WO2006125548A1 - Utilisation de pyrazolopyrimidines contre des maladies cardiovasculaires - Google Patents

Utilisation de pyrazolopyrimidines contre des maladies cardiovasculaires Download PDF

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Publication number
WO2006125548A1
WO2006125548A1 PCT/EP2006/004591 EP2006004591W WO2006125548A1 WO 2006125548 A1 WO2006125548 A1 WO 2006125548A1 EP 2006004591 W EP2006004591 W EP 2006004591W WO 2006125548 A1 WO2006125548 A1 WO 2006125548A1
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alkyl
group
alkoxy
cio
compounds
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PCT/EP2006/004591
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German (de)
English (en)
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Martin Hendrix
Frank Wunder
Adrian Tersteegen
Johannes-Peter Stasch
Martina Wuttke
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Bayer Healthcare Ag
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Priority to EP06753634A priority Critical patent/EP1888076A1/fr
Publication of WO2006125548A1 publication Critical patent/WO2006125548A1/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
    • 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

Definitions

  • the invention relates to the use of pyrazolopyrimidines for the preparation of medicaments for the treatment of cardiovascular diseases.
  • Inhibition of phosphodiesterases modulates levels of cyclic nucleotides 5'-3 'cyclic adenosine monophosphate (cAMP) and 5'-3' cyclic guanosine monophosphate (cGMP), respectively.
  • cAMP and cGMP cyclic nucleotides
  • cAMP and cGMP are important second messengers and therefore play a central role in the cellular signal transduction cascades. Both activate, inter alia, but not exclusively, again protein kinases.
  • the cAMP-activated protein kinase is called protein kinase A (PKA), and the cGMP-activated protein kinase is called protein kinase G (PKG).
  • PKA protein kinase A
  • PKG protein kinase G
  • Activated PKA or PKG can phosphorylate a variety of cellular effector proteins (e.g., ion channels, G protein-coupled receptors, structural proteins).
  • the second messengers cAMP and cGMP can control the most diverse physiological processes in various organs.
  • the cyclic nucleotides can also act directly on effector molecules.
  • cGMP can act directly on ion channels and thereby influence the cellular ion concentration (reviewed in: Wei et al., Prague Neurobiol., 1998, 56: 37-64).
  • PDE phosphodiesterases
  • the human PDE9A was cloned and sequenced in 1998.
  • the amino acid identity to other PDEs is a maximum of 34% (PDE8A) and a minimum of 28% (PDE5A).
  • Km value Michaelis-Menten constant
  • PDE9A is highly affine for cGMP.
  • PDE9A has no cGMP binding domain suggestive of allosteric enzyme regulation by cGMP.
  • PDE9A has been shown to be expressed in human, inter alia, in the testes, brain, small intestine, skeletal muscle, heart, lungs, thymus and spleen. The highest expression has been found in brain, small intestine, heart and spleen (Fisher et al., J. Biol. Chem., 1998, 273 (25): 15559-15564).
  • the gene for human PDE9A is located on chromosome 21q22.3 and contains 21 exons.
  • 20 alternative splice variants of PDE9A have been identified (Guipponi et al., Hum.
  • Mouse PDE9A was described by Soderling et al. (J. Biol. Chem., 1998, 273 (25): 15553-15558) and sequenced. Like the human form, this is highly affine for cGMP with a Km of 70 nM. In the mouse, a particularly high expression in the kidney, brain, lung and heart was found. The mouse PDE9A is also not inhibited by IBMX in concentrations below 200 ⁇ M; the IC 50 value for zaprinast is 29 ⁇ M (Soderling et al., J. Biol. Chem., 1998, 273 (19): 15553-15558). In the rat brain, it has been shown that PDE9A is strongly expressed in some brain regions.
  • hippocampus hippocampus
  • cortex basal ganglia
  • basal forebrain Basal forebrain
  • WO 04/099211, WO 04/099210, WO 04/026876, WO 04/018474 and the literature cited therein and US 2004/022018 already disclose pyrazolopyrimidines and their use for the production of medicaments for the treatment of various diseases.
  • the present invention relates to the use of compounds of the formula
  • R 1 is C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or C 3 -C 8 -cycloalkyl,
  • C r Cg-alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 8 -cycloalkyl optionally having up to 3 radicals independently selected from the group Cj-C ⁇ -alkyl, Cp C 6 alkoxy, hydroxycarbonyl, cyano, amino, nitro, hydroxy, Ci-C 6 -alkylamino, halogen, trifluoromethyl, trifluoromethoxy, C ⁇ -Cio-arylcarbonylamino, C r C 6 alkyl carbonylamino, C ö alkylaminocarbonyl, C r C 6 -alkoxycarbonyl, C 6 -C 10 -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C 1 -C 6 -alkylsulfonylamino,
  • R 2 is phenyl or heteroaryl, where phenyl having 1 to 3 radicals and heteroaryl optionally having 1 to 3 radicals each independently selected from the group Ci-C ⁇ -alkyl, CpC ö alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, amino, nitro , hydroxy, Ci-C ⁇ alkylamino, halogen, C ⁇ -Cio-arylcarbonylamino, Ci-C ⁇ -alkyl carbonylamino, Ci-C ö alkylaminocarbonyl, Ci-C 6 alkoxycarbonyl, C 6 -Cio arylamino-carbonyl, heteroarylaminocarbonyl , heteroarylcarbonylamino, Ci-C ⁇ -alkylsulfonylamino, CpC ö alkylsulfonyl, Ci-C 6 substituted alkylthio, wherein CpC ⁇ alkyl, C r
  • R 3 and R 4 independently of one another are hydrogen or C 1 -C 6 -alkyl
