferably at 180 to 200 ° C, in one Autoclave is being worked. In the process according to variant b), the 3-hydrazino-pyridazines of formula III are hydrogenated in a manner known per se to the person skilled in the art. For example, the compounds III are hydrogenated in an alcohol, preferably methanol, with the addition of a hydrogenation catalyst such as Raney nickel or palladium / carbon at temperatures between 20 and 65 ° C., preferably at room temperature. Alternatively, the compounds III can be subjected to catalytic transfer hydrogenolysis, as described, for example, by G. Brieger and TJNestrick in Chem. Rev. 74, 567 (1974). Accordingly, the compounds III are first converted into their salts with a mineral acid, such as hydrochloric or sulfuric acid, and then in an alcohol, such as, for example, methanol or ethanol, with palladium / carbon and a hydrogen donor, such as cyclohexene, cyclohexadiene, formic acid or hydrogenated ammonium formate at temperatures of 20 to 80 β C.
Die Hydrolyse der Phosphazene IV gemäß Verfahrensvariante c) erfolgt in an sich bekannter Weise, wobei bevorzugt in verdünnten Mineralsäuren, wie Salzsäure oder Schwefelsäure, oder in wäßrigen organischen Säuren, wie Es¬ sigsäure oder Ameisensäure gearbeitet wird.The hydrolysis of phosphazenes IV in process variant c) is carried out in a manner known per se, preferably in dilute mineral acids, such as hydrochloric acid or sulfuric acid, or in aqueous organic acids, such as acetic acid or formic acid.
Das Verfahren nach Verfahrensvariante d) wird ebenfalls in an sich bekann¬ ter Weise durchgeführt, wobei die Debenzylierung der BenzylVerbindungen V bevorzugt unter den Bedingungen der katalytischen Transfer-Hydrogenolyse erfolgt, wozu die Verbindungen V beispielsweise in einer Mischung aus Eis- essig/konz. Salzsäure und Cyclohexen in Gegenwart von Palladium/Kohle als Katalysator debenzyliert werden.The process according to process variant d) is also carried out in a manner known per se, the debenzylation of the benzyl compounds V preferably taking place under the conditions of catalytic transfer hydrogenolysis, for which purpose the compounds V, for example, in a mixture of glacial acetic acid / conc. Hydrochloric acid and cyclohexene can be debenzylated in the presence of palladium / carbon as a catalyst.
Säureadditionssalze erhält man durch Auflösen der freien Base in einem ge¬ eigneten Lösungsmittel, z.B. in einem chlorierten Kohlenwasserstoff, wie Methylenchlorid oder Chloroform, oder einem niedermolekularen aliphatischen Alkohol (Ethanol, Isopropanol), das die gewünschte Säure enthält, oder dem die gewünschte Säure anschließend zugegeben wird.Acid addition salts are obtained by dissolving the free base in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or to which the desired acid is subsequently added.
Die Salze werden durch Filtrieren, Umfallen, Ausfällen mit einem Nichtlö- sungsmittel für das Anlagerungssalz oder durch Verdampfen des Lösungsmit¬ tels gewonnen. Erhaltene Salze können durch Alkalisierung, z.B. mit wäßri- ger Ammoniaklösung, in die freien Basen umgewandelt werden, welche wiederum in Säureadditionssalze übergeführt werden können. Auf diese Weise lassen sich pharmakologisch nicht verträgliche Säureadditionssalze in pharmakolo¬ gisch verträgliche Säureadditionssalze umwandeln.The salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent. Salts obtained can by alkalization, for example with aqueous ammonia solution, are converted into the free bases, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically acceptable acid addition salts.
Die N-Oxidation wird auf eine dem Fachmann an sich vertraute Weise durch¬ geführt, wie sie beispielsweise von Eiji Ochiai in "Aromatic Amine Oxides", Seite 22 - 26, Elsevier Publishing Company, Amsterdam London New York, 1967, beschrieben ist. Als Oxidationsmittel kommen alle für die N-Oxidation üblicherweise verwendeten Reagenzien in Frage, insbesondere Wasserstoffper¬ oxid oder (gegebenenfalls in situ hergestellte) organische und anorganische Peroxyverbindungen, wie z.B. Peroxyessigsäure, Trifluorperoxyessigsäure, 3,5-Dinitroperoxybenzoesäure, Peroxy aleinsäure, m-Chlorperoxybenzoesäure oder Kaliumper anganat.The N-oxidation is carried out in a manner known per se to the person skilled in the art, as described, for example, by Eiji Ochiai in "Aromatic Amine Oxides", pages 22-26, Elsevier Publishing Company, Amsterdam London New York, 1967. Suitable oxidants are all reagents commonly used for N-oxidation, in particular hydrogen peroxide or (if necessary prepared in situ) organic and inorganic peroxy compounds, such as e.g. Peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, peroxy alic acid, m-chloroperoxybenzoic acid or potassium per anganate.
Die Verbindungen der Formel II sind bekannt oder sie können nach bekannten Verfahren hergestellt werden, wie sie z.B. in der EP-A-393500 beschrieben sind.The compounds of formula II are known or they can be prepared by known processes, e.g. are described in EP-A-393500.
Die 3-Hydrazino-pyridazine der Formel III erhält man beispielsweise, indem man Verbindungen der Formel II entsprechend CG. Wermuth et al . , J.Med. Chem., Q, 239, 1987, mit Hydrazinhydrat bei 100'C, bevorzugt in einem inerten Lösungsmittel, z.B. in einem Alkohol, wie 1-Butanol, oder ohne Lösungsmittel umsetzt.The 3-hydrazino-pyridazines of the formula III are obtained, for example, by compounds of the formula II corresponding to CG. Wermuth et al. , J.Med. Chem., Q, 239, 1987, with hydrazine hydrate at 100'C, preferably in an inert solvent, e.g. in an alcohol, such as 1-butanol, or without a solvent.
Die Phosphazene der Formel IV erhält man ebenfalls ausgehend von Verbin¬ dungen der Formel II, die man zunächst entsprechend Th. Kappe et al . , Synthesis 1989. 666, nach der Technik der Phasentransferkatalyse (siehe J.Dockx, Synthesis 1973. 441) zu Tetrazolo[l,5-b]pyridazinen umgesetzt.The phosphazenes of the formula IV are also obtained starting from compounds of the formula II, which are initially described in accordance with Th. Cap et al. , Synthesis 1989. 666, converted to tetrazolo [1,5-b] pyridazines by the technique of phase transfer catalysis (see J. Dockx, Synthesis 1973, 441).
Hierzu werden die Verbindungen II beispielsweise in einem Kohlenwasser¬ stoff, wie z.B. Toluol oder Xylol, oder in einem Ether, wie z.B. Dioxan, oder einem Keton, wie z.B. 2-Methyl-4-pentanon (Isobutylmethylketon), oder einem N,N-disubstituierten Säureamid, wie z.B. Dimethylformamid oder N-Me- thylpyrrolidon unter wasserfreien Bedingungen, bevorzugt in Gegenwart von 0.1 bis 1.0 Mol des Phasentransferkatalysators bei Temperaturen von 50 bis <:uu"C, insbesondere von 80 bis 150βC, bevorzugt beim Siedepunkt des Lö¬ sungsmittels, mit mindestens 1 Mol Alkaliazid umgesetzt. Als Phasentrans- ferkatalysatoren kommen die für nucleophile Verdrängungen, insbesondere für Halogenaustausch gebräuchlichen in Frage. Geeignet sind z.B. Kronenether, quartäre Phosphoniumsalze und insbesondere quartäre Ammoniumsalze, wie z.B. Tetrabutylammoniu chlorid.For this purpose, the compounds II are, for example, in a hydrocarbon, such as toluene or xylene, or in an ether, such as dioxane, or a ketone, such as 2-methyl-4-pentanone (isobutyl methyl ketone), or an N, N- disubstituted acid amide, such as dimethylformamide or N-methylpyrrolidone under anhydrous conditions, preferably in the presence of 0.1 to 1.0 mol of the phase transfer catalyst at temperatures from 50 to <:.. uu "C, in particular from 80 to 150 β C, preferably at the boiling point of the Lö¬ sungsmittels, reacted with at least 1 mole of alkali metal azide come ferkatalysatoren As Phasentrans- the usual for nucleophilic displacements, in particular for halogen exchange in question Suitable examples are crown ethers , quaternary phosphonium salts and especially quaternary ammonium salts, such as tetrabutylammonium chloride.
Anschließend werden die erhaltenen Tetrazolo[l,5-b]pyridazine durch Er¬ hitzen mit mindestens 1 Mol Triphenylphosphin in einem inerten Lösungsmit¬ tel, wie Benzol, Toluol, Xylol oder Chlorbenzol, bei 80 bis 150°C, insbe¬ sondere bei 80 bis 135βC, bevorzugt beim Siedepunkt des Lösungsmittels, in die Phosphazene IV übergeführt.The tetrazolo [1,5-b] pyridazines obtained are then heated at 80 to 150 ° C., in particular at 80, by heating with at least 1 mol of triphenylphosphine in an inert solvent, such as benzene, toluene, xylene or chlorobenzene to 135 β C, preferably at the boiling point of the solvent, converted into the phosphazenes IV.
Die Verbindungen der Formel V werden aus den entsprechenden Verbindungen II durch Erhitzen mit Benzylamin, bevorzugt ohne Lösungsmittel bei Temperatu¬ ren von 140 bis 200βC, bevorzugt bei 180 bis 190°C hergestellt.The compounds of formula V are prepared from the corresponding compounds II with benzylamine by heating, preferably without a solvent at from 140 to 200 Temperatu¬ ren β C, preferably prepared at 180 to 190 ° C.
