WO2010015587A1 - 5-benzyl-1,2,3,6-tetrahydro-4,6-diaza-cyclopenta[c]fluorene compounds and 5-benzyl-1,2,3,6-tetrahydro-4,6-diaza-cyclohepta[c]fluorene compounds - Google Patents

5-benzyl-1,2,3,6-tetrahydro-4,6-diaza-cyclopenta[c]fluorene compounds and 5-benzyl-1,2,3,6-tetrahydro-4,6-diaza-cyclohepta[c]fluorene compounds Download PDF

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WO2010015587A1
WO2010015587A1 PCT/EP2009/060000 EP2009060000W WO2010015587A1 WO 2010015587 A1 WO2010015587 A1 WO 2010015587A1 EP 2009060000 W EP2009060000 W EP 2009060000W WO 2010015587 A1 WO2010015587 A1 WO 2010015587A1
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compound
salt
oxide
group
diseases
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PCT/EP2009/060000
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French (fr)
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Björn BARTELS
Steffen Weinbrenner
Degenhard Marx
Jörg DIEFENBACH
Torsten Dunkern
Wiro M.P.B. Menge
Johannes A. M. Christiaans
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Nycomed Gmbh
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Publication of WO2010015587A1 publication Critical patent/WO2010015587A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to 5-Benzyl-1 ,2,3,6-tetrahydro-4,6-diaza-cyclopenta[c]fluorene compounds and ⁇ -Benzyl-I ⁇ S. ⁇ -tetrahydro ⁇ -diaza-cycloheptatclfluorene compounds, and their use, as well as the resulting pharmaceutical compositions and uses thereof in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases.
  • a further object of the present invention is to provide a method of manufacture of the compounds and compositions of the present invention.
  • the compounds of the present invention are characterized by Formula (I) as specified in the following.
  • the invention thus relates to compounds of Formula (I)
  • n and m are each independently selected from 0, 1 , 2 or 3, with the proviso that n + m is 1 or 3,
  • RA01 anc j RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-
  • R A01 anc j RA02 combine to form an oxo-group
  • RA03 anc j RA04 are each independently selected from the group consisting of hydrogen, C-
  • RA21 and R ⁇ 22 are each independently selected from the group consisting of hydrogen and C 1 . ⁇ -alkyl, wherein the C-
  • RB41 js selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy, nitro and amino;
  • RB51 JS selected from the group consisting of hydrogen, halogen, C 1 . ⁇ -alkyl, hydroxy, C 1 .3- alkoxy, nitro, amino, -NH-C(O)-C 1 .2-alkyl, -NH-C(0)-NH2 and a methoxy group substituted by 2 or 3 fluorine atoms; or R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and -CH 2 -CH 2 -O-;
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • R B ⁇ 1 JS selected from the group consisting of hydrogen and halogen
  • RB81 JS selected from the group consisting of hydrogen and halogen
  • R ⁇ 01 and R ⁇ 02 are each independently selected from the group consisting of hydrogen, hydroxy and NRA03RA04 or
  • RA01 anc j RA02 combine to form an oxo-group, wherein RA03 anc j RA04 nave ⁇ 16 S ame meaning as defined above, or preferably below
  • one of the substituents R ⁇ 01 and R ⁇ 02 is hydrogen and the other substituent is hydroxy or NRA03RA04 wherein RA03 anc j RA04 have the same meaning as defined above, or preferably below.
  • RA03 anc j RA04 are eacn independently selected from the group consisting of hydrogen, C(O)H and C(O)-Ci _ 6 -alkyl, wherein the C(O)-C- ] .
  • ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy.
  • one of the substituents R ⁇ 01 and RA02 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the substituents RA01 and R ⁇ 02 t ⁇ iincd has the S-configu ration.
  • RA22 ⁇ O ⁇ are hydrogen.
  • R B ⁇ 1 j selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy.
  • R B ⁇ 1 is selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C- j . ⁇ -alkoxy, nitro, amino and a methoxy group substituted by 2 or 3 fluorine atoms, or
  • R B41 and R B51 combine to form a group selected from -O-CH2-O-, -O-CH2-CH2- and
  • R B ⁇ 1 j s selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms.
  • n 0 and m is 3.
  • n 1 and m is 2.
  • n 2 and m is 1.
  • n is 3 and m is 0. According to yet another embodiment of the present invention n is 0 and m is 1.
  • n 1 and m is 0.
  • n + m is 1 and R ⁇ 01 and R ⁇ 02 are each independently selected from the group consisting of hydrogen, hydroxy, and NRA03RA04 or RA01 anc j RA02 com bine to form an oxo-group, and
  • RA21 and R ⁇ 22 b o th are hydrogen, wherein RA03 anc j RA04 have the same meaning as defined above.
  • n + m is 1 and R ⁇ 01 is hydroxy or NR A03 R A04 and R A02 is hydrogen, and R A21 and R ⁇ 22 both are hydrogen, wherein R A03 and R A04 nave t
  • R A02 j s hydrogen and the other substituent is hydroxy.
  • R ⁇ 41 j selected from the group consisting of hydrogen and halogen.
  • R ⁇ 51 is selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy.
  • R ⁇ 1 j s hydrogen
  • n + m is 1 and R ⁇ OI and R ⁇ 02 are each independently selected from the group consisting of hydrogen and hydroxy, or RA01 anc j RA02 combine to form an oxo-group, and R A 21 an d R A 22 both are hydrogen.
  • n + m is 1 and R ⁇ OI j s hydroxy and RA02 JS hydrogen, and R ⁇ 21 anc
  • the compounds of Formula (I) are selected from the group consisting of
  • substituents in the present invention bind to the same atom and the list of meanings of these substituents includes hydrogen
  • one of the substituents may be hydrogen and the other may have a meaning as defined.
  • halogen used in the specification of the present application means a fluorine atom, a chlorine atom and a bromine atom, wherein a fluorine atom is preferred.
  • C- ⁇ _Q-a ⁇ ky ⁇ used in the specification of the present application indicates linear or branched alkyl groups having 1 to 6 carbon atoms. Among these, linear or branched alkyl groups having 1 to 4 carbon atoms (C-
  • alkyl groups examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec- butyl group, a tert-butyl group, a n-pentyl group, a 1 ,1-dimethylpropyl group, a 1 ,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-ethylpropyl group, a 1-methyl-2- ethylpropyl group, a 1-ethyl-2-methylpropyl group, a 1 ,1 ,2-trimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1-ethylbutyl group, a 1 ,1-dimethylbutyl group, a 1 ,2-d
  • alkyl groups having 1 to 6 carbon atoms are a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group and a sec-butyl group, and still more preferred examples are a methyl group, an ethyl group, a n-propyl group, an isopropyl group and an isobutyl group, wherein a methyl group is particularly preferred.
  • Ci_3-alkoxy used in the specification of the present invention indicates alkoxy groups having 1 to 3 carbon atoms.
  • Examples of the C- j . ⁇ -alkoxy group include a methoxy group, an eth- oxy group, an n-propoxy group, an isopropoxy group, wherein a methoxy group and a ethoxy group are more preferred, and a methoxy group is most preferable.
  • .g-alkyl group may be substituted with one or more substituents selected from the group consisting of fluoro and hydroxy.
  • .g-alkyl group can be any group as specified above with respect to the C- j .g-alkyl, unless specified otherwise.
  • the C- j .g-alkyl substituted by at least one fluorine atom is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C- j .g-alkyl, wherein the mono-, tri- and perfluoro substituted C- j .g-alkyl groups are more preferred. Still more preferred are mono- and perfluoro substituted C-
  • .g-alkyl groups are fluoromethyl, 1-fluoroethyl, 2-fluoroyethyl, 1-fluoro-isopropyl, 1-fluoro-n-propyl, 2-fluoro-isopropyl, 2-fluoro-n-propyl, 3-fluoro-n-propyl, trifluoromethyl, pentafluoroethyl, perfluoroisopropyl, perfluoro- n-propyl and perfluoroisobutyl.
  • .g-alkyl group can be any group as specified above with respect to the C-
  • .g-alkyl substituted by at least one hydroxy is preferably a C-
  • ⁇ -alkyl groups substituted with at least one hydroxy group includes hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-isopropyl, 2- hydroxy-isopropyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl and 3-hydroxy-n-propyl, wherein a hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-isopropyl and 2-hydroxy-n-propyl are still more preferred, and hydroxymethyl is particularly preferred.
  • .g-alkoxy group may be substituted with one or more substituents selected from the group consisting of fluoro and hydroxy.
  • the C- j . ⁇ -alkoxy group can be any group as specified above with respect to C- j . ⁇ -alkoxy, unless specified otherwise. It is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C- j . ⁇ -alkoxy, wherein the mono-, tri- and perfluoro substituted C- j . ⁇ -alkoxy groups are more preferred. More preferred are mono- and perfluoro substituted C- j . ⁇ -alkoxy groups.
  • ⁇ -alkoxy groups are fluoromethoxy, 1-fluoroethoxy, 2-fluoroyethoxy, 1-fluoro- isopropoxy, 1-fluoro-n-propoxy, 2-fluoro-isopropoxy, 2-fluoro-n-propoxy, 3-fluoro-n-propoxy, trifluoromethoxy, pentafluoroethoxy, perfluoroisopropoxy and perfluoro-n-propoxy.
  • the C- j . ⁇ -alkoxy group is substituted by at least one hydroxy
  • the C- j . ⁇ -alkoxy group can be any group as specified above with respect to C- j . ⁇ -alkoxy, unless specified otherwise. It is prefera- bly a C- j . ⁇ -alkoxy group which is substituted by one or two hydroxy groups, preferably one hydroxy group. Examples of such C- j .
  • ⁇ - alkoxy groups substituted with at least one hydroxy group include hydroxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxy-isopropoxy, 2-hydroxy-isopropoxy, 1-hydroxy-n-propoxy, 2-hydroxy-n-propoxy and 3-hydroxy-n-propoxy, wherein a hydroxymethoxy, 2-hydroxyethoxy, 2-hydroxy-isopropoxy and 2-hydroxy-n-propoxy are still more preferred, and hy- droxymethoxy is particularly preferred.
  • the invention covers all tautomers of the compounds of formula (I), a salt thereof, an N-oxide of the tautomeric compound or the salt thereof, a stereoisomer of the tautomeric compound, the salt, the N-oxide of the stereoisomer of the tautomeric compound or the N-oxide of the salt thereof.
  • Salts of the compounds according to the invention, the N-oxides thereof, the stereoisomers of the salts and the N-oxides thereof include all inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, particularly all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.
  • acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates, trifluoroacetates, citrates, gluconates including D- gluconates and L-gluconates, glucuronates including D-glucuronates and L-glucuronates, benzo- ates, 2-(4-hydroxybenzoyl)benzoates, butyrates, salicylates, subsalicylates, maleates, laurates, malates including L-malates and D-malates, lactates including L-lactates and D-lactates, fu- marates, succinates, oxalates, tartarates including L-tartarates, D-tartarates and meso-tartarates, stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates), methanesulfonates (
  • salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine and guanidinium salts.
  • the salts include water-insoluble and, particularly, water-soluble salts.
  • the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof and the stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are, therefore, all solvates of the compounds of formula (I), the salts thereof, the N-oxides of the compounds and the salts thereof and the stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof. Hydrates are a preferred example of said solvates.
  • N-oxides of the compounds according to the invention, the salts thereof, the stereoisomers of the compounds and the salts thereof include compounds, wherein the nitrogen atom of the pyridine moiety is oxidized, as illustrated by formula (Ia) below:
  • the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof include stereoisomers.
  • R A01 being a hydroxy group
  • R A02 being hydrogen and R A21 and R A22 representing identical groups
  • the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof have one stereogenic center.