  • R 3 and R 4 together with the nitrogen atom to which they are attached, denote 5- to 8-membered heterocyclyl
  • a further embodiment of the invention relates to the use of compounds of the formula (I)
  • R 1 is C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or C 3 -C 8 -cycloalkyl, which are optionally selected with up to 3 radicals independently of one another from the group C r C 6 - Alkyl, C
  • C r C 6 alkyl CPCE alkoxy, C r C 6 alkylamino, C ö -Cio-arylcarbonylamino, C) -C6 alkyl carbonylamino, CpC ⁇ -alkylaminocarbonyl, Ci-C 6 alkoxycarbonyl, C 6 - Cio Arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonyl amino, C
  • R 2 is phenyl or heteroaryl, where phenyl having 1 to 3 radicals and heteroaryl optionally having 1 to 3 radicals each independently selected from the group Ci-C 6 - alkyl, CpC ⁇ -alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxy , Ci-C 6 -alkylamino, halogen, C ⁇ -Cio-arylcarbonylamino, Ci-C ⁇ -alkylcarbonylamino, C r C 6 alkylaminocarbonyl, Ci-C 6 alkoxycarbonyl, C ö -Cio-arylaminocarbonyl, heteroaryl, aminocarbonyl, heteroarylcarbonylamino, Ci C 6 alkylsulfonylamino, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -alkylthio are substituted,
  • R 3 and R 4 independently of one another are hydrogen or C 1 -C 6 -alkyl
  • R 3 and R 4 together with the nitrogen atom to which they are attached, denote 5- to 8-membered heterocyclyl
  • a further embodiment of the invention relates to the use of compounds of the formula (I)
  • R 1 Ci-C 5 alkyl or C 3 -C 6 cycloalkyl which is optionally substituted by up to 3 radicals independently selected from the group dC 4 alkyl, Ci-C4 alkoxy, trifluoromethyl, hydroxycarbonyl, cyano, amino, hydroxy, C r C 4 alkylamino, fluorine, chlorine, bromine, C 6 - Cio-arylcarbonylamino, Ci-C4-alkylcarbonylamino, Ci-C4-alkylaminocarbonyl, Ci-C 4-alkylaminocarbonyl, Ci-C 4 - alkoxycarbonyl, C 6 -C 0 arylaminocarbonyl , 4 alkylsulfonyl, CpC 4 -alkylthio heteroarylaminocarbonyl, Heteroarylcarb- carbonylamino, C r C 4 alkylsulfonylamino, Ci-C,
  • C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy optionally having a radical selected from the group consisting of hydroxyl, cyano, fluorine, chlorine and bromine
  • R 2 is phenyl, pyrimidyl, N-oxidopyridyl or pyridyl, phenyl having 1 to 3 radicals and pyrimidyl, N-oxidopyridyl and pyridyl optionally having 1 to 3 radicals, each independently selected from the group consisting of C 1 -C 4 -alkyl, C] - C 4 alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, hydroxy, C 1 -C 4 -alkylamino, fluorine, chlorine, bromine, C 6 -C 10 -arylcarbonylamino, C 1 -C 4 -alkylcarbonylamino, C 1 -C 4 -alkylaminocarbonyl,
  • Ci-C 4 alkoxycarbonyl C 6 -C 10 arylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl carbonylamino, C] -C4 alkylsulfonylamino, C] -C 4 alkylsulfonyl, C r C 4 -alkylthio,
  • C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy optionally having a radical selected from the group consisting of hydroxy, cyano, fluorine, chlorine, bromine and a group of the formula
  • R 3 and R 4 independently of one another are hydrogen or C 1 -C 4 -alkyl
  • R 3 and R 4 together with the nitrogen atom to which they are attached, denote 5- to 6-membered heterocyclyl
  • a further embodiment of the invention relates to the use of compounds of the formula (I)
  • R 1 has the meanings given above, and
  • R 2 is phenyl, N-oxidopyridyl or pyridyl, where phenyl having 1 to 3 radicals and pyridyl and N-oxidopyridyl optionally having 1 to 3 radicals are each independently selected from the group of methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, Fluorine and chlorine are substituted,
  • a further embodiment of the invention relates to the use of compounds of the formula (I)
  • R 1 is Q-Cs-alkyl or Cs-C ⁇ -cycloalkyl, which are optionally selected with up to 3 radicals independently of one another from the group Ci-Ci-alkyl, fluorine, trifluoromethyl, hydroxy,
  • Phenylcarbonylamino C 1 -C 4 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or phenylaminocarbonyl, and
  • R 2 is phenyl, N-oxidopyridyl or pyridyl, where phenyl having 1 to 3 radicals and pyridyl and N-oxidopyridyl optionally having 1 to 3 radicals are each independently selected from the group of methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, Ethoxy, fluorine and chlorine are substituted,
  • a further embodiment of the invention relates to the use of compounds of the formula (I)
  • R 1 is C 1 -C 5 -alkyl or C 5 -C 6 -cycloalkyl which is optionally selected with up to 3 radicals independently of one another from the group consisting of C 1 -C 4 -alkyl, fluorine, trifluoromethyl, hydroxy, Phenylcarbonylamino, C 1 -C 4 -alkylcarbonylamino, C 1 -C 4 -alkylaminocarbonyl or phenylaminocarbonyl, and
  • R 2 is phenyl, N-oxidopyridyl or pyridyl, wherein phenyl having one radical and pyridyl and N-oxidopyridyl optionally having a radical each independently selected from the group of methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and
  • Q-Cs-alkyl is a straight-chain or branched alkyl radical having 1 to 8, preferably 1 to 6, particularly preferably 1 to 5 carbon atoms. Preferred examples include methyl, ethyl, n-propyl, isopropyl, 2-butyl, 2-pentyl and 3-pentyl.
  • C? -Cyalkenyl is a straight-chain or branched alkenyl radical having 2 to 6, preferably 2 to 4 and particularly preferably having 2 to 3 carbon atoms.
  • Preferred examples include vinyl, allyl, n-prop-1-en-1-yl and n-but-2-en-1-yl.
