WO2001019818A1 - Derives de phthalazinone utilises comme inhibiteurs de pd3/4 - Google Patents

Derives de phthalazinone utilises comme inhibiteurs de pd3/4 Download PDF

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WO2001019818A1
WO2001019818A1 PCT/EP2000/008900 EP0008900W WO0119818A1 WO 2001019818 A1 WO2001019818 A1 WO 2001019818A1 EP 0008900 W EP0008900 W EP 0008900W WO 0119818 A1 WO0119818 A1 WO 0119818A1
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formula
compounds
hydrogen
alkyl
covalent bond
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PCT/EP2000/008900
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Jan Geert Sterk
Wolf-Rüdiger Ulrich
Ulrich Thibaut
Armin Hatzelmann
Daniela Bundschuh
Hildegard Boss
Hans-Peter Kley
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Byk Gulden Lomberg Chemische Fabrik Gmbh
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Priority to AU76542/00A priority Critical patent/AU7654200A/en
Publication of WO2001019818A1 publication Critical patent/WO2001019818A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators

Definitions

  • the invention relates to novel Phthalazinones, which are used in the pharmaceutical industry for the production of medicaments.
  • the invention thus relates to compounds of the formula I
  • R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R2 is 1-4C-alkyl and R3 is hydrogen or 1-4C-alkyl, or wherein ⁇ R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro- linked 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen or sulphur atom
  • R4 and R5 are both hydrogen or together form an additional bond, and in which either X is a covalent bond and
  • Y is a covalent bond
  • X is -C n H 2n - and
  • Y is O (oxygen), S (sulfur), carboxylate (-C(O)-O-), carboxamido (-C(O)NH-) or sulfonamido (-S(0) 2 -NH-), or
  • X is phenylene
  • Y is carboxylate (-C(O)O-), carboxamido (-C(O)NH-) or sulfonamido (-S(0) 2 NH-), R6 represents a radical of formula (a)
  • A is S (sulphur) or -CH(R61 )-
  • R61 is hydrogen or 1-4C-alkyl
  • R62 is hydrogen or 1-4C-alkyl, or wherein
  • n is an integer from 1 to 6, and the salts of these compounds.
  • 1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
  • 1-4C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
  • Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned in this context are, for example, the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, iso- propoxy, ethoxy and methoxy radicals.
  • 3-5C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.
  • 3-5C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy.
  • 1-4C-AIkoxy which is completely or predominantly substituted by fluorine is, for example, the 2,2,3, 3,3-pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy and in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxy radical, of which the difluoromethoxy radical is preferred.
  • "Predominantly" in this connection means that more than half of the hydrogen atoms of the 1-4C-alkoxy group are replaced by fluorine atoms.
  • spiro-linked 5-, 6- or 7-membered hydrocarbon rings optionally interrupted by an oxygen or sulphur atom
  • the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahydro- pyran and the tetrahydrothiophen ring may be mentioned the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahydro- pyran and the tetrahydrothiophen ring.
  • Possible radicals -C n H 2n - are straight chain or branched radicals. Examples which may be mentioned are the hexylene, pentylene, butylene, isobutylene, sec-butylene, tert-butylene, propylene, isopropyle- ne, ethylene and the methylene radical.
  • Suitable salts for compounds of the formula I - depending on substitution - are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically tolerable inorganic and organic acids and bases customarily used in pharmacy. Those suitable are, on the one hand, water- soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, tolu- enesulphonic acid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acids being employed in
  • salts with bases are - depending on substitution - also suitable.
  • salts with bases are mentioned the lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, meglumine or guanidinium salts, here, too, the bases being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
  • Pharmacologically intolerable salts which can be obtained, for example, as process products during the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
  • the compounds of the invention as well as their salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula I as well as all solvates and in particular all hydrates of the salts of the compounds of formula I.
