EP2212331A1 - Furopyrimidines trisubstituées et leur utilisation comme activateurs du récepteur ip - Google Patents

Furopyrimidines trisubstituées et leur utilisation comme activateurs du récepteur ip

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Publication number
EP2212331A1
EP2212331A1 EP08850886A EP08850886A EP2212331A1 EP 2212331 A1 EP2212331 A1 EP 2212331A1 EP 08850886 A EP08850886 A EP 08850886A EP 08850886 A EP08850886 A EP 08850886A EP 2212331 A1 EP2212331 A1 EP 2212331A1
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EP
European Patent Office
Prior art keywords
group
formula
alkyl
compound
hydrogen
Prior art date
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EP08850886A
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German (de)
English (en)
Inventor
Thomas Lampe
Raimund Kast
Friederike Stoll
Joachim Schuhmacher
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Bayer Pharma AG
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Bayer Schering Pharma AG
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Publication of EP2212331A1 publication Critical patent/EP2212331A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present application relates to novel 4,5,6-trisubstituted furo [2,3-d] pyrimidine derivatives, processes for their preparation, their use for the treatment and / or prophylaxis of diseases, and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular for the treatment and / or prophylaxis of cardiovascular diseases.
  • Prostacyclin belongs to the family of bioactive prostaglandins, which are derivatives of arachidonic acid.
  • PGI 2 is the major product of arachidonic acid metabolism in endothelial cells and has potent vasodilating and anti-aggregating properties.
  • PGI 2 is the physiological antagonist of thromboxane A 2 (TxA 2 ), a potent vasoconstrictor and platelet aggregation stimulator, thus contributing to the maintenance of vascular homeostasis.
  • TxA 2 thromboxane A 2
  • a reduction in PGI 2 levels is probably responsible for the development of various cardiovascular diseases [Dusting, GJ. et al., Pharmac. Ther. 1990, 48: 323-344; Vane, J. et al., Eur. J. Vase. Endovasc. Surg. 2003, 26: 571-578].
  • PGI 2 After release of arachidonic acid from phospholipids via phospholipases A 2 PGI 2 is synthesized by cyclooxygenases and then by the PGI 2 synthase. PGI 2 is not stored, but released immediately after synthesis, causing its effects locally. PGI 2 is an unstable molecule that is rapidly (half-life about 3 minutes) non-enzymatically rearranged to an inactive metabolite, 6-keto-prostaglandin Fl alpha [Dusting, GJ. et al., Pharmac. Ther. 1990, 48: 323-344].
  • PGI 2 The biological effects of PGI 2 are due to the binding to a membrane-bound receptor, the so-called prostacyclin or IP receptor [Narumiya, S. et al., Physiol. Rev. 1999, 79: 1193-1226].
  • the IP receptor belongs to the G protein-coupled receptors that are characterized by seven transmembrane domains.
  • rat and mouse prostacyclin receptors have also been cloned [Vane, J. et al., Eur. J. Vase. Endovasc. Surg. 2003, 26: 571-578].
  • PGI 2 Although the overall effects of PGI 2 are therapeutically useful, clinical use of PGI 2 is severely limited by its chemical and metabolic instability. More stable PGI 2 analogs such as iloprost [Badesch, DB et al., J. Am. Coli. Cardiol. 2004, 43: 56S-61S] and treprostinil [Chattaraj, SC, Curr. Opion. Invest. Drugs 2002, 3: 582-586] could be made available, but the duration of these compounds is still very short. Also, the substances can be administered to the patient only via complicated routes of administration, such as by continuous infusion, subcutaneously or via repeated inhalations. These routes of administration can also lead to additional side effects, such as infections or pain at the injection site. The use of the only PGI 2 derivative orally available to the patient, beraprost [Barst, RJ. et al., J. Am. Coli. Cardiol. 2003, 41: 2119-2125], again limited by its short duration of action.
  • the object of the present invention is to provide new substances which act as chemically and metabolically stable, orally available activators of the IP receptor and are suitable as such for the treatment of diseases, in particular of cardiovascular diseases.
  • WO 03/018589 discloses 4-aminofuro [2,3-d] pyrimidines as adenosine kinase inhibitors for the treatment of cardiovascular diseases. Furthermore, in WO 2007/079861 and WO 2007/079862 4-amino, 4-oxy or 4-thio-substituted 5,6-diphenylfuro [2,3-d] pyrimidine derivatives and their use for the treatment of cardiovascular diseases described.
  • Furo [2,3-d] pyrimidines substituted in the 5- and / or 6-position with alkyl and / or alkenyl radicals and their use for the treatment of various diseases are described in DE 1 817 146, WO 03/022852, WO 03 / 080064, WO 2005/092896, WO 2005/121149 and WO 2006/004658.