  • C 2 -C 4 alkynyl represents a straight-chain or branched alkynyl radical having 2 to 6, preferably 2 to 4 and particularly preferably 2 to 3 carbon atoms.
  • Preferred examples include ethynyl, n-prop-1-yn-2-yl, n-prop-1-yn-3-yl and n-but-2-yn-1-yl.
  • C 1 -CyAlkoxy is a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms.
  • Preferred examples include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • C 1 -C 6 -alkoxy-carbonyl 1 represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3, carbon atoms.
  • Preferred examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tertbutoxycarbonyl.
  • Examples include methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino and n-hexylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropyl amino, di-t-butylamino, di-n-pentylamino, di-n-hexylamino, ethylmethylamino, isopropylmethylamino, n-butylethylamino and n-hexyl-i-pentylamino.
  • alkylcarbonyl radical linked via an amino group, where the alkyl radical can be straight-chain or branched and contains 1 to 6, preferably 1 to 4, and particularly preferably 1 to 3, carbon atoms.
  • Preferred examples include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.
  • alkyl radicals may be identical or different, are straight-chain or branched and contain in each case 1 to 6, preferably 1 to 4, and particularly preferably 1 to 3, carbon atoms.
  • Preferred examples include methylaminocarbonyl, ethylaminocarbonyl, n -propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n -pentylaminocarbonyl, n-hexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, diisopropylaminocarbonyl, di-t-butylaminocarbonyl, di-n-pentylaminocarbonyl, di -n-hexylaminocarbonyl, ethylmethylaminocarbonyl, isopropylmethylaminocarbonyl, n-butylethylaminocarbonyl and n-hexyl-i-pentylaminocarbonyl. Furthermore, in the case of a dialkylamino radical, the two alky
  • Cfi-Cio-arylaminocarbonyl is an arylamino radical linked via a carbonyl group.
  • Preferred examples include phenylaminocarbonyl and naphthylaminocarbonyl.
  • Cft-C j n-arylcarbonylamino is an arylamino radical linked via an amino group.
  • Preferred examples include phenylaminocarbonyl and naphthylaminocarbonyl.
  • C 1 -C 12 -alkyl-sulfonylamino represents a straight-chain or branched alkylsulfonylamino radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3, carbon atoms.
  • Preferred examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.
  • dVQs-alkylsulfonyl represents a straight-chain or branched alkylsulfonyl radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms.
  • Preferred examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.
  • straight-chain or branched alkylthio radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms.
  • Preferred examples include methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.
  • Halogen is fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine, bromine, more preferably fluorine and chlorine.
  • Heteroaryl is an aromatic, mono- or bicyclic radical having 5 to 10 ring atoms and up to 5 heteroatoms from the series S, O and / or N. Preference is given to 5- to 6-membered heteroaryls having up to 4 heteroatoms.
  • the heteroaryl group may be bonded via a carbon or nitrogen atom.
  • Preferred examples include thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, pyridyl, N-oxidopyridyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl.
  • Heteroarylaminocarbonyl represents a group linked via a carbonyl heteroarylamino radical.
  • Preferred examples include Thienylaminocarbonyl, Furylaminocarbonyl, pyrrolyl aminocarbonyl, Thiazolylaminocarbonyl, Oxazolylaminocarbonyl, Imidazolylaminocarbonyl, tetra- zolylaminocarbonyl, pyridylaminocarbonyl, Pyrimidinylaminocarbonyl, Pyridazinylaminocarbonyl, Indolylaminocarbonyl, Indazolylaminocarbonyl, Benzofuranylaminocarbonyl, benzothiophenyl aminocarbonyl , Quinolinylaminocarbonyl and isoquinolinylaminocarbonyl.
  • Heteroarylcarbonylamino represents a heteroarylcarbonyl radical linked via an amino group.
  • Preferred examples include thienylcarbonylamino, furylcarbonylamino, pyrrolylcarbonylamino, thiazolylcarbonylamino, oxazolylcarbonylamino, imidazolylcarbonylamino, tetrazolylcarbonylamino, pyridylcarbonylamino, pyrimidinylcarbonylamino, pyridazinylcarbonylamino, indolylcarbonylamino, indazolylcarbonylamino, benzofuranylcarbonylamino, benzothiophenylcarbonylamino, quinolinylcarbonylamino and isoquinolinylcarbonylamino.
  • 3- to 8-membered cycloalkyl represents saturated and partially unsaturated non-aromatic cycloalkyl radicals having 3 to 8, preferably 3 to 6 and more preferably 5 to 6 carbon atoms in the cycle.
  • Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
  • 5- to 8-membered heterocyclyl is a mono- or polycyclic, heterocyclic radical having 5 to 8 ring atoms and up to 3, preferably 2 heteroatoms or hetero groups from the series N, O, S, SO, SO 2 .
  • Mono- or bicyclic heterocyclyl is preferred. Particularly preferred is monocyclic heterocyclyl.
  • heteroatoms N and O are preferred.
  • the heterocyclyl radicals may be saturated or partially unsaturated. Saturated heterocyclyl radicals are prefers. Particularly preferred are 5- to 7-membered heterocyclyl radicals.
  • Preferred examples include oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidinyl, thiopyranyl, morpholinyl, perhydroazepinyl.
  • radicals in the compounds according to the invention are optionally substituted, unless otherwise specified, a substitution with up to three identical or different substituents is preferred.