  • R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R2 is 1-4C-alkyl and R3 is hydrogen or 1-4C-alkyl, or wherein R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro- linked cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring
  • R4 and R5 are both hydrogen or together form an additional bond, and in which either X is a covalent bond and
  • Y is a covalent bond
  • X is -C n H 2n - and
  • Y is O (oxygen), carboxamido (-C(O)NH-) or sulfonamido (-S(0) 2 NH-), or
  • X is phenylene
  • Y is carboxamido (-C(O)NH-) or sulfonamido (-S(0) 2 NH-), R6 represents a radical of the formula (a)
  • A is S (sulphur) or -CH(R61 )-
  • R61 is hydrogen or 1-2C-alkyl
  • R62 is hydrogen or 1-2C-alkyl, or wherein
  • n is an integer from 1 to 6, and the salts of these compounds.
  • R1 is 1-2C-alkoxy or 1-2C-aIkoxy which is completely or predominantly substituted by fluorine,
  • R2 is 1-4C-alkyl
  • R3 is hydrogen or 1-4C-alkyl, or wherein
  • R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro- linked cyclopentane or cyclohexane ring, R4 and R5 are both hydrogen or together form an additional bond, and in which either X is a covalent bond and
  • Y is a covalent bond
  • X is -C n H 2n - and
  • Y is O (oxygen) or carboxamido (-C(O)NH-) or
  • X is phenylene
  • Y is carboxamido (-C(O)NH-),
  • R6 represents a radical of formula (a)
  • A is S (sulphur) or -CH(R61 )-
  • R61 is hydrogen
  • R62 is methyl, or wherein
  • n is an integer from 1 to 6, and the salts of these compounds.
  • Preferred compounds of formula I are those in which R1 is methoxy or difluoromethoxy, R2 is methyl, R3 is hydrogen, or wherein
  • R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro- linked cyclopentane ring, R4 and R5 together form an additional bond, and in which either
  • X is a covalent bond
  • Y is a covalent bond
  • X is -C n H 2n - and
  • Y is O (oxygen) or carboxamido (-C(O)NH-) or
  • X is phenylene
  • Y is carboxamido (-C(O)NH-),
  • R6 represents a radical of formula (a)
  • A is S (sulphur) or -CH(R61 )-
  • R61 is hydrogen
  • R62 is methyl, or wherein
  • n is an integer from 1 to 6, and the salts of these compounds.
  • R1 is methoxy
  • R2 is methyl
  • R3 is hydrogen, or wherein
  • R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro- linked cyclopentane ring, R4 and R5 together form an additional bond, and in which either X is a covalent bond and Y is a covalent bond or X is -(CH 2 ) 6 - and Y is O (oxygen),
  • R6 represents a radical of formula (a)
  • R61 is hydrogen
  • R62 is methyl, and the salts of these compounds
  • the compounds of formula I are chiral compounds with a chiral center in the dihydrofuran-nng, if the substituents -R2 and -CH 2 R3 are not identical However, preferred are those compounds, in which the substituents -R2 and -CH 2 R3 are identical or together and with inclusion of the carbon atoms to which they are bonded form a spiro-connected 5-, 6- or 7-membered hydrocarbon ring Additional chiral centers exist in the positions 4a and 8a
  • the invention includes all conceiveable pure diastereomers and pure enantiomers, as well as all mixtures thereof independent from the ratio, including the racemates
  • Preferred are those compounds, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated
  • Racemates can be split up into the corresponding enantiomers by methods known by a person skilled in the art
  • the racemic mixtures are separated into two diastereomers with the help of an optical active separation agent on the stage of the cyclohexanecarboxylic acids or the 1 ,2,3,6-tetrahydrobenzoic acids (for example, starting compound A3)
  • optical active 9 amines such as the (+)- and (-)-forms of ⁇ -methylbenzylamine and ephedrine
  • the invention further relates to processes for the preparation of compounds of formula I and their salts (compare Table 1 ).