  • the present invention relates to compounds of the general formula (I)
  • R 1A (C r C 6 ) alkyl, hydroxy, (C r C 6 ) alkoxy, (C 2 -C 6 ) alkenyloxy, amino, mono (C r C 6 ) alkylamino or mono (C 2 -C 6 ) alkenylamino
  • R 1B is (C r C 6 ) -alkyl
  • R 2 is hydrogen or (C r C 4) -alkyl
  • R 3 represents a substituent selected from the group consisting of halogen, cyano, nitro, (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 4 ) -alkynyl, (C 3 -C 7 ) cycloalkyl, (C 4 -C 7) cycloalkenyl, (C 1 -C 6) - alkoxy, trifluoromethyl, trifluoromethoxy, (Ci-C 6) alkylthio, (Ci-C ö) -acyl, amino, mono-
  • n 0, 1 or 2
  • A is O or NR 4 , in which
  • Tet R 4 is hydrogen, (C r C6) alkyl, (C 3 -C 7) -cycloalkyl or (C 4 -C 7) cycloalkenyl significance,
  • R 5 is hydrogen or (C 1 -C 4 ) -alkyl which may be substituted by hydroxyl or amino,
  • L 1 is (C 1 -C 7 ) -alkanediyl or (C 2 -C 7 ) -alkendiyl, which may be mono- or di-substituted by fluorine, or a group of formula * -L IA -VL 1B - **, in which
  • L 1A (Ci-C 5) -alkanediyl which may be mono- or disubstituted by identical or different (Ci-C 4) -alkyl and / or (C r C 4) alkoxy,
  • L 1B is a bond or (C 1 -C 3 ) -alkanediyl which may be mono- or disubstituted by fluorine,
  • R 6 is hydrogen, (C r C6) alkyl or (C 3 -C 7) cycloalkyl,
  • L 2 is a bond or (C 1 -C 4 ) -alkanediyl
  • L 3 (C r C 4 ) alkanediyl which may be mono- or disubstituted by fluorine and in which a methylene group may be replaced by O or NR 7 , wherein
  • R 7 is hydrogen, (C r C6) alkyl or (C 3 -C 7) cycloalkyl,
  • Q is (C 3 -C 7 ) -cycloalkyl, (C 4 -C 7 ) -cycloalkenyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl, which may each be up to twice, identical or different, with radicals selected from the group fluorine, chlorine, (C 1 -C 4 ) -alkyl, trifluoromethyl, hydroxy, (C 1 -C 4 ) -alkoxy, trifluoromethoxy, amino, mono (C 1 -C 4 ) - alkylamino and di- (C 1 -C 4 ) -alkylamino may be substituted,
  • (Ci-C 4) -alkyl for its part may be substituted by hydroxy, (C r C 4) alkoxy, amino, mono- or di- (C] -C4) alkylamino,
  • Z is a group of the formula
  • R 8 is hydrogen or (C r C 4) alkyl
  • Compounds of the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts encompassed by formula (I) and those of the formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • physiologically acceptable salts of the compounds according to the invention are preferred in the context of the present invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic acid
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, trisethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).
  • Z is a group of the formula
  • esters which can be hydrolyzed in physiological media, under the conditions of the biological tests described below, and in particular in vivo enzymatically or chemically to the free carboxylic acids, as the biologically mainly active compounds.
  • esters (C 1 -C 4 ) -alkyl esters in which the alkyl group may be straight-chain or branched are preferred.
  • Particularly preferred are methyl, ethyl or terf.-butyl ester (see also corresponding definitions of the radical R 8 ).
  • (C 1 -CJ-AlkVl (C 1 -CQ-AlkVl, (C 1 -Ca) -AUcVl and (C r CV) alkyl are in the context of the invention for a straight-chain or branched alkyl radical having 1 to 6, 1 to 5 1 to 4 or 1 to 3 carbon atoms is preferred, a straight-chain or branched alkyl radical having 1 to 4, particularly preferably 1 to 3, carbon atoms being given by way of example and preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl where n-butyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.
  • a straight-chain or branched alkenyl radical having 2 to 6, 2 to 5 or 2 to 4 carbon atoms and one or two double bonds Preference is given to a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms and one double bond. Examples which may be mentioned are: vinyl, allyl, isopropenyl, n-but-2-en-1-yl, 2-methylprop-2-en-1-yl and n-but-3-en-1-yl.
  • C 1 -C 4 -alkynyl is a straight-chain or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond, a straight-chain alkynyl radical having 2 to 4 carbon atoms being preferred in-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-yn-1-yl.
  • a straight-chain or branched divalent alkyl radical having 1 to 4 or 1 to 3 carbon atoms. In each case, a straight-chain alkanediyl radical having 1 to 4 or 1 to 3 carbon atoms is preferred.
  • methylene ethane-1,2-diyl (1,2-ethylene), ethane-1,1-diyl, propane-1,3-diyl (1,3-propylene), propane-1, l-diyl, propane-l, 2-diyl, propane-2,2-diyl, butane-1,4-diyl (1,4-butylene), butane-1,2-diyl, butane-l, 3-diyl and butane-2,3-diyl.