  • a further embodiment of the invention relates to the use of compounds of the formula (II),
  • R 5 is phenyl, pyridyl or thiophenyl, which are optionally selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxyl, C 6 alkylamino, halogen, C ö -Cio-arylcarbonylamino, Ci-C ⁇ -alkylcarbonylamino, Ci-C ⁇ -alkylaminocarbonyl, Ci-C ⁇ -alkylaminocarbonyl, Ci-C 6 -
  • Alkylsulfonylamino, C 1 -C 6 -alkylsulfonyl and CpC ⁇ -alkylthio optionally with a radical selected from the group consisting of hydroxyl, cyano, halogen, hydroxycarbonyl and a group of the formula -NR 7 R 8 ,
  • R 7 and R 8 are independently hydrogen or C r C 6 alkyl
  • R 6 is phenyl or heteroaryl, where phenyl having 1 to 3 radicals and heteroaryl optionally having 1 to 3 radicals are each independently selected from the group consisting of Ci-C 6 -
  • a further embodiment of the invention relates to the use of compounds of the formula (II),
  • R 5 is phenyl, pyridyl, or thiophenyl, which are optionally substituted by up to 3 radicals independently selected from the group C r C 4 alkyl, Ci-Q-alkoxy, hydroxycarbonyl,
  • R 7 and R 8 are independently hydrogen or C r C 4 alkyl, or
  • R 7 and R 8 together with the nitrogen atom to which they are attached, denote 5- to 6-membered heterocyclyl
  • R 6 is phenyl, pyrimidyl or pyridyl, wherein the phenyl by 1 to 3 groups and pyrimidyl and pyridyl optionally substituted with 1 to 3 groups each independently selected from the group Ci-C 4 alkyl, C r C 4 -alkoxy, hydroxycarbonyl, cyano, Trifluoromethyl, amino,
  • Ci-C4-alkylamino fluorine, chlorine, bromine, C ⁇ -Cio-arylcarbonylamino, C r C 4 alkyl carbonylamino, Cj-Q-alkylaminocarbonyl, Ci-C 4 alkoxycarbonyl, C 6 -C 0 arylamino - carbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, Ci-C4 alkylsulfonylamino, C, -C 4 alkylsulfonyl, C r C 4 -alkylthio,
  • -C 4 alkyl and Ci-C 4 alkoxy optionally substituted with a radical selected from the group hydroxy, cyano, fluorine, chlorine, bromine, hydroxycarbonyl and a group of the formula -NR 7 R 8,
  • a further embodiment of the invention relates to the use of compounds of the formula (II),
  • R 6 is phenyl or pyridyl, phenyl having 1 to 2 radicals and pyridyl optionally having 1 to 2 radicals each independently selected from the group consisting of methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and chlorine, and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.
  • a further embodiment of the invention relates to the use of compounds of the formula (II),
  • R 5 is phenyl, pyridyl or thiophenyl, which optionally substituted with up to 2 radicals independently of one another from the group dC 4 alkyl, fluorine, chlorine, trifluoromethyl, hydroxy, phenylcarbonylamino, Ci-Gj-alkylcarbonylamino, Ci-Gi-alkylaminocarbonyl or phenylaminocarbonyl substituted are,
  • R 6 is phenyl or pyridyl, phenyl having 1 to 2 radicals and pyridyl optionally having 1 to 2 radicals each independently selected from the group consisting of methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and chlorine,
  • C j -CFT-Alkoxy represents a straight or branched alkoxy group having 1 to 6, preferably 1 to 4, particularly preferably having 1 to 3 carbon atoms.
  • Preferred examples include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • C 1 -C 5 -alkyl represents a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms.
  • Preferred examples include methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl and n-hexyl.
  • Halogen is fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine, bromine, more preferably fluorine and chlorine.
  • straight-chain or branched mono- or dialkylamino radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms.
  • Preferred examples include methylamine, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino and n-hexylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-t-butylamino, di-n-pentylamino , Di-n-hexylamino, ethylmethylamino, isopropylmethylamino, n-butylethylamino and n-hexyl-i-pentylamino.
  • CVCU-alkylcarbonylamino is an alkylcarbonyl radical linked via an amino group, where the alkyl radical can be straight-chain or branched and contains 1 to 6, preferably 1 to 4, and particularly preferably 1 to 3 carbon atoms.
  • Preferred examples include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.
  • dVCV alkylaminocarbonyl is a mono- or dialkylamino radical linked via a carbonyl group, where the alkyl radicals may be identical or different, are straight-chain or branched and contain in each case 1 to 6, preferably 1 to 4, and particularly preferably 1 to 3, carbon atoms.
  • Preferred examples include methylaminocarbonyl, ethylaminocarbonyl, n -propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n -pentylaminocarbonyl, n-hexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, diisopropylaminocarbonyl, di-t-butylaminocarbonyl, di-n-pentylaminocarbonyl, di-n -hexylaminocarbonyl, ethylmethylaminocarbonyl, isopropylmethylaminocarbonyl, n-butylethylaminocarbonyl and n-hexyl-i-pentylaminocarbonyl. Furthermore, in the case of a dialkylamino radical, the two alky
  • Cfi-C j n-arylaminocarbonyl represents a group linked via a carbonyl arylamino.
  • Preferred examples include phenylaminocarbonyl and naphthylaminocarbonyl.
  • Cft-C j n-arylcarbonylamino represents an arylcarbonyl radical linked via an amino group.
  • Preferred examples include phenylcarbonylamino and naphthylcarbonylamino.
  • CVCU-alkylsulfonylamino represents a straight-chain or branched alkylsulfonylamino radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3, carbon atoms.
  • Preferred examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.
  • alkylsulfonyl radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms.
  • Preferred examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, t-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.
  • C 1 -C 6 -alkylthio represents a straight-chain or branched alkylthio radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3, carbon atoms.
  • Preferred examples include methylthio, ethylthio, n-propylthio, isopropylthio, tertbutylthio, n-pentylthio and n-hexylthio.
  • Heteroaryl is an aromatic, mono- or bicyclic radical having 5 to 10 ring atoms and up to 5 heteroatoms from the series S, O and / or N. Preference is given to 5- to 6-membered heteroaryls having up to 4 heteroatoms.
  • the heteroaryl group may be bonded via a carbon or nitrogen atom.
  • Preferred examples include thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl.
  • Heteroarylaminocarbonyl is a heteroaryl-amino radical linked via a carbonyl group.