  • R1 , R2, R3, R4 and R5 have the above-mentioned meanings with a hydrazine derivative of the formula R6-NH-NH 2 in which R6 has the above-mentioned meanings.
  • the reaction of the keto acids of formula II or one of their reactive derivatives with a hydrazine derivative of formula R6-NH-NH 2 is advantageously carried out with one to three equivalents of the hydrazine derivatives of formula R6-NH-NH 2 .
  • solvent are preferably used alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isoamylalcohol, ethers, glycols and their ethers such as ethylene glycol, diethylene glycol, ethylene glycol monomethyl or ethylene glycol monoethyl ether and especially water soluble ethers such as tetrahydrofuran or dioxane; further toluene or benzene, especially when the method of azeotropic destination is used to remove the reaction water.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isoamylalcohol
  • ethers glycols and their ethers such as ethylene glycol, diethylene glycol, ethylene glycol monomethyl or ethylene glycol monoethyl ether and especially water soluble ethers such as tetrahydrofuran or dio
  • Keto acids of the formula II, in which R1 , R2, R3, R4 and R5 have the above-mentioned meanings can, for example, be prepared from compounds of the formula III,
  • R1 , R2 and R3 have the above-mentioned meanings and Z represents hydrogen (H) by Friedel-Crafts acylation with compounds of the formula IV,
  • R4 and R5 have the above-mentioned meanings.
  • the Friedel-Crafts acylation is carried out in a manner which in known by the skilled person (for example as described in M. Yamaguchi et al., J. Med. Chem. 36: 4052-4060, 1993) in presence of a suitable catalyst, such as for example, AICI 3 , ZnCI 2 , FeCI 3 or iodine, in an appropriate inert solvent, such as methylene chloride or nitrobenzene or another inert solvent such as diethylether, preferably at raised temperature, in particular at the boiling point of the solvent used.
  • a suitable catalyst such as for example, AICI 3 , ZnCI 2 , FeCI 3 or iodine
  • the compounds of formula II in which R1 , R2, R3, R4 and R5 have the above-mentioned meanings, can be prepared from compounds of the formula III, in which R1 , R2 and R3 have the above-mentioned meanings and Z represents a halogen atom through reaction with compounds of the formula IV, in which R4 and R5 have the above-mentioned meanings.
  • hydrazine derivatives of formula R6-NH-NH 2 are described, for example, by A. Mertens et al. in J.Med.Chem. 33, 2870-2875, 1990. Further hydrazine derivatives of formula R6-NH-NH 2 , of which the preparation is explicitly not described, can be prepared in an analogous way or in a way which is known by a person skilled in the art using customary preparation methods.
  • R1 , R2, R3, R4 and R5 have the above-mentioned meanings and X represents -C n H 2n - or phenylene with a phenol of formula R6-OH or an amine of formula R6-NH 2 , in which R6 has the above-mentioned meanings.
  • the reactions can be performed using customary reaction conditions for example as described in the following examples.
  • the carboxamide linkage can also be prepared using any coupling method described by M. Bodansky and A. Bodansky in "The Practice of Peptide Synthesis", Springer Verlag, Berlin 1984.
  • Acids of formula V or sulfonic acids of formula VI in which X represents phenylene can be prepared analogously to the method described under method A starting from compounds of formula II using a hydrazine derivative such as for example hydrazinobenzoic acid or hydrazinobenzenesulfonic acid.
  • a hydrazine derivative such as for example hydrazinobenzoic acid or hydrazinobenzenesulfonic acid.
  • Acids of formula V or sulfonic acids of formula VI in which X represents -C n H 2n - can in a first step also be prepared analogously to the method described under method A starting from compounds of formula II using hydrazine hydrate instead of a hydrazine derivative of formula R6-NH-NH 2 .
  • Deprotonation of the N-H group followed by an alkylation step yields the acids of formula V or the sulfonic acids of formula VI.
