EP2240461A1 - Furanes substitués et leur utilisation - Google Patents

Furanes substitués et leur utilisation

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Publication number
EP2240461A1
EP2240461A1 EP09707538A EP09707538A EP2240461A1 EP 2240461 A1 EP2240461 A1 EP 2240461A1 EP 09707538 A EP09707538 A EP 09707538A EP 09707538 A EP09707538 A EP 09707538A EP 2240461 A1 EP2240461 A1 EP 2240461A1
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EP
European Patent Office
Prior art keywords
formula
group
methyl
compounds
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP09707538A
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German (de)
English (en)
Inventor
Thomas Lampe
Raimund Kast
Friederike Stoll
Joachim Schuhmacher
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Bayer Intellectual Property GmbH
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Bayer Schering Pharma AG
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Publication of EP2240461A1 publication Critical patent/EP2240461A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • the present application relates to novel, substituted furan 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.
  • 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.
  • 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.
  • beraprost Barst, RJ. et al., J. Am. Coli. Cardiol. 2003, 41: 2119-2125] again limited by its short duration of action.
  • the compounds described in the present application are chemically and metabolically stable, non-prostanoid activators of the IP receptor, which mimic the biological activity of PGI 2 and can thus be used for the treatment of diseases, in particular of cardiovascular diseases ,
  • EP 1 535 915 describes substituted furans and thiophenes as PPAR modulators for the treatment of arteriosclerosis, diabetes mellitus and lipid metabolism disorders.
  • the present invention relates to compounds of the general formula (I)
  • R 4 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 5 is hydrogen or (C r C 4) alkyl
  • alkyl may be substituted with one substituent selected from the group hydroxy and amino,
  • L 1 is (C 1 -C 7 ) -alkanediyl, (C 2 -C 7 ) -alkendiyl or a group of formula * _L 1A -VL IB - ** ;
  • alkanediyl and alkenediyl may be substituted with 1 or 2 substituents fluorine,
  • IA is (C, -C 5 ) -alkanediyl
  • alkanediyl having 1 or 2 substituents independently may be selected from the group consisting of (Ci-C 4) -alkyl and (C r C 4) alkoxy.
  • IB is a bond or (C 1 -C 3 ) -alkanediyl
  • alkanediyl may be substituted by 1 or 2 substituents fluorine,
  • V is O or NR 6 ,
  • R 6 is hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl,
  • L 2 is a bond or (C 1 -C 4 ) -alkanediyl
  • Q is (C 3 -C 7 ) -cycloalkyl, (C 4 -C 7 ) -cycloalkenyl, 5- to 7-membered heterocyclyl,
  • alkyl is substituted with a substituent selected from the group of hydroxy, (C r C4) alkoxy, amino, mono- (C r C 4) -alkylamino and di- (Ci-C4) - alkylamino may be substituted,
  • L 3 is (C r C 4 ) -alkanediyl or (C 2 -C 4 ) -alkendiyl
  • alkanediyl may be substituted by 1 or 2 substituents fluorine,
  • R 7 is hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl
  • Z is a group of the formula
  • R 8 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 1 represents halogen, cyano, nitro, (C r C6) alkyl, trifluoromethyl, (C 2 -C 6) alkenyl, (C 2 -C 4) - alkynyl, (C 3 -C 7) cycloalkyl, (C 4 -C 7) cycloalkenyl, (C r C 6) alkoxy, trifluoromethoxy, (C r C6) alkylthio, (Ci-C 6) alkylcarbonyl, amino, mono- (C r C6) - alkylamino, di- (C 1 -C 6 ) -alkylamino or (C 1 -C 6 ) -alkylcarbonylamino,
  • (C 1 -C 6 ) -alkyl and (C 1 -C 6 ) -alkoxy in turn have a substituent selected from the group cyano, hydroxy, (C 1 -C 4 ) -alkoxy, (C 1 -C 4 ) -alkylthio, amino, mono- (Ci-C 4) -alkylamino and di- (Ci -C 4) alkylamino can be substituted,
  • R 1 bound to adjacent carbon atoms of the 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 - Form O- or -O-CF 2 -CF 2 -O-,
  • n is the number O, 1 or 2
  • R 2 is phenyl or 5- or 6-membered heteroaryl
  • alkyl and alkoxy having a substituent selected from the group consisting of cyano, hydroxy, (C r C4) alkoxy, (Ci-C 4) alkylthio, amino, mono (C] -C4) - alkylamino and di- ( C 1 -C 4 ) -alkylamino may be substituted,
  • R 3 is methyl, ethyl or trifluoromethyl
  • Compounds according to 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 and of the formula (I) encompassed by 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.