  • methylene ethane-1,2-diyl (1,2-ethylene
  • ethane-1,1-diyl propane-1,3-diyl (1,3-propylene
  • propane-1, l-diyl propane-l, 2-diyl, propane-2,2-diyl, butane-1,4-diyl (1,4-butylene)
  • a straight-chain alkanediyl radical having 1 to 7, 1 to 5 or 3 to 7 carbon atoms is preferred.
  • (C 2 -Cd) -Alkendiyl and (C ⁇ -CCl-alkenediyl in the context of the invention are a straight-chain or branched divalent alkenyl radical having 2 to 4 or 2 to 3 carbon atoms and up to 2 double bonds 2 to 4 or 2 to 3 carbon atoms and one double bond, by way of example and preferably: ethene-1, 1-diyl, ethene-1,2-diyl, propene-1, 1-diyl, propylene-1,2-diyl Propen-1, 3-diyl, but-1-ene-1,4-diyl, but-1-en-1, 3-diyl, but-2-ene-1,4-diyl and buta-1, 3 -diene-l, 4-diyl. in the context of the invention for a straight-chain or branched divalent alkenyl radical having 2 to 7 or 3 to 7 carbon atoms and up to 3
  • Double bonds In each case, a straight-chain alkenediyl radical having 2 to 7 or 3 to 7 is preferred
  • Carbon atoms and a double bond By way of example and preferably:
  • Ethene-1 1-diyl, ethene-1, 2-diyl, propene-1,1-diyl, propylene-1,2-diyl, propen-1, 3-diyl, but-1-ene-1,4- diyl, but-1-en-1, 3-diyl, but-2-ene-1,4-diyl, buta-1,3-dien-1, 4-diyl, pent-2-en-1, 5 diyl, hex-3-ene-1, 6-diyl and hexa-2,4-diene-l, 6-diyl.
  • (C 1 -Q) -alkoxy and (C 2 -C 4) -alkoxy represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms, preference being given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms called: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • (C 2 -C 4) -Alkenyloxy in the context of the invention represents a straight-chain or branched alkenyloxy radical having 2 to 6 carbon atoms and one double bond in the alkenyl group. Preference is given to a straight-chain or branched alkenyloxy radical having 3 or 4 carbon atoms. Examples which may be mentioned are: allyloxy, (n-but-2-en-1-yl) oxy, (2-methylprop-2-en-1-yl) oxy and (n-but-3-en-1-yl ) oxy. in the context of the invention are a straight-chain or branched alkylthio radical having 1 to 6 or 1 to 4 carbon atoms.
  • exemplary and forward may be mentioned: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio.
  • (C 1 -GO-AcVl [(C r C 6 ) alkanoyl], (C 1 -C 1 VACvI [(C, -Cs) -AlkEnOyI] and (C r GiVAcyl [(C, -C 4 ) alkanoyl ] represent in the context of the invention a straight-chain or branched alkyl radical having 1 to 6, 1 to 5 or 1 to 4 carbon atoms which carries a doubly bonded oxygen atom in the 1-position and is linked via the 1-position straight-chain or branched acyl radical having 1 to 4 carbon atoms, by way of example and preferably: formyl, acetyl, propionyl, n-butyryl, isobutyryl and pivaloyl.
  • Di- (C 1 -C 6) -alkylamino and di- (C 1 -C 4 -alkyl ) vinylamine are in the context of the invention an amino group having two identical or different straight-chain or branched alkyl substituents, each having 1 to 6 or 1 to 4
  • straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms, examples of which are preferably: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N- Methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.
  • Mono- (C 2 -C 12 -alkenylamino means in the context of the invention an amino group having a straight-chain or branched alkenyl substituent which has 2 to 6 carbon atoms and one double bond, preference is given to a straight-chain or branched monoalkenylamino radical having 3 or 4 carbon atoms
  • Allylamino, (n-but-2-en-1-yl) amino, (2-methylprop-2-en-1-yl) -amino and (n-but-3-en-1-yl) -amino may be mentioned as preference
  • in the context of the invention are an amino group having a straight-chain or branched acyl substituent which has 1 to 6 or 1 to 4 carbon atoms and is linked via the carbonyl group.
  • (C 1 -C 2 VCvClOalkyl ) (C 1 -C 4 ) cycloalkyl and (C 1 -C 4 -cycloalkyl in the context of the invention represent a monocyclic, saturated cycloalkyl group having 3 to 7, 3 to 6 or 4 to 6 carbon atoms. atoms. Preference is given to a cycloalkyl radical having 3 to 6 carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a cycloalkenyl radical having 4 to 6, particularly preferably 5 or 6, carbon atoms may be mentioned by way of example and preferably: cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • 5- to 7-membered heterocyclyl represents a saturated or partially unsaturated heterocycle having a total of 5 to 7 ring atoms which contains one or two ring heteroatoms from the series N and / or O and via ring carbon atoms and or optionally ring nitrogen atoms is linked.