  • the hydrogen atom of the NH-group is removed by a base such as, for example, potassium carbonate, sodium hydroxide, sodium hydride, sodium methanolat or sodium ethanolat in a suitable inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or diethylether.
  • a base such as, for example, potassium carbonate, sodium hydroxide, sodium hydride, sodium methanolat or sodium ethanolat in a suitable inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or diethylether.
  • alkylation reagents may be mentioned, for example, 4-bromobutanoic acid, ethyl bromacetate or 4-bromo- butanesulfonic acid.
  • Amines of formula R6-NH 2 can be prepared, for example, as described by Edgar A. Steck et al., J. Heterocyclic Chem. 1974, 1_1_, 75
  • R1 , R2, R3, R4 and R5 have the above-mentioned meanings
  • X represents -C n H 2n -
  • W represents a suitable leaving group, for example a halogen atom, preferably bromine, with a phenol of formula R6-OH or a thiophenol of formula R6-SH, in which R6 has the above-mentioned meanings.
  • the reaction is preferably carried out under basic conditions in an inert solvent like dimethylformamide, dimethylsulfoxide or tetrahydrofuran.
  • the compounds of formula VII can be prepared analogously to the method described for the corresponding acids of formula V under method B using in the alkylation step ⁇ . ⁇ '-dihalogenalkanes instead of the ⁇ , ⁇ '-halogenalkanoic acids.
  • the substances according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or a subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
  • Salts are obtained by dissolving the free compound in a suitable solvent (for example a ketone like acetone, methylethylketone, or methylisobutylketone, an ether, like diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol, such as ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basification or by acidifying into the free compounds which, in turn, can be converted into salts. In this manner, pharmacologically non-tolerable salts can be converted into pharmacologically tolerable salts.
  • a mixture of 1.0 g of starting compound A1 , 0.5 g of starting compound A7 and 1.0 g of potassium carbonate in 10 ml of DMF is stirred for 40 h at RT. After the addition of 50 ml of water, the mixture is extracted with diethyl ether (3x100 ml). The ether layer is dried over magnesium sulfate and evaporated. The residue is purified by chromatography [silica; ethyl acetate:petroleum ether (60-80°C)/1 :1]. The title compound is crystallised from diethyl ether. M. p. 166-169°C.
  • a mixture of 5 g of A2, 20 g of 1 ,6-dibromohexane and 10 g of potassium carbonate in 50 ml of DMF is stirred at RT for 18 h. After the addition of 200 ml of water, the mixture is extracted with diethyl ether (3 x 200ml). The ether layer is dried over magnesium sulfate and evaporated. The residue is crystallised from petroleum ether (60-80°C). M. p. 80-82°C
  • a solution of 35 g of compound A4 in 350 ml tetrahydrofuran is added slowly to 3.5 g of magnesium in 50 ml of tetrahydrofuran. After complete addition, the mixture is refluxed for 5 h and left at room temperature for additional 18 h. This mixture is added slowly to a solution of 18.8 g of (cis)-1 ,2,3,6-tetrahydro- phthalic anhydride in tetrahydrofuran at 0°C. After complete addition the mixture is refluxed for 6 h and left at room temperature for additional 18 hours after which the reaction is quenched with ammonium chloride and the solvent removed under reduced pressure.
  • the compounds according to the invention have valuable pharmacological properties which make them commercially utilizable.
  • selective inhibitors of type 3 and 4 of cyclic nucleotide phosphodiesterase (PDE3, PDE4) they are suitable on the one hand as bronchial therapeutics (for the treatment of airway obstructions on account of their dilating and cilium-stimulating action but also on account of their respiratory rate- and respiratory drive-increasing action), but on the other hand especially for the treatment of disorders of inflammatory nature, e.g.