  • Suitable salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts suitable for pharmaceutical Applications themselves are not suitable, but can be used for example for the isolation or purification of the inventive compounds.
  • 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 according to the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but are reacted during their residence time in the body 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 assays described below, and in particular in vivo enzymatically or chemically to the free carboxylic acids, as the main biologically 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 or ethyl esters (see also corresponding definitions of the radical R 8 ).
  • alkyl is a linear or branched alkyl radical having 1 to 6 carbon atoms. Preference is given to a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.
  • Alkenyl in the context of the invention represents a linear or branched alkenyl radical having 2 to 6 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.
  • Alkynyl in the context of the invention represents a linear or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond.
  • alkynyl in the context of the invention represents a linear or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond.
  • ethynyl n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-one in-l-yl.
  • Alkanediyl in the context of the invention is a linear or branched divalent alkyl radical having 1 to 7 carbon atoms.
  • alkyl radical having 1 to 7 carbon atoms.
  • Alkenediyl in the context of the invention is a linear or branched divalent alkenyl radical having 2 to 7 carbon atoms and up to 2 double bonds. Examples which may be mentioned by way of example and are preferably: ethene-1, 1-diyl, ethene-1,2-diyl, propene-1,1-diyl, propylene-1,2-diyl, propene-1,3-diyl, but-1-one en-1, 4-diyl, but-1-en-1, 3-diyl, but-2-en-1, 4-diyl and buta-1,3-dien-1, 4-diyl.
  • Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. By way of example and preferably mention may be made of: methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Alkylthio in the context of the invention is a linear or branched alkylthio radical having 1 to 6 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.
  • Alkylcarbonyl in the context of the invention is a linear or branched alkyl radical having 1 to 6 carbon atoms and a carbonyl group attached in position 1.
  • Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 6 carbon atoms. Examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.
  • Di-alkylamino in the context of the invention is an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 6 carbon atoms. Examples which may be mentioned are: 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.
  • Alkylcarbonylamino in the context of the invention represents an amino group which is linked via a carbonyl group with a linear or branched alkyl substituent having 1 to 6 carbon atoms.
  • alkylcarbonylamino in the context of the invention represents an amino group which is linked via a carbonyl group with a linear or branched alkyl substituent having 1 to 6 carbon atoms.
  • Cycloalkyl in the context of the invention is a monocyclic, saturated cycloalkyl group having 3 to 7 carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkenyl is in the context of the invention a monocyclic cycloalkyl group having 4 to 7 carbon atoms and a double bond. Examples which may be mentioned by way of example include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • Heterocvclyl in the context of the invention is a saturated, monocyclic, heterocyclic radical having 5 to 7 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series ⁇ , O, S, SO, SO 2 , where a nitrogen atom also a ⁇ Oxide can form.
  • Preferred are 5- or 6-membered saturated heterocyclyl radicals having one or two ring heteroatoms from the series N and O.
  • pyrrolidinyl pyrazolidinyl
  • tetrahydrofuranyl piperidinyl
  • piperazinyl tetrahydropyranyl
  • morpholinyl hexahydroazepinyl and hexahydro-1, 4-diazepinyl.
  • Heteroaryl is in the context of the invention for an aromatic heterocycle (heteroaromatic) with 5 or 6 ring atoms and up to 3 heteroatoms from the series N, O and S, wherein a nitrogen atom can also form an N-oxide.
  • aromatic heterocycle heterocycle
  • Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.
  • Halogen is in the context of the invention for fluorine, chlorine, bromine and iodine, preferably 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 one another 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.