  • Preference is given to a 5- or 6-membered saturated heterocycle having one or two ring heteroatoms from the series N and / or O.
  • pyrrolidinyl pyrrolinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, morpholinyl , Hexahydroazepinyl and hexahydro-1,4-diazepinyl.
  • 5- or 6-membered heteroaryl in the context of the invention represents an aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing one or two ring heteroatoms from the series N, O and / or S and via ring carbon atoms and / or optionally a ring nitrogen atom is linked.
  • Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.
  • Thienyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl are preferred.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Particularly preferred is a substitution with one or two identical or different substituents, very particularly preferably the substitution with a substituent.
  • R 2 is hydrogen, methyl or ethyl
  • R 3 is a substituent selected from the group fluorine, chlorine, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy,
  • n 0, 1 or 2
  • A is O or NH
  • R 5 is hydrogen, methyl or ethyl
  • L 1 is (C 3 -C 7 ) alkanediyl, (C 3 -C 7 ) alkylenediyl or a group of formula * -L 1A -VL 1B - ** in which
  • L 1A (C 1 -C 3 ) -alkanediyl which may be monosubstituted or disubstituted by methyl
  • L 2 is a bond, methylene, ethane-1, 1-diyl or ethane-1, 2-diyl,
  • R 7 is hydrogen or (C 1 -C 3 ) -alkyl
  • Q is cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or phenyl which are each up to twice, identically or differently, selected from fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy and Ethoxy can be substituted,
  • Z is a group of the formula
  • # means the point of attachment to the group L 1 or L 3 , and their salts, solvates and solvates of the salts.
  • R 1 ⁇ is ethyl, n-propyl, ethoxy, allyloxy, ethylamino, n-propylamino or allylamino,
  • R 2 is hydrogen or methyl
  • R 3 is fluorine, chlorine or methyl
  • n is the number 0 or 1
  • A is O or NH
  • R 5 is hydrogen or methyl
  • L 1 is butan-l, 4-diyl, pentan-l, 5-diyl or a group of the formula * -L 1A -OL 1B - **, in which
  • L 1A is methylene or ethane-1,2-diyl which may be monosubstituted or disubstituted by methyl, NND
  • the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention in which Z is -COOH or -C (OO) -COOH, which comprises reacting a compound of the formula (II)
  • X 1 represents a leaving group such as, for example, halogen, in particular chlorine,
  • Z 1 is cyano or a group of the formula - [C (O)] y -COOR 8A in which
  • R> 8 8 A A denotes (C 1 -C) -alkyl
  • R 9 is hydrogen or (C 1 -C 4 ) -alkyl or both radicals R 9 together form a -CH 2 -CH 2 -, -C (CH 3 ) 2 -C (CH 3 ) 2 - or -CH 2 -C Form (CH 3 ) 2 -CH 2 -bridge,
  • R 1 is phenyl or o-, m- or p-tolyl
  • R 1 is (C 1 -C 4 ) -alkyl
  • Inert solvents for process step (II) + (HT) - »(IV) are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, Cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidon
  • AIs base for process step (II) + (HI) -> (IV) are customary inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates such as sodium or potassium terf.-butylate, alkali metal hydrides such as sodium or Potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds such as butyl lithium or phenyllithium, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine or pyridine.
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or
  • tertiary amines in particular N, N-diisopropylethylamine, sodium tert-butoxide or sodium hydride are preferably used as the base. If appropriate, however, these reactions can also be carried out-without the use of an auxiliary base-if an excess of the amine component (TS) is used.
  • auxiliary base if an excess of the amine component (TS) is used.
  • sodium hydride, potassium or cesium carbonate or the phosphazene bases P2-t-Bu and P4-t-Bu are preferred.
  • the process step (II) + (HI) -> (IV) may optionally be carried out advantageously with the addition of a crown ether.
  • Inert solvents for process steps (IV) + (V) ⁇ (VTT) and (IV) + (VTS) ⁇ (TX) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol , Ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene Glykoldimethylether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, NN-dimethylpropyleneurea, N-methylpyrrolidone, pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to a mixture of tetrahydrofuran
  • Suitable bases for process steps (IV) + (V) ⁇ (VII) and (IV) + (Vm) ⁇ (JX) are customary inorganic bases. These include in particular alkali hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, or alkali metal hydrogen phosphates such as disodium or dipotassium hydrogenphosphate. phat. Preferably, sodium or potassium carbonate is used.
  • alkali hydroxides such as, for example, lithium, sodium or potassium hydroxide
  • alkali hydrogen carbonates such as sodium or potassium bicarbonate
  • alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
  • alkali metal hydrogen phosphates such as disodium or dipotassium hydrogenphosphate.
  • sodium or potassium carbonate is used.
  • the reactions (IV) + (V) ⁇ (VII) and (IV) + (Vm) ⁇ (DC) are generally in a temperature range of +20 0 C to +150 0 C, preferably at +50 0 C to + 100 0 C performed.
