WO2008131859A2 - Utilisation de dérivés de furopyrimidine à substitution cyclique dans le traitement de l'hypertonie artérielle pulmonaire - Google Patents

Utilisation de dérivés de furopyrimidine à substitution cyclique dans le traitement de l'hypertonie artérielle pulmonaire Download PDF

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WO2008131859A2
WO2008131859A2 PCT/EP2008/003008 EP2008003008W WO2008131859A2 WO 2008131859 A2 WO2008131859 A2 WO 2008131859A2 EP 2008003008 W EP2008003008 W EP 2008003008W WO 2008131859 A2 WO2008131859 A2 WO 2008131859A2
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mmol
alkyl
group
amino
formula
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PCT/EP2008/003008
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German (de)
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WO2008131859A3 (fr
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Thomas Lampe
Eva-Maria Becker
Raimund Kast
Hartmut Beck
Mario Jeske
Joachim Schuhmacher
Friederike Stoll
Martina Klein
Metin Akbaba
Andreas Knorr
Johannes-Peter Stasch
Lars BÄRFACKER
Alexander Hillisch
Gunter Karig
Mark Meininghaus
Karl-Heinz Schlemmer
Rudolf Schohe-Loop
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Bayer Schering Pharma Aktiengesellschaft
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Priority to CA002685134A priority Critical patent/CA2685134A1/fr
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Publication of WO2008131859A3 publication Critical patent/WO2008131859A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic 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
    • 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 the use of cyclically substituted furopyrimidine derivatives of the formula (I) for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension and their use for the preparation of medicaments for the treatment and / or prophylaxis of the pulmonary arterial hypertension and other forms of pulmonary hypertension.
  • Pulmonary arterial hypertension is a progressive lung disease that, if untreated, leads to an average death within 2.8 years of diagnosis. An increasing constriction of the pulmonary circulation leads to an increase in the burden on the right heart, which can lead to right heart failure.
  • chronic pulmonary hypertension has a pulmonary arterial mean pressure (mPAP) of> 25 mmHg at rest or> 30 mmHg under exercise (normal value ⁇ 20 mmHg).
  • mPAP pulmonary arterial mean pressure
  • the pathophysiology of pulmonary arterial hypertension is characterized by vasoconstriction and remodeling of the pulmonary vessels.
  • neomuscularization of primarily non-muscularized pulmonary vessels occurs, and the vascular musculature of the already muscularized vessels increases in size.
  • Standard therapies on the market e.g., prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors
  • prostacyclin analogs e.g., prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors
  • phosphodiesterase inhibitors are able to improve the quality of life, exercise tolerance, and prognosis of patients.
  • the applicability of these drugs is limited by the z.T. restricted serious side effects and / or complex application forms.
  • the period of time during which a patient's clinical situation can be improved or stabilized under specific monotherapy is limited.
  • therapy escalation and thus a combination therapy in which several drugs have to be given at the same time.
  • pulmonary arterial hypertension includes certain forms of pulmonary hypertension, such as e.g. by the World Health Organization (WHO) [Clinical Classification of Pulmonary Hypertension, Venice 2003; G. Simonneau et al., J. Am. Coli. Cardiol. 2004, 43, 5S-12S].
  • WHO World Health Organization
  • pulmonary arterial hypertension includes idiopathic pulmonary arterial hypertension (IPAH, also referred to as primary pulmonary hypertension), familial pulmonary arterial hypertension (FPAH), and associated pulmonary arterial hypertension (APAH), which is associated with collagenosis congenital systemic pulmonary shunt veins, portal hypertension, HIV infection, use of certain drugs and medicines, with other diseases (thyroid disorders, glycogen storage disorders, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy), with significant venous disease capillary involvement such as pulmonary veno-occlusive disease and pulmonary-capillary haemahgiomatosis, as well as persistent pulmonary hypertension of newborns.