Für die Herstellung der Verbindungen der Ausgestaltungen a und b werden entsprechende Ausgangsverbindungen der allgemeinen Formel II, III, IV und V, worin Rl und R2 die oben jeweils angegebenen Bedeutungen haben, einge¬ setzt.Corresponding starting compounds of the general formulas II, III, IV and V, in which R 1 and R 2 have the meanings indicated above, are used for the preparation of the compounds of embodiments a and b.
Die folgenden Beispiele dienen zur näheren Erläuterung der Erfindung. Fp. bedeutet Schmelzpunkt, Sdp. bedeutet Siedepunkt. The following examples serve to explain the invention in more detail. Mp. Means melting point, Sdp. Means boiling point.
BeispieleExamples
1. 3-Amino-6-(3-methoxy-4-propoxyphenyllpyridazin1. 3-Amino-6- (3-methoxy-4-propoxyphenyllpyridazine
10 g (35,9 mmol) 3-Chlor-6-(3-methoxy-4-propoxyphenyl)pyridazin werden in 50 ml Ethylenglykol, das bei 0°C mit Ammoniak gesättigt wurde, in einem Autoklaven 6 Stunden auf 220°C erhitzt. Nach dem Abkühlen wird das Reak¬ tionsgemisch mit 500 ml Wasser verdünnt und der sich bildende Niederschlag abgesaugt. Nach dem Trocknen des Rohprodukts wird dieses durch Säulenchro¬ matographie an Kieselgel mit Chloroform als Elutionsmittel gereinigt. Man erhält 7,6 g (81,7 %) der TitelVerbindung vom Fp. 147°C.10 g (35.9 mmol) of 3-chloro-6- (3-methoxy-4-propoxyphenyl) pyridazine are heated in an autoclave at 220 ° C. for 6 hours in 50 ml of ethylene glycol which has been saturated with ammonia at 0 ° C. . After cooling, the reaction mixture is diluted with 500 ml of water and the precipitate that forms is filtered off with suction. After the crude product has dried, it is purified by column chromatography on silica gel using chloroform as the eluent. 7.6 g (81.7%) of the title compound of mp 147 ° C. are obtained.
2. 3-Amino-6-r4-methoxy-3-f2-methylpropoχy)Dhenvnpyridazin2. 3-Amino-6-r4-methoxy-3-f2-methylpropoχy) Dhenvnpyridazin
7,0 g (24 mmol) 3-Chlor-6-[4-methoxy-3-(2-methylpropoxy)phenyl]pyridazin werden wie im Beispiel 1 beschrieben in 40 ml mit Ammoniak gesättigtem Ethylenglykol umgesetzt. Das durch Fällung mit Wasser gewonnene Rohprodukt wird in Chloroform gelöst, die Lösung mit Kaliumcarbonat getrocknet und das Produkt mit Petrolether (Sdp.50-70βC) ausgefällt. Man erhält 3,5 g (53,8 %) der TitelVerbindung vom Fp. 187βC.7.0 g (24 mmol) of 3-chloro-6- [4-methoxy-3- (2-methylpropoxy) phenyl] pyridazine are reacted as described in Example 1 in 40 ml of ethylene glycol saturated with ammonia. The crude product obtained by precipitation with water, dissolved in chloroform, the solution was dried with potassium carbonate and the product was precipitated with petroleum ether (Sdp.50-70 β C). 3.5 g (53.8%) of the title compound of mp 187 β C. are obtained.
Analog erhält man unter Einsatz entsprechender 3-Chlor-6-aryl-pyridazine:Analogously, using appropriate 3-chloro-6-aryl-pyridazines, one obtains:
3-Amino-6-[4-methoxy-3-(l-methylethoxy)phenyl]pyridazin Fp. 184βC (81,7 %) 3-Amino-6-[3-methoxy-4-(2-methylpropoxy)phenyl]pyridazin Fp. 140βC (76,1 %) 3-Amino-6-[3-methoxy-4-(l-methylethoxy)phenyl]pyridazin Fp. 153βC (89,8 %) 3-Amino-6-(3-cyclopentyloxy-4-methoxyphenyl)pyridazin Fp. 207"C (99,2 %) 3-Amino-6-(3-cyclohexyloxy-4-methoxyphenyl)pyridazin Fp. 199βC (72,3 %) 3-Amino-6-(3-cycloheptyloxy-4-methoxyphenyl)pyridazin Fp. 142°C (88,1 %) 3-Amino-6-[4-ethoxy-3-(2-methylpropoxy)phenyl]pyridazin Fp. 144"C (91,5 %) 3-Amino-6-(4-difluormethoxy-3-ethoxyphenyl)pyridazin Fp. 141°C (98,4 %) 3-Amino-6-(4-difluormethoxy-3-methoxyphenyl)pyridazin Fp. 187-188°C (86,5 %)3-amino-6- [4-methoxy-3- (l-methylethoxy) phenyl] pyridazine mp 184 β C (81.7%) 3-amino-6- [3-methoxy-4- (2-methylpropoxy) phenyl] pyridazine mp 140 β C (76.1%) 3-amino-6- [3-methoxy-4- (l-methylethoxy) phenyl] pyridazine mp 153 β C (89.8%) 3-amino- 6- (3-cyclopentyloxy-4-methoxyphenyl) pyridazine mp 207 "C (99.2%) 3-amino-6- (3-cyclohexyloxy-4-methoxyphenyl) pyridazine mp 199 β C (72.3%) 3-amino-6- (3-cycloheptyloxy-4-methoxyphenyl) pyridazine mp 142 ° C (88.1%) 3-amino-6- [4-ethoxy-3- (2-methylpropoxy) phenyl] pyridazine mp. 144 "C (91.5%) 3-amino-6- (4-difluoromethoxy-3-ethoxyphenyl) pyridazine mp 141 ° C (98.4%) 3-amino-6- (4-difluoromethoxy-3-methoxyphenyl ) pyridazine mp 187-188 ° C (86.5%)
3-Amino-6-(3-difluormethoxy-4-ethoxyphenyl)pyridazin Fp. 170°C (96,7 %) 3-Amino-6-(3-cyclobutylmethoxy-4-methoxyphenyl)pyridazin Fp. 197°C (34,5 %) 3-Amino-6-(3-cyclopentyloxy-4-difluormethoxyphenyl)pyridazin Fp. U1-2°C (91,1 ) 3-Amino-6-[4-difluormethoxy-3-(l-methylethoxy)phenyl]pyridazin Fp. 153βC (100,0 %)3-Amino-6- (3-difluoromethoxy-4-ethoxyphenyl) pyridazine mp 170 ° C (96.7%) 3-amino-6- (3-cyclobutylmethoxy-4-methoxyphenyl) pyridazine mp 197 ° C (34 , 5%) 3-amino-6- (3-cyclopentyloxy-4-difluoromethoxyphenyl) pyridazine mp U1-2 ° C (91.1) 3-amino-6- [4-difluoromethoxy-3- (l-methylethoxy) phenyl] pyridazine mp 153 β C (100.0%)
3-Amino-6-[4-difluormethoxy-3-(2,2,2-trifluorethoxy)phenyl]pyridazin Fp. 96°C (88,3 %)3-amino-6- [4-difluoromethoxy-3- (2,2,2-trifluoroethoxy) phenyl] pyridazine mp 96 ° C (88.3%)
3-Amino-6-[4-difluormethoxy-3-(2-methylpropoxy)phenyl]pyridazin Fp. 120-1°C (88,0 )3-amino-6- [4-difluoromethoxy-3- (2-methylpropoxy) phenyl] pyridazine mp 120-1 ° C (88.0)
3-Amino-6-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)pyridazin Fp. 106°C (64,1 %)3-amino-6- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) pyridazine mp 106 ° C (64.1%)
3. 3-Amino-6-π-cvclopentyloxy-4-methoxyDhenvl)pvridazin3. 3-amino-6-π-cvclopentyloxy-4-methoxyDhenvl) pvridazine
a) 14 g (46 mmol) 3-Chlor-6-(3-cyclopentyloxy-4-methoxyphenyl)pyridazin werden in 74 g (0,69 mol) Benzylamin 3 Stunden auf 200βC erhitzt. Anschlie¬ ßend wird die Mischung auf Eis gegeben, mit Dichlormethan extrahiert und die organische Phase nach dem Trocknen über Kaliumcarbonat eingeengt. Man versetzt den Rückstand mit Petrolether (Sdp. 50-70°C), saugt den entstan¬ denen Niederschlag ab und kristallisiert aus Essigester/Cyclohexan um. Man erhält 15,9 g (92,4 %) 3-Benzylamino-6-(3-cyclopentyloxy-4-methoxyphenyl)- pyridazin vom Fp. 116βC.a) 14 g (46 mmol) of 3-chloro-6- (3-cyclopentyloxy-4-methoxyphenyl) pyridazine are heated in 74 g (0.69 mol) of benzylamine at 200 ° C. for 3 hours. The mixture is then poured onto ice, extracted with dichloromethane and the organic phase is concentrated after drying over potassium carbonate. Petroleum ether (b.p. 50-70 ° C.) is added to the residue, the precipitate formed is filtered off with suction and recrystallized from ethyl acetate / cyclohexane. 15.9 g (92.4%) of 3-benzylamino-6- (3-cyclopentyloxy-4-methoxyphenyl) pyridazine of mp 116 ° C. are obtained.
b) 15 g (40 mmol) 3-Benzylamino-6-(3-cyclopentyloxy-4-methoxyphenyl)pyri- dazin werden in einer Mischung von 100 ml Eisessig, 6,5 ml konz. Salzsäure, 9,8 g (0.12 mol) Cyclohexen und 3 Spatelspitzen Pd/C (10-proz.) 4 Stunden zum Rückfluß erhitzt. Man fügt nochmals 9,8 g Cyclohexen und Pd/C hinzu und kocht weitere 16 Stunden. Der Katalysator wird abfiltriert, die Lösung mitb) 15 g (40 mmol) of 3-benzylamino-6- (3-cyclopentyloxy-4-methoxyphenyl) pyridazine are in a mixture of 100 ml of glacial acetic acid, 6.5 ml of conc. Hydrochloric acid, 9.8 g (0.12 mol) of cyclohexene and 3 spatula tips Pd / C (10 percent) heated to reflux for 4 hours. Another 9.8 g of cyclohexene and Pd / C are added and the mixture is boiled for a further 16 hours. The catalyst is filtered off, the solution with
1 1 Wasser verdünnt, mit konz. Ammoniak neutralisiert und der entstandene Niederschlag abgesaugt. Zur Reinigung wird das Produkt an Kieselgel mit Dichlormethan Chromatographiert. Man erhält 4,8 g (42,1 %) 3-Amino-6-(3- cyclopentyloxy-4-methoxyphenyl)pyridazin vom Fp. 207°C.1 1 water diluted with conc. Neutralized ammonia and suctioned off the resulting precipitate. For purification, the product is chromatographed on silica gel with dichloromethane. 4.8 g (42.1%) of 3-amino-6- (3-cyclopentyloxy-4-methoxyphenyl) pyridazine, mp. 207 ° C., are obtained.