  • Preferred examples include thienylaminocarbonyl, furylaminocarbonyl, pyrrolylaminocarbonyl, thiazolylaminocarbonyl, oxazolylaminocarbonyl, imidazolylaminocarbonyl, tetrazolylaminocarbonyl, pyridylaminocarbonyl, pyrimidinylaminocarbonyl, pyridazinylaminocarbonyl, indolylaminocarbonyl, indazolylaminocarbonyl, benzofuranylaminocarbonyl, benzothiophenylaminocarbonyl, quinolinylaminocarbonyl and isoquinolinylaminocarbonyl.
  • Heteroarylcarbonylamino represents a heteroarylcarbonyl radical linked via an amino group.
  • Preferred examples include thienylcarbonylamino, furylcarbonylamino, pyrrolylcarbonylamino, thiazolylcarbonylamino, oxazolylcarbonylamino, imidazolylcarbonylamino, tetrazolylcarbonylamino, pyridylcarbonylamino, pyrimidinylcarbonylamino, pyridazinylcarbonylamino, indolylcarbonylamino, indazolylcarbonylamino, benzofuranylcarbonylamino, benzothiophenylcarbonylamino, quinolinylcarbonylamino and isoquinolinylcarbonylamino.
  • 5- to 8-membered heterocyclyl is a mono- or polycyclic, heterocyclic radical having 5 to 8 ring atoms and up to 3, preferably 2 heteroatoms or hetero groups of the
  • Mono- or bicyclic heterocyclyl is preferred. Particularly preferred is monocyclic heterocyclyl. As heteroatoms, N and O are preferred.
  • Residues may be saturated or partially unsaturated.
  • Saturated heterocyclyl radicals are preferred. Particularly preferred are 5- to 7-membered heterocyclyl radicals.
  • Preferred examples include oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidinyl, thiopyranyl, morpholinyl, perhydroazepinyl.
  • 6-membered heteroaryl is an aromatic radical having 6 ring atoms and up to 2 nitrogen atoms.
  • the heteroaryl radical is bonded via a carbon atom.
  • Preferred examples include pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.
  • radicals in the compounds according to the invention are optionally substituted, unless otherwise specified, substitution with up to three identical or different substituents is preferred.
  • the compounds of the formula (II) and their preparation are known from WO 04/099210.
  • a further embodiment of the invention relates to the use of compounds of the formula (III)
  • R 13 is C 1 -C 6 -alkyl
  • R 14 and R 15 are independently hydrogen, C 6 -C 0-aryl, Ci-C 6 alkyl, or
  • R 10 is hydrogen, C r C 6 alkyl, trifluoromethyl, C r C 6 alkoxy,
  • R 16 is C 1 -C 6 -alkyl or benzyl
  • R 1 ' is hydrogen or C r C 6 alkyl
  • R 12 is pentan-3-yl, C 3 -C 6 -cycloalkyl,
  • a further embodiment of the invention relates to the use of compounds of the formula (III)
  • R 13 is C, -C 6 -alkyl
  • R 14 and R 15 are each independently hydrogen, C ö -Cio-aryl, Cj-C ⁇ -alkyl, or
  • R 10 is hydrogen, C r C 6 alkyl, C, -C 6 alkoxy,
  • R 9 and R 10 together with the carbon atom to which they are attached form C 3 -Cg -cycloalkyl, C 3 -C 8 -cycloalkenyl or 4- to 10-membered heterocyclyl, which may optionally have up to 2 substituents the group Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy,
  • R 16 is C r C 6 alkyl or benzyl
  • R 11 is hydrogen or C 1 -C 6 -alkyl
  • R 12 is pentan-3-yl, C 4 -C 6 -cycloalkyl,
  • a further embodiment of the invention relates to the use of compounds of the formula (III)
  • R 13 is C r C 4 alkyl
  • R 14 and R 15 independently of one another represent hydrogen, phenyl, C 1 -C 4 -alkyl, or
  • R 10 is hydrogen, C r C 4 -AlkyI, Ci-C 4 alkoxy, trifluoromethyl,
  • R 16 is C 1 -C 4 -alkyl or benzyl
  • R 11 is hydrogen
  • R 12 is pentan-3-yl, C 5 -C 6 -cycloalkyl,
  • a further embodiment of the invention relates to the use of compounds of the formula (III)
  • R 14 is phenyl
  • R 15 is hydrogen
  • R 10 is hydrogen, methyl, trifluoromethyl, or
  • R 9 and R 10 together with the carbon atom to which they are attached form cyclopentyl, cyclohexyl, cyclopentenyl or tetrahydrofuryl, where cyclohexyl is optionally substituted by methyl, and
  • R 11 is hydrogen
  • R 12 is pentan-3-yl, C 5 -C 6 -cycloalkyl,
  • a further embodiment of the invention relates to the use of compounds of the formula (III)
  • R 14 is phenyl
  • R 15 are hydrogen
  • R 10 is hydrogen, methyl, or
  • R 9 and R 10 together with the carbon atom to which they are attached form cyclopentyl, cyclohexyl, cyclopentenyl or tetrahydrofuryl, where cyclohexyl is optionally substituted by methyl, and R "hydrogen,
  • R 12 is pentan-3-yl, C 5 -C 6 -cycloalkyl,
  • C 1 -CyAlkoxy is a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.
  • C 1 -CyAlkVl is a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, tert -butyl, n -pentyl and n -hexyl.
  • Cfi-O-aryl is phenyl or naphthyl.
  • C r C 9 cycloalkyl is cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Cyclopropyl, cyclopentyl and cyclohexyl may be mentioned as preferred.
  • Ci-Cg-Cycloalkenyl is partially unsaturated, non-aromatic cycloalkyl radicals containing one or more multiple bonds, preferably double bonds.
  • Non-limiting examples include cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • Halogen is fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine, bromine, more preferably fluorine and chlorine.