  • diseases thyroid disorders, glycogen storage disorders, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy
  • venous disease capillary involvement such as pulmonary veno-occ
  • pulmonary hypertension examples include, for example, pulmonary hypertension associated with left ventricular disease, e.g. in ventricular or valvular diseases, pulmonary hypertension associated with respiratory and / or pulmonary diseases, e.g. in chronic obstructive pulmonary disease, interstitial lung disease or pulmonary fibrosis, the pulmonary causes of chronic thrombotic and / or embolic diseases
  • Hypertension e.g. in the case of thromboembolic obstruction of pulmonary arteries, as well as pulmonary inflammation caused by generalized inflammatory processes or by special causes
  • Hypertension e.g., schistosomiasis, sarcoidosis, tumors.
  • 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.
  • PGI 2 is synthesized by cyclooxygenases and then by the PGl 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 compounds described in the present application are characterized by a 5,6-diphenylfuro [2,3-d] pyrimidine core structure, which differs via the 4-position in a specific case spatial distance is associated with a carboxylic acid or carboxylic acid-like functionality.
  • the present invention relates to the use of compounds of the general formula (I)
  • A is O, S or NR 4 , in which
  • R 4 is hydrogen, (C r C6) alkyl, (C 3 -C 7) -cycloalkyl or (G "-C 7) cycloalkenyl,
  • L 1 is a bond or (C r C 4 ) alkanediyl
  • the ring Q is (C 3 -C 7 ) -cycloalkyl, (C 4 -C 7 ) -cycloalkenyl, a 5- to 7-membered heterocycle,
  • Phenyl or 5- or 6-membered heteroaryl which are each up to twice, identically or differently, with fluorine, chlorine, (Ci-Gi) -alkyl, trifluoromethyl, hydroxy, (Ci-C 4 ) -
  • Alkoxy, trifluoromethoxy, amino, mono- (C 1 -C 4 ) -alkylamino and / or di- (C 1 -C 4 ) -alkyl-amino may be substituted
  • (Ci-C 4) alkyl may in turn be substituted with hydroxy, (Ci-C 4) alkoxy, amino, mono- or di- (C r C 4) alkylamino,
  • L 2 is (C 1 -C 4 ) -alkanediyl which is mono- or disubstituted by fluorine and in which a methylene group is substituted by O or NR 5 , in which
  • R 5 is hydrogen, (C r C6) alkyl or (C 3 -C 7) -cycloalkyl,
  • Z is a group of the formula
  • R 6 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 1 and R 2 independently of one another are selected from the group 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 -
  • R 1 and / or R 2 bound to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CH 2 -O-, -O-CHF-O-, -O-CF 2 -O-, -O- CH 2 -CH 2 -O- or -O-CF 2 -CF 2 -O- form,
  • n and o are independently of one another the number O, 1, 2 or 3,
  • R 3 is hydrogen, (C r C4) alkyl or cyclopropyl
  • Compounds which can be used according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds of the formula (I) of the formulas below and their salts, solvates and solvates the salts and the compounds of 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 Salts acts.
  • 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.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the 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 according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example 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.
  • 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 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 salt
  • 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.
  • prodrugs include 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, in physiological media, under the conditions of the biological tests described below and in particular in vivo, enzymatically or chemically to the free carbon acids, as the main biologically active compounds, can be hydrolyzed.
  • esters (C 1 -C 4 ) -alkyl esters in which the alkyl group may be straight-chain or branched are preferred.
  • Particularly preferred are methyl or ethyl esters (see also corresponding definitions of the radical R 6 ).
  • (C 1 -C n VAIkVl. (C 1 -C 5 VAIkVl. (C 1 -C 4 VAIkVl and (C 1 -CV) -alkyl are in the context of the invention a straight-chain or branched alkyl radical having from 1 to 6, 1 to A straight-chain or branched alkyl radical having 1 to 4, more preferably having 1 to 3, carbon atoms is preferred, and may be mentioned by way of example and preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 1-ethyl-propyl, n-pentyl and n-hexyl.
  • (C 7 -Q-alkenyl and (C 7 -C 5) -alkenyl are a straight-chain or branched alkenyl radical having 2 to 6 or 2 to 5 carbon atoms and one or two double bonds
  • vinyl, AHyI, isopropenyl and n-but-2-en-1-yl By way of example and preferably, mention may be made of vinyl, AHyI, isopropenyl and n-but-2-en-1-yl.