  • E is O or NR 4 ,
  • R 4 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 5 is hydrogen, methyl or ethyl
  • L 1 is (C 3 -C 7 ) -alkanediyl, (C 3 -C 7 ) -alkendiyl or a group of formula * -L 1A -VL 1B - **,
  • L 1A is (C r C 3 ) -alkanediyl
  • alkanediyl may be substituted with 1 or 2 substituents independently of one another selected from the group consisting of methyl and ethyl,
  • L 1B is (C 1 -C 3 ) -alkanediyl
  • V is O or NR 6 ,
  • R 6 is hydrogen, (C 1 -C 3 ) -alkyl or cyclopropyl
  • L 2 is a bond, methylene, ethane-1, 1-diyl or ethane-1, 2-diyl,
  • Q is cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, polypholinyl or phenyl,
  • cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, Mo ⁇ holinyl and phenyl may be substituted with 1 or 2 substituents independently selected from the group fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy and ethoxy, and
  • L 3 is (C r C 3 ) -alkanediyl or a group of the formula "-W-CR 9 R 10 - **, -W-CH 2 -CR 9 R ' 0 -" or e-CH 2 -W- CR 9 R 10 - Jardin stands,
  • alkanediyl may be substituted by 1 or 2 substituents fluorine,
  • the point of attachment to the ring Q means
  • W is O or NR 7 ,
  • R 7 is hydrogen, (C 1 -C 3 ) -alkyl or cyclopropyl,
  • R 9 is hydrogen or fluorine
  • R 10 is hydrogen or fluorine
  • Z is a group of the formula
  • R 8 is hydrogen
  • R 1 is fluorine, chlorine, methyl, ethyl, vinyl, trifluoromethyl or methoxy
  • n is the number 0, 1 or 2, wherein, in the event that R 1 occurs several times, its meaning may be the same or different,
  • R 2 is phenyl or 2-pyridyl
  • phenyl and 2-pyridyl having 1 or 2 substituents independently selected from the group fluorine, chlorine, cyano, methyl, ethyl, n-propyl, vinyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, methylthio, ethylthio, amino, methylamino and ethylamino can be substituted
  • R 3 is methyl or trifluoromethyl
  • E is O or NR 4 ,
  • R 4 is hydrogen
  • R 5 is hydrogen or methyl
  • L 1 A is methylene or ethane-1, 2-diyl
  • L 1B is methylene or ethane-1, 2-diyl
  • V is O or NR 6 ,
  • R 6 is methyl
  • L 2 is a bond
  • L 3 is ethane-1, 2-diyl, propane-1,3-diyl or a group of the formula "-W-CR 9 R 10 - * or.-W-CH 2 -CR 9 R 10 - **,
  • the point of attachment to the ring Q means
  • R 9 is hydrogen
  • R 10 is hydrogen
  • Z is a group of the formula
  • R 8 is hydrogen
  • R 1 is fluorine, chlorine, methyl or trifluoromethyl
  • n is the number 0 or 1
  • R 2 is phenyl
  • phenyl may be substituted by a substituent selected from the group consisting of methyl, ethyl, vinyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy,
  • R 3 is methyl
  • R 5 is hydrogen or methyl
  • L 1 is butanedi-1,4-diyl, pentan-l, 5-diyl or a group of the formula * -L IA -VL 1B - **,
  • L 1 A is methylene or ethane-1, 2-diyl
  • L 1 B is methylene or ethane-1, 2-diyl
  • V is O or NR 6 ,
  • R 6 is methyl
  • L 2 is a bond
  • L 3 is ethane-l, 2-diyl, propane-l, 3-diyl or a group of the formula "-W-CR 9 R 10 - ** or ⁇ -W-CH 2 -CR 9 R 10 - ⁇ ,
  • the point of attachment to the ring Q means
  • R 9 is hydrogen
  • R 10 is hydrogen
  • R 2 is phenyl
  • phenyl may be substituted with one substituent selected from the group of methyl, ethyl, vinyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy.