  • Inert solvents for process step (IV) + (VI) -> (VE) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethylformamide , Dimethylsulfoxide, N, N'-dimethylpropyleneurea, N-methylpyrrolidone, pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using dimethylformamide.
  • the process step (IV) + (VI) -> (VII) is usually carried out in the presence of a tertiary amine base.
  • a tertiary amine base Particularly suitable for this purpose are amines such as triethylamine, tri-n-butylamine, N, N-diisopropylethylamine, N-methylpiperidine or N-methylmorpholine. Preference is given to using triethylamine or N, N-diisopropylethylamine.
  • reaction (IV) + (VI) -> (VE) is usually carried out in a temperature range from +50 0 C to +200 0 C, preferably at +80 0 C to +150 0 C.
  • the ozonolysis in process step (EX) -> (X) is carried out by known methodology with the aid of an ozone generator preferably in alcohol / dichloromethane mixtures as solvent in a temperature range from -100 0 C to -60 0 C.
  • an ozone generator preferably in alcohol / dichloromethane mixtures as solvent in a temperature range from -100 0 C to -60 0 C.
  • Inert solvents for process step (X) + (XI) or (XU) - »(VE) are, for example, ethers, such as diethyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, Xylene, pentane, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylsulfoxide, N, N'-dimethylpropyleneurea or N-methylpyrrolidone. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran.
  • Suitable bases for process step (X) + (XI) or (XU) ⁇ (VIT) are the bases customary for Wittig or Wittig-Horner reactions of this type. These include in particular alkali metal hydrides such as sodium or potassium hydride, alkali metal alcoholates such as sodium or potassium tert-butoxide, amides such as lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium. Preferably, sodium hydride is used.
  • the reactions (X) + (XI) or (XU) -> (VIT) are generally carried out in a temperature range from -20 0 C to + 60 0 C, preferably at 0 0 C to + 40 0 C.
  • the hydrolysis of the ester or nitrile group Z 1 in process step (VIT) -> (IA) is carried out by customary methods by treating the esters or nitriles in inert solvents with acids or bases, wherein the latter initially formed salts be converted by treatment with acid into the free carboxylic acids.
  • acids or bases wherein the latter initially formed salts be converted by treatment with acid into the free carboxylic acids.
  • tert-butyl ester ester cleavage is preferably carried out with acids.
  • Suitable inert solvents for these reactions are water or the organic solvents customary for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned.
  • Suitable bases are the customary inorganic bases. These include preferably alkali or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Particularly preferred are sodium or lithium hydroxide.
  • Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water.
  • Hydrogen chloride or trifluoroacetic acid are preferred in the case of the tert-butyl esters and hydrochloric acid in the case of the methyl esters.
  • the ester cleavage is generally carried out in a temperature range from 0 0 C to + 100 0 C, preferably at +0 0 C to +50 0 C.
  • the nitrile hydrolysis is generally in a temperature range from +50 0 C to +150 0 C, preferably at +80 0 C to +120 0 C performed.
  • the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar), in general the reaction is carried out at normal pressure.
  • Inert solvents for this reaction are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethyl sulfoxide, dimethylformamide, N, N'-dimethylpropyleneurea or N-methylpyrrolidine. lidon. It is likewise possible to use mixtures of the solvents mentioned. Preferably, toluene is used.
  • sodium azide in the presence of ammonium chloride or trimethylsilyl azide is suitable as the azide reagent.
  • the latter reaction can advantageously be carried out in the presence of a catalyst.
  • Compounds such as di-n-butyltin oxide, trimethylaluminum or zinc bromide are particularly suitable for this purpose.
  • trimethylsilyl azide is used in combination with di-n-butyltin oxide.
  • the reaction is generally carried out in a temperature range of +50 0 C to +150 0 C, preferably at +60 0 C to +110 0 C.
  • the reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). As a rule, one works at normal pressure.
  • phosgene or a phosgene equivalent such as NN'-carbonyldiimidazole.
  • Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether are suitable as inert solvents for the first step of this reaction sequence. It is also possible to use mixtures of these solvents. Preference is given to Mixture of methanol and tetrahydrofuran used.
  • the second reaction step is preferably carried out in an ether, in particular in tetrahydrofuran.
  • the reactions are generally carried out in a temperature range of 0 0 C to +70 0 C under atmospheric pressure.
  • X 2 represents a leaving group such as halogen, mesylate, tosylate or triflate
  • the compounds of the formula (I) according to the invention in which L 3 is a group of the formula ## STR3 ## may be W-CH 2 -... Or -W-CH 2 -CH 2 -**, where W is the above also has the meaning indicated, that compounds of the formula (IT)
  • n stands for the number 1 or 2
  • X is a leaving group such as halogen, mesylate, tosylate or triflate
  • the compounds of the formula (H) in turn can be prepared, for example, by reacting phenacylbromides of the formula (XXI)
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
  • the compounds according to the invention are chemically and metabolically stable, non-prostanoid activators of the EP receptor which mimic the biological activity of PGI 2 .