  • the invention relates to a straight-chain or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond. Preference is given to a straight-chain alkynyl radical having 2 to 4 carbon atoms.
  • alkanediyl in the context of the invention a straight-chain or branched divalent alkyl radical having 1 to 4 or 1 to 3 carbon atoms.
  • Preferred is in each case a straight-chain alkanediyl radical having 1 to 4 or 1 to 3 Examples which may be mentioned are: methylene, 1,2-ethylene, ethane-1,1-diyl, 1,3-propylene, propane-1,1-diyl, propane-1,2-diyl, propane-2, 2-diyl, 1,4-butylene, butane-1,2-diyl, butane-l, 3-diyl and butane-2,3-diyl.
  • fC 2 -glyVAlkendiyl and ( " C 1 -C 4) -alkendiyl 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 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, Propene-1,3-diyl, but-1-en-1, 4-diyl, but-1-en-1, 3-diyl, but-2-en-1, 4-diyl and buta- 1,3 - dien-1,4-diyl.
  • (C 1 -C j ) -alkoxy and (C 1 -Q) -alkoxy are in the context of the invention a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • (C 1 -Cg) -AlkVlUiJo and (C 1 -Ca) -AlkVUhJo in the context of the invention represent a straight-chain or branched alkylthio radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkylthio radical having 1 to 4 carbon atoms. Examples which may be mentioned are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio.
  • (C 1 -C j ) -AcVl [(C r C 6 ) alkanoyl], (C 1 -CS) -ACVI [(C, C 5 ) alkanoyl] and (C r Ca) acyl [(C r C 4 ) - alkanoyl] are in the context of the invention for a straight-chain or branched alkyl radical having 1 to 6, 1 to 5 or 1 to 4 carbon atoms, which carries a double-bonded oxygen atom in the 1-position and the 1-position is linked. Preference is given to a straight-chain or branched acyl radical having 1 to 4 carbon atoms.
  • the invention relates to an amino group having a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.
  • Di (C 1 -C 6) -alkylamino and di (C 1 -C 4) -alkylamino in the context of the invention are an amino group having two identical or different straight-chain or branched alkyl substituents, each of which has 1 to 6 or 1 to Have 4 carbon atoms.
  • Straight-chain or branched dialkylamino radicals having in each case 1 to 4 carbon atoms are preferred.
  • 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.
  • (C 1 -C j ) acylamino and (C 1 -C 4 -cyclo-amino in the context of the invention represent 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 2 -C 4 -ClOalkyl) and (C 1 -C 6 -cycloalkyl represent a monocyclic, saturated cycloalkyl group having 3 to 7 or 3 to 6 carbon atoms, preferably a cycloalkyl radical having 3 to 6 carbon atoms may be mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • (C 1 -C 4 -cycloalkenyl) (C 1 -C 6 -cycloalkenyl and C 2 -C 8 -cycloalkenyl represent a monocyclic cycloalkyl group having 4 to 7, 4 to 6 or 5 or 6 carbon atoms and one double bond a cycloalkenyl radical having 4 to 6, particularly preferably 5 or 6, carbon atoms, by way of example and preferably: cyclobutyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • a 5- to 7-membered heterocycle in the context of the invention is a saturated or partially unsaturated heterocycle having 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
  • tetrahydropyranyl morpholinyl
  • hexahydroazepinyl hexahydro-1,4-diazepinyl.
  • 5- or 6-membered heteroaryl in the context of the invention represents an aromatic heterocycle (heteroaromatic) having 5 or 6 ring atoms which contains 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.
  • 6-membered heteroaryl radicals such as, for example, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.
  • 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. Very particular preference is given to the substitution with a substituent.