  • R A01 and R A02 being hydrogen or R A01 and R A02 combining to form an oxo group and R A21 and R A22 representing different groups
  • the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof have one stereogenic center.
  • the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof have two stereogenic centers.
  • Each of said stereogenic centers may have the absolute configuration R or the absolute configuration S (according to the rules of Cahn, lngold and Prelog). Accordingly, the stereoisomers (1 R), (1S), (3R), (3S), (1 R,3R), (1 R,3S), (1S,3R) and (1S,3S), wherein the numbers refer to the atoms indicated in formula (Ib) below,
  • the invention relates to stereoisomers of formula (Ib) having the configuration (1 R) or (1 S), with the carbon atom at position number 3 not being an asymmetric carbon atom.
  • the invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.
  • Some of the compounds, salts thereof, N-oxides of the compounds and the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof according to the invention may exist in different crystalline forms (polymorphs), which are within the scope of the invention.
  • derivatives of the compounds of formula (I), the salts thereof, the N-oxides of the compounds or the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds or N-oxides of the salts thereof which are converted into compound (I) or a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N- oxide of the compound or the N-oxide of the salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention.
  • Said biological system is e.g. a mammalian organism, particularly a human subject.
  • the bioprecursor is, for example, converted into the compound of formula (I), a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof by metabolic processes.
  • the compounds according to the invention can be prepared as follows.
  • a compound of formula (I) can be obtained by reacting a com- pound of formula (II) or (Na) or (lib) or a mixture thereof with ammonia in an appropriate solvent, e.g. acetonitrile or methanol, preferably under microwave heating.
  • the compound of formula (II) or (Na) or (lib) or a mixture thereof can be prepared by cyclization of a compound of formula (IV) with a compound of formula (III) in the presence of a strong inorganic acid, e.g. perchloric acid, in a suitable solvent, e.g. nitromethane.
  • a compound of formula (IV) can be reacted with a compound of formula (V), in which X is a suitable leaving group, e.g. halogen, such as chlorine or bromine, or a conjugate base of an acid, such as trifluoroacetate, acetate, methylsul- fonate, in a Friedel-Crafts acylation reaction in the presence of an appropriate Lewis acid, e.g. zinc chloride, boron trifluoride etherate or orthophosphoric acid, in a suitable aprotic solvent, e.g.
  • halogen such as chlorine or bromine
  • a conjugate base of an acid such as trifluoroacetate, acetate, methylsul- fonate
  • the compound of formula (II) or (Ma) or (Mb) or a mixture thereof can be subjected to a cyclization condensation reaction with ammonium acetate in an appropriate solvent, e.g. acetic acid, preferably at elevated temperature, more preferably at 70-100 0 C, and / or a cyclization condensation reaction with ammonia in an appropriate solvent, e.g. methanol, preferably at elevated temperature, more preferably at 70-100 0 C, to give a corresponding compound of formula (I).
  • an appropriate solvent e.g. acetic acid
  • a cyclization condensation reaction with ammonia in an appropriate solvent e.g. methanol
  • a compound of formula (IVa) or (IVb) or (IVc) or a mixture thereof are obtainable via an aldol-type condensation of a compound of formula (Vl), in which PG stands for a suitable temporary protecting group, e.g. acetyl, formyl, allyl or methoxycarbonyl, with a compound of formula (VII), and subsequent removal of PG.
  • PG stands for a suitable temporary protecting group, e.g. acetyl, formyl, allyl or methoxycarbonyl
  • the compound of formula (IVa) or (IVb) or (IVc) or a mixture thereof can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Ic).
  • a compound of formula (Id), in which R A01 and R A02 are hydrogen, can be obtained as shown in reaction scheme 4.
  • indole (IX) can be reacted with a compound of formula (X) in an art-known nucleophilic substitution reaction [see e.g. Heterocycles 31 (8), 1497-1504 (1990)].
  • the thus obtained hydroxy-com pound can be oxidized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroacetic anhydride as activator [see e.g. J. Org. Chem.
  • Indole (IX) is commercially available, the compounds of formula (X) are known, commercially available or can be obtained according to known procedures.
  • reaction scheme 5 a compound of formula (Id), in which R A01 and R A02 are hydrogen, can be obtained as illustrated in reaction scheme 5.
  • indole (IX) is reacted with a compound of formula (Xl) in an art-known oxidative coupling reaction [see e.g. JACS 129, 12857 (2007)], in the presence of a suitable base, e.g. lithium diisopropylamide or lithium hexamethyldisilazide, and a suitable oxidation agent, e.g. copper-(ll)2-ethylhexanoate.
  • a suitable base e.g. lithium diisopropylamide or lithium hexamethyldisilazide
  • a suitable oxidation agent e.g. copper-(ll)2-ethylhexanoate.
  • the thus obtained compound of formula (VIII) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of
  • Indole (IX) is commercially available, the compounds of formula (Xl) are known, commercially available or can be obtained according to known procedures.
  • a compound of formula (Id) can be obtained as illustrated in reaction scheme 6.
  • indole (IX) is reacted with a compound of formula (XII) in an art-known condensation reaction in the presence of a base, e.g. pyrrolidine or potassium hydroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 17, 3099 (2007)].
  • a base e.g. pyrrolidine or potassium hydroxide
  • the thus obtained unsaturated compound of formula (XIII) can be hydroxylated in a hydroboration - oxidation reaction known to the person skilled in the art, e.g. by using borane and sodium hydroxide / hydrogen peroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 16, 3524 (2006)].
  • the resulting hydroxy-compound (XIV) can be oxidized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroacetic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (VIII).
  • the compound of formula (VIII) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id).
  • a compound of formula (Id) can be obtained as illustrated in reaction scheme 7.
  • isatine (XV) is reacted with a compound of formula (Xl) in an art-known aldol addition reaction [see e.g. Tetrahedron 58, 8399 (2002)].
  • the thus obtained hydroxy compound of formula (XVI) can be transformed into a compound of formula (XIV) by using reductive agents, such as, for example, borane tetrahydrofuran complex or lithium aluminium hydride [see e.g. Tetrahedron 58, 8399 (2002)].
  • the resulting hydroxy-com pound of formula (XIV) can be oxi- dized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroacetic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (VIII).
  • the compound of formula (VIII) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id).
  • Isatine (XV) is commercially available, compounds of formula (Xl) are known, commercially available or can be obtained according to known procedures.
  • reaction scheme 8 An alternative synthetic route to a compound of formula (Ic) is depicted in reaction scheme 8.
  • X being a leaving group, such as halogen, pref- erably bromine or chlorine, can be reacted in a multi-component unsymmetric Hantzsch reaction in the presence of catalytic amounts of acid, e.g. acetic acid, and amine, e.g. benzylamine [see e.g. Tetrahedron Letters 42, 4507 (2001 ) or Tetrahedron 63, 1946 (2007)].
  • acid e.g. acetic acid
  • amine e.g. benzylamine
  • the resulting nitro- dihydropyridine of formula (XX) can be converted to amino-pyridine of formula (XXI) either in two steps (oxidation of dihydropyridine and reduction of nitro group) or, preferably, in one step by using, e.g., elementary iron in the presence of concentrated hydrochloric acid or elementary zinc in the presence of acetic acid.
  • the final ring closing reaction to obtain compounds of formula (I) can be achieved by reacting compounds of formula (XXI) under nitrogen atmosphere with catalytic amounts of a suitable palladium source, e.g.
  • a compound of formula (XIX) can be obtained, as shown in reaction scheme 9, by reacting the corresponding acid of formula (XXII) with carbonyl diimidazole in the presence of ni- tromethane and a suitable base, e.g. potassium tertbutylate [see e.g. J. Am. Chem. Soc. 125, 157 (2003)].
  • a suitable base e.g. potassium tertbutylate
  • a compound of formula (I), wherein R A01 is hydroxy and R A02 is hydrogen can be prepared from a compound of formula (I), wherein R A01 and R A02 combine to form an oxo group, by reduction reaction, e.g. with the aid of a suitable reduction agent, such as sodium borohydride;
  • a compound of formula (I), wherein R A01 and R A02 are hydrogen can be prepared from a compound of formula (I), wherein R A01 and R A02 combine to form an oxo group, by reduction reaction, e.g. with the aid of a suitable reduction agent, such as hydrazine (e.g. according to a Wolff-Kishner reduction); • a compound of formula (I), wherein R A01 is amino and R A02 is hydrogen can be prepared from a compound of formula (I), wherein the R A01 and R A02 combine to form an oxo group, by reductive amidation reaction, e.g. with the aid of a suitable amide, e.g.
  • a suitable reduction agent such as formic acid or ammonium formiate in a suitable solvent, e.g. formic acid, at elevated temperatures, preferably 14O 0 C - 18O 0 C, followed by amide hydrolysis reaction, e.g. with the aid of a strong acid, such as hydrogen chloride, in a suitable solvent, such as methanol;
  • a compound of formula (I), wherein R A01 is amino and R A02 is hydrogen can be prepared from a compound of formula (I), wherein the R A01 and R A02 combine to form an oxo group, by reductive amination reaction, e.g. with the aid of a suitable amine, e.g. benzylamine, in combination with a suitable reduction agent, such as sodium cyanoborohydride or sodium borohydride, in the presence of a suitable acid, e.g. acetic acid or p-toluenesulfonic acid, or a suitable Lewis acid, e.g. titanium(IV) tetraisopropyl oxide, in a suitable solvent, e.g.
  • a suitable acid e.g. acetic acid or p-toluenesulfonic acid
  • a suitable Lewis acid e.g. titanium(IV) tetraisopropyl oxide
  • methanol followed by hydrogenation, e.g. with the aid of a transition metal catalyst, such as palladium(O), in combination with a suitable hydrogen source, e.g. hydrogen gas or ammonium formiate, in a suitable solvent, such as methanol;
  • a suitable hydrogen source e.g. hydrogen gas or ammonium formiate
  • a compound of formula (I), wherein R A01 is mono- or di-Ci_ 6 -alkylamino, and R A02 is hydrogen can be prepared from a compound of formula (I), wherein the R A01 and R A02 combine to form an oxo group, by reductive amination reaction, e.g. with the aid of a suitable amine, e.g. methylamine or diethylamine, in combination with a suitable reduction agent, such as sodium cyanoborohydride or sodium borohydride, in the presence of a suitable acid, e.g. acetic acid or p-toluenesulfonic acid, or a suitable Lewis acid, e.g. titanium(IV) tetraisopropyl oxide, in a suitable solvent, e.g. methanol;
  • . 6 -alkyl, wherein said C- ⁇ - 6 -alkyl may be substituted as defined above, and R A02 is hydrogen, can be prepared e.g. from a compound of formula (I), wherein R A01 is amino and R A02 is hydrogen, by reaction with an appropriate carboxylic acid chloride, e.g. Ci_ 6 -alkylC(O)CI, wherein said Ci_ 6 -alkyl may be substituted as defined above, or carboxylic anhydride, e.g. (Ci.
  • a compound of formula (I), wherein R B41 and/or R B51 represent(s) a nitro group can be converted into the corresponding amino compound by reduction reaction, e.g. with the aid of a suitable reduction agent, such as tin dichloride or hydrogen gas and a palladium on carbon catalyst;
  • a suitable reduction agent such as tin dichloride or hydrogen gas and a palladium on carbon catalyst
  • a compound of formula (I), wherein R B51 represents a group -NH-C(O)-I -2C-alkyl can be prepared e.g. from a compound of formula (I), wherein R B51 represents an amino group by reaction with an appropriate carboxylic acid chloride or carboxylic anhydride, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide;
  • a compound of formula (I), wherein R B51 represents -NH-C(O)-NH 2 can be obtained e.g. from a compound of formula (I), wherein R B51 represents an amino group by reaction with potassium cyanate in the presence of a mineral acid, such as hydrochloric acid, or by condensation with urea;
  • a compound of formula (I), wherein R B51 is hydroxy can be synthesized e.g. from a compound of formula (I), wherein R B51 is 1-3C-alkoxy by dealkylation with a Lewis acid, such as boron tribromide.