4. 3-Amino-6-(4-difluormethoxy-3-methoxyphenyl)pyridazin4. 3-Amino-6- (4-difluoromethoxy-3-methoxyphenyl) pyridazine
a) 5 g (17 mmol) 3-Chlor-6-(4-difluormethoxy-3-methoxyphenyl )pyridazin werden in 30 ml Benzylamin 1 Stunde auf 180°C erhitzt. Das Gemisch wird in 500 ml gesättigte Kaliu carbonat-Lösung eingerührt, der entstandene Nieder¬ schlag abgesaugt, mit Wasser ausgewaschen, getrocknet und aus Essigester umκrιstallisiert. Man erhält 4,8 g (77,4 %) 3-Benzylamino-6-(4-difluor- methoxy-3-methoxyphenyl)pyridazin vom Fp. 136βC.a) 5 g (17 mmol) of 3-chloro-6- (4-difluoromethoxy-3-methoxyphenyl) pyridazine are heated to 180 ° C. in 30 ml of benzylamine for 1 hour. The mixture is stirred into 500 ml of saturated potassium carbonate solution, the resulting precipitate is filtered off with suction, washed out with water, dried and extracted from ethyl acetate reinstalled. This gives 4.8 g (77.4%) of 3-benzylamino-6- (4-methoxy-difluoro-3-methoxyphenyl) pyridazine, mp. 136 C. β
b) 1,8 g (50,4 mmol) 3-Benzylamino-6-(4-difluormethoxy-3-methoxyphenyl)- pyridazin werden in 30 ml Ethanol gelöst, mit 0,42 ml konz. Salzsäure versetzt und am Rotationsverdampfer bis zur Trockne eingedampft. Man löst das gebildete Hydrochlorid wieder in 30 ml Ethanol, fügt 0,95 g Ammonium¬ formiat und 0,5 g Palladium/Kohle (10-proz.) zu und kocht am Rückfluß. Der Fortgang der Debenzylierung wird dünnschichtchromatografisch verfolgt und gegebenenfalls weiteres Ammoniumformiat und Katalysator zugesetzt. Nach beendeter Reaktion wird der Katalysator abfiltriert, die Lösung mit 2 N Natronlauge alkalisch gestellt und mit Essigester extrahiert. Die organi¬ sche Phase wird über geglühtem Kaliumcarbonat getrocknet, vom Trockenmittel abgesaugt, eingedampft und der Rückstand an Kieselgel mit Essigester chro- matografiert. Nach dem Eindampfen der entsprechenden Fraktionen erhält man 0,9 g (69,2 %) 3-Amino-6-(4-difluormethoxy-3-methoxyphenyl)pyridazin vom Fp. 184βC.b) 1.8 g (50.4 mmol) of 3-benzylamino-6- (4-difluoromethoxy-3-methoxyphenyl) pyridazine are dissolved in 30 ml of ethanol, with 0.42 ml of conc. Hydrochloric acid added and evaporated to dryness on a rotary evaporator. The hydrochloride formed is redissolved in 30 ml of ethanol, 0.95 g of ammonium formate and 0.5 g of palladium / carbon (10 percent) are added and the mixture is boiled under reflux. The progress of the debenzylation is monitored by thin layer chromatography and, if appropriate, further ammonium formate and catalyst are added. When the reaction is complete, the catalyst is filtered off, the solution is made alkaline with 2 N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over annealed potassium carbonate, suctioned off from the drying agent, evaporated and the residue is chromatographed on silica gel with ethyl acetate. After evaporation of the appropriate fractions 184 β C. are obtained 0.9 g (69.2%) of 3-amino-6- (4-difluoromethoxy-3-methoxyphenyl) pyridazine, mp.
5. 3-Amino-6-r4-methoxv-3-fl-methvlethoxvlphenvnpyridazin5. 3-Amino-6-r4-methoxv-3-fl-methvlethoxvlphenvnpyridazin
a) 25 g (90 mmol) 3-Chlor-6-[4-methoxy-3-(l-methylethoxy)phenyl]pyridazin werden mit 22,5 g (0,45 mol) Hydrazinhydrat in 200 ml Butanol 12 Stunden am Rückfluß gekocht. Anschließend wird die Reaktionsmischung mit Eiswasser auf das drei- bis vierfache Volumen verdünnt, der Niederschlag abfiltriert und aus Isopropanol/Cyclohexan umkristallisiert. Man erhält 18,9 g (76,8 %) 3-Hydrazino-6-[4-methoxy-3-(l-methylethoxy)phenyl]pyridazin vom Fp. 116°C.a) 25 g (90 mmol) of 3-chloro-6- [4-methoxy-3- (1-methylethoxy) phenyl] pyridazine are refluxed with 22.5 g (0.45 mol) of hydrazine hydrate in 200 ml of butanol for 12 hours cooked. The reaction mixture is then diluted to three to four times the volume with ice water, the precipitate is filtered off and recrystallized from isopropanol / cyclohexane. 18.9 g (76.8%) of 3-hydrazino-6- [4-methoxy-3- (l-methylethoxy) phenyl] pyridazine, mp 116 ° C., are obtained.
b) 10 g (36 mmol) 3-Hydrazino-6-[4-methoxy-3-(l-methylethoxy)phenyl]pyrida- zin werden in 100 ml Methanol in Anwesenheit von 1 g Raney-Nickel mit Was¬ serstoff unter gutem Rühren bei Normaldruck und Raumtemperatur hydriert. Nach 4 Stunden ist kein Ausgangsmaterial mehr nachzuweisen. Die Lösung wird vom Katalysator abfiltriert, im Vakuum eingeengt und der Rückstand aus Iso¬ propanol/Cyclohexan kristallisiert. Man erhält 4,3 g (46 %) 3-Amino-6-[4- methoxy-3-(1-methylethoxy)phenyljpyridazin vom Fp. 184°C. 6. 3-Amino-6-(4-difluormethoxy-3-methoxyphenyl)pyridazinb) 10 g (36 mmol) of 3-hydrazino-6- [4-methoxy-3- (1-methylethoxy) phenyl] pyridazine are mixed with hydrogen in 100 ml of methanol in the presence of 1 g of Raney nickel with good hydrogen Stirring hydrogenated at normal pressure and room temperature. After 4 hours there is no longer any evidence of starting material. The solution is filtered off from the catalyst, concentrated in vacuo and the residue is crystallized from isopropanol / cyclohexane. 4.3 g (46%) of 3-amino-6- [4-methoxy-3- (1-methylethoxy) phenylpyridazine, mp. 184 ° C. 6. 3-Amino-6- (4-difluoromethoxy-3-methoxyphenyl) pyridazine
a) 20,0 g (69,8 mmol) 3-Chlor-6-(4-difluormethoxy-3-methoxyphenyl)pyridazin werden in 100 ml n-Butanol mit 17 ml (350 mmol) Hydrazinhydrat 8 Stunden am Rückfluß gekocht. Die Lösung wird auf etwa 80βC abgekühlt und mit 100 ml gesättigter Soda-Lösung und 200 ml Wasser verrührt. Der Niederschlag wird abgesaugt, mit Wasser gewaschen und in Vakuum getrocknet. Man erhält 18,4 g (93,4 %) 3-Hydrazino-6-(4-difluormethoxy-3-methoxyphenyl)pyridazin vom Fp. 154βC.a) 20.0 g (69.8 mmol) of 3-chloro-6- (4-difluoromethoxy-3-methoxyphenyl) pyridazine are refluxed in 100 ml of n-butanol with 17 ml (350 mmol) of hydrazine hydrate for 8 hours. The solution is cooled to about 80 ° C. and stirred with 100 ml of saturated sodium carbonate solution and 200 ml of water. The precipitate is filtered off, washed with water and dried in vacuo. This gives 18.4 g (93.4%) of 3-hydrazino-6- (4-difluoromethoxy-3-methoxyphenyl) pyridazine, mp. 154 C. β
b) 5,0 g (18 mmol) 3-Hydrazino-6-(4-difluormethoxy-3-methoxyphenyl)pyrida- zin werden in 50 ml Ethanol und 2,3 ml (27 mmol) konz. Salzsäure gelöst, mit 1 g Palladium/Kohle und 3,4 g (54 mmol) Ammoniumformiat versetzt und auf 80°C erhitzt. Nach beendeter Gasentwicklung wird das Gemisch noch 3 Stunden gerührt, vom Katalysator abfiltriert, die Lösung in 1 1 Wasser eingerührt, mit konz. Ammoniak alkalisch gestellt und der entstandene Nie¬ derschlag auf einer Nutsche gesammelt. Nach Auswaschen mit Wasser wird der Filterkuchen getrocknet und in einer Mischung von Dichlor ethan/Methanol 95:5 an Kieselgel chromatographiert. Die entsprechenden Fraktionen werden im Vakuum eingeengt. Man erhält 3 g (63,6 %) 3-Amino-6-(4-difluormethoxy-3- methoxyphenyl)pyridazin vom Fp. 184βC.b) 5.0 g (18 mmol) of 3-hydrazino-6- (4-difluoromethoxy-3-methoxyphenyl) pyridazine are concentrated in 50 ml of ethanol and 2.3 ml (27 mmol). Hydrochloric acid dissolved, mixed with 1 g palladium / carbon and 3.4 g (54 mmol) ammonium formate and heated to 80 ° C. After the evolution of gas has ended, the mixture is stirred for a further 3 hours, filtered off from the catalyst, the solution is stirred into 1 liter of water, concentrated. Ammonia made alkaline and the resulting precipitate collected on a suction filter. After washing with water, the filter cake is dried and chromatographed on silica gel in a mixture of dichloroethane / methanol 95: 5. The corresponding fractions are concentrated in vacuo. To give 3 g (63.6%) of 3-amino-6- (4-difluoromethoxy-3-methoxyphenyl) pyridazine, mp. 184 C. β