  • 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, which comprises reacting either
  • X 1 is chlorine or hydroxy
  • Z 1 is cyano or a group of the formula COOR 8A ,
  • R 1 8A is (Ci-GO-alkyl
  • n, A 1 , E, M, Z 1 , R 1 and R 3 each have the meanings given above,
  • R 11 is hydrogen or both radicals R 11 together form a -C (CHj) 2 -C (CH 3 );, - bridge,
  • n, A 1 , E, M, Z 1 , R 1 , R 2 and R 3 are each as defined above,
  • R 12 is (CrO-alkyl
  • n, A 1 , R 1 , R 2 , R 3 and R 12 each have the meanings given above,
  • a 2 stands for -CH 2 -
  • X 2 for a leaving group such as halogen or Trifluormethansulfonyloxy, in particular bromine or
  • n, A 2 , E 1 , M, Z 1 , R 1 , R 2 and R 3 are each as defined above,
  • E 2 is NR 4 ,
  • R 4 is hydrogen or (C 1 -C 4 ) -alkyl
  • n, A 2 , E 2 , M, Z 1 , R 1 , R 2 and R 3 are each as defined above,
  • n, A, E, M, R, R and R each have the meanings given above, and optionally with the corresponding (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.
  • Inert solvents for the coupling reactions (II-A) + (ffl-A) ⁇ (IV-A) and (VB) + (Ul-A) -> (VII-A) 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, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as acetone, Acetonitrile, ethyl acetate, pyridine, dimethyl sulfoxide, dimethylformamide, N, N'-di
  • Suitable bases in the coupling reactions are alkali carbonates, e.g. Sodium or potassium carbonate, or organic bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine or 4-NN-dimethylaminopyridine.
  • organic bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine or 4-NN-dimethylaminopyridine.
  • triethylamine is used.
  • Suitable acids in the coupling reactions are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid.
  • the acid is used here in catalytic amounts.
  • the couplings (II-A) + (IH-A) ⁇ (IV-A) and (VB) + (EI-A) ⁇ (VTI-A) are typically in a temperature range of 0 0 C to +60 0 C, preferably carried out at 0 0 C to + 35 ° C.
  • the reactions can be carried out at normal, at elevated or at reduced pressure (for example from 0.5 to 5 bar); generally one works at normal pressure.
  • HATU 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
  • Suitable inert solvents in the bromination in process step (FV-A) ⁇ (VA) are halohydrocarbons such as carbon tetrachloride or 1, 2-dichloroethane or other solvents such as acetonitrile.
  • the bromination is carried out in a temperature range from -20 0 C to + 50 0 C.
  • Suitable brominating agents are elemental bromine and in particular N-bromosuccinimide ( ⁇ BS), optionally with addition of ⁇ , ⁇ '-azobis (isobutyronitrile) (AIBN) as initiator.
  • Inert solvents for process steps are, for example, alcohols such as methanol, ethanol, n-propanol,
  • Suitable bases for the (VA) + (VI) ⁇ (VH-A), (HB) + (VI) ⁇ (IV-B) and (HC) + (VI) ⁇ (IV-C) 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. Preferably, sodium or potassium carbonate is used.
  • 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.
  • Triphenylphosphine palladium (H) chloride, bis (acetonitrile) palladium ( ⁇ ) chloride and [1,1'-bis (diphenylphosphino) ferrocene] dichlo ⁇ alladium (H) -dichloromethane complex suitable [see. eg J. Hassan et al., Chem. Rev. 102, 1359-1469 (2002)].
  • the reactions (VA) + (VI) ⁇ (VD-A), (HB) + (VI) ⁇ (IV-B) and (FI-C) + (VI) ⁇ (IV-C) are generally used in one Temperature range of +20 0 C to +150 0 C, preferably carried out at +50 0 C to +100 0 C.
  • Suitable inert solvents for process step (FV-C) ⁇ (VC) are alcohols such as methanol, ethanol, n-propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or halogenated hydrocarbons such as dichloromethane, trichloromethane, Carbon tetrachloride or 1,2-dichloroethane, or other solvents such as dimethylformamide. It is also possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran.
  • Suitable reducing agents for the process step (FV-C) - »(VC) borohydrides such as sodium borohydride, sodium triacetoxyborohydride, lithium borohydride or sodium cyanoborohydride, aluminum hydrides such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride or diisobutylaluminum hydride or borane-tetrahydrofuran Complex used.