  • the compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material, e.g. silica gel, reversed phase silica gel, amino modified silica gel, aluminium oxide.
  • a suitable support material e.g. silica gel, reversed phase silica gel, amino modified silica gel, aluminium oxide.
  • Salts of the compounds of formula (I), the N-oxides thereof and the stereoisomers of the compounds and the N-oxides thereof according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or me- thylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxan, a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol, a low molecular weight aliphatic ester such as ethyl acetate or isopropyl acetate, or water) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent for example a ketone such as acetone, methylethylketone or me- thylis
  • acids include hydrochloric acid, hydrobromic acid, p-tolylsulfonic acid, methylsulfonic acid, trifluoromethylsulfonic acid, succinic acid, malic acid, citric acid, maleic acid, formic acid, acetic acid or pyroglutamic acid.
  • bases include metal hydrides, such as sodium hydride or calcium hydride, metal hydroxides, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide, or amines, e.g. am- monia, trimethylamine or methylamine.
  • the acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.
  • the compounds of formula (I), the salts thereof and the stereoisomers of the compounds and the salts according to the invention can be converted into their N-oxides, for example, by reaction with peracids, such as m-chloroperbenzoic acid or peracetic acid.
  • peracids such as m-chloroperbenzoic acid or peracetic acid.
  • the person skilled in the art is familiar with the reaction conditions for carrying out the N-oxidation.
  • Pure diastereomers and pure enantiomers of the compounds of formula (I), the salts thereof, the N- oxides of the compounds and the N-oxides of the salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and/or by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis.
  • the pure diastereo- meric and pure enantiomeric compounds of the invention are obtainable by asymmetric synthesis and/or by using chiral starting compounds in synthesis.
  • the (IS)-enantiomers of the compounds of formula (I), the salts thereof, the N-oxides of the compounds and the salts thereof according to the invention can be obtained by reduction of the corresponding ketone precursors (wherein R A01 and R A02 combine to form an oxo group) with sodium borohydride in the presence of (4S,5S)-2-(3-nitro-phenyl)-[1 ,3,2]dioxaborolane- 4,5-dicarboxylic acid in a suitable aprotic solvent, preferably tetrahydrofuran or dioxan, preferably at room temperature.
  • a suitable aprotic solvent preferably tetrahydrofuran or dioxan
  • (4S,5S)-2-(3-Nitro-phenyl)-[1 ,3,2]dioxaborolane-4,5-dicarboxylic acid can be prepared by esterification of 3-nitrophenyl boronic acid and D-tartaric acid in the presence of a dehydrating agent such as calcium hydride, preferably at temperatures of 60-80 0 C.
  • a dehydrating agent such as calcium hydride
  • the (1 R)-enantiomers of the compounds of formula (I), the salts thereof, the N-oxides of the compounds and the salts thereof according to the invention can be obtained using (4R,5R)-2- (3-nitro-phenyl)-[1 ,3,2]dioxaborolane-4,5-dicarboxylic acid in a suitable aprotic solvent, preferably tetrahydrofuran or dioxan, preferably at room temperature.
  • a suitable aprotic solvent preferably tetrahydrofuran or dioxan
  • (4R,5R)-2-(3-Nitro-phenyl)- [1 ,3,2]dioxaborolane-4,5-dicarboxylic acid can be prepared by esterification of 3-nitrophenyl bo- ronic acid and L-tartaric acid in the presence of a dehydrating agent such as calcium hydride, preferably at temperatures of 60-80 0 C.
  • a dehydrating agent such as calcium hydride
  • Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure di- astereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent.
  • chiral auxiliary agents for example, chiral acids, such as (+)- or (-)-tartaric acid, (+)- or (-)-malic acid, (+)- or (-)- mandelic acid, (+)- or (-)-lactic acid or (+)- or (-)-camphersulfonic acid, can be used to separate enantiomeric bases and chiral bases, such as (+)- or (-)-brucine, (+)- or (-)-quinidine or (+)- or (-)- quinine, can be used to separate enantiomeric acids via formation of diastereomeric salts.
  • chiral acids such as (+)- or (-)-tartaric acid, (+)- or (-)-malic acid, (+)- or (-)- mandelic acid, (+)- or (-)-lactic acid or (+)- or (-)-camphersulfonic acid
  • chiral bases such as (+)- or (-)-brucine, (+)- or (-
  • diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids, such as (+)- or (-)-lactic acid or (+)- or (-)-mandelic acid, or chiral alcohols, such as (+)- or (-)-1- phenylethanol, respectively, as chiral auxiliary agents.
  • diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures.
  • enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.
  • 1 H nmr spectra are recorded on a Bruker DPX200 ( 1 H 200 MHz), a Bruker Avance ( 1 H 300 MHz) or a Bruker AV400 ( 1 H 400 MHz) spectrometer. Spectra are calibrated on tetramethylsilane (TMS) as internal standard (0.00 ppm for 1 H). Chemical shifts are given in ppm ( ⁇ ) relative to TMS, multiplicities are indicated by s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), m (multi- plet) and b (broadened). Coupling constants, J, are reported in Hz.
  • Melting points, mp., are measured on a B ⁇ chi B-540 or a B ⁇ chi B-541 instrument and are uncor- rected.
  • Reactions are performed in dry (water free) solvents and under air atmosphere unless otherwise noted. Glassware is heated to 15O 0 C in a vacuum of 10 ⁇ 1 mbar for 5 min prior to use, unless otherwise noted. Furthermore, reactions and single processes, such as dissolutions, additions, filtering, extractions or chromatography, are performed at room temperature and under air atmosphere unless otherwise noted.
  • Reactions using microwave radiation are performed using Biotage Initiator Sixty (0 - 300 W) and Biotage Emry's Optimizer (0 - 300 W) instruments.
  • the temperatures and times indicated for these reactions refer to the input data using the user interface of these instruments.
  • the reaction mixtures are stirred in closed (sealed) reaction vials for the indicated time at the indicated internal temperature, the microwave radiation power is controlled by the internal temperature. Heating and cooling phase are not considered. Purchased chemicals and solvents are used without further purification.
  • Preparative HPLC purification is performed on a customary instrument from Gilson using a re- versed phase column (C18, Phenomenex, Gemini, 75x30 mm, 5 ⁇ m) as stationary phase and an acetonitrile / water gradient as mobile phase at a flow of 40 ml/min.
  • Step 1 2-(1-Acetyl-1 H-indol-S-yO-S-hydroxycyclopent ⁇ -enone.
  • 1-Acetyl-1 ,2-dihydro-indol-3-one (7.0 g) is suspended in acetic acid (80 ml) and 1 ,3-cyclopentane-dione (3.92 g) is added.
  • the reaction mixture is stirred for 20 min and triethylamine (5.56 ml) is added.
  • the mixture is partitioned into 4 microwave vials and each portion is heated for 2 h at 185 0 C in the microwave.
  • the reaction mixtures are recombined and concentrated in vacuo.
  • Step 2 2-(1 H-lndol-3-yl)-cyclopentane-1 ,3-dione.
  • 2-(1-Acetyl-1 H-indol-3-yl)-3-hydroxycyclopent-2- enone (4.17 g) is dissolved in aqueous 1 N NaOH solution (53.1 ml) and stirred for 17 h.
  • the reac- tion mixture is diluted with dichloromethane (200 ml) and acidified with 2M aqueous HCI solution (pH 6.5).
  • the organic layer is separated and the aqueous layer is extracted thoroughly with dichloromethane / isopropanol 9:1 (v/v).
  • the combined organic layers are dried and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with gradient dichloromethane to dichloromethane / ethyl acetate 1 :1 (v/v)) to give rise to 3.8 g (32%) of 2-(1 H-indol-3- yl)cyclopentanol.
  • Step 2 2-(1 H-lndol-3-yl)cyclopentanone.
  • Dimethylsulfoxide (3.1 ml) is dissolved in dry dichloromethane (40 ml), the solution is cooled to -75 0 C and trifluoroacetic anhydride (4.5 ml) is added drop-wise at a rate, that internal temperature does not exceed -7O 0 C.
  • trifluoroacetic anhydride 4.5 ml
  • a solution of 2-(1 H-indol-3-yl)cyclopentanol (3.8 g) in dry THF (25 ml) was added drop-wise. The mixture is stirred for 1 h at -7O 0 C.
  • Triethyl amine (12.1 ml) is added and the temperature is raised to room temperature within 18 h. Distilled water (25 ml) is then added, after phase separation the aqueous phase is extracted with dichloromethane (3 x 40 ml), the combined organic extracts are washed with distilled water (1 x 100 ml), dried (magnesium sulfate) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient dichloro- methane to dichloromethane / ethyl acetate 9:1 (v/v)) to give 1.20 g (32%) of the title compound.
  • Step 1 5-Benzylidene-2,3,5,6-tetrahydro-1 H-cyclopenta[b]indeno[1 ,2-d]pyran-1-one.
  • 2-(1 H-lndol- 3-yl)-cyclopentane-1 ,3-dione (example A1 ) (533 mg) and phenyl acetic acid anhydride (6.36 g) are suspended in nitromethane (16 ml).
  • the resulting slurry is treated with 70% (v/v) aqueous HCIO 4 solution (215 ⁇ l, 3 portions, every 10 minutes) and stirred for one additional hour at room tempera- ture.
  • the reaction mixture is diluted with dichloromethane (20 ml) and saturated aqueous sodium hydrogencarbonate solution (10 ml).
  • the organic layer is separated and the aqueous layer is extracted again with dichloromethane (2 x 10 ml).
  • the combined organic extracts are dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by flash column chromatography (silica gel, eluting with gradient n-hexane / ethyl acetate) to give rise to 5-benzylidene-2,3,5,6-tetrahydro- 1 H-cyclopenta[b]indeno[1 ,2-d]pyran-1-one (330 mg, 42%), which is used in the next step without further purification.
  • Step 2 5-Benzyl-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one.
  • 5-Benzylidene-2,3,5,6- tetrahydro-1 H-cyclopenta[b]indeno[1 ,2-d]pyran-1-one (330 mg) is suspended in acetonitrile (21 ml) and treated with 25% (w/v) aqueous ammonia solution (21 ml).
  • the reaction mixture is heated in two portions in a sealed vial for 25 min at 13O 0 C using microwave radiation.
  • 2-(1 H-lndol-3-yl)-cyclopentane-1 ,3-dione (example A1 ) (1.10 g) is suspended in dichloroethane (5 ml) and a 1 M zinc(ll) chloride solution in ether (15 ml) and 3-fluoro-4-methoxy-phenylacetyl- chloride (2.0 g) is added. The mixture is heated in a sealed vial for 8 min at 8O 0 C using microwave radiation. After cooling, a 7N ammonia solution in methanol (7 ml) is added and the mixture is again heated in a sealed vial for 30 min at 16O 0 C using microwave radiation.
  • 3,5-Difluoro-4-methoxyphenylacetic acid (2.0 g) is stirred with trifluoroacetic anhydride (1.4 ml) at room temperature. After 15 min the solution is diluted with dichloroethane (3 ml) and added to a cooled (O 0 C) solution of 2-(1/-/-indol-3-yl)-cyclopentane-1 ,3-dione (example A1 ) (1.1 g) in dichloroethane (7 ml) and a 1 M zinc(ll) chloride solution in ether (7.5 ml). The mixture is stirred at room temperature for 1 h.