7. 3-Amino-6-(4-difluormethoxv-3-ethoxyphenyl)pyridazin-2-oxid7. 3-Amino-6- ( 4-difluoromethoxv-3-ethoxyphenyl) pyridazin-2-oxide
8,9 g (31,6 mmol) 3-Amino-6-(4-difluormethoxy-3-ethoxyphenyl )pyridazin wer¬ den in 60 ml Eisessig mit 10,9 g (63,2 mmol) m-Chlorperoxybenzoesäure unter Rühren 2 Std. auf 60βC erhitzt. Nach dem Abkühlen wird die Lösung in 100 ml Wasser eingerührt, die Lösung mit Essigester erschöpfend extrahiert, der organische Extrakt über Magnesiumsulfat getrocknet, in Vakuum eingeengt und an Kieselgel neutral zuerst mit Essigester, dann mit Essigester/Metha¬ nol 8:2 chromatografiert. Die entsprechenden Fraktionen werden eingeengt, der Rückstand in wenig Essigester aufgenommen, mit Petrolether (Sdp. 40-70°C) bis zur beginnenden Trübung versetzt und das Produkt unter Kühlung kristallisiert. Die Kristalle werden abgesaugt, mit Petrolether gewaschen und in Vakuum bei 80°C getrocknet. Man erhält 5,7 g (60,7 %) der Titelver¬ bindung vom Fp. 202-3°C. 8. 3-Amino-6-f4-difluormethoxv-3-methoxvDhenvl)Dvridazin-2-oxid8.9 g (31.6 mmol) of 3-amino-6- (4-difluoromethoxy-3-ethoxyphenyl) pyridazine are in 60 ml of glacial acetic acid with 10.9 g (63.2 mmol) of m-chloroperoxybenzoic acid with stirring 2 Heated to 60 ° C for hours. After cooling, the solution is stirred into 100 ml of water, the solution is extracted exhaustively with ethyl acetate, the organic extract is dried over magnesium sulfate, concentrated in vacuo and chromatographed on silica gel neutral first with ethyl acetate, then with ethyl acetate / methanol 8: 2. The corresponding fractions are concentrated, the residue is taken up in a little ethyl acetate, petroleum ether (bp. 40-70 ° C.) is added until the cloudiness begins and the product crystallizes with cooling. The crystals are filtered off, washed with petroleum ether and dried in vacuo at 80 ° C. 5.7 g (60.7%) of the title compound of mp 202-3 ° C. are obtained. 8. 3-Amino-6-f4-difluoromethoxv-3-methoxvDhenvl) dvridazin-2-oxide
20,0 g (74,8 mmol) 3-Amino-6-(4-difluormethoxy-3-methoxyphenyl)pyridazin werden in 100 ml Eisessig gelöst, unter Rühren mit 30,6 ml (300 mmol) 30 %igem Wasserstoffperoxid versetzt und die Mischung bei 80βC 2,5 Std. ge¬ rührt. Die Reaktionslösung wird mit 1 kg Eis und 200 ml konz. Ammoniaklö¬ sung verdünnt, der gebildete Niederschlag auf einer Nutsche gesammelt, zu¬ erst mit Wasser, dann mit Ethanol und Petrolether (Sdp. 40-70°C) gewaschen und in Vakuum bei 75"C getrocknet. Man erhält 18,1 g (85,4 %) der TitelVer¬ bindung vom Fp. 214°C.20.0 g (74.8 mmol) of 3-amino-6- (4-difluoromethoxy-3-methoxyphenyl) pyridazine are dissolved in 100 ml of glacial acetic acid, 30.6 ml (300 mmol) of 30% hydrogen peroxide are added with stirring and the mixture at 80 C for 2.5 h β. ge stirred. The reaction solution is concentrated with 1 kg of ice and 200 ml. Diluted ammonia solution, the precipitate formed was collected on a suction filter, washed first with water, then with ethanol and petroleum ether (bp. 40-70 ° C.) and dried in vacuo at 75 ° C. 18.1 g ( 85.4%) of the title compound of mp 214 ° C.
Analog erhält man unter Einsatz entsprechender 3-Amino-6-phenyl-pyridazine:The following are obtained analogously using appropriate 3-amino-6-phenylpyridazines:
3-Amino-6-(3-difluormethoxy-4-ethoxyphenyl)pyridazin-2-oxid Fp. 188°C (53,4 %)3-amino-6- (3-difluoromethoxy-4-ethoxyphenyl) pyridazin-2-oxide mp 188 ° C (53.4%)
3-Amino-6-[4-difluormethoxy-3-(l-methylethoxy)phenyl]pyridazin-2-oxid Fp. 207βC (29,2 )3-Amino-6- [4-difluoromethoxy-3- (l-methylethoxy) phenyl] pyridazin-2-oxide mp 207 β C (29.2)
3-Amino-6-[4-difluormethoxy-3-(2-methylpropoxy)phenyl]pyridazin-2-oxid Fp. 134-35βC (51,0 %)3-amino-6- [4-difluoromethoxy-3- (2-methylpropoxy) phenyl] pyridazin-2-oxide mp 134-35 β C (51.0%)
3-Amino-6-(3-cyclopentyloxy-4-difluormethoxyphenyl)pyridazin-2-oxid Fp. 167βC (52,4 %)3-amino-6- (3-cyclopentyloxy-4-difluoromethoxyphenyl) pyridazin-2-oxide mp 167 β C (52.4%)
3-Amino-6-[4-difluormethoxy-3-(2,2,2-trifluorethoxy)phenyl]pyridazin-2- oxid Fp. 222βC (42,3 %)3-amino-6- [4-difluoromethoxy-3- (2,2,2-trifluoroethoxy) phenyl] pyridazin-2-oxide mp 222 β C (42.3%)
3-Amino-6-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)pyridazin-2-oxid Fp. I59°C (86,4 %) 3-Amino-6- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) pyridazin-2-oxide mp.159 ° C (86.4%)
gewerbliche Anwendbarkeitindustrial applicability
Die erfindungsgemäßen 3-Amino-6-aryl-pyridazine sowie ihre Salze und N-Oxi¬ de besitzen wertvolle pharmakologische Eigenschaften, die sie gewerblich verwertbar machen. Sie zeichnen sich vor allem durch solche Eigenschaften aus, die sie für die Therapie von Atemwegserkrankungen verschiedener Genese geeignet erscheinen lassen. Insbesondere können entzündliche und allergen- induzierte Bronchialerkrankungen aufgrund der antiinflammatorisehen und broncholytischen Wirksamkeit der erfindungsgemäßen Verbindungen behandelt werden. Daneben zeichnen sich die erfindungsgemäßen Verbindungen durch eine geringe Toxizität, eine große therapeutische Breite und das Fehlen wesent¬ licher Nebenwirkungen aus.The 3-amino-6-aryl-pyridazines according to the invention and their salts and N-oxides have valuable pharmacological properties which make them commercially usable. They are characterized above all by those properties that make them appear suitable for the therapy of respiratory diseases of various origins. In particular, inflammatory and allergen-induced bronchial diseases can be treated due to the anti-inflammatory and broncholytic activity of the compounds according to the invention. In addition, the compounds according to the invention are notable for low toxicity, a wide therapeutic range and the absence of significant side effects.
Die broncholytische und antiinflammatorisehe Wirksamkeit der erfindungsge¬ mäßen Verbindungen ermöglicht ihren Einsatz in der Human- und Veterinär¬ medizin, wobei sie zur Behandlung und Prophylaxe von Krankheiten, die auf Erkrankungen der Bronchien beruhen, verwendet werden. Beispielsweise können akute und chronisch obstruktive Atemwegserkrankungen verschiedener Genese (Bronchitis, allergische Bronchitis, Asthma bronchiale) bei Mensch und Tier behandelt werden.The broncholytic and anti-inflammatory activity of the compounds according to the invention enables their use in human and veterinary medicine, where they are used for the treatment and prophylaxis of diseases which are based on diseases of the bronchi. For example, acute and chronic obstructive respiratory diseases of various origins (bronchitis, allergic bronchitis, bronchial asthma) can be treated in humans and animals.