  • cardiovascular diseases such as stable and unstable angina pectoris, hypertension and heart failure, pulmonary hypertension
  • cardiovascular diseases such as stable and unstable angina pectoris, hypertension and heart failure, pulmonary hypertension
  • prophylaxis and / or treatment of thromboembolic disorders and ischaemias such as myocardial infarction, stroke, transitori and for inhibiting restenosis
  • thrombolytic therapies percutaneous transluminal angioplasties (PTA), coronary angioplasties (PTCA) and bypass.
  • PTA percutaneous transluminal angioplasties
  • PTCA coronary angioplasties
  • the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of pulmonary hypertension (PH) including its various forms.
  • the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of pulmonary arterial hypertension (PAH) and its sub-forms, such as idiopathic, familial and, for example, with portal hypertension, fibrotic diseases, HIV infection or improper medication or Toxins associated with pulmonary arterial hypertension.
  • PAH pulmonary arterial hypertension
  • the compounds according to the invention can also be used for the treatment and / or prophylaxis of other forms of pulmonary hypertension.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of pulmonary hypertension in chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, diseases with alveolar hypoventilation, altitude sickness and pulmonary developmental disorders.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of pulmonary hypertension due to chronic thrombotic and / or embolic diseases, such as thromboembolism of the proximal pulmonary arteries, obstruction of the distal pulmonary arteries and pulmonary embolism.
  • the compounds according to the invention can be used for the treatment and / or prophylaxis of pulmonary hypertension in connection with sarcoidosis, histiocytosis X or lymphangioleiomyomatosis as well as pulmonary hypertension caused by external vascular compression (lymph node, tumor, fibrosing mediastinitis).
  • the compounds according to the invention can also be used for the treatment and / or prophylaxis of peripheral and cardial vascular diseases, of peripheral occlusive diseases (PAOD, PVD) as well as of peripheral circulatory disorders.
  • PAOD peripheral occlusive diseases
  • PVD peripheral occlusive diseases
  • the compounds of the present invention may be useful in the treatment of arteriosclerosis, hepatitis, asthmatic diseases, chronic obstructive pulmonary disease (COPD), pulmonary edema, fibrosing lung diseases such as idiopathic pulmonary fibrosis (IPF) and ARDS, inflammatory vascular diseases such as scleroderma and lupus erythematosus, renal failure, arthritis and osteoporosis and for the prophylaxis and / or treatment of cancer, in particular of metastatic tumors.
  • COPD chronic obstructive pulmonary disease
  • pulmonary edema fibrosing lung diseases such as idiopathic pulmonary fibrosis (IPF) and ARDS
  • inflammatory vascular diseases such as scleroderma and lupus erythematosus, renal failure, arthritis and osteoporosis and for the prophylaxis and / or treatment of cancer, in particular of metastatic tumors.
  • the compounds of the invention may also be used as an adjunct to the preservative medium of an organ transplant, such as e.g. in kidneys, lungs, heart or islet cells.
  • Another object of the present invention is the use of compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-I, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • PDE phosphodiesterases
  • NO-independent, but heme-dependent guanylate cyclase stimulators in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;
  • Guanylate cyclase NO- and heme-independent activators in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
  • HNE human neutrophil elastase
  • Sivelestat Sivelestat
  • DX-890 Reltran
  • Elafin or in particular those described in WO 03/053930, WO 2004/020410, WO 2004/020412, WO 2004/024700, WO 2004/024701, WO 2005/080372, WO 2005/082863 and WO 2005/082864 described compounds;
  • the signal transduction cascade inhibiting compounds for example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine / threonine kinase inhibitors; • compounds which inhibit soluble epoxide hydrolase (sEH), such as N 1 N'-dicyclohexylurea, 12- (3 -Adamantan- 1-yl-ureido) dodecanoic acid or 1 -Adamantan- 1 -yl 3- ⁇ 5- [2- (2-ethoxyethoxy) ethoxy] pentyl ⁇ urea;
  • SEH soluble epoxide hydrolase
  • VPAC receptors such as by way of example and preferably the vasoactive intestinal polypeptide (VIP);
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin Aü antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor Antagonists, Rho kinase inhibitors and diuretics; and or
  • Lipid metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.
  • cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid
  • the compounds according to the invention are administered in combination with a kinase inhibitor such as, for example and preferably, canertinib, imatinib, gefitinib, erlotinib, lapatinib, lestaurtinib, lonafarnib, pegaptinib, pelitinib, semaxanib, tandutinib, tipifarnib, vatalanib, Sorafenib, sunitinib, bortezomib, lonidamine, leflunomide, fasudil or Y-27632.
  • a kinase inhibitor such as, for example and preferably, canertinib, imatinib, gefitinib, erlotinib, lapatinib, lestaurtinib, lonafarnib, pegaptinib, pelitinib, semaxanib, tandutin
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPUb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982 , EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaraban, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982 , EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor - Antagonists, Rho-kinase inhibitors and diuretics understood.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol
  • the compounds according to the invention are administered in combination with an angiotensin Aü antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • an angiotensin Aü antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
  • the compounds according to the invention are administered in combination with a rho-kinase inhibitor, such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962A or BA-1049.