  • 3-Nitrophenylboronic acid (0.62 g), D-tartaric acid (0.56 g) and calcium hydride (0.30 g) are suspended in THF (10 ml) and heated under reflux for 2 h. The suspension is cooled and filtered under nitrogen atmosphere.
  • 5-(3-Fluoro-4-methoxy-benzyl)-3,6-dihydro-2H-4,6-diaza- cyclopenta[c]fluoren-1-one (example 3) (0.45 g) is dissolved in the filtrate and sodium borohydride (0.14 g) is added in 6 portions at O 0 C. After the last addition, stirring is continued for 90 min at room temperature.
  • the compounds, salts thereof, N-oxides of the compounds and the salts thereof, and the stereoisomers of the compounds, the salts, the N-oxides of the compounds and the N-oxides of the salts thereof according to the invention are hereinafter referred to as the compounds of the invention.
  • the compounds of the invention are pharmaceutically acceptable.
  • the compounds of the invention have valuable pharmaceutical properties which make them commercially utilizable.
  • PDE5 type 5 phosphodiesterase
  • they are able to influence the physiological and pathophysiological function of various cells, e.g., but not limited to, smooth muscle cells, fibroblasts, myofibroblasts and platelets, which are involved in a great variety of physiological and pathophysiological mechanisms.
  • the PDE5 inhibiting compounds of the invention can effect relaxation of the vasculature, thus increasing blood flow, improve the spatial balance between blood perfusion and ventilation within the lung ("re-matching" effect) thereby reducing the amount of so-called low V/Q-areas [areas within the lung with high perfusion (Q) but no or reduced ventilation (V)] and high V/Q-areas (areas within the lung with low perfusion but high ventilation), induce neurogenesis, inhibit platelet function, such as aggregation, adhesion and mediator release and, thus, have an anti-inflammatory effect.
  • the compounds of the invention are distinguished by valuable and desirable properties, such as, for example, high efficacy, high selectivity, low toxicity, superior bioavailability in general (e.g. good enteral absorption), superior therapeutic window, superior pharmacokinetics (e.g. half-life), absence of significant side effects, and further beneficial effects related with their therapeutic and pharmaceutical suitability.
  • the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by inhibition of the type 5 phosphodiesterase.
  • the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, such as, but not limited to, male erectile dysfunction, premature ejaculation, Peyronie ' s disease; acute and chronic airway diseases, such as, but not limited to, COPD (chronic obstructive pulmonary disease), bronchitis, emphysema, pulmonary vascular remodeling, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, cystic fibrosis, bronchiectasis, bronchiolitis obliterans, connective tissue diseases, sarcoidosis, kyphoscoliosis, pneumoconiosis, amyotrophic lateral
  • ARDS adult respiratory distress syndrome
  • gastrointestinal inflammations e.g., but not limited to, Crohn ' s disease and ulcerative colitis
  • disorders which are based on allergic and/or chronic, immunological false reactions e.g., but not limited to, allergic rhinitis, allergic sinusitis, chronic rhinitis, chronic sinusitis, allergic conjunctivitis, nasal polyps
  • pain such as, but not limited to, inflammatory pain
  • right-heart failure right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia
  • ischaemic diseases such as, but not limited to, diabetes mellitus, stroke, coronary artery disease, angina (including, but not limited to, vasospastic angina), myocardial infarction, peripheral artery disease, cerebrovascular obstruction, sleep apnea, macular ischaemia, arterial and venous occlusion, congestive heart failure; diabetic gastroparesis
  • the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by inhibition of the type 5 phosphodiesterase.
  • the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease
  • pulmonary hypertension in particular embraces - pulmonary arterial hypertension including primary pulmonary hypertension (e.g. sporadic or familial) and pulmonary arterial hypertension related, for example, but without limitation, to collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, human immunodeficiency virus infection, drugs or toxins (e.g., but not limited to, anorexigens), persistent pulmonary hypertension of the newborn; pulmonary venous hypertension due to, for example, but without limitation, left-sided atrial or ventricular heart disease, left-sided valvular heart disease, extrinsic compression of central pulmonary veins (e.g.
  • pulmonary hypertension associated with disorders of the respiratory system or hypoxemia including, for example, but without limitation, chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia; pulmonary hypertension caused by chronic thrombotic or embolic diseases including thromboembolic obstruction of proximal pulmonary arteries and obstruction of distal pulmonary arteries, such as pulmonary embolism (due to thrombus, tumor, ova, parasites, or foreign material), in situ thrombosis and sickle-cell disease, in particular chronic thromboembolic pulmonary hypertension (CTEPH); pulmonary hypertension caused by disorders directly affecting the pulmonary vasculature including inflammatory disorders (e.g., but not
  • the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepa- titis and liver fibrosis.
  • acute and chronic airway diseases such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease
  • portal hypertension liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepa- titis and liver fibrosis.
  • the invention further relates to the compounds of the invention for use in the treat- ment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
  • acute and chronic airway diseases such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease
  • portal hypertension liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
  • the invention also relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition inhibiting the type 5 phosphodiesterase, in particular a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase, preferably, a pharmaceutical composition for the treatment or prophylaxis of the diseases exemplified above.
  • the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, such as, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
  • an acute or chronic airway disease such as, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
  • the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, such as, but not limited to, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
  • an acute or chronic airway disease such as, but not limited to, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
  • the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis.
  • the invention further relates to a method of treating or preventing a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • the invention relates to a method of treating or preventing one of the above mentioned diseases comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • the invention relates to a method of treating or preventing a disease which is alleviated by inhibition of the type 5 phosphodiesterase comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • the invention relates to a method of treating or preventing male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington ' s disease, Parkinson's disease, multiple sclerosis and preeclamp
  • the invention relates to a method of treating or preventing an acute or chronic airway disease, for example, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • an acute or chronic airway disease for example, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease
  • the invention preferably relates to a method of treating or preventing an acute or chronic airway disease, for example, but not limited to, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • an acute or chronic airway disease for example, but not limited to, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease
  • the invention preferably relates to a method of treating or preventing portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • the patient is preferably a mammal, more preferably a human.
  • at least one of the compounds of the invention can be used.
  • one or two of the compounds of the invention are used, more preferably, one of the compounds of the invention is used.
  • the above methods of treating or preventing one of the above mentioned diseases comprise administering to a patient in need thereof a therapeutically effective amount of one compound of the examples according to the present invention.
  • the invention furthermore relates to a pharmaceutical composition which comprises at least one of the compounds of the invention together with at least one pharmaceutically acceptable auxiliary.
  • the invention additionally relates to a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, in particular for the treatment or prophylaxis of pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
  • the invention further relates to a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, in particular for the treatment or prophylaxis of pulmonary hyper- tension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
  • pulmonary hyper- tension lung fibrosis
  • idiopathic pulmonary lung fibrosis IPF
  • asthma bronchitis
  • emphysema chronic obstructive pulmonary disease
  • the pharmaceutical composition comprises one or two of the compounds of the invention. More preferably, the pharmaceutical composition comprises one of the compounds of the invention.
  • the pharmaceutical composition comprises a compound of the examples according to the present invention together with at least one pharmaceutically acceptable auxiliary.
  • the invention additionally relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the compounds of the invention, at least one pharmaceutically acceptable auxiliary and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta- mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta- blockers, type 4 phosphodiesterase inhibitors, antidepressants, antibiotics, anticoagulants, diuretics and digitalis glycosides.
  • the therapeutic agent includes the corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics in form of the free compounds, the pharmaceutically acceptable salts thereof, the pharmaceutically acceptable derivatives thereof (e.g., but not limited to, ester derivatives), the solvates thereof and the stereoisomers of the compounds, salts, derivatives and solvates.
  • corticosteroids examples include without limitation budesonide, fluticasone such as fluticasone propionate, beclometasone such as beclometasone dipropionate, triamcinolone such as triamcinolone acetonide, and ciclesonide.
  • anticholinergics include without limitation in- dacaterol, tiotropium such as tiotropium bromide, and ipratropium such as ipratropium bromide.
  • beta-mimetics include without limitation formoterol such as formoterol fumarate, and salmeterol such as salmeterol xinafoate.
  • lung surfactants include without limitation lusupultide, poractant alfa, sinapultide, beractant, bovactant, colfosceril such as colfosceril palmi- tate, surfactant-TA, and calfactant.
  • endothelin antagonists include without limitation bosentan, ambrisentan and sitaxsentan such as sitaxsentan sodium.
  • prostacyclins include without limitation iloprost such as iloprost tromethamine, epoprostenol such as epopros- tenol sodium and treprostinil such as treprostinil sodium.
  • Examples of calcium channel blockers include without limitation amlodipine such as amlodipine besylate and amlodipine maleate, nifedipine, diltiazem such as diltiazem hydrochloride, verapamil such as verapamil hydrochloride, and felodipine.
  • Examples of beta-blockers include without limitation bisoprolol such as bisoprolol fumarate, nebivolol, metoprolol such as metoprolol succinate and metoprolol tartrate, carvedilol, at- enolol and nadolol.
  • Examples of type 4 phosphodiesterase inhibitors include without limitation ro- flumilast, roflumilast N-oxide, cilomilast, tetomilast and oglemilast.
  • Examples of antidepressants include without limitation bupropion such as bupropion hydrochloride.
  • Examples of antibiotics include without limitation amoxicillin, ampicillin, levofloxacin, clarithromycin, ciprofloxacin such as ciprofloxacin hydrochloride, telithromycin and azithromycin.
  • Examples of anticoagulants include without limitation clopidogrel, enoxaparin, cilostazol, nadroparin, warfarin and abciximab.
  • Examples of diuretics include without limitation furosemide, bumetanide and torsemide.
  • Examples of digitalis glycosides include without limitation digoxin and digitoxin.
  • the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid.
  • the pharmaceutical composition comprises: a compound of the invention and budesonide, a compound of the invention and fluticasone, a compound of the invention and beclometasone, a compound of the invention and triamcinolone, or a compound of the invention and ciclesonide.
  • the pharmaceutical composition comprises a compound of the invention in combination with an anticholinergic.
  • the phar- maceutical composition comprises: a compound of the invention and indacaterol, a compound of the invention and tiotropium, or a compound of the invention and ipratropium.
  • the pharmaceutical composition comprises a compound of the invention in combination with a beta-mimetic.
  • the pharmaceutical composition comprises: a compound of the invention and formoterol, or a compound of the invention and salmeterol.
  • the pharmaceutical composition comprises a compound of the invention in combination with a lung surfactant.
  • the pharmaceutical composition comprises: a compound of the invention and lusupultide, a compound of the invention and poractant alfa, a compound of the invention and sinapultide, a compound of the invention and beractant, a compound of the invention and bovactant, a compound of the invention and colfosceril, a compound of the invention and surfactant-TA, or a compound of the invention and calfactant.
  • the pharmaceutical composition comprises a compound of the invention in combination with an endothelin antagonist.
  • the pharmaceutical composition comprises: a compound of the invention and bosentan, a compound of the invention and ambrisentan, or a compound of the invention and sitaxsentan.
  • the pharmaceutical composition comprises a compound of the invention in combination with a prostacyclin.
  • the pharmaceutical composition comprises: a compound of the invention and iloprost, a compound of the invention and epoprostenol, a compound of the invention and triprostinil.
  • the pharmaceutical composition comprises a compound of the invention in combination with a calcium channel blocker.
  • the pharmaceutical composition comprises: a compound of the invention and amlodipine, a compound of the invention and nifedipine, a compound of the invention and diltiazem, a compound of the invention and verapamil, or a compound of the invention and felodipine.
  • the pharmaceutical composition comprises a compound of the invention in combination with a beta-blocker.