  • R 4 is hydrogen, (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl or (C 4 -C 7 ) -cycloalkenyl,
  • L 1 is a bond or (C 1 -C 4 ) -alkanediyl
  • the ring Q is (C 3 -C 7 ) -cycloalkyl, (C 4 -C 7 ) -cycloalkenyl, a 5- to 7-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which is up to twice, the same or differently, with fluorine, chlorine, (C 1 -C 4 ) -alkyl, trifluoromethyl, hydroxy, (C 1 -C 4 ) -alkoxy, trifluoromethoxy, amino, mono- (C 1 -C 4 ) -alkylamino and / or di- ( C 1 -C 4 ) -alkylamino may be substituted,
  • L 2 is (C 1 -C 4 ) -alkanediyl which is mono- or disubstituted by fluorine and in which a methylene group is substituted by O or NR 5 , in which
  • R 5 is hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl,
  • Z is a group of the formula
  • R 6 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 1 and R 2 independently represent a substituent selected from the group halogen
  • (C 1 -C 6 ) -alkyl and (C 1 -C 6 ) -alkoxy in turn may each be substituted by hydroxyl, (C 1 -C 4 ) -alkoxy, amino, mono- or di (C 1 -C 4 ) -alkylamino,
  • R 1 and / or R 2 attached to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CH 2 -O-, -O-CHF-O-, -O-CF 2 -O-, -O- CH 2 -CH 2 -O- or -O-CF 2 -CF 2 -O- form,
  • n and o are independently of one another the number O, 1, 2 or 3,
  • R 3 is hydrogen, (C 1 -C 4 ) -alkyl or cyclopropyl
  • A is O or NR 4 , in which
  • R 4 is hydrogen, (C 1 -C 4 ) -alkyl or (C 3 -C 6 ) -cycloalkyl,
  • L 1 is a bond or (C 1 -C 3 ) -alkanediyl
  • the ring Q is (C 3 -C 6 ) -cycloalkyl, (C 4 -C 6 ) -cycloalkenyl, a 5- or 6-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which may be up to twice, identical or different, with fluorine, chlorine, (Ci-C 3 ) alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, amino, methylamino, ethylamino, dimethylamino and / or diethylamino may be substituted,
  • Ethylamino, dimethylamino or diethylamino may be substituted,
  • L 2 is (C 1 -C 3 ) -alkanediyl which may be mono- or disubstituted by fluorine, (C 2 -C 3 ) -alkendiyl or a group of the formula * -M-CR 7 R 8 -, * -M-CH 2 -CR 7 R 8 - or * -CH 2 -M-CR 7 R 8 - in which
  • R 5 represents hydrogen, (C r C 3 ) -alkyl or cyclopropyl
  • R 7 and R 8 are independently hydrogen or fluorine
  • Z is a group of the formula
  • R 6 is hydrogen, methyl or ethyl
  • R 1 and R 2 independently represents a substituent chosen from the series fluorine, chlorine, cyano, (C r C 5) alkyl, (C 2 -C 5) -alkenyl, (C 3 -C 6) cycloalkyl, ( C 4 -C 6) -cycloalkenyl, (C 1 - C 4) alkoxy, trifluoromethyl, trifluoromethoxy, (Ci-C 4) alkylthio, (Ci-C5) acyl, amino, mono- (Ci-C 4 ) alkylamino, di- (C r C 4) alkylamino and (C r C4) acylamino stand,
  • n and o are independently of one another the number O, 1, 2 or 3, wherein, in the event that R 1 or R 2 occur several times, their meanings may be the same or different,
  • R 3 is hydrogen or (C 1 -C 3 ) -alkyl
  • A is O or NR 4 , in which
  • R 4 is hydrogen or (C r C 4) alkyl
  • L 1 is a bond or (C 1 -C 3 ) -alkanediyl
  • the ring Q is (GrC ⁇ J-cycloalkyl, (C 5 -C 6 ) -cycloalkenyl, a 5- or 6-membered heterocycle or phenyl, each of which is up to twice, identically or differently, with fluorine,
  • Chlorine (C 1 -C 3 ) -alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, trifluoromethoxy,
  • Amino, methylamino, ethylamino, dimethylamino and / or diethylamino may be substituted
  • L 2 is (C 1 -C 3 ) -alkanediyl which may be mono- or disubstituted by fluorine, (C 2 -C 3 ) -alkendiyl or a group of the formula * -M-CR 7 R 8 -, * -M-CH 2 -CR 7 R 8 - or * -CH 2 -M-CR 7 R 8 - in which
  • R 5 is hydrogen or (C 1 -C 3 ) -alkyl