  • mediators such as interferons, members of the tumor necrosis factor family, interleukins, chemokines, colony-stimulating factors, growth factors, lipid mediators (e.g., inter alia, PAF, platelet-activating factor), bacterial factors (e.g. LPS), immunoglobulins, oxygen free radicals and related free radicals (e.g. nitrogen monoxide NO), biogenic amines (e.g. histamine, serotonin), kinins (e.g.
  • bradykinin neurogenic mediators (such as substance P, neurokinin), proteins such as, for example, granular contents of leukocytes (inter alia cationic proteins of eosinophils) and adherent proteins (e.g. integrins).
  • the compounds according to the invention have smooth muscle-relaxant action, e.g. in the region of the bronchial system, of the blood circulation, and of the efferent urinary passages. Furthermore they have a cilium-frequency increasing action, e.g. in the bronchial system.
  • the compounds according to the invention are distinguished by low toxicity, good human acceptance, good enteral absorption and high bioavailability, great therapeutic breadth, the absence of significant side effects and good water solubility.
  • the compounds according to the invention can be employed as therapeutics in human and veterinary medicine, where they can be used, for example, for the treatment and prophylaxis of the following diseases: acute and chronic (in particular inflammatory and allergen-induced) airway disorders of various origin (bronchitis, allergic bronchitis, bronchial asthma, COPD); disorders with a reduction of the cilium activity or with increased demands on the ciliar clearance (bronchitis, mucoviscidose); dermatoses (especially of proliferative, inflammatory and allergic type) such as, for example, psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritis in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and widespread
  • the compounds according to the invention can also be used for the treatment of high blood pressure disorders of various origin such as, for example, pulmonary high blood pressure and the concomitant symptoms associated therewith, for the treatment of erectile dysfunction or colics of the kidneys and the ureters in connection with kidney stones.
  • PDE inhibitors such as, for example, cardiac insufficiency, and also as anti- thrombotic, platelet aggregation-inhibiting substances.
  • the invention further relates to a method for the treatment of mammals including humans who are suffering from one of the above-mentioned diseases.
  • the method comprises administering a therapeutically effective and pharmacologically tolerable amount of one or more of the compounds according to the invention to the sick mammal.
  • the invention further relates to the compounds according to the invention for use in the treatment and/or prophylaxis of diseases, especially the diseases mentioned.
  • the invention also relates to the use of the compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the diseases mentioned.
  • the invention furthermore relates to medicaments for the treatment and/or prophylaxis of the diseases mentioned and which contain one or more of the compounds according to the invention.
  • the substances according to the invention are also suitable for combination with other substances which bring about stimulation of cAMP, such as prostaglandins (PGE2, PGI2 and prosta- cyclin) and their derivatives, direct adenylate cyclase stimulators such as forskolin and related substances, or substances indirectly stimulating adenylate cyclase, such as catecholamines and adrenergic receptor agonists, in particular beta mimetics.
  • PGE2 prostaglandins
  • PGI2 prostaglandins
  • prosta- cyclin direct adenylate cyclase stimulators
  • adenylate cyclase such as catecholamines and adrenergic receptor agonists, in particular beta mimetics.
  • they in this case display a synergistic, superadditive activity. This comes to bear, for example, in their use in combination with PGE2 for the treatment of pulmonary hypertension.
  • the invention relates to an article of manufacture, which comprises packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective for antagonizing the effects of the cyclic nucleotide phosphodiesterases of type 3 and 4 (PDE3/4), ameliorating the symptoms of an PDE3/4-mediated disorder, and wherein the packaging material comprises a label or package insert which indicates that the pharmaceutical agent is useful for preventing or treating PDE3/4-mediated disorders, and wherein said pharmaceutical agent comprises one or more compounds of formula I according to the invention.
  • the packaging material, label and package insert otherwise parallel or resemble what is generally regarded as standard packaging material, labels and package inserts for pharmaceuticals having related utilities.