  • the pharmaceutical composition comprises: a compound of the invention and bisoprolol, a compound of the invention and nebivolol, a compound of the invention and metoprolol, a compound of the invention and carvedilol, a compound of the invention and atenolol, or a compound of the invention and nadolol.
  • the pharmaceutical composition comprises a compound of the invention in combination with a type 4 phosphodiesterase inhibitor.
  • the pharmaceutical composition comprises: a compound of the invention and roflumilast, a compound of the invention and roflumilast N-oxide, a compound of the invention and cilomilast, a compound of the invention and tetomilast, or a compound of the invention and oglemilast.
  • the pharmaceutical composition comprises a compound of the invention in combination with an antidepressant.
  • the pharmaceutical composition comprises: a compound of the invention and bupropion.
  • the pharmaceutical composition comprises a compound of the invention in combination with an antibiotic.
  • the pharmaceutical composition comprises: a compound of the invention and amoxicillin, a compound of the invention and ampicillin, a compound of the invention and levofloxacin, a compound of the invention and clarithromycin, a compound of the invention and ciprofloxacin, a compound of the invention and telithromycin, or a compound of the invention and azithromycin.
  • the pharmaceutical composition comprises a compound of the invention in combination with an anticoagulant.
  • the pharmaceutical composition comprises: a compound of the invention and clopidogrel, a compound of the invention and enoxaparin, a compound of the invention and cilostazol, a compound of the invention and nadroparin, a compound of the invention and warfarin, or a compound of the invention and abciximab.
  • the pharmaceutical composition comprises a compound of the invention in combination with a diuretic.
  • the pharmaceutical composition comprises: a compound of the invention and furosemide, a compound of the invention and bumetanide, or a compound of the invention and torsemide.
  • the pharmaceutical composition comprises a compound of the invention in combination with a digitalis glycoside.
  • the pharmaceutical composition comprises: a compound of the invention and digoxin, or a compound of the invention and digitoxin.
  • the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid and a beta-mimetic.
  • the pharmaceutical composition comprises: a compound of the invention, budesonide and indacaterol, a compound of the invention, budesonide and formoterol, a compound of the invention, budesonide and salmeterol, a compound of the invention, fluticasone and indacaterol, a compound of the invention, fluticasone and formoterol, a compound of the invention, fluticasone and salmeterol, a compound of the invention, beclometasone and indacaterol, a compound of the invention, beclometasone and formoterol, a compound of the invention, beclometasone and salmeterol, a compound of the invention, triamcinolone and indacaterol, a compound of the invention, triamcinolone and formoterol, a compound of the invention, triamcinolone and salmeterol, a compound of the invention, ciclesonide and indacaterol, a compound of the compound of the invention, cicl
  • the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid and an anticholinergic.
  • the pharmaceutical composition comprises: a compound of the invention, budesonide and tiotropium, a compound of the invention, budesonide and ipratropium, a compound of the invention, fluticasone and tiotropium, a compound of the invention, fluticasone and ipratropium, a compound of the invention, beclometasone and tiotropium, a compound of the invention, beclometasone and ipratropium, a compound of the invention, triamcinolone and tiotropium, a compound of the invention, triamcinolone and ipratropium, a compound of the invention, ciclesonide and tiotropium, or a compound of the invention, ciclesonide and ipratropium.
  • the above mentioned compound of the invention is preferably a compound according to the examples.
  • the invention furthermore relates to pharmaceutical compositions according to the invention, as defined above, inhibiting the type 5 phosphodiesterase, especially for the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterase, in particular for the treatment or prophylaxis of the diseases exemplified above.
  • the invention also encompasses pharmaceutical compositions according to the invention, as defined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
  • acute and chronic airway diseases such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease
  • portal hypertension liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
  • the invention also encompasses pharmaceutical compositions according to the inven- tion, as defined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
  • acute and chronic airway diseases such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease
  • portal hypertension liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
  • the pharmaceutical compositions according to the invention preferably contain the compound or compounds of the invention in a total amount of from 0.1 to 99.9 wt%, more preferably 5 to 95 wt%, in particular 20 to 80 wt%.
  • the total amount of said therapeutic agent or therapeutic agents in the pharmaceutical compositions is preferably in the range of from 0.1 to 99.9 wt%, more preferably 5 to 95 wt%, in particular 20 to 80 wt%, under the provision that the total amount of the compound or compounds of the invention and the therapeutic agent or therapeutic agents is less than 100 wt%.
  • auxiliaries any auxiliaries known to be suitable for preparing pharmaceutical compositions can be used. Examples thereof include, but are not limited to, sol- vents, excipients, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrating agents, buffers, permeation promoters, polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, flavorings, sweeteners and dyes.
  • auxiliaries of a type appropriate to the desired formulation and the desired mode of administration are used.
  • the pharmaceutical compositions can be formulated, for example, into tablets, coated tablets (dra- gees), pills, cachets, capsules (caplets), granules, powders, suppositories, solutions (e.g., but not limited to, sterile solutions), emulsions, suspensions, ointments, creams, lotions, pastes, oils, gels, sprays and patches (e.g., but not limited to, transdermal therapeutic systems).
  • the pharmaceutical compositions can be prepared as e.g. liposome delivery systems, systems in which the compound of the invention is coupled to monoclonal antibodies and systems in which the compound of the invention is coupled to polymers (e.g., but not limited to, soluble or biodegradable polymers).
  • compositions comprising at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics
  • the compound of the invention and the therapeutic agent may be formulated together into the same dosage form (e.g., but not limited to, tablets), separately into the same dosage form (e.g., but not limited to, tablets), or into different dosage forms (without limitation e.g. the compound of the invention may be formulated as tablet and the therapeutic agent may be formulated as powder, solution or suspension).
  • compositions can be manufactured in a manner known to a person skilled in the art, e.g. by dissolving, mixing, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • the selected formulation depends inter alia on the route of administering the pharmaceutical composition.
  • the pharmaceutical compositions of the invention can be administered by any suitable route, for example, by the oral, sublingual, buccal, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, topical, transdermal, intranasal, intraocular, intraperitoneal, intrasternal, intracoronary, transurethral, rectal or vaginal route, by inhalation or by insufflation. Oral administra- tion is preferred.
  • compositions comprising at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants, antibiotics, anticoagulants, diuretics and digitalis glycosides
  • the compound of the invention and the therapeutic agent may be administered by the same route, e.g., without limitation, orally, or by different routes, e.g., without limitation, the compound of the invention can be administered orally and the therapeutic agent can be administered by inhalation or instillation.
  • Tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are e.g. suitable for oral administration.
  • said formulations can be adapted so as to represent, for example, an enteric form, an immediate release form, a delayed release form, a repeated dose release form, a prolonged release form or a sustained release form.
  • Said forms can be obtained, for example, by coating tablets, by dividing tablets into several compartments separated by layers disintegrating under different conditions (e.g. pH conditions) or by coupling the compound of the invention to a biodegradable polymer.
  • Administration by inhalation or instillation is preferably made by using an aerosol.
  • the aerosol is a liquid-gaseous dispersion, a solid-gaseous dispersion or a mixed liquid/solid-gaseous dispersion.
  • the aerosol may be generated by means of aerosol-producing devices such as dry powder inhal- ers (DPIs), pressurized metered dose inhalers (PMDIs) and nebulizers.
  • the aerosol-producing device can contain the compound and, optionally, the therapeutic agent in form of a powder, a solution or a dispersion.
  • the powder may contain, for example, one or more of the following auxiliaries: carriers, stabilizers and fillers.
  • the solution may contain in addition to the sol- vent, for example, one or more of the following auxiliaries: propellants, solubilizers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and flavorings.
  • the dispersion may contain in addition to the dispersant, for example, one or more of the following auxiliaries: propellants, surfactants, stabilizers, buffers, preservatives and flavorings.
  • carriers include, but are not limited to, saccharides, e.g. lactose and glucose.
  • propellants in- elude but are not limited to, fluorohydrocarbons, e.g. 1 ,1 ,1 ,2-tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
  • the particle size of the aerosol particles is preferably less than 100 ⁇ m, more preferably it is in the range of from 0.5 to 10 ⁇ m, in particular in the range of from 2 to 6 ⁇ m (D50 value, measured by laser diffraction).
  • Aerosol-producing devices which may be used for inhaled administration include, but are not limited to, Cyclohaler®, Diskhaler®, Rotadisk®, Turbohaler®, Autohaler®, Turbohaler®, No- volizer®, Easyhaler®, Aerolizer®, Jethaler®, Diskus®, Ultrahaler® and Mystic® inhalers.
  • the aerosol-producing devices may be combined with spacers or expanders, e.g. Aerochamber®, Nebulator®, Volumatic® and Rondo®, for improving inhalation efficiency.
  • suitable pharmaceutical formulations are, for example, ointments, creams, lotions, pastes, gels, powders, solutions, emulsions, suspensions, oils, sprays and patches (e.g., but not limited to, transdermal therapeutic systems).
  • parenteral modes of administration such as, for example, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, intraperitoneal and intrasternal administration
  • solutions e.g., but not limited to, sterile solutions, isotonic solutions
  • they are preferably administered by injection or infusion techniques.
  • intranasal administration for example, sprays and solutions to be applied in drop form are preferred formulations.
  • solutions to be applied in drop form gels and ointments are exemplified formulations.
  • the pharmaceutical compositions according to the invention can be administered such that the dose of the compound of the invention is in the range customary for type 5 phosphodiesterase inhibitors.
  • a dose in the range of from 0.01 to 4000 mg of the compound of the invention per day is preferred.
  • the dose is dependent, for example, on the specific compound used, the species treated, age, body weight, general health, sex and diet of the subject treated, mode and time of administration, rate of excretion, severity of the disease to be treated and drug combination.
  • composition of the invention comprises at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, anticoagulants, diuretics and digitalis glycosides,the same dose ranges apply to the therapeutic agent.
  • therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, anticoagulants, diuretics and digitalis glycosides,the same dose ranges apply to the therapeutic agent.
  • compositions according to the invention can be administered in a single dose per day or in multiple subdoses, for example, 2 to 4 doses per day.
  • a single dose unit of the pharmaceutical composition can contain e.g. from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1000 mg, most preferably 1 to 500 mg, of the compound of the invention.
  • a single dose unit of the pharmaceutical composition can contain e.g. from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1000 mg, most preferably 1 to 500 mg, of the therapeutic agent.
  • the pharmaceutical composition can be adapted to weekly, monthly or even more infrequent administration, for example by using an implant, e.g. a subcutaneous or intramuscular implant, by using the compound of the invention in form of a spar- ingly soluble salt or by using the compound of the invention coupled to a polymer. Administration of the pharmaceutical composition in a single dose per day is preferred.
  • composition of the invention comprises at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticos- teroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics
  • administration of the compound of the invention and administration of the therapeutic agent can be made simultaneously or sequentially.
  • sequential administration the compound of the invention can be administered before or after administration of the therapeutic agent.
  • platelets were used as a source for human PDE5.
  • 150 ml fresh blood from human donors anticoagulated with citrate [final concentration 0.3% (w/v)] was centrifuged at 200 g for 10 min to obtain the so-called platelet-rich-plasma (PRP) as a supernatant.
  • PRP platelet-rich-plasma
  • 1/10 volume of ACD solution 85 mM Na 3 -citrate, 1 11 mM D-glucose, 71 mM citric acid, pH 4.4 was added to 9/10 volume of PRP.
  • the cell pellet was resuspended in 3 ml homogenization buffer (NaCI 140 mM, KCI 3.8 mM, EGTA 1 mM, MgCI 2 1mM, Tris-HCI 20 mM, beta-mercaptoethanol 1 mM, pH 8.2) plus protease-inhibitor mix giving rise to the final concentrations of 0.5 mM Pefablock (Roche), 10 ⁇ M Leupeptin, 5 ⁇ M Trypsininhibitor, 2 mM Benzamidin and 10 ⁇ M Pepstatin A. The suspension was sonified and thereafter centrifuged for 15 min at 10,000 g. The resulting supernatant (platelet lysate) was used for enzymatic testings.