  • R 7 and R 8 are independently hydrogen or fluorine
  • Z is a group of the formula
  • R 6 is hydrogen, methyl or ethyl
  • R 1 and R 2 independently of one another are selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C 5 ) -alkyl, (C 2 -C 5 ) -alkenyl, (C 3 -C 6 ) -cycloalkyl, (C 4 -C 6 ) -cycloalkenyl, (C 1 -C 4 ) -alkoxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 ) -alkylthio, (C 1 -C 5 ) -acyl, amino, mono- (C 1 -C 4 -alkyl) 4 ) -alkylamino, di (C 1 -C 4 ) -alkylamino and (C 1 -C 4 ) -acylamino,
  • n and o are independently of one another the number O, 1 or 2,
  • R 3 is hydrogen or (C 1 -C 3 ) -alkyl
  • A is O or NH
  • L ' is a bond, methylene, ethane-1, 1 -diy 1 or ethane-1, 2-diyl,
  • the ring Q is cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or phenyl, each of which being bis may be substituted by fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino and / or dimethylamino in duplicate, identically or differently,
  • L 2 is (C 1 -C 3 ) -alkanediyl, (C 2 -C 3 ) -alkendiyl or a group of the formula * -M-CH 2 - or "-M-CH 2 -CH 2 -" wherein
  • R 5 is hydrogen or (C, -C 3 ) -alky 1,
  • Z is a group of the formula
  • R 6 is hydrogen, methyl or ethyl
  • R 1 and R 2 independently represents a substituent chosen from the series fluorine, chlorine, cyano, (C r C 5) alkyl, (C 2 -C 5) -alkenyl, (C 3 -C 6) cycloalkyl, ( C 4 -C 6) -cycloalkenyl, (C, - C 4) alkoxy, trifluoromethyl, trifluoromethoxy, (C r C4) alkylthio, (C, -C 5) acyl, amino, mono- (Ci-C 4) -alkylamino, di- (C r C 4) alkylamino and (C r C4) acylamino stand,
  • n and o independently of one another represent the number 0, 1 or 2, wherein, in the event that R 1 or R 2 occur twice, their meanings may be the same or different,
  • R 3 is hydrogen
  • A is O or NH
  • L ' is a bond, methylene or ethane-1, 1 -diyl
  • the ring Q is cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl or phenyl, which may each be up to twice, identically or differently, substituted by fluorine, methyl, hydroxy and / or methoxy,
  • L 2 is (C 1 -C 3 ) -alkanediyl, (C 2 -C 3 ) -alkendiyl or a group of formula * -M-CH 2 - or * -M-CH 2 -CH 2 -, wherein
  • M is O or NH
  • Z is a group of the formula
  • R 6 is hydrogen, methyl or ethyl
  • R 1 represents a substituent selected from the group fluorine, chlorine, methyl, ethyl, vinyl, trifluoromethyl and methoxy
  • R 2 is a substituent selected from the group fluorine, chlorine, cyano, methyl, ethyl, n-propyl, vinyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methylthio, ethylthio, amino, methylamino and ethylamino,
  • n and o independently of one another represent the number 0, 1 or 2
  • R 3 is hydrogen
  • X 1 represents a leaving group such as, for example, halogen, in particular chlorine, in the presence of a base, optionally in an inert solvent, with a compound of the formula (III)
  • Z is cyano or a group of the formula - [C (O)] y -COOR 6A. stands in which
  • R 6A is (C 1 -C 4 ) -alkyl
  • Inert solvents for process steps (II) + (III) ⁇ (IV), (VI) + (III) ⁇ (VI-I) and (V-2) + (III) - »(VI-2) 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, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetrachloro - ethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF), dimethyl sul
  • Suitable bases for the process steps (II) + (III) ⁇ (IV), (VI) + (III) ⁇ (VI-I) and (V-2) + (III) ⁇ (VI-2) are customary inorganic or organic bases. These include preferably alkali 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 tert.-butoxide
  • 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 butyllithium or phenyllithium
  • organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine or pyridine.