Ein weiterer Gegenstand der Erfindung ist daher ein Verfahren zur Behand¬ lung von Säugetieren einschließlich Menschen, die an einer der oben genann¬ ten Krankheiten erkrankt sind. Das Verfahren ist dadurch gekennzeichnet, daß man dem erkrankten Säugetier eine therapeutisch wirksame und pharmako¬ logisch verträgliche Menge einer oder mehrer der erfindungsgemäßen Verbin¬ dungen verabreicht.Another object of the invention is therefore a method for the treatment of mammals, including humans, who are suffering from one of the above-mentioned diseases. The method is characterized in that the sick mammal is administered a therapeutically effective and pharmacologically compatible amount of one or more of the compounds according to the invention.
Weiterer Gegenstand der Erfindung sind die erfindungsgemäßen Verbindungen zur Anwendung bei der Behandlung und/oder Prophylaxe von Krankheiten, die auf Erkrankungen der Bronchien beruhen.The invention further relates to the compounds according to the invention for use in the treatment and / or prophylaxis of diseases which are based on diseases of the bronchi.
Ebenso betrifft die Erfindung die Verwendung der erfindungsgemäßen Verbin¬ dungen zur Herstellung von Arzneimitteln, die zur Behandlung und/oder Pro¬ phylaxe von Krankheiten, die auf Erkrankungen der Bronchien beruhen, einge¬ setzt werden. Weiterhin sind Arzneimittel zur Behandlung und/oder Prophylaxe von Krank¬ heiten, die auf Erkrankungen der Bronchien beruhen und die eine oder mehrere der erfindungsgemäßen Verbindungen und/oder ihre pharmakologisch verträglichen Salze enthalten, Gegenstand der Erfindung.The invention also relates to the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of diseases which are based on diseases of the bronchi. The invention furthermore relates to medicaments for the treatment and / or prophylaxis of diseases which are based on diseases of the bronchi and which contain one or more of the compounds according to the invention and / or their pharmacologically tolerable salts.
Die erfindungsgemäßen Arzneimittel werden nach an sich bekannten Verfahren hergestellt, wobei bezüglich der Zubereitungen, Dosierungen, Darreichungs¬ formen etc. beispielsweise auf die Ausführungen im Europäischen Patent 163 965 verwiesen wird.The medicaments according to the invention are produced by methods known per se, reference being made, for example, to the explanations in European patent 163 965 with regard to the preparations, dosages, dosage forms, etc.
Die erfindungsgemäßen 3-Amino-6-aryl-pyridazine sowie ihre Salze und N-Oxide eignen sich weiterhin in hervorragender Weise zur Behandlung von Dermatosen.The 3-amino-6-aryl-pyridazines according to the invention and their salts and N-oxides are furthermore outstandingly suitable for the treatment of dermatoses.
Als Dermatosen seien insbesondere proliferative, entzündliche und allergi¬ sche Hauterkrankungen erwähnt. So können die Verbindungen der Formel I bei¬ spielsweise zur Verhütung und Behandlung folgender Hauterkrankungen einge¬ setzt werden: Psoriasis vulgaris, toxisches und allergisches Kontaktekzem, atopisches Ekzem, seborrhoisches Ekzem, follikuläre und flächenhafte Pyo- dermien, endogene und exogene Akne, Akne rosacea sowie andere proliferati¬ ve, entzündliche und allergische Hauterkrankungen. Weiterer Gegenstand der Erfindung ist somit die Verwendung von Verbindungen der Formel I und ihren pharmakologisch verträglichen Salzen und N-Oxiden zur Behandlung von sol¬ chen Individuen, die an Dermatosen erkrankt sind.In particular, proliferative, inflammatory and allergic skin diseases are mentioned as dermatoses. For example, the compounds of the formula I can be used to prevent and treat the following skin diseases: psoriasis vulgaris, toxic and allergic contact dermatitis, atopic dermatitis, seborrheic dermatitis, follicular and areal pyoderma, endogenous and exogenous acne, rosacea and acne other proliferative, inflammatory and allergic skin diseases. The invention thus furthermore relates to the use of compounds of the formula I and their pharmacologically tolerable salts and N-oxides for the treatment of such individuals who are suffering from dermatoses.
Die Anwendung der Verbindungen der Formel I erfolgt insbesondere in Form solcher Arzneimittel, die für eine topische Applikation geeignet sind. Für die Herstellung der Arzneimittel werden die Verbindungen der Formel I und/oder ihre pharmakologisch verträglichen Salze und/oder ihre N-Oxide (= Wirkstoffe) vorzugsweise mit geeigneten pharmazeutischen Hilfsstoffen vermischt und zu geeigneten Arzneiformulierungen weiterverarbeitet. Als ge¬ eignete Arzneiformulierungen seien beispielsweise Puder, Emulsionen, Sus¬ pensionen, Sprays, Öle, Salben, Fettsalben, Cremes, Pasten, Gele oder Lö¬ sungen genannt, in denen der Wirkstoffgehalt vorteilhafterweise zwischen 0,1 und 99 % beträgt. Welche Hilfsstoffe für die gewünschten Arzneiformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemitteln, Gelbildnern, Salbengrundlagen und anderen Wirkstoffträgem können bei¬ spielsweise Antioxidantien, Dispergiermittel, E ulgatoren, Konservierungs¬ mittel, Lösungsvermittler oder Permeationspromotoren verwendet werden.The compounds of the formula I are used in particular in the form of those medicaments which are suitable for topical application. For the preparation of the medicaments, the compounds of the formula I and / or their pharmacologically acceptable salts and / or their N-oxides (= active ingredients) are preferably mixed with suitable pharmaceutical auxiliaries and processed further to form suitable medicament formulations. Suitable pharmaceutical formulations include, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions in which the active substance content is advantageously between 0.1 and 99%. The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, ointment bases and other active substance carriers, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters can be used.
Außerdem eignen sich die erfindungsgemäßen 3-Amino-6-aryl-pyridazine sowie ihre Salze und N-Oxide zur Verhütung und Behandlung von Krankheitszustän- den,'die durch bestimmte Zytokine (insbesondere durch Interleukine und vor allem durch den Tumornekrosefaktor) sowie Leukotriene ausgelöst werden, wo¬ bei die Behandlung des septischen Schocks bzw. des toxischen Schocksyndroms besonders hervorzuheben ist.In addition, 3-amino-6-aryl-pyridazines to the invention are as well as their salts and N-oxides, 'the released (in particular by interleukins and mainly by tumor necrosis factor) as well as leukotrienes by certain cytokines for the prevention and treatment of the Krankheitszustän- , where the treatment of the septic shock or the toxic shock syndrome should be particularly emphasized.
Weiterhin können die erfindungsgemäßen 3-Amino-6-aryl-pyridazine sowie ihre Salze und N-Oxide zur Verhütung und Behandlung von allergischen und/oder chronischen Fehlreaktionen im Bereich der oberen Atemwege (Rachenraum, Nase) und der angrenzenden Regionen (Nasennebenhöhlen, Auge), wie z.B. der allergischen Rhinitis/Sinusitis, chronischen Rhinitis/Sinusitis, allergi¬ schen Conjunctivitis und von Nasenpolypen eingesetzt werden. Furthermore, the 3-amino-6-aryl-pyridazines according to the invention and their salts and N-oxides for the prevention and treatment of allergic and / or chronic incorrect reactions in the area of the upper respiratory tract (throat, nose) and the adjacent regions (paranasal sinuses, eye) , such as allergic rhinitis / sinusitis, chronic rhinitis / sinusitis, allergic conjunctivitis and nasal polyps.