  • a rho-kinase inhibitor such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962A or BA-1049.
  • the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide.
  • the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of example and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • a CETP inhibitor such as by way of example and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • the compounds according to the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) ,
  • a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) ,
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
  • statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • compositions containing at least one inventive compound are pharmaceutical compositions containing at least one inventive compound, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates
  • capsules e.g. Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • the parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • involvement of resorption eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • paren- tereral administration are suitable as application forms, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecy
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; Flow: 0.0 min 1 ml / min ⁇ 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Device Type MS Waters ZQ
  • Device type HPLC Waters Alliance 2795
  • Eluent A 1 l of water + 0.5 ml of 50% formic acid
  • eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
  • Flow 2 ml / min
  • Oven 40 ° C
  • UV detection 210 nm.
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 mm
  • Eluent A 1 l of water + 0.5 ml of 50% formic acid
  • eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
  • Flow 0.0 min 1 ml / min - »2.5 min / 3.0 min / 4.5 min 2 ml / min
  • Oven 50 ° C .
  • UV detection 210 nm.
  • Instrument Micromass GCT, GC 6890; Column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Inlet: 250 ° C; Gradient: 70 0 C, 30 ° C / min ⁇ 310 0 C (3 min hold).
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Phenomenex syn ergi 2.5 ⁇ MAX-RP 100A Mercury, 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A ⁇ 0.1 min 90% A ⁇ 3.0 min 5% A ⁇ 4.0 min 5% A ⁇ 4.01 min 90% A; Flow: 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • the crude product was purified by chromatography on silica gel (eluent: dichloromethane). The product was stirred in methanol for further purification, filtered off with suction and dried under high vacuum. 32 g of the target product were obtained (55.5% of theory).
  • Solution A 10.71 g (267.7 mmol) of 60% sodium hydride were dissolved in 150 ml of abs. Suspended THF and dropwise with cooling with 43.3 ml (276.7 mmol) of P, P-Dimethylphosphonoessigklare- tert. butyl ester added. The mixture was stirred at RT, after about 30 min, a solution was formed.
  • Ozone gas was generated in the ozonizer and passed through the reaction mixture in the oxygen stream for about 10 minutes, whereby it turned green-blue. After switching off the ozonizer, the excess ozone was expelled from the reaction solution by the gas stream. Subsequently, the still cold, light-green reaction mixture was mixed with 8 ml of dimethyl sulfide and slowly warmed to RT. It was then concentrated and the residue dried under high vacuum.
  • the organic phase was dried over sodium sulfate, concentrated and the residue stood dried in a high vacuum.
  • the crude product was purified by chromatography on silica gel (eluent: dichloromethane / methanol 100: 1). To remove remaining residues of DMF and NN-diisopropylethylamine, the product obtained was taken up in ethyl acetate and washed thrice with sat. Washed ammonium chloride solution. The organic phase was then dried over sodium sulfate, concentrated in vacuo and the residue was thoroughly dried under high vacuum. 0.91 g of the target product were obtained (about 65% purity, 90.7% of theory).
  • the reaction mixture was stirred at RT overnight, then diluted with ethyl acetate and washed with water and sat. Sodium chloride solution washed. The organic phase was dried over sodium sulfate, concentrated and the residue dried under high vacuum.
  • the crude product was purified by chromatography on silica gel (eluent: dichloromethane / methanol 200: 1). 38.4 mg of the target product were obtained (72.6% of theory).
  • platelet membranes 50 ml of human blood (buffy coats with CDP stabilizer, Maco Pharma, Langen) are centrifuged for 20 min at 160 ⁇ g. The supernatant (platelet-rich plasma, PRP) is removed and then centrifuged again at 2000 xg for 10 min at room temperature. The sediment is dissolved in 50 mM tris (hydroxymethyl) amino methane, which is adjusted with 1N hydrochloric acid to a pH of 7.4, re-suspended and stored at -20 0 C overnight. The following day, the suspension is centrifuged at 80,000 xg and 4 ° C for 30 minutes. The supernatant is discarded.
  • the sediment is re-suspended in 50 mM tris- (hydroxymethyl) -aminomethane / hydrochloric acid, 0.25 mM ethylenediaminetetraacetic acid (EDTA), pH 7.4 and then centrifuged again at 80,000 ⁇ g and 4 ° C. for 30 minutes.
  • the membrane bransediment is added to binding buffer ((50 mM Tris-hydroxymethyl) aminomethane / hydrochloric acid, 5 mM magnesium chloride, pH 7.4) and stored at -70 0 C until the binding assay.