  • 3 ml homogenization buffer NaCI 140 mM, KCI 3.8 mM, EGTA 1 mM, MgCI 2 1mM, Tris-HCI 20 mM, beta-mercaptoethanol 1 mM,
  • PDE5A1 activity is inhibited by the compounds of the invention in a modified SPA (scintillation proximity assay) test, supplied by Amersham Biosciences (see procedural instructions "phosphodiesterase [3H]cAMP SPA enzyme assay, code TRKQ 7090"), carried out in 96-well microtitre plates (MTP's).
  • modified SPA sintillation proximity assay
  • the test volume is 100 ⁇ l and contains 20 mM Tris buffer (pH 7.4), 0.1 mg of BSA (bovine serum albumin)/ml, 5 mM Mg 2+ , 1 ⁇ M motapizone, 10 nM PDE2 inhibitor BAY-60-7550, 0.5 ⁇ M cGMP (including about 50,000 cpm of [3H]cGMP as a tracer), 1 ⁇ l of the respective compound dilution in dimethylsulfoxide (DMSO) and sufficient PDE5-containing platelet lysat (10,000xg supernatant, see above) to ensure that 10-20 wt% of the cGMP is converted under the said experimental conditions.
  • DMSO dimethylsulfoxide
  • the final concentration of DMSO in the assay does not substantially affect the activity of the PDE investigated.
  • the reaction was started by adding the substrate (cGMP) and the assay was incubated for a further 15 min; after that, it was stopped by adding SPA beads (50 ⁇ l).
  • the SPA beads had previously been resuspended in water, but were then diluted 1 :3 (v/v) in water; the diluted solution also contains 3 mM 8-methoxymethyl-3-isobutyl- 1-methylxanthine (IBMX) to ensure a complete PDE activity stop.
  • IBMX 3 mM 8-methoxymethyl-3-isobutyl- 1-methylxanthine
  • the MTP's are analyzed in commercially available luminescence detection devices.
  • the corresponding IC 50 values of the compounds for the inhibition of PDE activity are determined from the concentration-effect curves by means of non-linear regression.

Abstract

The present invention pertains to 5 -Benzyl-1, 2, 3, 6- tetrahydro-4, 6-diazacyclopenta [c] fluorene compounds and 5 -Benzyl-1, 2, 3, 6- tetrahydro-4, 6-diaza-cyclohepta [c] fluorene compounds of formula (I), as well as the resulting pharmaceutical compositions, and their use in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases. Furthermore, the present invention pertains to the methods of manufacturing these 5-Benzyl-1, 2, 3, 6- tetrahydro-4, 6-diaza-cyclopenta [c] fluorene compounds and 5-Benzyl-1, 2, 3, 6- tetrahydro-4, 6-diaza-cyclohepta [c] fluorene compounds.

Description

Description
5-Benzyl-1,2,3,6-tetrahydro-4,6-diaza-cyclopenta[c]fluorene compounds and 5-Benzyl- 1 ,2,3,6-tetrahydro-4,6-diaza-cyclohepta[c]fluorene compounds
Field of application of the invention
The invention relates to 5-Benzyl-1 ,2,3,6-tetrahydro-4,6-diaza-cyclopenta[c]fluorene compounds and δ-Benzyl-I ^S.Θ-tetrahydro^θ-diaza-cycloheptatclfluorene compounds, and their use, as well as the resulting pharmaceutical compositions and uses thereof in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases.
Background of the Invention
6-Benzyl-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one is described in Khimiya Get- erotsiklicheskikh Soedinenii (1985) 3, 363-6 without mentioning any pharmaceutical activity thereof. WO02/064590 and EP1953159 disclose nitrogen-containing heterocyclic PDE5 inhibiting compounds. WO2008027182 discloses indoloquinoline compounds as calcium channel blockers.
It is an object of the present invention to provide novel compounds and pharmaceutical compositions which may be used in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases.
A further object of the present invention is to provide a method of manufacture of the compounds and compositions of the present invention.
It is a further object of the present invention to provide a method for treating diseases alleviated by inhibition of type 5 phosphodiesterases in a subject in need thereof.
Description of the invention
It has now been found that the δ-Benzyl-I ^S.Θ-tetrahydro^θ-diaza-cyclopentatclfluorene compounds and δ-Benzyl-I ^S.Θ-tetrahydro^θ-diaza-cycloheptatclfluorene compounds, which are described in detail below, have surprising and advantageous properties, and making them especially useful in the treatment and prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases.
The compounds of the present invention are characterized by Formula (I) as specified in the following. The invention thus relates to compounds of Formula (I)
Figure imgf000003_0001
wherein n and m are each independently selected from 0, 1 , 2 or 3, with the proviso that n + m is 1 or 3,
wherein
RA01 ancj RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-|.β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA03RA04. or
RA01 ancj RA02 combine to form an oxo-group;
RA03 ancj RA04 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C(O)H and C(O)-C1.6-alkyl, wherein the C(O)-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA21 and R^22 are each independently selected from the group consisting of hydrogen and C1. β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy, nitro and amino;
RB51 JS selected from the group consisting of hydrogen, halogen, C1.β-alkyl, hydroxy, C1.3- alkoxy, nitro, amino, -NH-C(O)-C1.2-alkyl, -NH-C(0)-NH2 and a methoxy group substituted by 2 or 3 fluorine atoms; or RB41 and RB51 combine to form a group selected from -0-CH2-O-, -0-CH2-CH2- and -CH2-CH2-O-;
RB61 JS selected from the group consisting of hydrogen and halogen;
RB^1 JS selected from the group consisting of hydrogen and halogen;
RB81 JS selected from the group consisting of hydrogen and halogen;
a salt thereof, an N-oxide of the compound or the salt thereof or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
Special embodiments of the present application are described in the following.
According to one embodiment of the present invention, R^01 and R^02 are each independently selected from the group consisting of hydrogen, hydroxy and NRA03RA04 or
RA01 ancj RA02 combine to form an oxo-group, wherein RA03 ancj RA04 nave ^16 Same meaning as defined above, or preferably below According to another embodiment of the present invention, one of the substituents R^01 and R^02 is hydrogen and the other substituent is hydroxy or NRA03RA04 wherein RA03 ancj RA04 have the same meaning as defined above, or preferably below.
According to another embodiment of the present invention, RA03 ancj RA04 are eacn independently selected from the group consisting of hydrogen, C(O)H and C(O)-Ci _6-alkyl, wherein the C(O)-C-] .β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy.
According to yet another embodiment of the present invention, one of the substituents R^01 and RA02 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the substituents RA01 and R^02 t^iincd has the S-configu ration.
According to another embodiment of the present invention, R^21 anc| RA22 ^O^ are hydrogen.
According to another embodiment of the present invention, RB^1 js selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy.
Acccording to another embodiment of the present invention, RB^1 is selected from the group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C-j.β-alkoxy, nitro, amino and a methoxy group substituted by 2 or 3 fluorine atoms, or
RB41 and RB51 combine to form a group selected from -O-CH2-O-, -O-CH2-CH2- and
-CH2-CH2-O-.
According to another embodiment of the present invention, RB^1 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms.
According to another embodiment of the present invention n is 0 and m is 3.
According to another embodiment of the present invention n is 1 and m is 2.
According to another embodiment of the present invention n is 2 and m is 1.
According to another embodiment of the present invention n is 3 and m is 0. According to yet another embodiment of the present invention n is 0 and m is 1.
According to yet another embodiment of the present invention n is 1 and m is 0.
According to another embodiment of the present invention, n + m is 1 and R^01 and R^02 are each independently selected from the group consisting of hydrogen, hydroxy, and NRA03RA04 or RA01 ancj RA02 combine to form an oxo-group, and
RA21 and R^22 both are hydrogen, wherein RA03 ancj RA04 have the same meaning as defined above.
According to another embodiment of the present invention, n + m is 1 and R^01 is hydroxy or NRA03RA04 and RA02 is hydrogen, and RA21 and R^22 both are hydrogen, wherein RA03 and RA04 nave t|ηe same meaning as defined above.
According to yet another embodiment of the present invention, one of the substituents R^OI anc| RA02 js hydrogen and the other substituent is hydroxy.
According to yet another embodiment of the present invention, R^41 js selected from the group consisting of hydrogen and halogen.
According to yet another embodiment of the present invention, R^51 is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy.
According to another embodiment of the present invention, R^71 js hydrogen.
According to another embodiment of the present invention, R^^1 js hydrogen.
According to yet another embodiment of the present invention, n + m is 1 and R^OI and R^02 are each independently selected from the group consisting of hydrogen and hydroxy, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and RA22 both are hydrogen.
According to yet another embodiment of the present invention, n + m is 1 and R^OI js hydroxy and RA02 JS hydrogen, and R^21 anc| RA22 both are hydrogen. According to yet another embodiment of the present invention, the compounds of Formula (I) are selected from the group consisting of
5-Benzyl-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one; 5-(4-Methoxybenzyl)-3,6- dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one; 5-(3-Fluoro-4-methoxy-benzyl)-3,6-dihydro-2H- 4,6-diaza-cyclopenta[c]fluoren-1-one; 5-(3,5-Difluoro-4-methoxy-benzyl)-3,6-dihydro-2H-4,6-diaza- cyclopenta[c]fluoren-1-one; 5-(3-Fluoro-4-methoxy-benzyl)-1 ,2,3,6-tetrahydro-4,6-diaza- cyclopenta[c]fluorine; Benzyl-1 ,2,3,6-tetrahydrocyclopenta[5,6]pyrido[3,4-b]indol-1-ol; 5-(4- methoxybenzyl)-1 ,2,3,6-tetrahydrocyclopenta[5,6]pyrido[3,4-b]indol-1-ol; 5-(3-Fluoro-4-methoxy- benzyO-I ^.S.Θ-tetrahydro^.θ-diaza-cyclopentatclfluoren-i-ol; (S)-5-(3-Fluoro-4-methoxy-benzyl)- 1 ^Λθ-tetrahydro^θ-diaza-cyclopentatclfluoren-i-ol; 5-(4-Methoxybenzyl)-3,6- dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one 4-oxide; 5-(4-Methoxybenzyl)-1 ,2,3,6- tetrahydrocyclopenta[5,6]pyrido[3,4-b]indol-1-ol 4-oxide;
Wherever two substituents in the present invention bind to the same atom and the list of meanings of these substituents includes hydrogen, one of the substituents may be hydrogen and the other may have a meaning as defined.
It is to be understood that the invention covers all combinations of substituent groups referred to hereinabove. In particular, the invention covers all combinations of preferred groups described herein.
The term "halogen" used in the specification of the present application means a fluorine atom, a chlorine atom and a bromine atom, wherein a fluorine atom is preferred.
The term "C-\_Q-a\ky\" used in the specification of the present application indicates linear or branched alkyl groups having 1 to 6 carbon atoms. Among these, linear or branched alkyl groups having 1 to 4 carbon atoms (C-|_4-alkyl) are preferred, linear or branched alkyl groups having 1 to 3 carbon atoms (C-j.β-alkyl) are more preferred and alkyl groups having 1 to 2 carbon atoms (C-] .2- alkyl) are still more preferred. Examples of the above-defined alkyl groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec- butyl group, a tert-butyl group, a n-pentyl group, a 1 ,1-dimethylpropyl group, a 1 ,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-ethylpropyl group, a 1-methyl-2- ethylpropyl group, a 1-ethyl-2-methylpropyl group, a 1 ,1 ,2-trimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1-ethylbutyl group, a 1 ,1-dimethylbutyl group, a 1 ,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1 ,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 2- ethylbutyl group or a n-hexyl group. More preferred examples of the alkyl groups having 1 to 6 carbon atoms are a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group and a sec-butyl group, and still more preferred examples are a methyl group, an ethyl group, a n-propyl group, an isopropyl group and an isobutyl group, wherein a methyl group is particularly preferred.