  • the reactions (II) + (III) ⁇ (IV), (VI) + (III) ⁇ (VI-I) and (V-2) + (III) - »(VI-2) can also be used in a two-phase mixture consisting of an aqueous alkali metal hydroxide solution as the base and one of the abovementioned hydrocarbons or halogenated hydrocarbons as further solvent, using a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate or tetrabutylammonium bromide.
  • a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate or tetrabutylammonium bromide.
  • the bromination in process steps (VII) -> (VII-I) or (VI-2) -> (VII-2) is preferably in a halogenated hydrocarbon as solvent, in particular in tetrachloromethane, in a temperature range of +50 0 C to + 100 0 C performed.
  • Suitable brominating agents are elemental bromine and in particular N-bromosuccinimide ( ⁇ BS), optionally with the addition of ⁇ , ⁇ '-azobis (isobutyronitrile) (AIB ⁇ ) as initiator.
  • Inert solvents for the process steps (VII-I) + (VHl-1) ⁇ (TV) and (VII-2) + (V ⁇ I-2) ⁇ (IV) 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 glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylsulfoxide, N, N-dimethylpropyleneurea (DMPU ), N-methylpyrrolidone ( ⁇ MP), pyridine, acetonitrile or even water. It is likewise possible to use mixtures of the solvents mentioned. Preference is
  • Suitable bases for process steps (VII-I) + (VIII-I) ⁇ (IV) and (VII-2) + (VIII-2) ⁇ (IV) are customary inorganic bases.
  • These include in particular alkali metal 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 hydrogen phosphates such as disodium or dipotassium hydrogen phosphate.
  • alkali metal 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 hydrogen phosphates such as disodium or dipotassium hydrogen phosphate.
  • sodium or potassium carbonate is used.
  • the reactions (VII-I) + (VIII-I) ⁇ (TV) and (VII-2) + (Vffl-2) ⁇ (TV) are generally in a temperature range of +20 0 C to + 15O 0 C, preferably carried out at +50 0 C to +100 0 C.
  • the hydrolysis of the ester or nitrile group Z 1 in process step (IV) -> (I-A) is carried out by customary methods by treating the esters or nitriles in inert solvents with acids or bases, wherein the latter resulting salts are treated by treatment with acid in the free carboxylic acids.
  • the 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 tert-butyl esters and hydrochloric acid in the case of 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, one works 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 (DMPU). or N-methylpyrrolidone ( ⁇ MP). It is likewise possible to use mixtures of the solvents mentioned. Preferably, toluene is used.
  • DMPU dimethylformamide, N, N'-dimethylpropyleneurea
  • ⁇ MP N-methylpyrrolidone
  • sodium azide in the presence of ammonium chloride or trimethylsilyl azide is suitable as an 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 + 15O 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). Generally, 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. Preferably, a mixture of methanol and tetrahydrofuran is used.
  • the second reaction step will be preferred example in an ether, in particular carried out 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 is a leaving group such as halogen, mesylate or tosylate,
  • the compounds of the formula (X) can be prepared from a compound of the formula (II), (V-I) or (V-2) by base-catalysed reaction with a compound of the formula (XIII)
  • reaction sequence (VI) or (V-2) -> (IV-A) the order of the individual process steps, if expedient, can also be varied (see also the following reaction schemes 2-9).
  • the compounds of the invention are chemically and metabolically stable, non-prostanoid activators of the IP receptor with good physicochemical and pharmacokinetic properties. In particular, they have a sufficiently high bioavailability after oral administration and / or good solubility for parenteral administration.
  • the compounds according to the invention are therefore particularly suitable for the treatment and / or prophylaxis of pulmonary arterial hypertension including their subforms, such as idiopathic, familial and, for example, with portal hypertension, fibrotic disorders, HIV infection or improper medication or toxins associated pulmonary arterial hypertension.
  • the compounds of the invention may also be used for the treatment and / or prophylaxis of other forms of pulmonary hypertension. Thus, they can be used, for example, for the treatment and / or prophylaxis of pulmonary hypertension in left atrial or left ventricular diseases and in left-sided heart valve diseases.