  • 4- to 10-membered heterocyclyl is a mono- or polycyclic, heterocyclic radical having 4 to 10 ring atoms and up to 3, preferably 1 heteroatoms or hetero groups from the series N, O, S, SO, SO 2 .
  • 4- to 8-membered heterocyclyl is preferred.
  • Mono- or bicyclic heterocyclyl is preferred.
  • heteroatoms N and O are preferred.
  • the heterocyclyl radicals may be saturated or partially unsaturated. Saturated heterocyclyl radicals are preferred.
  • the heterocyclyl radicals can be bonded via a carbon atom or a heteroatom. Particular preference is given to 5- to 7-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S.
  • oxetane 3-yl pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidinyl, thiopyranyl, morpholinyl, perhydroazepinyl.
  • radicals in the compounds according to the invention are optionally substituted, substitution with up to three identical or different substituents is preferred, unless otherwise specified.
  • a further embodiment of the invention relates to the use of compounds of the formula (IV),
  • R 17 is phenyl which is substituted by 1 to 5 substituents independently of one another selected from the group consisting of halogen, C 1 -C 6 -alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro and C 1 -C 6 -alkoxy,
  • R 18 is pentan-3-yl, C 4 -C 6 -cycloalkyl,
  • a further embodiment of the invention relates to the use of compounds of the formula (IV),
  • R 17 is phenyl which is substituted by 1 to 3 substituents independently of one another selected from the group fluorine, chlorine, bromine, C 1 -C 4 -alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro and CpCrAlkoxy,
  • R 18 is pentan-3-yl, C 5 -C 6 -cycloalkyl,
  • a further embodiment of the invention relates to the use of compounds of the formula (IVa)
  • R 19 is hydrogen or chlorine
  • R 20 is fluorine, chlorine, bromine, methyl, trifluoromethyl
  • a further embodiment of the invention relates to the use of compounds of the formulas (IV) and (IVa),
  • R 19 is hydrogen or chlorine
  • R 20 is fluorine, chlorine, bromine, methyl, trifluoromethyl
  • R 18 pentan-3-yl, cyclopentyl
  • C j -CyAlkoxy represents a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms.
  • Preferred examples are methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • C r C6-Alkyl is a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, more preferably 1 to 3 carbon atoms. Preferred examples are methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • C4 ⁇ Cg- and C5-Cg-cycloalkyl are saturated or partially unsaturated cycloalkyl radicals having 4 to 6, preferably 5 to 6 carbon atoms.
  • Preferred examples are cyclobutyl, cyclopentyl and cyclohexyl.
  • Halogen is fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine, bromine, more preferably fluorine and chlorine.
  • radicals in the compounds of the formulas (IV) and (IVa) according to the invention are optionally substituted, unless otherwise specified, substitution with up to three identical or different substituents is preferred.
  • the compounds of the formulas (IV) and (FVa) and their preparation are known from WO 04/018474.
  • Compounds of the invention are the compounds of formula (F), (II), (FII), (FV) and (FVa) and their salts, solvates and solvates of the salts; the compounds of the formulas (I), (II), (FFF), (FV) and (FVa) mentioned below of the following formulas and their salts, solvates and solvates of the salts and of the formulas (T), (ET), ( IFI), (FV) and (FVa), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as those of the formulas (I), (FF), (FFI), (FV) and (FVa), 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 relates to 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.
  • Physiologically acceptable salts of the compounds of formulas (T), (II), (FFI), (FV) and (FVa) 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, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds of the formulas (F), (FI), (FIF), (FV) and (FVa) also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg.
  • ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dehydroabietylamine, Arginine, lysine, ethylenediamine and methylpiperidine.
  • ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,
  • Solvates in the context of the invention are those forms of the compounds 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.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
  • the compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic activity spectrum. They are characterized in particular by an inhibition of PDE9A.
  • the compounds according to the invention are suitable for the preparation of medicaments for the treatment of cardiovascular diseases.
  • the compounds according to the invention can be used alone or in combination with other medicaments for the treatment of cardiovascular diseases.
  • cardiovascular diseases such as hypertension and cardiac insufficiency, acute heart failure, stable and unstable angina pectoris, peripheral and cardiovascular diseases, arrhythmias
  • thromboembolic disorders and ischemia such as myocardial infarction, stroke , transitory and ischemic attacks, peripheral circulatory disorders, prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasty (PTCA), bypass and for the treatment of arteriosclerosis, asthmatic diseases and diseases of the genitourinary system such as prostatic hypertrophy, erectile dysfunction, female sexual dysfunction, osteoporosis, glaucoma, pulmonary hypertension, portal hypertension, ischemic kidney disease, nephrosis such as nephrotic syndrome, renal stenoses, renal insufficiency, acute renal failure, metabolic syndrome, gastroparesis, incontinence, liver fibrosis
  • cardiovascular diseases such as hypertension and cardiac insuffici
  • Examples of the compounds according to the invention are known from WO 04/018474, WO 04/026870, WO 04/099210 and WO 04/099211.
  • PDE1C GenBank / EMBL Accession Number: NM 005020, Loughney et al, J. Biol. Chem., 1996 271, 796-806
  • PDE2A GenBank / EMBL Accession Number: NM_002599, Rosman et al., Gene 1997, 191, 89- 95
  • PDE3B GenBank / EMBL Accession Number: NM_000922, Miki et al, Genomics 1996, 36, 476-485
  • PDE4B GenBank / EMBL Accession Number: NM_002600, Obernolte et al., Gene, 1993, 129, 239-247
  • PDE5A GenBank / EMBL Accession Number: NM 001083, Loughney et al Gene 1998, 216, 139-147
  • PDE7B GenBank / EMBL Accession Number: NM_018945, Hetman et al., Proc.