The term "Ci_3-alkoxy" used in the specification of the present invention indicates alkoxy groups having 1 to 3 carbon atoms. Examples of the C-j.β-alkoxy group include a methoxy group, an eth- oxy group, an n-propoxy group, an isopropoxy group, wherein a methoxy group and a ethoxy group are more preferred, and a methoxy group is most preferable.
The above-mentioned C-|.g-alkyl group may be substituted with one or more substituents selected from the group consisting of fluoro and hydroxy.
In case the C-|.g-alkyl group is substituted by at least one fluorine atom, the C-|.g-alkyl group can be any group as specified above with respect to the C-j.g-alkyl, unless specified otherwise. The C-j.g-alkyl substituted by at least one fluorine atom is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C-j.g-alkyl, wherein the mono-, tri- and perfluoro substituted C-j.g-alkyl groups are more preferred. Still more preferred are mono- and perfluoro substituted C-|.g-alkyl groups. Examples of these still more preferred mono- and perfluoro substituted C-|.g-alkyl groups are fluoromethyl, 1-fluoroethyl, 2-fluoroyethyl, 1-fluoro-isopropyl, 1-fluoro-n-propyl, 2-fluoro-isopropyl, 2-fluoro-n-propyl, 3-fluoro-n-propyl, trifluoromethyl, pentafluoroethyl, perfluoroisopropyl, perfluoro- n-propyl and perfluoroisobutyl.
In case the C-|.g-alkyl is substituted by at least one hydroxy, the C-|.g-alkyl group can be any group as specified above with respect to the C-|.g-alkyl, unless specified otherwise. The C-|.g-alkyl substituted by at least one hydroxy is preferably a C-|.g-alkyl group which is substituted by one or two hydroxy groups, more preferably a C-j.β-alkyl group which is substituted with one or two hydroxy groups, preferably one hydroxy group. Examples of such C-j.β-alkyl groups substituted with at least one hydroxy group includes hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-isopropyl, 2- hydroxy-isopropyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl and 3-hydroxy-n-propyl, wherein a hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-isopropyl and 2-hydroxy-n-propyl are still more preferred, and hydroxymethyl is particularly preferred.
The above-mentioned C-|.g-alkoxy group may be substituted with one or more substituents selected from the group consisting of fluoro and hydroxy.
In case the C-j.β-alkoxy group is substituted by at least one fluorine atom, the C-j.β-alkoxy group can be any group as specified above with respect to C-j.β-alkoxy, unless specified otherwise. It is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C-j.β-alkoxy, wherein the mono-, tri- and perfluoro substituted C-j.β-alkoxy groups are more preferred. More preferred are mono- and perfluoro substituted C-j.β-alkoxy groups. Examples of these more preferred mono- and perfluoro substituted C-j.β-alkoxy groups are fluoromethoxy, 1-fluoroethoxy, 2-fluoroyethoxy, 1-fluoro- isopropoxy, 1-fluoro-n-propoxy, 2-fluoro-isopropoxy, 2-fluoro-n-propoxy, 3-fluoro-n-propoxy, trifluoromethoxy, pentafluoroethoxy, perfluoroisopropoxy and perfluoro-n-propoxy.
In case the C-j.β-alkoxy group is substituted by at least one hydroxy, the C-j.β-alkoxy group can be any group as specified above with respect to C-j.β-alkoxy, unless specified otherwise. It is prefera- bly a C-j.β-alkoxy group which is substituted by one or two hydroxy groups, preferably one hydroxy group. Examples of such C-j.β- alkoxy groups substituted with at least one hydroxy group include hydroxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxy-isopropoxy, 2-hydroxy-isopropoxy, 1-hydroxy-n-propoxy, 2-hydroxy-n-propoxy and 3-hydroxy-n-propoxy, wherein a hydroxymethoxy, 2-hydroxyethoxy, 2-hydroxy-isopropoxy and 2-hydroxy-n-propoxy are still more preferred, and hy- droxymethoxy is particularly preferred.
It is to be understood that the invention covers all tautomers of the compounds of formula (I), a salt thereof, an N-oxide of the tautomeric compound or the salt thereof, a stereoisomer of the tautomeric compound, the salt, the N-oxide of the stereoisomer of the tautomeric compound or the N-oxide of the salt thereof.
It is to be understood that the invention covers all combinations of substituent groups referred to hereinabove. In particular, the invention covers all combinations of preferred groups described herein.
Salts of the compounds according to the invention, the N-oxides thereof, the stereoisomers of the salts and the N-oxides thereof include all inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, particularly all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.
Examples of acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates, trifluoroacetates, citrates, gluconates including D- gluconates and L-gluconates, glucuronates including D-glucuronates and L-glucuronates, benzo- ates, 2-(4-hydroxybenzoyl)benzoates, butyrates, salicylates, subsalicylates, maleates, laurates, malates including L-malates and D-malates, lactates including L-lactates and D-lactates, fu- marates, succinates, oxalates, tartarates including L-tartarates, D-tartarates and meso-tartarates, stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates), methanesulfonates (mesi- lates), laurylsulfonates, 3-hydroxy-2-naphthoates, lactobionates (salts of 4-O-beta-D- galactopyranosyl-D-gluconic acid), galactarates, embonates and ascorbates.
Examples of salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine and guanidinium salts.
The salts include water-insoluble and, particularly, water-soluble salts.
The compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof and the stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are, therefore, all solvates of the compounds of formula (I), the salts thereof, the N-oxides of the compounds and the salts thereof and the stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof. Hydrates are a preferred example of said solvates.
The N-oxides of the compounds according to the invention, the salts thereof, the stereoisomers of the compounds and the salts thereof include compounds, wherein the nitrogen atom of the pyridine moiety is oxidized, as illustrated by formula (Ia) below:
Figure imgf000010_0001
The compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof include stereoisomers. In case RA01 being a hydroxy group, RA02 being hydrogen and RA21 and RA22 representing identical groups, the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof have one stereogenic center. In case RA01 and RA02 being hydrogen or RA01 and RA02 combining to form an oxo group and RA21 and RA22 representing different groups, the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof have one stereogenic center. In case RA01 being a hydroxy group, RA02 being hydrogen and RA21 and RA22 representing different groups, the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof have two stereogenic centers. Each of said stereogenic centers may have the absolute configuration R or the absolute configuration S (according to the rules of Cahn, lngold and Prelog). Accordingly, the stereoisomers (1 R), (1S), (3R), (3S), (1 R,3R), (1 R,3S), (1S,3R) and (1S,3S), wherein the numbers refer to the atoms indicated in formula (Ib) below,
Figure imgf000011_0001
(Ib) the salts thereof, the N-oxides of the stereoisomers and the salts thereof are part of the invention.
In a preferred embodiment, the invention relates to stereoisomers of formula (Ib) having the configuration (1 R) or (1 S), with the carbon atom at position number 3 not being an asymmetric carbon atom.
The invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates. Some of the compounds, salts thereof, N-oxides of the compounds and the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof according to the invention may exist in different crystalline forms (polymorphs), which are within the scope of the invention.
Furthermore, derivatives of the compounds of formula (I), the salts thereof, the N-oxides of the compounds or the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds or N-oxides of the salts thereof which are converted into compound (I) or a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N- oxide of the compound or the N-oxide of the salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention. Said biological system is e.g. a mammalian organism, particularly a human subject. The bioprecursor is, for example, converted into the compound of formula (I), a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof by metabolic processes.
The compounds according to the invention can be prepared as follows.
As shown in reaction scheme 1 , a compound of formula (I) can be obtained by reacting a com- pound of formula (II) or (Na) or (lib) or a mixture thereof with ammonia in an appropriate solvent, e.g. acetonitrile or methanol, preferably under microwave heating. The compound of formula (II) or (Na) or (lib) or a mixture thereof can be prepared by cyclization of a compound of formula (IV) with a compound of formula (III) in the presence of a strong inorganic acid, e.g. perchloric acid, in a suitable solvent, e.g. nitromethane.
Compounds of formula (III) are commercially available or can be obtained according to procedures known in the art.
Reaction scheme 1 :
Figure imgf000013_0001
Figure imgf000013_0003
Figure imgf000013_0002
In an alternative procedure, as illustrated in reaction scheme 2, a compound of formula (IV) can be reacted with a compound of formula (V), in which X is a suitable leaving group, e.g. halogen, such as chlorine or bromine, or a conjugate base of an acid, such as trifluoroacetate, acetate, methylsul- fonate, in a Friedel-Crafts acylation reaction in the presence of an appropriate Lewis acid, e.g. zinc chloride, boron trifluoride etherate or orthophosphoric acid, in a suitable aprotic solvent, e.g. di- chloromethane, 1 ,2-dichloroethane, diethylether, toluene, nitromethane and/or chlorobenzene, preferably 1 ,2-dichloroethane or dichloromethane and/or nitromethane, to give the corresponding compound of formula (II) or (Na) or (lib) or a mixture thereof. Said Friedel-Crafts acylation reaction can be based on, for example, work of Duval et al. [see e.g. Tetrahedron Letters 45, 5411-5413 (2004)]. The compound of formula (II) or (Ma) or (Mb) or a mixture thereof can be subjected to a cyclization condensation reaction with ammonium acetate in an appropriate solvent, e.g. acetic acid, preferably at elevated temperature, more preferably at 70-1000C, and / or a cyclization condensation reaction with ammonia in an appropriate solvent, e.g. methanol, preferably at elevated temperature, more preferably at 70-1000C, to give a corresponding compound of formula (I). Both the Friedel-Crafts acylation reaction and the cyclization condensation reaction can be performed in one pot.
Compounds of formula (V) are commercially available or can be obtained according to procedures known in the art. Reaction scheme 2:
Figure imgf000014_0001
As shown in reaction scheme 3, a compound of formula (IVa) or (IVb) or (IVc) or a mixture thereof are obtainable via an aldol-type condensation of a compound of formula (Vl), in which PG stands for a suitable temporary protecting group, e.g. acetyl, formyl, allyl or methoxycarbonyl, with a compound of formula (VII), and subsequent removal of PG. The compound of formula (IVa) or (IVb) or (IVc) or a mixture thereof can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Ic).
Reaction scheme 3:
Figure imgf000014_0002
(Ic) Compounds of formulae (Vl) and (VII) are commercially available or can be obtained according to procedures known in the art.
Furthermore, a compound of formula (Id), in which RA01 and RA02 are hydrogen, can be obtained as shown in reaction scheme 4. In particular, indole (IX) can be reacted with a compound of formula (X) in an art-known nucleophilic substitution reaction [see e.g. Heterocycles 31 (8), 1497-1504 (1990)]. The thus obtained hydroxy-com pound can be oxidized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroacetic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (VIII). The compound of formula (VIII) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id).
Reaction scheme 4:
Figure imgf000015_0001
(IX) (X) (VIII) (Id)
Indole (IX) is commercially available, the compounds of formula (X) are known, commercially available or can be obtained according to known procedures.
Alternatively, a compound of formula (Id), in which RA01 and RA02 are hydrogen, can be obtained as illustrated in reaction scheme 5. In a first step, indole (IX) is reacted with a compound of formula (Xl) in an art-known oxidative coupling reaction [see e.g. JACS 129, 12857 (2007)], in the presence of a suitable base, e.g. lithium diisopropylamide or lithium hexamethyldisilazide, and a suitable oxidation agent, e.g. copper-(ll)2-ethylhexanoate. The thus obtained compound of formula (VIII) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id).