  • the compounds according to the invention are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries, e.g. in the form of tablets, coated tablets, capsules, suppositories, patches, emulsions, suspensions, gels or solutions, the active compound content advantageously being between 0.1 and 95%.
  • auxiliaries which are suitable for the desired pharmaceutical formulations.
  • Beside solvents, gel-forming agents, ointments bases and other active compound excipients it is possible to use, for example, antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters.
  • the compounds according to the invention are preferably also administered by inhalation.
  • these are administered either directly as a 2V powder (preferably in micronized form) or by atomization of solutions or suspensions which contain them.
  • a 2V powder preferably in micronized form
  • atomization of solutions or suspensions which contain them are administered either directly as a 2V powder (preferably in micronized form) or by atomization of solutions or suspensions which contain them.
  • the compounds according to the invention are used in particular in the form of those medicaments which are suitable for topical application.
  • suitable pharmaceutical formulations which may be mentioned are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.
  • the medicaments according to the invention are prepared by methods known per se.
  • the dosage of the active compounds takes place in the order of magnitude customary for PDE inhibitors.
  • topical application forms (such as, for example, ointments) for the treatment of dermatoses contain the active compounds in a concentration of, for example, 0.1-99%.
  • the dose for administration by inhalation is customarily between 0.1 and 3 mg per day.
  • the customary dose in the case of systemic therapy (p.o. or i.v.) is between 0.01 and 10 mg/kg per day.
  • Substances which inhibit chemiluminescence, and/or cytokine secretion, and/or the secretion of inflammation-increasing mediators in inflammatory cells like T-lymphocytes, monocytes, macrophages and granulocytes are those which inhibit PDE4 or PDE3 and PDE4.
  • the latter isoenzyme of the phosphodi- esterase families is particularly represented in granulocytes. Its inhibition leads to an increase in the intracellular cyclic AMP concentration and thus to the inhibition of cellular activation.
  • PDE4 inhibition by the substances according to the invention is thus a central indicator of the suppression of inflammatory processes.
  • the PDE activity was determined according to Thompson et al. (1 ) with some modifications (2).
  • the test samples contained 40 mM tris HCl (pH 7.4), 5 mM MgCI 2 , 0.5 ⁇ M cAMP or cGMP, [ 3 H] cAMP or [ 3 H]cGMP (about 50,000 cpm/sample), the PDE isoenzyme-specific additions described in greater detail below, the indicated concentrations of inhibitor and an aliquot of the enzyme solution in a total sample volume of 200 ⁇ l.
  • Stock solutions of the compounds to be investigated in DMSO were prepared in concentrations such that the DMSO content in the test samples did not exceed 1% by volume - to avoid an effect on the PDE activity.
  • the reaction was started by addition of the substrate (cAMP or cGMP).
  • the samples were incubated at 37°C for a further 15 min.
  • the reaction was terminated by addition of 50 ⁇ l of 0.2N HCl.
  • 25 ⁇ g of 5'-nucleotidase (snake venom from Crotalus atrox)
  • the mixture was again incubated at 37°C for 10 min and the samples were then applied to QAE Sephadex A-25 columns.
  • the columns were eluted with 2 ml of 30 mM ammonium formate (pH 6.0).
  • the radioactivity of the eluate was measured and corrected by the corresponding blank values.
  • the proportion of hydroly- zed nucleotide in no case exceeded 20% of the original substrate concentration.
  • PDE1 Ca 2 7calmodulin-dependent
  • PDE2 (cGMP-stimulated) from rat hearts was purified chromatographically [Schudt et al. (4)] and investigated in the presence of cGMP (5 ⁇ M) using cAMP as a substrate.
  • PDE3 cGMP-inhibited
  • PDE5 cGMP-specific
  • PDE4 cAMP-specific was investigated in the cytosol of human polymorphonuclear leukocytes (PMNL) [isolated from leukocyte concentrates, see Schudt et al. (5)] using cAMP as a substrate.