Biologische UntersuchungenBiological studies
In den anschl eßenden Tabellen sind die untersuchten Verbindungen durch Nummern gekennzeichnet, die wie folgt zugeordnet sind:In the following tables, the examined compounds are identified by numbers, which are assigned as follows:
1 3-Amino-6-(3-methoxy-4-propoxyphenyl)pyridazin1 3-Amino-6- (3-methoxy-4-propoxyphenyl) pyridazine
23-Amino-6-[4-methoxy-3-(2-methylpropoxy)phenyl]pyridazin23-amino-6- [4-methoxy-3- (2-methylpropoxy) phenyl] pyridazine
33-Amino-6-[4-methoxy-3-(l-methylethoxy)phenyl]pyridazin33-amino-6- [4-methoxy-3- (l-methylethoxy) phenyl] pyridazine
43-Amino-6-[3-methoxy-4-(2-methylpropoxy)phenyl]pyridazin43-amino-6- [3-methoxy-4- (2-methylpropoxy) phenyl] pyridazine
53^Amino-6-[3-methoxy-4-(l-methylethoxy)phenyljpyridazin53 ^ Amino-6- [3-methoxy-4- (l-methylethoxy) phenylpyridazine
63-Amino-6-(3-cyclopentyloxy-4-methoxyphenyl)pyridazin63-amino-6- (3-cyclopentyloxy-4-methoxyphenyl) pyridazine
73-Amino-6-(3-cyclohexyloxy-4-methoxyphenyl)pyridazin73-amino-6- (3-cyclohexyloxy-4-methoxyphenyl) pyridazine
83-Amino-6-(3-cycloheptyloxy-4-methoxyphenyl)pyridazin83-amino-6- (3-cycloheptyloxy-4-methoxyphenyl) pyridazine
93-Amino-6-[4-ethoxy-3-(2-methylpropoxy)phenyl]pyridazin93-amino-6- [4-ethoxy-3- (2-methylpropoxy) phenyl] pyridazine
103-Amino-6-(4-difluormethoxy-3-ethoxyphenyl)pyridazin103-amino-6- (4-difluoromethoxy-3-ethoxyphenyl) pyridazine
11 3-Amino-6-(4-difluormethoxy-3-methoxyphenyl)pyridazin11 3-Amino-6- (4-difluoromethoxy-3-methoxyphenyl) pyridazine
123-Amino-6-(3-difluormethoxy-4-ethoxyphenyl)pyridazin123-amino-6- (3-difluoromethoxy-4-ethoxyphenyl) pyridazine
133-Amino-6-(3-cyclobutylmethoxy-4-methoxyphenyl)pyridazin133-amino-6- (3-cyclobutylmethoxy-4-methoxyphenyl) pyridazine
143-Amino-6-(3-cyclopentyloxy-4-difluormethoxyphenyl)pyridazin143-amino-6- (3-cyclopentyloxy-4-difluoromethoxyphenyl) pyridazine
153-Amino-6-[4-difluormethoxy-3-(l-methylethoxy)phenyl]pyridazin153-amino-6- [4-difluoromethoxy-3- (l-methylethoxy) phenyl] pyridazine
163-Amino-6-[4-difluormethoxy-3-(2,2,2-trifluorethoxy)pyridazin163-Amino-6- [4-difluoromethoxy-3- (2,2,2-trifluoroethoxy) pyridazine
173-Amino-6-[4-difluormethoxy-3-(2-methylpropoxy)phenyl]pyridazin173-amino-6- [4-difluoromethoxy-3- (2-methylpropoxy) phenyl] pyridazine
183-Amino-6-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)pyridazin183-amino-6- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) pyridazine
193-Amino-6-(4-difluormethoxy-3-ethoxyphenyl)pyridazin-2-oxid193-Amino-6- (4-difluoromethoxy-3-ethoxyphenyl) pyridazin-2-oxide
203-Amino-6-(4-difluormethoxy-3-methoxyphenyl)pyridazin-2-oxid203-amino-6- (4-difluoromethoxy-3-methoxyphenyl) pyridazin-2-oxide
21 3-Amino-6-(3-difluormethoxy-4-ethoxyphenyl)pyridazin-2-oxid21 3-Amino-6- (3-difluoromethoxy-4-ethoxyphenyl) pyridazin-2-oxide
223-Amino-6-[4-difluormethoxy-3-(l-methylethoxy)phenyl]pyridazin-2-oxid223-Amino-6- [4-difluoromethoxy-3- (1-methylethoxy) phenyl] pyridazin-2-oxide
233-Amino-6-[4-difluormethoxy-3-(2-methylpropoxy)phenyl]pyridazin-2-oxid233-Amino-6- [4-difluoromethoxy-3- (2-methylpropoxy) phenyl] pyridazin-2-oxide
243-Amino-6-(3-cyclopentyloxy-4-difluormethoxyphenyl)pyridazin-2-oxid243-amino-6- (3-cyclopentyloxy-4-difluoromethoxyphenyl) pyridazin-2-oxide
253-Amino-6-[4-difluormethoxy-3-(2,2,2-trifluorethoxy)phenyl]pyridazin- oxid253-Amino-6- [4-difluoromethoxy-3- (2,2,2-trifluoroethoxy) phenyl] pyridazine oxide
263-Amino-6-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)pyridazin-2-oxid263-Amino-6- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) pyridazin-2-oxide
Die bronchospasmolytische Wirkung der Verbindungen auf die Trachealspangen-The bronchospasmolytic effect of the compounds on the tracheal braces
Kette des Meerschweinchens wurde in vitro wie folgt geprüft:The guinea pig chain was tested in vitro as follows:
Vier parallele, aus jeweils 6 Einzelringen bestehende Trachealspangen- Ketten des Meerschweinchens (weibl. und männl., 430 - 600 g) im Organbad [5Four parallel tracheal braces, each consisting of 6 individual rings Chains of the guinea pig (female and male, 430 - 600 g) in an organ bath [5
_5 ml, Krebs-Henseleit-Lösung mit Zusatz von Phentolamin (10 mol/1), 37°C,_ 5 ml, Krebs-Henseleit solution with the addition of phentolamine (10 mol / 1), 37 ° C,
Vorspannung der Organe 2 g, Begasung mit Carbogen] entwickeln nach etwa 20 bis 30 Minuten eine stabile, tonische Spontankontraktur. An diesen dauerkontrahierten Organen kann unter isometrischen Meßbedingungen durchTension of the organs 2 g, fumigation with carbogen] develop a stable, tonic spontaneous contracture after about 20 to 30 minutes. On these permanently contracted organs, isometric measurement conditions can be used
Applikation der Prüfsubstanz in kumulativ halblogarithmisch ansteigenderApplication of the test substance in a cumulative semi-logarithmic increase
C C rC C r
Konzentration (z.B. 1x10 + 2x10 + 7x10 + 2x10 usw. mol/1) eine Relaxation herbeigeführt werden, wobei nach jeder Einzeldosis der Testsub¬ stanz eine konstante Relaxations-Antwort abgewartet wird, bevor die nächst höhere Konzentration appliziert wird. Über einen Zeitraum von 20 bis 30 Minuten wird somit eine vollständige Dosis-Wirkungskurve der Testsubstanz erhalten. Die jeweilige Relaxation wird als Prozentbruchteil der durch Gabe von (-)Isoprenalin (10" mol/1) maximal erreichbaren Relaxation ausge¬ drückt. Als Maß für die bronchodilatorische Aktivität dient die Konzentra¬ tion der Testsubstanz, welche 50 % der maximal erreichbaren Relaxation be¬ wirkt, ausgedrückt durch den negativen Logarithmus der EC5Q mol/1 :Concentration (for example 1x10 + 2x10 + 7x10 + 2x10 etc. mol / 1) a relaxation can be brought about, with a constant relaxation response being waited for after each individual dose of the test substance before the next higher concentration is applied. A complete dose-response curve of the test substance is thus obtained over a period of 20 to 30 minutes. The respective relaxation is expressed as a percentage of the maximum relaxation which can be achieved by administration of (-) isoprenaline (10 " mol / 1). The concentration of the test substance, which is 50% of the maximum achievable relaxation, serves as a measure of the bronchodilatory activity ¬ acts, expressed by the negative logarithm of the EC 5Q mol / 1:
-ig[Ec50].-ig [Ec 50 ].
In der Tabelle 1 sind die Werte -lg[EC5Q] und die Quotienten aus den ECςo- Werten für Theophyllin und die untersuchte Substanz angegeben. Die gefun¬ denen Werte zeigen eine große Überlegenheit der erfindungsgemäßen Verbin¬ dungen gegenüber Theophyllin bezüglich der bronchospasmolytisehen Aktivi¬ tät.Table 1 shows the values -lg [EC 5Q ] and the quotients from the EC ςo values for theophylline and the substance investigated. The values found show a great superiority of the compounds according to the invention over theophylline in terms of bronchospasmolytic activity.
Tabelle 1Table 1
Lfd.Nr.Serial no.
66
77
88th
99
1010
1111
12 Fortsetzung Tabelle 1 in/ 12 Continuation of table 1 in /
Die bronchospasmolytische Wirkung wurde weiterhin am Modell "Hista inindu- zierter Bronchospasmus am narkotisierten Meerschweinchen" bestimmt:The bronchospasmolytic effect was also determined using the model "Hista-induced bronchospasm in anesthetized guinea pigs":
Bei diesem Modell werden pharmakodynamische bzw. toxische Effekte an inneren sensiblen Rezeptoren, auf die Atmung und am Herz-Kreislauf-System vom Meerschweinchen simultan registriert [U. Kilian, E. Müller, E. Ch. Dittmann und J. Hamacher, Arzneimittel-Forschung 28 (II) 1699-1708, 1978]. An narkotisierten (Ethylurethan 1,25 g/kg i.p.) monovagotomierten, spontan¬ atmenden Meerschweinchen (männl., 350 - 450 g) wurde das Pneumotachogramm registriert und zur Charakterisierung des durch Hista in (0,09 - 0,18 μmol/kg i.v.) ausgelösten Bronchospasmus die maximale Strömungsgeschwin¬ digkeit der Atemluft während der Exspiration (V ax ) gemessen.In this model, pharmacodynamic or toxic effects on inner sensitive receptors, on breathing and on the cardiovascular system of guinea pigs are registered simultaneously [U. Kilian, E. Müller, E. Ch. Dittmann and J. Hamacher, drug research 28 (II) 1699-1708, 1978]. The pneumotachogram was recorded on anesthetized (ethyl urethane 1.25 g / kg ip) monovagotomized, spontaneously breathing guinea pigs (male, 350 - 450 g) and used to characterize the (0.09 - 0.18 μmol / kg iv ) triggered bronchospasm the maximum flow rate of the breathing air during expiration (V ax) was measured.
Ein Histaminspasmus vor Substanzgabe wurde mit mehreren Hista inspasmen nach Substanzgabe verglichen. Die PrüfSubstanzen wurden intravenös (i.v.) und/oder intrajejunal (i.j.) appliziert.A histamine spasm before substance administration was compared with several Hista inspasmas after substance administration. The test substances were administered intravenously (IV) and / or intrajejunal (IV).