  • PDE10A GenBank / EMBL Accession Number: NM_06661, Fujishige et al J Biol Chem., 1999, 274, 18438-45
  • PDEI IA GenBank / EMBL Accession Number : NM_016953, Fawcett et al., Proc Natl Acad., 2000, 97, 3702-3707
  • GibcoBRL p FASTBAC baculovirus expression system
  • test substances are dissolved in 100% DMSO and serially diluted to determine their in vitro effect on PDE 9A.
  • serial dilutions 200 ⁇ M to 1.6 ⁇ M are prepared (resulting final concentrations in the assay: 4 ⁇ M to 0.032 ⁇ M).
  • 2 ⁇ L each of the diluted substance solutions are placed in the wells of microtiter plates (Isoplate, Wallac Inc., Atlanta, GA). Subsequently, 50 ⁇ L of a dilution of the PDE9A preparation described above is added.
  • the dilution of the PDE9A preparation is chosen such that during the later incubation less than 70% of the substrate is reacted (typical dilution: 1: 10,000; dilution buffer: 50 mM Tris / HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA, 0.2% BSA).
  • the substrate, [8- 3 H] guanosine 3 ', 5'-cyclic phosphate (1 ⁇ Ci / ⁇ L; Ameram Pharmacia Biotech., Piscataway, NJ) is diluted 1: 2000 with assay buffer (50 mM Tris / HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA) to a concentration of 0.0005 ⁇ Ci / ⁇ L.
  • assay buffer 50 mM Tris / HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA
  • test mixtures are incubated for 60 min at room temperature and the reaction is stopped by addition of 25 ⁇ l of a PDE9A inhibitor dissolved in assay buffer (eg the inhibitor from Preparation Example 1, 10 ⁇ M final concentration). Immediately thereafter, 25 ⁇ l of a suspension containing 18 mg / ml of Yttrium Scintillation Proximity Beads (Amersham Pharmacia Biotech., Piscataway, NJ) is added. The microtiter plates are sealed with a foil and allowed to stand at room temperature for 60 min. The plates are then measured for 30 s per well in a microbeta scintillation counter (Wallac Inc., Atlanta, GA). IC 50 values are determined by plotting the concentration of the substance against the percent inhibition.
  • a PDE9A inhibitor dissolved in assay buffer (eg the inhibitor from Preparation Example 1, 10 ⁇ M final concentration).
  • the in vitro effect of test substances on recombinant PDE3B, PDE4B, PDE7B, PDE8A, PDE10A and PDEI IA is determined according to the test protocol described above for PDE 9A with the following adaptations:
  • the substrate used is [5 ', 8- 3 H] adenosine 3', 5'-cyclic phosphates (1 ⁇ Ci / ⁇ L; Amersham Pharmacia Biotech., Piscataway, NJ).
  • the addition of an inhibitor solution to stop the reaction is not necessary. Instead, following the incubation of substrate and PDE, the addition of the Yttrium Scintillation Proximity Beads is continued as described above, thereby stopping the reaction.
  • PDE2A PDE5 and the protocol is additionally adjusted as follows: In pdel Calmodulin 10 -7 M and CaCl 2 are added 3 mM to the reaction mixture in addition. PDE2A is stimulated in the assay by addition of cGMP 1 ⁇ M and tested with a BSA concentration of 0.01%.
  • pdel and PDE2A as a substrate [5 ', 8- 3 H] adenosine 3', 5'-cyclic phosphate (1 uCi / ul;.
  • Rabbits are stunned and bled by a stroke of the neck.
  • the saphenous artery is harvested, detached from adherent tissue, divided into 3 mm wide rings and individually prestressed in 5 ml organ baths with 37 ° C warm, carbogen-fumigated Krebs-Henseleit solution following
  • KH 2 PO 4 1.2; NaHCO3: 25; Glucose: 10.
  • the force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D converters (DAS-1802 HC, Keithley Instruments Munich) and registered in parallel on chart recorders.
  • DAS-1802 HC A / D converters
  • phenylephrine is added to the bath added cumulatively in increasing concentration.
  • the substance to be examined is examined in each subsequent passage in increasing dosages and the height of the contraction is compared with the height of the contraction achieved in the last predistortion. This is used to calculate the concentration required to reduce the level of the control value by 50% (IC 50 ).
  • the standard application volume is 5 ⁇ l, the DMSO content in the bath solution corresponds to 0.1%.
  • mice Three to six animals are used per treatment group and weighed immediately before the start of the experiment.
  • the substances are dissolved in Transcutol (GATTEFOSSE GmbH) and diluted in a ratio of 3/7 with a 20% cremophor solution (Cremophor (BASF), water).
  • a volume of 0.5 ml / kg is injected into the ear vein.
  • Water-soluble substances are injected in 0.9% saline.
  • the test substances are dissolved in a mixture of glycerol: water: polyethylene glycol 6: 10: 9.69 and applied in a volume of 1 ml / kg with the gavage.
  • mice Male Wistar rats weighing 300-350 g (Harlan Winkelmann, Germany) were anesthetized with 1-2.5% isofluoran in a nitrous oxide / C> 2 (2: 1) mixture.
  • a catheter was inserted into the femoral artery, the substance was administered via a femoral vein catheter and urine collection via a bladder catheter. After the operation, 5 ml / kg of phys. NaCl were given intravenously as a bolus for fluid compensation and the animals were infused continuously with physi. NaCl for 1 h at a rate of 100 ⁇ l / kg / min via the venous catheter. The body temperature of the animals was kept constant over a hot plate.
  • test substances along with ANP were continuously infused via the venous catheter at a rate of 100 ⁇ l / kg / min.
  • Urine was collected every 15 min and the volume, cGMP content (RIA), and Na + and K + concentrations (flame photometry) were measured.
  • the substance to be examined is administered to animals (eg mouse, rat, dog) intravenously as a solution, the oral administration is carried out as a solution or suspension via a gavage. After substance administration, the animals are bled at fixed times, this is heparinized and then plasma is recovered therefrom by centrifugation. The substance is analytically quantified in the plasma via LC / MSMS. From the plasma Concentration time courses are the pharmacokinetic parameters calculated using a validated pharmacokinetic calculation program.