  • PMNL human polymorphonuclear leukocytes
  • IC 50 values were determined from the concentration-inhibition curves by nonlinear regression using the GraphPad InPlotTM program (GraphPad Software Inc., Philadelphia, USA). 3. References

Abstract

La présente invention concerne des composés de la formule (I), dans laquelle R1, R2, R3, R4, R5, R6, X et Y sont tels que définis dans le descriptif, lesquels composés constituent un nouveau traitement bronchique efficace.
PCT/EP2000/008900 1999-09-14 2000-09-12 Derives de phthalazinone utilises comme inhibiteurs de pd3/4 WO2001019818A1 (fr)

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EP99118235 1999-09-14
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WO2002085885A1 (fr) * 2001-04-25 2002-10-31 Altana Pharma Ag Derives piperazines et leur utilisation en tant qu'inhibiteurs de pde4
WO2004018449A1 (fr) * 2002-08-10 2004-03-04 Altana Pharma Ag Derives de piperidine utilises comme inhibiteurs de la phospodiesterase-4 (pde4)
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US7494990B2 (en) 2004-02-04 2009-02-24 Nycomed Gmbh 2-(piperidin-4-yl)-4,5-dihydro-2H-pyridazin-3-one derivatives as PDE4 inhibitors
CN102964340A (zh) * 2012-12-12 2013-03-13 中国药科大学 一类治疗阿尔茨海默病的选择性多巴胺d1受体激动剂
WO2013106547A1 (fr) 2012-01-10 2013-07-18 President And Fellows Of Harvard College Composés promoteurs de réplication des cellules bêta et leurs procédés d'utilisation

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US7531540B2 (en) 2001-02-15 2009-05-12 Nycomed Gmbh Phthalazinone-piperidino-derivatives as PDE4 inhibitors
US6953853B2 (en) 2001-02-15 2005-10-11 Altana Pharma Ag Phthalazinone-piperidino-derivatives as PDE4 inhibitors
US7179810B2 (en) 2001-02-15 2007-02-20 Altana Pharma Ag Phthalazinone-piperidino-derivatives as PDE4 inhibitors
WO2002085885A1 (fr) * 2001-04-25 2002-10-31 Altana Pharma Ag Derives piperazines et leur utilisation en tant qu'inhibiteurs de pde4
US7022696B2 (en) 2001-04-25 2006-04-04 Altana Pharma Ag Piperazino-derivatives and their use as PDE4 inhibitor
US7186710B2 (en) 2001-04-25 2007-03-06 Altana Pharma Ag Phthalazinones
US7220746B2 (en) 2002-08-10 2007-05-22 Altana Pharma Ag Pyrrolidinedione substituted piperidine-phthalazones as PDE4 inhibitors
WO2004018449A1 (fr) * 2002-08-10 2004-03-04 Altana Pharma Ag Derives de piperidine utilises comme inhibiteurs de la phospodiesterase-4 (pde4)
US7494990B2 (en) 2004-02-04 2009-02-24 Nycomed Gmbh 2-(piperidin-4-yl)-4,5-dihydro-2H-pyridazin-3-one derivatives as PDE4 inhibitors
US7820669B2 (en) 2004-02-04 2010-10-26 Nycomed Gmbh 2-(piperidin-4-yl)-4,5-dihydro-2H-pyridazin-3-one derivatives as PDE4 inhibitors
WO2013106547A1 (fr) 2012-01-10 2013-07-18 President And Fellows Of Harvard College Composés promoteurs de réplication des cellules bêta et leurs procédés d'utilisation
CN102964340A (zh) * 2012-12-12 2013-03-13 中国药科大学 一类治疗阿尔茨海默病的选择性多巴胺d1受体激动剂
CN102964340B (zh) * 2012-12-12 2015-10-07 中国药科大学 一类治疗阿尔茨海默病的选择性多巴胺d1受体激动剂

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