  • 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 are particularly suitable for the treatment and / or prophylaxis of pulmonary arterial hypertension and pulmonary hypertension associated with chronic obstructive and / or fibrotic lung diseases and pulmonary hypertension due to chronic thrombotic and / or embolic diseases.
  • 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 according to the invention can be used alone or in combination with other active substances.
  • Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients for the treatment and / or prophylaxis 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 such as, 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
  • 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;
  • 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 AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor B-relaxer, 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, the ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR 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, the ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption
  • 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, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, by way of example and by way of preference, 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.
  • 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 GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • a GPIIb / 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.
  • a vitamin K antagonist such as by way of example and preferably coumarin.
  • the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII 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 AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • an angiotensin AII 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 used 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.
  • the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide.
  • 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.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR alpha PPAR alpha
  • PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as, by way of example and by way of preference, torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • a CETP inhibitor such as, by way of example and by way of preference, torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • the compounds of 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 by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of 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 according to the invention are administered in combination with a PPAR-gamma agonist, such as by way of example and preferably 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 according to the invention are administered in combination with a polymeric bile acid adsorber, such as by way of example and with preference cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorber such as by way of example and with preference cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • AZD-7806 S-8921
  • AK-105 AK-105
  • BARI-1741 AK-105
  • SC-435 SC-635.
  • 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.
  • Another object of the present invention is the use of the compounds of the invention alone or in combination with one or more of the aforementioned active ingredients for the manufacture of a medicament for the treatment and / or prophylaxis of idiopathic, familial or associated with drugs, toxins or other diseases pulmonary arterial hypertension , for the treatment and / or prophylaxis of pulmonary hypertension in left atrial or left ventricular diseases, left-sided heart valve diseases, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, diseases with alveolar hypoventilation, altitude sickness, pulmonary developmental disorders, chronic thrombotic and / or embolic diseases such as thromboembolism of the proximal pulmonary arteries, obstruction of the distal pulmonary arteries and pulmonary embolism, or in association with sarcoidosis, histiocytosis X or lymph angioleiomyomatosis, as well as for the treatment and / or prophylaxis
  • Another object of the present invention is a method for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension in humans and animals by administering an effective amount of at least one of the compounds of the invention or a drug containing at least one of the compounds of the invention.
  • the medicaments to be produced according to the invention or to be used according to the invention comprise at least one of the compounds according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients.
  • 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
  • Parenteral administration can be done bypassing a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (for example by inhalation, intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • a resorption step eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly
  • absorption for example by inhalation, intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally.
  • parenteral administration are suitable as forms of application, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalants, 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 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 Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD 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
  • 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 Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 100 x 4.6 mm; Eluent A: water + 500 ⁇ l 50% formic acid / 1, eluent B: acetonitrile + 500 ⁇ l 50% formic acid / 1; Gradient: 0.0 min 10% B ⁇ 7.0 min 95% B ⁇ 9.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min ⁇ 7.0 min 2.0 ml / min ⁇ 9.0 min 2.0 ml / min; 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, GC6890; 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: 7O 0 C, 30 ° C / min ⁇ 310 0 C (hold for 3 min).
  • Instrument Micromass GCT, GC6890; 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 (12 min hold).
  • the black solid is filtered off, re-slurried three times with water, filtered off with suction again and dried under high vacuum.
  • the solid is dissolved in dichloromethane and column-filtered on silica gel (eluent: dichloromethane). This gives 1371 mg (80.6% of theory) of the target compound as a yellow solid.
  • Example 9 800 mg (1.66 mmol) of methyl 3 - ⁇ [5- (4-methoxyphenyl) -phenylmro [2,3-d] pyrimidin-4-yl] amino ⁇ phenoxyacetate (Example 9) are treated with ammonia at RT in methanol (14.2 ml of a ca. 7 M solution) and stirred overnight. The mixture is concentrated in vacuo, stirred with a little methanol and filtered with suction. The filter residue is washed downstream with diisopropyl ether and dried overnight at 50 0 C in a high vacuum. 663 mg (86.5% of theory) of the target product are obtained as an almost white solid.