  • Reaction (IV-C) ⁇ (VC) is generally carried out in a temperature range of 0 0 C to +60 0 C, preferably from 0 0 C to +40 0 C.
  • Inert solvents for process step (VC) + (EH-C) - (VFI-C) 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, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N ' -Dimethylpropyleneurea (DMPU), N
  • process step (V-C) + (FH-C) -> (VFI-C) can also be carried out without a solvent.
  • Suitable bases for the process step (VC) + (HI-C) - »(VFI-C) 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 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 butyl lithium or phenyl lithium, or organic amines such as triethylamine, N-Methylmo ⁇ holin, N-methylpiperidine, N, N-diisopropylethylamine or pyridine.
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • the process step (V-C) + (EI-C) -> (VII-C) may optionally be carried out advantageously with the addition of a crown ether.
  • reaction (VC) + (DI-C) -> (VH-C) also in a two-phase mixture consisting of an aqueous alkali hydroxide solution as the base and one of the above hydrocarbons or halogenated hydrocarbons as further Solvent, be carried out 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 process step (VC) + (HI-C) -> (VII-C) is generally carried out in a temperature range from -20 0 C to +120 0 C, preferably at 0 0 C to + 60 0 C.
  • Suitable inert solvents for process step (IV-C) + (IH-D) - »(VII-D) are alcohols such as methanol, ethanol, n-propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or Diethylene glycol dimethyl ether, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, or other solvents such as dimethylformamide. It is also possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran.
  • Boron hydrides such as, for example, sodium borohydride, sodium triacetoxyborohydride, lithium borohydride or sodium cyanoborohydride, if appropriate with addition of acids such as formic acid or acetic acid, or Lewis acids, are suitable as reducing agents for process step (IV-C) + (DI-D) ⁇ (VD-D) such as titanium (IV) tetrachloride or titanium (IV) isopropylate.
  • reaction (IV-C) + (DI-D) -> (VD-D) can be carried out with ammonium formate or formic acid, or under a hydrogen atmosphere with catalysts such as Raney- ⁇ ickel, palladium, palladium on activated carbon or platinum.
  • reaction (FV-C) + (DI-D) -> (VII-D) is generally carried out in a temperature range from 0 0 C to +60 0 C, preferably from 0 0 C to +40 0 C.
  • the hydrolysis of the cyano or ester group Z 1 of the compounds (VII-A), (VII-C) or (VH-D) to compounds of the formula (I-1) and the ester of the formula (IV-B ) to carboxylic acids of the formula (VB) is carried out by customary methods by treating the esters or nitriles in inert solvents with acids or bases, wherein in the latter, the salts initially formed are converted by treatment with acid in the free carboxylic acids.
  • the 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 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, if appropriate 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 Esterspaltung is generally carried out in a temperature range of 0 0 C to +100 0 C, preferably at +0 0 C to +50 0 C.
  • 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 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 ° C to +110 0 C.
  • the reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). In general, you work at normal pressure.
  • n, A, E, M, R 1 , R 2 and R 3 have the meanings given above,
  • phosgene or a phosgene equivalent such as N, N'-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 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.
  • n, A, E, IA , V, R 1 , R 2 , R 3 and R 5 are each as defined above,
  • X 2 is a leaving group such as halogen, mesylate or tosylate,
  • n, A, E, L 1A , L 1B , V, Z 1 , R 1 , R 2 , R 3 and R 5 are each as defined above,
  • n, A, E, L 2 , Q, W, R 1 , R 2 and R 3 are each as defined above,
  • n is the number 0 or 1
  • n, m, A, E, L 2 , Q, W, Z 1 , R 1 , R 2 , R 3 , R 9 , R 10 and m are each as defined above,
  • Other compounds of the invention may optionally also be prepared by conversions of functional groups of individual substituents, in particular those listed under R 1 and R 2 , starting from the compounds of the formula (I) obtained by the above methods.
  • transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of Carbonamides, as well as introduction and removal of temporary protecting groups.
  • 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 IP receptor.
  • 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 of the invention may also be used for the treatment and / or prophylaxis of other forms of pulmonary hypertension.