  • Recombinant enzymes eg CYP 1A2, 2C8, 2C9, 2CI9, 2D6 or 3A4
  • substrates generally containing fluorescein or coumarin substructures are used in the assay for the formation of fluorescent metabolites.
  • a substrate concentration and 8 concentrations of the potential inhibitor are used.
  • the extent of fluorescent metabolites in comparison to the control (without inhibitor) is determined by means of fluorescence readers and an IC 50 value is calculated [Anal. Biochem. 248, 188 (1997)].
  • the second assay uses human liver microsomes as the enzyme source and phenacetin (CYP 1A2), diclofenac (CYP2C9), dextromethorphan (CYP2D6) and midazolam (CYP3A4) as CYP isoform-selective substrates.
  • CYP 1A2 phenacetin
  • CYP2C9 diclofenac
  • CYP2D6 dextromethorphan
  • midazolam CYP3A4
  • the hepatocytes are treated for 5 days in duplicate with different concentrations of the test substances compared with the inducers rifampicin (RIF, 50 ⁇ M), omeprazole (OME, 100 ⁇ M) and phenobarbital (PB, 2 mM).
  • the final concentrations of the test substances are 0.01-10 ⁇ g / ml.
  • P450 enzymes 1A2, 2B6, 2C19 and 3A4 were determined by adding the substrates 7-ethoxyresorufin (CYP1A2), [ 14 C] -S-mephenytoin (CYP2B6 and 2C19) and [ 14 C] -testosterone (CYP3A4) at day 8. From the thus measured enzyme activities CYP 1A2, 2B6, 2Cl 9 and 3 A4 treated cells compared to untreated cells, the inductive potential of the test substances is determined.
  • Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention and at least one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • 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.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalant medicines including powder inhalers, nebulizers
  • nasal drops solutions, 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 (such as patches)
  • milk Pastes, foams, scattering powders, implants or stents.
  • the compounds according to the invention can be converted into the mentioned administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • Such adjuvants include, but are not limited to, excipients (e.g., microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitol oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g. Albumin), stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides), and flavor and / or odoriferous agents.
  • excipients e.g., microcrystalline cellulose, lactose, mannitol
  • solvents eg, liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents e.g., sodium dodecyl sulfate, polyoxysorbitol
  • 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.
  • parenteral administration per day amounts of about 0.001 to 10 mg / kg body weight to achieve effective results.
  • the amount per day is about 0.005 to 3 mg / kg of body weight.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows: Tablet:
  • 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 of the invention is fed to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • Orally administrable solution :
  • 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 sterile at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5%, and / or PEG 400 solution.)
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5%, and / or PEG 400 solution.
  • the solution is sterile filtered and sterile and pyrogen-free injection wells are filled.
  • the compound of the present invention is dissolved in the water with stirring together with polyethylene glycol 400.
  • the solution is sterile-filtered (pore diameter 0.22 ⁇ m) and filled under raseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and bristle caps.

Abstract

L'invention concerne l'utilisation de pyrazolopyrimidines dans la fabrication de médicaments destinés au traitement de maladies cardiovasculaires.
PCT/EP2006/004591 2005-05-27 2006-05-16 Utilisation de pyrazolopyrimidines contre des maladies cardiovasculaires WO2006125548A1 (fr)

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US8623879B2 (en) 2008-04-02 2014-01-07 Boehringer Ingelheim International Gmbh 1-heterocyclyl-1,5-dihydro-pyrazolo[3,4-D] pyrimidin-4-one derivates and their use as PDE9A modulators
US8648085B2 (en) 2007-11-30 2014-02-11 Boehringer Ingelheim International Gmbh 1, 5-dihydro-pyrazolo (3, 4-D) pyrimidin-4-one derivatives and their use as PDE9A mudulators for the treatment of CNS disorders
US8809345B2 (en) 2011-02-15 2014-08-19 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders
US8822479B2 (en) 2003-05-09 2014-09-02 Boehringer Ingelheim International Gmbh 6-cyclylmethyl-and 6-alkylmethyl-substituted pyrazolepyrimidines
US8912201B2 (en) 2010-08-12 2014-12-16 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders
US9067945B2 (en) 2002-08-23 2015-06-30 Boehringer Ingehleim International GmbH Selective phosphodiesterase 9A inhibitors as medicaments for improving cognitive processes
US9079905B2 (en) 2008-09-08 2015-07-14 Boehringer Ingelheim International Gmbh Compounds for the treatment of CNS disorders

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US8822479B2 (en) 2003-05-09 2014-09-02 Boehringer Ingelheim International Gmbh 6-cyclylmethyl-and 6-alkylmethyl-substituted pyrazolepyrimidines
US8648085B2 (en) 2007-11-30 2014-02-11 Boehringer Ingelheim International Gmbh 1, 5-dihydro-pyrazolo (3, 4-D) pyrimidin-4-one derivatives and their use as PDE9A mudulators for the treatment of CNS disorders
US8623879B2 (en) 2008-04-02 2014-01-07 Boehringer Ingelheim International Gmbh 1-heterocyclyl-1,5-dihydro-pyrazolo[3,4-D] pyrimidin-4-one derivates and their use as PDE9A modulators
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US9079905B2 (en) 2008-09-08 2015-07-14 Boehringer Ingelheim International Gmbh Compounds for the treatment of CNS disorders
US8623901B2 (en) 2009-03-31 2014-01-07 Boehringer Ingelheim International Gmbh Compounds for the treatment of CNS disorders
US9102679B2 (en) 2009-03-31 2015-08-11 Boehringer Ingelheim International Gmbh Compounds for the treatment of CNS disorders
US8912201B2 (en) 2010-08-12 2014-12-16 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders
US9328120B2 (en) 2010-08-12 2016-05-03 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders
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