Es wurde gefunden, daß die untersuchten Verbindungen den hista in-indu- zierten Bronchospasmus am narkotisierten Meerschweinchen etwa 2 - 5 mal stärker hemmen als Theophyllin. Tabel le 2It was found that the compounds examined inhibited hista-induced bronchospasm in the anesthetized guinea pig by about 2 to 5 times more than theophylline. Table 2
Mittlere prozentuale bronchspasmolytische Wirkung 0-1 Std. p.appl. und pro¬ zentuale bronchospasmolytische Wirkung nach 1 Std. p.appl., gemessen an der Hemmung der histamininduzierten Abnahme von VmaxAverage percentage bronchospasmolytic effect 0-1 hours p.appl. and percentage bronchospasmolytic effect after 1 hour per application, measured on the inhibition of the histamine-induced decrease in Vmax
Zusätzlich wurde die bronchospasmolytische Wirkung am Modell "Schutzwirkung gegen den Acetylcholin-induzierten Bronchospasmus am wachen Meerschwein¬ chen" geprüft:In addition, the bronchospasmolytic effect was tested using the model "protective effect against acetylcholine-induced bronchospasm in awake guinea pigs":
Die Versuchsführung erfolgt in Anlehnung an T. Olsson, Acta Allergologica 26, 438-447 (1971). Meerschweinchen (250 - 350 g) werden in einem ver¬ schlossenen Plexiglaszylinder (Volumen 5 1) vor Substanzgabe zweimal im Abstand von 20 Minuten nach Substanzgabe einem Acetylcholin-Nebel (0,06 % in 0,9 % Natriumchloridlösung; Ultraschallvernebler Heyer Use 77) ausge¬ setzt. Die Zeit vom Beginn der Verneblung bis zum Einsetzen deutlicher Atemanstrengungen (unter Umständen hypoxischer Krampfanfall in Seitenlage) wird gemessen und als Latenzzeit bezeichnet. Eine Verlängerung der Latenz¬ zeit nach Substanzgabe auf mindestens die dreifache mittlere Latenzzeit vor Substanzgabe wird als Schutzwirkung angesehen und die Anzahl der in dem Kollektiv geschützten Tiere ermittelt. Die Applikation der Prüfsubstanzen erfolgt oral mittels Schlundsonde (Dosis 100 μmol/kg, Volumen 1 ml/kg, Suspensionsmittel 4 ige MethocelSuspension in 0,9 iger Natriumchlorid¬ lösung).The experimental procedure is based on T. Olsson, Acta Allergologica 26, 438-447 (1971). Guinea pigs (250 - 350 g) are sealed in a sealed plexiglass cylinder (volume 5 l) twice before the administration of the substance with an acetylcholine mist (0.06% in 0.9% sodium chloride solution; ultrasonic nebulizer Heyer Use 77) at intervals of 20 minutes after the administration of the substance. set out. The time from the beginning of the nebulization until the onset of significant breathing efforts (possibly hypoxic seizure in a lateral position) is measured and referred to as latency. An extension of the latency period after administration of the substance to at least three times the average latency before administration of the substance is regarded as a protective effect and the number of animals protected in the collective is determined. The test substances are administered orally by means of a pharyngeal tube (dose 100 μmol / kg, volume 1 ml / kg, suspension medium 4% methocel suspension in 0.9% sodium chloride solution).
Im Kontrollversuch (ohne Substanzapplikation) liegt die Latenzzeit bei 2 Minuten. Die Applikation der Prüfsubstanz erfolgt per oral mittels Schlund¬ sonde (Standarddosis 100 μ ol , Volumen 1 ml 4 ige MethocelSuspension in 0,9 %iger Natriumchloridlösung/kg). Nach 30 Minuten werden die Tiere erneut dem Acetylcholin-Nebel ausgesetzt und die Latenzzeiten gemessen. Eine Ver¬ längerung der Latenzzeit auf mindestens die dreifache Länge wird als Schutzwirkung angesehen.In the control experiment (without substance application), the latency is 2 minutes. The test substance is administered orally using a pharyngeal tube (standard dose 100 μol, volume 1 ml of 4% methocel suspension in 0.9% sodium chloride solution / kg). After 30 minutes, the animals are again exposed to the acetylcholine mist and the latency times are measured. An extension of the latency to at least three times the length is regarded as a protective effect.
Tabelle 3Table 3
Schutzwirkung gegen den Acetylcholin-induzierten Bronchospasmus am wachen Meerschweinchen, ermittelt 30 Minuten nach oraler Substanz- bzw. Placebo- Gabe. Angegeben ist die prozentuale Anzahl geschützter Tiere im Vergleich zur Kontrollgruppe.Protective action against the acetylcholine-induced bronchospasm in the guinea pig, determined 30 minutes after oral substance or placebo administration. The percentage of protected animals is given in comparison to the control group.
o t b e 3 otbe 3
% Schutzwirkung% Protective effect
50 65 50 80 50 65 75 75 50 50 60 60 45 70 70 20 40 7050 65 50 80 50 65 75 75 50 50 60 60 45 70 70 20 40 70
Als besonders aussagekräftig für eine zu erwartende bronchospasmolytische und/oder antiinflammatorisehe Wirkung wird die spezifische Hemmung der Phosphodiesterase IV (PDE IV = hoch affine cAMP-PDE durch cGMP nicht hemm¬ bar, Rolipra -sensitiv) angesehen. Die Spezifizität der Hemmung wird dabei durch den Quotienten aus [IC50]pDE- JJj./[IC50]pDE JV (PDE III = hoch affine cAMP-PDE durch cGMP hemmbar) beschrieben [H.Hidaka et al . , Adv.Cycl .Nucl . Res. 13, 145 (1984); TiPS 5, 237 (1984); R.Weishaar et al . , J.Med.Chem. £8, (1985); S.A.Harrison et al . , Molec. Pharmac. ZU, 506 (1986); J.Klein-Tebbe et al., Allergologie 12, 12 (1989); C.Schudt et al . , Allergologie 12, 12 (1989); C.Schudt et al . , Agents and Aetion 1991 im Druck; C.D.Nicholson et al., TiPS 1Z, (1), 19 (1991)]. Deshalb wurde die PDE-Hemmung der erfindungsgemäßen Verbindungen an einer aus humanen Thro bozyten isolierten PDE III bzw. aus humanen neutrophilen polymorphkernigen Zellen (PMN's) sowie aus der Hundetrachea isolierten PDE IV bestimmt. Die Phosphodiesterasen III und IV werden nach Polson et al., Bioche . Phar acol .21, 3403-3406 (1982) chromatographisch isoliert.The specific inhibition of phosphodiesterase IV (PDE IV = high affinity cAMP-PDE cannot be inhibited by cGMP, Rolipra-sensitive) is regarded as particularly meaningful for an expected bronchospasmolytic and / or anti-inflammatory effect. The specificity of the inhibition is described by the quotient from [IC 50 ] pDE - JJj./[IC 50 ] pDE JV (PDE III = high affinity cAMP-PDE inhibitable by cGMP) [H.Hidaka et al. , Adv.Cycl .Nucl. Res. 13, 145 (1984); TiPS 5, 237 (1984); R. Weishaar et al. , J.Med.Chem. £ 8, (1985); SA Harrison et al. , Molec. Pharmac. ZU, 506 (1986); J. Klein-Tebbe et al., Allergologie 12, 12 (1989); C. Schudt et al. , Allergologie 12, 12 (1989); C. Schudt et al. , Agents and Aetion 1991 in press; CDNicholson et al., TiPS 1Z, (1), 19 (1991)]. The PDE inhibition of the compounds according to the invention was therefore determined on a PDE III isolated from human thrombocytes or from human neutrophilic polymorphonuclear cells (PMN's) and from PDE IV isolated from the dog trachea. The phosphodiesterases III and IV are according to Polson et al., Bioche. Phar acol .21, 3403-3406 (1982) chromatographically isolated.
Die Substanzen werden in DMSO gelöst und weiter verdünnt. Aus einer Reihe von bis hundertfach verdünnten Lösungen werden jeweils 2,1 μl vorgelegt und mit 212 μl Reaktionsgemisch versetzt. Das Reaktionsgemisch enthält Hepes (100 mrnol/1), DTE (5 mmol/1), MgCl2 (5 mmol/1), CaCl2 (10 μmol/1), BSA Fraktion V 0,5 mg/ml, cAMP 0,5 μmol/1, 2,8 - 3H-cAMP 250000 cpm/ml (0,3 μCi/ml, s.A. 33,5 μCi/mmol), SV (snake venom) 25 μg/212 μl Testan¬ satz).The substances are dissolved in DMSO and further diluted. 2.1 .mu.l of each are introduced from a series of solutions diluted up to 100 times and 212 .mu.l of reaction mixture are added. The reaction mixture contains Hepes (100 mmol / 1), DTE (5 mmol / 1), MgCl 2 (5 mmol / 1), CaCl 2 (10 μmol / 1), BSA fraction V 0.5 mg / ml, cAMP 0, 5 mol / 1, 2.8 to 3 H-cAMP 250,000 cpm / ml (0.3 uCi / ml, SA 33.5 Ci / mmol), SV (snake venom) 25 ug / 212 ul Testan¬ set).
In der Tabelle 4 sind die negativen Logarithmen der gefundenen ICςQWerte und die Quotienten aus den für die PDE III- und PDE IV-Hemmung ermittelten IC50-Werten der erfindungsgemäßen Substanzen aufgeführt. Die erfindungsge¬ mäßen Substanzen hemmen die PDE IV bedeutend spezifischer und stärker als Theophyllin.Table 4 shows the negative logarithms of the IC ςQ values found and the quotients from the IC 50 values of the substances according to the invention determined for PDE III and PDE IV inhibition. The substances according to the invention inhibit PDE IV significantly more specifically and more strongly than theophylline.