  • 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 can also be used for the treatment and / or prophylaxis of peripheral and cardiac 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 for the treatment of arteriosclerosis, hepatitis, asthmatic diseases, chronic obstructive pulmonary diseases (COPD), pulmonary edema, pulmonary fibroids 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 diseases
  • pulmonary edema pulmonary fibroids
  • IPF idiopathic pulmonary fibrosis
  • ARDS idiopathic pulmonary fibrosis
  • 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 the 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.
  • Another object of the present invention are the inventive compound of formula (I) for use in a method for the treatment and / or prophylaxis of angina pectoris, pulmonary hypertension, thromboembolic diseases and peripheral occlusive diseases.
  • the compounds according to the invention can be used alone or as needed in combination with other active substances.
  • Another object of the present invention are medicaments, 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 SESf-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
  • Elafrn Compounds which inhibit human neutrophil elastase (HNE), such as, for example, Sivelestat, DX-890 (Reltran), Elafrn 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;
  • 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;
  • connections affecting the energy metabolism of the heart such as exemplary and preferably etomoxir, dichloroacetate, ranolazines or trimetazidines;
  • VPAC receptors such as by way of example and preferably the vasoactive intestinal polypeptide
  • Antithrombotic agents by way of example and preferably from the group of thrombocyte 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, 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 of the invention are used in combination with a GPBb / IIIa antagonist, as exemplified and preferably 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 Aü antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor B-relaxer, beta-receptor blocker, mineralocorticoid receptor Tor 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 by way of preference, 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 by way of preference, propranolol, atenolol
  • the compounds according to the invention are administered in combination with an angiotensin AQ antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • an ACE inhibitor such as by way of example and preferably 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.
  • 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 gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile acid rea
  • 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 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).
  • T3 3,5,3'-triiodothyronine
  • CGS 23425 CGS 23425
  • 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
  • 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 by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as by way of 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 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.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • 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 compound of the invention 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, conjunctival, 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 (for example Hart - or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalation medicaments including Pulverinhala- tors, Nebulizer
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets to be applied
  • films / wafers or capsules films / wafers or capsules
  • suppositories ear or eye preparations
  • vaginal capsules aqueous Suspensions (lotions, shake mixtures)
  • lipophilic suspensions Ointments
  • creams transdermal therapeutic systems (eg patches)
  • 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.
  • GC-MS (Method I): 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 o C / min ⁇ 310 ° C (hold for 3 min).
  • LC-MS (Method 3): 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; 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.
  • LC-MS (Method 4): Instrument: Micromass QuattroPremier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD l, 9 ⁇ 50 x 1 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 -> 1.5 min 10% A - »2.2 min 10% A Furnace: 50 ° C; Flow: 0.33 ml / min; UV detection: 210 nm.
  • LC-MS (Method 5): Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 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 - »4.1 min 90% A; Flow: 2 ml / min; Oven: 50 ° C .; UV detection: 208-400 nr.
  • LC-MS (Method 6): Device type MS: Waters ZQ; Device Type HPLC: Agilent 1100 Series; UV DAD; Column: Thermo Hypersil GOLD 3 ⁇ 20mm x 4mm; 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 100% A ⁇ 3.0 min 10% A ⁇ 4.0 min 10% A ⁇ 4.1 min 100%; Flow: 2.5 ml / min; Oven: 55 ° C; UV detection: 210 nm.
  • LC-MS (Method 7): Instrument: Micromass Quattro Micro MS with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3 ⁇ 20 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 100% A-> 3.0 min 10% A -> 4.0 min 10% A- * 4.01 min 100% A (flow 2.5 ml / min) - »5.00 min 100% A; Oven: 50 ° C .; Flow: 2 ml / min; UV detection: 210 nm.
  • Solution A 10.71 g (267.7 mmol) of 60% sodium hydride are dissolved in 150 ml of abs. Suspended THF and added dropwise with cooling with 43.3 ml (276.7 mmol) of P.P-Dimethylphosphonoessigklare- tert-butyl ester. The mixture is stirred at RT, after about 30 min, a solution is formed.
  • aqueous phase is re-extracted with ethyl acetate.
  • organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.