  • the free aniline is obtained by washing a solution (or suspension) of the hydrochloride in dichloromethane with saturated sodium bicarbonate solution and concentration in vacuo.
  • the free aniline is obtained by washing a solution (or suspension) of the hydrochloride in dichloromethane with saturated sodium bicarbonate solution and concentration in vacuo.
  • Example 28 To 100 mg (0.215 mmol) of methyl 3 - ⁇ [5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino ⁇ phenylacetate (Example 28), dissolved in 1.5 ml THF and 2 ml of methanol are added at RT 215 mg (4.3 mmol) of hydrazine hydrate. The mixture is stirred for 1 h at 65 ° C and overnight at RT and then concentrated in vacuo. After stirring with diisopropyl ether, the solid is filtered off with suction and dried in vacuo. 89.3 mg (89.3% of theory) of the target product are obtained.
  • the target compound can be obtained by crystallization from alcoholic solvents (eg methanol), by chromatography on silica gel (preferred eluant systems are dichloromethane / methanol and cyclohexane / ethyl acetate), by preparative RP-HPLC (eluent: water / acetonitrile) or by a combination of these Methods are isolated and purified.
  • alcoholic solvents eg methanol
  • silica gel preferred eluant systems are dichloromethane / methanol and cyclohexane / ethyl acetate
  • preparative RP-HPLC eluent: water / acetonitrile
  • the mixture is stirred for 30 min to 6 h at RT. It is then diluted with dichloromethane or ethyl acetate and worked up with water. The organic phase is washed with 1 N hydrochloric acid, saturated sodium bicarbonate solution and / or sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.
  • the target compound can be obtained by crystallization from alcoholic solvents (eg methanol), by chromatography on silica gel (preferred eluant systems are dichloromethane / methanol and cyclohexane / ethyl acetate), by preparative RP-HPLC (eluent: water / acetonitrile) or by a combination of these Methods are isolated and purified.
  • alcoholic solvents eg methanol
  • silica gel preferred eluant systems are dichloromethane / methanol and cyclohexane / ethyl acetate
  • preparative RP-HPLC eluent: water / acetonitrile
  • reaction mixture is stirred for 1 h at RT, added to water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.
  • (+/-) - c / 5-3 - ⁇ [5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy ⁇ cyclohexanol (Example 33A) and 640 mg of (+/-) - / raws-3 - ⁇ [5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy ⁇ -cyclohexanol (Example 34A).
  • the crude product is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 2: 1 ⁇ 1: 2). 1.05 g (85.1% of theory) of the target product are obtained as cw / fraHS mixture.
  • the residue is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1 ⁇ 8: 1).
  • the target product is obtained after further purification by means of RP-HPLC (eluent: acetonitrile / water). 380 mg (41.2% of theory) are isolated.

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Abstract

La présente invention concerne l'utilisation de dérivés de furopyrimidine à substitution cyclique de formule (I) dans le traitement et/ou la prophylaxie de l'hypertonie artérielle pulmonaire et d'autres formes de l'hypertonie pulmonaire ainsi que l'utilisation desdits dérivés dans la production de médicaments destinés au traitement et/ou à la prophylaxie de l'hypertonie artérielle pulmonaire et d'autres formes de l'hypertonie pulmonaire.
PCT/EP2008/003008 2007-04-26 2008-04-16 Utilisation de dérivés de furopyrimidine à substitution cyclique dans le traitement de l'hypertonie artérielle pulmonaire WO2008131859A2 (fr)

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DE102007019690A DE102007019690A1 (de) 2007-04-26 2007-04-26 Verwendung von cyclisch substituierten Furopyrimidin-Derivaten zur Behandlung der pulmonalen arteriellen Hypertonie
DE102007019690.5 2007-04-26

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11071730B2 (en) 2018-10-31 2021-07-27 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11203591B2 (en) 2018-10-31 2021-12-21 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11071730B2 (en) 2018-10-31 2021-07-27 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11203591B2 (en) 2018-10-31 2021-12-21 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof

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