Tabelle 4Table 4
Hemmung der PDE III und PDE IVInhibition of PDE III and PDE IV
Lfd. PDE III PDE IV PDE IV [IC5Q]PDE 111/ [IC5Q]PDE 111/Current PDE III PDE IV PDE IV [IC 5Q ] PDE 111 / [IC 5Q ] PDE 111 /
Nr. hum.Thromb. Hund Trachea hum.PMN's [IC5Q]PDE IV [IC5Q]PDE IVNo. hum.thromb. Dog Trachea hum.PMN's [IC 5Q ] PDE IV [IC 5Q ] PDE IV
-lg[IC50] -lg IC50] -lg[IC50] PMN's-lg [IC 50 ] -lg IC 50 ] -lg [IC 50 ] PMN's
6,18 > 1516.18> 151
Fortsetzung Tabelle 4 Continuation of table 4
Lfd. PDE III PDE IV PDE IV [IC50]PDE 111/ [IC5Q]PDE 111/Current PDE III PDE IV PDE IV [IC 50 ] PDE 111 / [IC 5Q ] PDE 111 /
Nr. hum.Thro b. Hund Trachea hum.PMN's [IC5Q]PDE IV [IC50]PDE IV -1g[IC50] -lg[IC50] -lg[IC50] Hund-Tr. PMN'sNo. hum.Thro b. Dog Trachea hum.PMN's [IC 5Q ] PDE IV [IC 50 ] PDE IV -1g [IC 50 ] -lg [IC 50 ] -lg [IC 50 ] Hund-Tr. PMN's

Claims

Patentansprüche Claims
1. 3-Amino-6-aryl-pyridazine der allgemeinen Formel I1. 3-amino-6-aryl-pyridazines of the general formula I
worin einer der Substituenten Rl und R2 Methoxy, Difluormethoxy oder Ethoxy, und der andere l-5C-Alkoxy, 4-7C-Cycloalkoxy, 3-7C-Cycloalkyl- methoxy, 3-5C-Alkenyloxy oder l-4C-Polyfluoralkoxy bedeutet, X Amino bedeutet, und ihre Salze mit Säuren und ihre N-Oxide.wherein one of the substituents R1 and R2 is methoxy, difluoromethoxy or ethoxy, and the other is 1-5C-alkoxy, 4-7C-cycloalkoxy, 3-7C-cycloalkyl-methoxy, 3-5C-alkenyloxy or 1-4C-polyfluoroalkoxy, X Amino means and their salts with acids and their N-oxides.
2. 3-Amino-6-aryl-pyridazine der allgemeinen Formel I nach Anspruch 1, worin2. 3-amino-6-aryl-pyridazines of the general formula I according to claim 1, wherein
Rl Methoxy, Difluormethoxy oder Ethoxy,Rl methoxy, difluoromethoxy or ethoxy,
R2 l-4C-Alkoxy, 4-7C-Cycloalkoxy, 3-6C-Cycloalkylmethoxy, 3-4C-Alkenyloxy oder l-2C-Polyfluoralkoxy und X Amino bedeutet, und ihre Salze mit Säuren und ihre N-Oxide.R2 is 1-4C-alkoxy, 4-7C-cycloalkoxy, 3-6C-cycloalkylmethoxy, 3-4C-alkenyloxy or 1--2C-polyfluoroalkoxy and X is amino, and their salts with acids and their N-oxides.
3. 3-Amino-6-aryl-pyridazine der allgemeinen Formel I nach Anspruch 1, worin3. 3-amino-6-aryl-pyridazines of the general formula I according to claim 1, wherein
Rl 3-4C-Alkoxy, 4-7C-Cycloalkoxy, 3 -6C-Cycloalkyl methoxy, 3-4C-Alkenyloxy oder l-2C-Polyfluoralkoxy, R2 Methoxy, Difluormethoxy oder Ethoxy und X Amino bedeutet, und ihre Salze mit Säuren und ihre N-Oxide.Rl is 3-4C-alkoxy, 4-7C-cycloalkoxy, 3-6C-cycloalkyl methoxy, 3-4C-alkenyloxy or l-2C-polyfluoroalkoxy, R2 is methoxy, difluoromethoxy or ethoxy and X is amino, and their salts with acids and their N-oxides.
4. Verbindungen der Formel I nach Anspruch 1, worin einer der Substituenten Rl und R2 Methoxy, Difluormethoxy oder Ethoxy, und der andere l-4C-Alkoxy, 4-7C-Cycloalkoxy, 3-6C-Cycloalkyl methoxy oder l-2C-Polyfluoral oxy bedeutet und X Amino bedeutet, und ihre Salze mit Säuren und ihre N-Oxide. 4. Compounds of formula I according to claim 1, wherein one of the substituents Rl and R2 methoxy, difluoromethoxy or ethoxy, and the other 1-4C-alkoxy, 4-7C-cycloalkoxy, 3-6C-cycloalkyl methoxy or l-2C-polyfluoral oxy means and X means amino, and their salts with acids and their N-oxides.
5. Verbindungen der Formel I nach Anspruch 1, worin Rl 2-4C-Alkoxy, Cyclo¬ pentyloxy, Cyclopropylmethoxy, Cyclobutylmethoxy, Difluormethoxy oder 2,2,2-Trifluorethoxy bedeutet, R2 Methoxy, Ethoxy oder Difluormethoxy be¬ deutet und X Amino bedeutet, und ihre pharmakologisch verträglichen Salze mit Säuren und ihre N-Oxide.5. Compounds of formula I according to claim 1, wherein Rl is 2-4C-alkoxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, difluoromethoxy or 2,2,2-trifluoroethoxy, R2 is methoxy, ethoxy or difluoromethoxy and X is amino , and their pharmacologically acceptable salts with acids and their N-oxides.
6. Verfahren zur Herstellung der 3-Amino-6-aryl-pyridazine der allgemeinen Formel I nach Anspruch 1, worin Rl, R2 und X die in Anspruch 1 angegebene Bedeutung haben, und ihrer Salze mit Säuren und ihrer N-Oxide, dadurch ge¬ kennzeichnet, daß man6. A process for the preparation of the 3-amino-6-aryl-pyridazines of the general formula I according to claim 1, wherein Rl, R2 and X have the meaning given in claim 1, and their salts with acids and their N-oxides, thereby ge ¬ indicates that one
a) Verbindungen der Formel II,a) compounds of the formula II,
worin Rl und R2 die in Anspruch 1 angegebene Bedeutung besitzen und Y eine nucleophil verdrängbare Abgangsgruppe bedeutet, mit Ammoniak um¬ setzt, oder daß manwherein Rl and R2 have the meaning given in claim 1 and Y is a nucleophilically displaceable leaving group, reacted with ammonia, or that
b) 3-Hydrazino-pyridazin der Formel III,b) 3-hydrazino-pyridazine of the formula III,
worin Rl und R2 die in Anspruch 1 angegebene Bedeutung haben, kata¬ lytisch hydriert, oder daß man c) Phosphazene der Formel IV,wherein Rl and R2 have the meaning given in claim 1, catalytically hydrogenated, or that c) phosphazenes of the formula IV,
worin Rl und R2 die in Anspruch 1 angegebene Bedeutung haben, hydroly- siert, oder daß manwherein Rl and R2 have the meaning given in claim 1, hydrolyzed, or that
d) BenzylVerbindungen der Formel V,d) benzyl compounds of the formula V,
worin Rl und R2 die in Anspruch 1 angegebene Bedeutung haben, kata¬ lytisch hydriert,wherein R1 and R2 have the meaning given in claim 1, catalytically hydrogenated,
und daß man gewünschtenfalls anschließend die nach a), b), c) oder d) er¬ haltenen Verbindungen I in ihre Salze überführt, oder daß man gewünschten¬ falls anschließend aus erhaltenen Salzen der Verbindungen I die Verbin¬ dungen I freisetzt, oder daß man gewünschtenfalls anschließend die nach a), b), c) oder d) erhaltenen Verbindungen I in ihre N-Oxide überführt.and that, if desired, the compounds I obtained according to a), b), c) or d) are subsequently converted into their salts, or if desired the compounds I are subsequently released from the salts of the compounds I obtained, or that if desired, the compounds I obtained according to a), b), c) or d) are subsequently converted into their N-oxides.
7. Arzneimittel enthaltend eine oder mehrere Verbindungen nach Anspruch 1.7. Medicament containing one or more compounds according to claim 1.
8. Verbindungen nach Anspruch 1 zur Anwendung bei der Behandlung und/oder Prophylaxe von Erkrankungen der Bronchien.8. Compounds according to claim 1 for use in the treatment and / or prophylaxis of diseases of the bronchi.
9. Verwendung der Verbindungen nach Anspruch 1 zur Herstellung von Arznei¬ mitteln zur Behandlung und/oder Prophylaxe von Erkrankungen der Bronchien. 9. Use of the compounds according to claim 1 for the manufacture of medicaments for the treatment and / or prophylaxis of diseases of the bronchi.
10. Verbindungen nach Anspruch 1 zur Anwendung bei der Behandlung und/oder Prophylaxe von Dermatosen bei Säugern, insbesondere Menschen.10. Compounds according to claim 1 for use in the treatment and / or prophylaxis of dermatoses in mammals, especially humans.
11. Verbindungen nach Anspruch 1 zur Anwendung bei der Behandlung und/oder Prophylaxe von proliferativen, entzündlichen oder allergischen Hauterkran¬ kungen bei Säugern, insbesondere Menschen.11. Compounds according to claim 1 for use in the treatment and / or prophylaxis of proliferative, inflammatory or allergic skin diseases in mammals, especially humans.
12. Verbindungen nach Anspruch 1 zur Anwendung bei der Behandlung und/oder Prophylaxe von Psoriasis oder atopischer Dermatitis bei Säugern, insbeson¬ dere Menschen.12. Compounds according to claim 1 for use in the treatment and / or prophylaxis of psoriasis or atopic dermatitis in mammals, in particular humans.
13. Verwendung der Verbindungen nach Anspruch 1 zur Herstellung von Arznei¬ mitteln für die Behandlung von Dermatosen. 13. Use of the compounds according to claim 1 for the manufacture of medicaments for the treatment of dermatoses.
EP92908818A 1991-04-26 1992-04-21 Novel pyridazines Withdrawn EP0581805A1 (en)

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