  • 3 mM 3 H-iloprost (592 GBq / mmol, Amersham Bioscience) are incubated for 60 min with 300-1000 ⁇ g / ml human platelet membranes per batch (maximum 0.2 ml) in the presence of the test substances at room temperature. After stopping, the membranes are mixed with cold binding buffer and washed with 0.1% bovine serum albumin. After addition of Ultima Gold scintillator, the radioactivity bound to the membranes is quantified by means of a scintillation counter. Non-specific binding is defined as radioactivity in the presence of 1 ⁇ M iloprost (Cayman Chemical, Ann Arbor) and is typically ⁇ 25% of the total bound radioactivity.
  • the binding data (IC 50 values) are determined by means of the program GraphPad Prism Version 3.02.
  • the IP agonist activity of test substances is determined using the human erythroleukemia cell line (HEL), which endogenously expresses the IP receptor [Murray, R., FEBS Letters 1989, 1: 172-174].
  • HEL human erythroleukemia cell line
  • the suspension cells (4 x 10 7 cells / ml) in buffer [10 mM HEPES (4- (2-hydroxyethyl) -1-piperazinethansulfonkla) / PBS (phosphate-buffered saline, Fa.
  • Male Wistar rats weighing 300-350 g are anesthetized with thiopental (100 mg / kg i.p.). After tracheostomy, the femoral artery is catheterized for blood pressure measurement.
  • the substances to be tested are administered as a solution orally by gavage or via the femoral vein intravenously in a suitable vehicle.
  • pulmonary artery in the pulmonary artery is flooded (distal lumen for measuring the pulmonary arterial pressure, proximal lumen for measuring the central venous pressure).
  • Left ventricular pressure is measured after the introduction of a Mikro-Tip catheter (Millar Instruments ®) through the carotid artery into the left ventricle and derived from the dP / dt value as a measure of contractility.
  • Substances are administered iv via the femoral vein.
  • the hemodynamic signals are recorded and evaluated by means of pressure transducers / amplifiers and PONEMAH ® as data acquisition software.
  • hypoxia a continuous infusion of thromboxane A 2 or a thromboxane A 2 analogue is used as the stimulus.
  • Acute hypoxia is induced by gradual lowering of the oxygen in the ventilation air to about 14%, so that the mPAP increases to values of> 25 mm Hg.
  • a thromboxane A 2 analogue stimulus 0.21-0.32 ⁇ g / kg / min U-46619 [9, 11-dideoxy-9 ⁇ , 11 ⁇ -epoxy-methano-prostaglandin F 2 ⁇ (Sigma)] is infused to obtain to increase the mPAP to> 25 mm Hg.
  • pulmonary artery in the pulmonary artery is flooded (distal lumen for measuring the pulmonary arterial pressure, proximal lumen for measuring the central venous pressure).
  • Left ventricular pressure is measured after the introduction of a Mikro-Tip catheter (Millar Instruments ®) through the carotid artery into the left ventricle and derived from the dP / dt value as a measure of contractility.
  • Substances are administered iv via the femoral vein.
  • the hemodynamic signals are recorded and evaluated by means of pressure-sensitive devices / amplifiers and PONEMAH ® as data acquisition software.
  • a continuous infusion of a thromboxane A 2 analogue is used as the stimulus.
  • 0.12-0.14 ⁇ g / kg / min of U-46619 9, 11-dideoxy-9 ⁇ , 11 ⁇ -epoxymethano-prostaglandin F 2 ⁇ (Sigma)] is infused to increase the mPAP to> 25 mm Hg.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the mixture of the compound according to the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • the compound according to the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • the compound of the invention is dissolved in a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%).
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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Abstract

La présente invention concerne de nouveaux dérivés de furo[2,3-d]pyrimidine 4,5,6-trisubstituées de formule (I), un procédé permettant leur préparation, leur utilisation pour le traitement et/ou la prévention de maladies et leur utilisation pour la préparation de médicaments destinés au traitement et/ou à la prévention de maladies, en particulier le traitement et/ou la prévention de troubles cardio-vasculaires.
EP08850886A 2007-11-16 2008-11-03 Furopyrimidines trisubstituées et leur utilisation comme activateurs du récepteur ip Withdrawn EP2212331A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007054786A DE102007054786A1 (de) 2007-11-16 2007-11-16 Trisubstituierte Furopyrimidine und ihre Verwendung
PCT/EP2008/009237 WO2009062605A1 (fr) 2007-11-16 2008-11-03 Furopyrimidines trisubstituées et leur utilisation comme activateurs du récepteur ip

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EP2212331A1 true EP2212331A1 (fr) 2010-08-04

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US (1) US20100267749A1 (fr)
EP (1) EP2212331A1 (fr)
JP (1) JP2011503126A (fr)
CA (1) CA2705689A1 (fr)
DE (1) DE102007054786A1 (fr)
WO (1) WO2009062605A1 (fr)

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WO2009062605A1 (fr) 2009-05-22
CA2705689A1 (fr) 2009-05-22
DE102007054786A1 (de) 2009-05-20
US20100267749A1 (en) 2010-10-21

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