  • the residue is purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 5: 1). This gives 32.2 g (90.1% of theory) of the target product which contains small amounts of the cis isomer.
  • aqueous phase is washed with conc. Hydrochloric acid carefully acidified and the resulting suspension is extracted with methyl tert-butyl ether.
  • the organic phase is monitored with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated in vacuo and the solid is dried in a high vacuum. 113.0 mg of target product are obtained (47.3% of theory).
  • the crude product is purified by chromatography on silica gel (cyclohexane / ethyl acetate 10: 1 to 9: 1). 660.2 mg of target product are obtained (44.1% of theory)
  • aqueous phase is extracted three times with ethyl acetate, and the combined organic extracts are dried
  • the mixture is warmed to RT and stirred for 2 h, before adding a little water.
  • the precipitated, white precipitate is filtered off with suction and washed three times with water, twice with methanol and dichloromethane.
  • the filtrate is diluted with water and the organic phase separated.
  • the aqueous phase is extracted twice with dichloromethane.
  • the product is purified by preparative RP-HPLC (acetonitrile / water). 26.6 mg of target product are obtained (10.9% of theory).
  • butyl ester is dissolved in a mixture of 2 ml of isohexane and 0.2 ml of ethanol and separated by chromatography on a chiral phase into the enantiomers; Column: Daicel Chiralpak AD-H, 5 ⁇ m, 250 mm x 30 mm; Flow: 15 ml / min; Detection: 220 nm; Injection volume: 1.1 ml; Temperature: 30 ° C .; Eluent: 95% isohexane / 5% ethanol. The following examples are isolated:
  • the target compound is isolated directly from the crude product, optionally after extractive work-up with dichloromethane or ethyl acetate, by preparative RP-HPLC (eluent: Water / acetonitrile gradient) or by stirring with an inert solvent.
  • RP-HPLC eluent: Water / acetonitrile gradient
  • 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 to a pH of 7.4 with 1N hydrochloric acid, resuspended, 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-hydroxvmethyl) 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.
  • aggregation measurements For the aggregation measurements, aliquots of the platelet suspension are incubated with the test substance at 37 ° C. for 10 min. Subsequently, the aggregation is induced by addition of ADP and determined by the turbidimetric method according to Born in the aggregometer at 37 ° C [Born G.V.R., J. Physiol. (London) 168, 178-179 (1963)].
  • 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 as a stimulus to be 0:21 to 0:32 ug / kg / min U-46619 [9, l l-dideoxy-9 ⁇ , l l ⁇ -epoxy-methano-prostaglandin F 2o (Sigma.)] Infused 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 transducers / 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 compound of 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 of 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 des dérivés furaniques substitués de formule (I), des procédés de production desdits dérivés, leur utilisation dans le traitement et/ou la prophylaxie de maladies et leur utilisation dans la production de médicaments destinés au traitement et/ou à la prophylaxie de maladies, en particulier au traitement et/ou à la prophylaxie de maladies cardiovasculaires.
EP09707538A 2008-02-04 2009-01-29 Furanes substitués et leur utilisation Withdrawn EP2240461A1 (fr)

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DE102008007400A DE102008007400A1 (de) 2008-02-04 2008-02-04 Substituierte Furane und ihre Verwendung
PCT/EP2009/000553 WO2009097991A1 (fr) 2008-02-04 2009-01-29 Furanes substitués et leur utilisation

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EP2576532B1 (fr) 2010-06-07 2018-07-18 Novomedix, LLC Composés furanyliques et leur utilisation
MX2016000675A (es) * 2013-07-18 2016-05-10 Novartis Ag Derivados de amino-metil-biarilo como inhibidores del factor de complemento d y usos de los mismos.

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CA1283923C (fr) * 1986-08-30 1991-05-07 Hans-Juergen Neubauer Furan- et thiophenecarboxylates de propargyle
US5068237A (en) 1990-05-21 1991-11-26 Warner-Lambert Company Substituted furans and derivatives thereof acting at muscarinic receptors
JPH10114765A (ja) 1996-10-15 1998-05-06 Sankyo Co Ltd フラン化合物
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US20110054017A1 (en) 2011-03-03

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