Reaction scheme 5:
Figure imgf000016_0001
(IX) (Xl) (VIII) (Id)
Indole (IX) is commercially available, the compounds of formula (Xl) are known, commercially available or can be obtained according to known procedures.
Moreover, a compound of formula (Id) can be obtained as illustrated in reaction scheme 6. In a first step, indole (IX) is reacted with a compound of formula (XII) in an art-known condensation reaction in the presence of a base, e.g. pyrrolidine or potassium hydroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 17, 3099 (2007)]. The thus obtained unsaturated compound of formula (XIII) can be hydroxylated in a hydroboration - oxidation reaction known to the person skilled in the art, e.g. by using borane and sodium hydroxide / hydrogen peroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 16, 3524 (2006)]. The resulting hydroxy-compound (XIV) can be oxidized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroacetic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (VIII). The compound of formula (VIII) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id).
Reaction scheme 6:
Figure imgf000016_0002
(IX) (XII) (XIII) (XIV)
Figure imgf000016_0003
(VIII)
Figure imgf000016_0004
Indole is commercially available, compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
As an alternative approach, a compound of formula (Id) can be obtained as illustrated in reaction scheme 7. In a first step, isatine (XV) is reacted with a compound of formula (Xl) in an art-known aldol addition reaction [see e.g. Tetrahedron 58, 8399 (2002)]. The thus obtained hydroxy compound of formula (XVI) can be transformed into a compound of formula (XIV) by using reductive agents, such as, for example, borane tetrahydrofuran complex or lithium aluminium hydride [see e.g. Tetrahedron 58, 8399 (2002)]. The resulting hydroxy-com pound of formula (XIV) can be oxi- dized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroacetic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (VIII). The compound of formula (VIII) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id).
Reaction scheme 7:
Figure imgf000017_0001
(XV) (Xl) (XVI) (XIV)
Figure imgf000017_0002
(VIII) (Id)
Isatine (XV) is commercially available, compounds of formula (Xl) are known, commercially available or can be obtained according to known procedures.
An alternative synthetic route to a compound of formula (Ic) is depicted in reaction scheme 8. Compounds of formulae (XVII), (XVIII) and (XIX), with X being a leaving group, such as halogen, pref- erably bromine or chlorine, can be reacted in a multi-component unsymmetric Hantzsch reaction in the presence of catalytic amounts of acid, e.g. acetic acid, and amine, e.g. benzylamine [see e.g. Tetrahedron Letters 42, 4507 (2001 ) or Tetrahedron 63, 1946 (2007)]. The resulting nitro- dihydropyridine of formula (XX) can be converted to amino-pyridine of formula (XXI) either in two steps (oxidation of dihydropyridine and reduction of nitro group) or, preferably, in one step by using, e.g., elementary iron in the presence of concentrated hydrochloric acid or elementary zinc in the presence of acetic acid. The final ring closing reaction to obtain compounds of formula (I) can be achieved by reacting compounds of formula (XXI) under nitrogen atmosphere with catalytic amounts of a suitable palladium source, e.g. tris(dibenzylideneacetone)dipalladium (0) or tetrakis(triphenylphosphine)palladium (0), and, if necessary, of a suitable phosphine ligand, in the presence of a suitable base, e.g. sodium tert-butoxide or sodium carbonate [see e.g. Bioorganic & Medicinal Chemistry Letters 17, 1043 (2007)].
Reaction scheme 8:
Figure imgf000018_0001
(XVIl) (XVIII) (XIX) (XX)
Figure imgf000018_0002
(XXI) (Ic)
Compounds of formulae (XVII), (XVIII) and (XIX) are known, commercially available or can be ob- tained according to known procedures.
As an example, a compound of formula (XIX) can be obtained, as shown in reaction scheme 9, by reacting the corresponding acid of formula (XXII) with carbonyl diimidazole in the presence of ni- tromethane and a suitable base, e.g. potassium tertbutylate [see e.g. J. Am. Chem. Soc. 125, 157 (2003)].
Reaction scheme 9:
Figure imgf000019_0001
Compounds of formula (XXII) are known, commercially available or can be obtained according to known procedures.
Compounds of formula (I) can be converted into different compounds of formula (I) by methods known in the art. For example,
• a compound of formula (I), wherein RA01 is hydroxy and RA02 is hydrogen, can be prepared from a compound of formula (I), wherein RA01 and RA02 combine to form an oxo group, by reduction reaction, e.g. with the aid of a suitable reduction agent, such as sodium borohydride;
• a compound of formula (I), wherein RA01 and RA02 are hydrogen, can be prepared from a compound of formula (I), wherein RA01 and RA02 combine to form an oxo group, by reduction reaction, e.g. with the aid of a suitable reduction agent, such as hydrazine (e.g. according to a Wolff-Kishner reduction); • a compound of formula (I), wherein RA01 is amino and RA02 is hydrogen can be prepared from a compound of formula (I), wherein the RA01 and RA02 combine to form an oxo group, by reductive amidation reaction, e.g. with the aid of a suitable amide, e.g. formamide, in combination with a suitable reduction agent, such as formic acid or ammonium formiate in a suitable solvent, e.g. formic acid, at elevated temperatures, preferably 14O0C - 18O0C, followed by amide hydrolysis reaction, e.g. with the aid of a strong acid, such as hydrogen chloride, in a suitable solvent, such as methanol;
• a compound of formula (I), wherein RA01 is amino and RA02 is hydrogen can be prepared from a compound of formula (I), wherein the RA01 and RA02 combine to form an oxo group, by reductive amination reaction, e.g. with the aid of a suitable amine, e.g. benzylamine, in combination with a suitable reduction agent, such as sodium cyanoborohydride or sodium borohydride, in the presence of a suitable acid, e.g. acetic acid or p-toluenesulfonic acid, or a suitable Lewis acid, e.g. titanium(IV) tetraisopropyl oxide, in a suitable solvent, e.g. methanol, followed by hydrogenation, e.g. with the aid of a transition metal catalyst, such as palladium(O), in combination with a suitable hydrogen source, e.g. hydrogen gas or ammonium formiate, in a suitable solvent, such as methanol;
• a compound of formula (I), wherein RA01 is mono- or di-Ci_6-alkylamino, and RA02 is hydrogen can be prepared from a compound of formula (I), wherein the RA01 and RA02 combine to form an oxo group, by reductive amination reaction, e.g. with the aid of a suitable amine, e.g. methylamine or diethylamine, in combination with a suitable reduction agent, such as sodium cyanoborohydride or sodium borohydride, in the presence of a suitable acid, e.g. acetic acid or p-toluenesulfonic acid, or a suitable Lewis acid, e.g. titanium(IV) tetraisopropyl oxide, in a suitable solvent, e.g. methanol;
• a compound of formula (I), wherein RA01 is carbonylamino-, e.g. -NH-C(O)-C-|.6-alkyl, wherein said C-ι-6-alkyl may be substituted as defined above, and RA02 is hydrogen, can be prepared e.g. from a compound of formula (I), wherein RA01 is amino and RA02 is hydrogen, by reaction with an appropriate carboxylic acid chloride, e.g. Ci_6-alkylC(O)CI, wherein said Ci_6-alkyl may be substituted as defined above, or carboxylic anhydride, e.g. (Ci.6-alkyl-C(O))2O, wherein said C-ι-6-alkyl may be substituted as defined above, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid, e.g. Ci.6-alkylC(O)OH, wherein said C-|.6-alkyl may be substituted as defined above, in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, a suitable base, e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1-hydroxybenzotriazole;
• a compound of formula (I), wherein RB41 and/or RB51 represent(s) a nitro group can be converted into the corresponding amino compound by reduction reaction, e.g. with the aid of a suitable reduction agent, such as tin dichloride or hydrogen gas and a palladium on carbon catalyst;
• a compound of formula (I), wherein RB51 represents a group -NH-C(O)-I -2C-alkyl can be prepared e.g. from a compound of formula (I), wherein RB51 represents an amino group by reaction with an appropriate carboxylic acid chloride or carboxylic anhydride, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide;
• a compound of formula (I), wherein RB51 represents -NH-C(O)-NH2 can be obtained e.g. from a compound of formula (I), wherein RB51 represents an amino group by reaction with potassium cyanate in the presence of a mineral acid, such as hydrochloric acid, or by condensation with urea;
• a compound of formula (I), wherein RB51 is hydroxy can be synthesized e.g. from a compound of formula (I), wherein RB51 is 1-3C-alkoxy by dealkylation with a Lewis acid, such as boron tribromide.
It is known to the person skilled in the art that, if there are a number of reactive centers on a starting or intermediate compound, it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center.
Starting materials or building blocks, that are necessary for the synthesis of compounds according to the invention are either commercially available, or are prior art, or can be synthesized by a person skilled in the art, or are described within this document as an example or as a general methodology. The compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material, e.g. silica gel, reversed phase silica gel, amino modified silica gel, aluminium oxide.
Salts of the compounds of formula (I), the N-oxides thereof and the stereoisomers of the compounds and the N-oxides thereof according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or me- thylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxan, a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol, a low molecular weight aliphatic ester such as ethyl acetate or isopropyl acetate, or water) which contains the desired acid or base, or to which the desired acid or base is then added. Examples for acids include hydrochloric acid, hydrobromic acid, p-tolylsulfonic acid, methylsulfonic acid, trifluoromethylsulfonic acid, succinic acid, malic acid, citric acid, maleic acid, formic acid, acetic acid or pyroglutamic acid. Examples for bases include metal hydrides, such as sodium hydride or calcium hydride, metal hydroxides, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide, or amines, e.g. am- monia, trimethylamine or methylamine. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.
The compounds of formula (I), the salts thereof and the stereoisomers of the compounds and the salts according to the invention can be converted into their N-oxides, for example, by reaction with peracids, such as m-chloroperbenzoic acid or peracetic acid. The person skilled in the art is familiar with the reaction conditions for carrying out the N-oxidation.
Pure diastereomers and pure enantiomers of the compounds of formula (I), the salts thereof, the N- oxides of the compounds and the N-oxides of the salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and/or by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis. Preferably, the pure diastereo- meric and pure enantiomeric compounds of the invention are obtainable by asymmetric synthesis and/or by using chiral starting compounds in synthesis. In particular, for example the (IS)-enantiomers of the compounds of formula (I), the salts thereof, the N-oxides of the compounds and the salts thereof according to the invention can be obtained by reduction of the corresponding ketone precursors (wherein RA01 and RA02 combine to form an oxo group) with sodium borohydride in the presence of (4S,5S)-2-(3-nitro-phenyl)-[1 ,3,2]dioxaborolane- 4,5-dicarboxylic acid in a suitable aprotic solvent, preferably tetrahydrofuran or dioxan, preferably at room temperature. (4S,5S)-2-(3-Nitro-phenyl)-[1 ,3,2]dioxaborolane-4,5-dicarboxylic acid can be prepared by esterification of 3-nitrophenyl boronic acid and D-tartaric acid in the presence of a dehydrating agent such as calcium hydride, preferably at temperatures of 60-800C. Likewise, for example the (1 R)-enantiomers of the compounds of formula (I), the salts thereof, the N-oxides of the compounds and the salts thereof according to the invention can be obtained using (4R,5R)-2- (3-nitro-phenyl)-[1 ,3,2]dioxaborolane-4,5-dicarboxylic acid in a suitable aprotic solvent, preferably tetrahydrofuran or dioxan, preferably at room temperature. (4R,5R)-2-(3-Nitro-phenyl)- [1 ,3,2]dioxaborolane-4,5-dicarboxylic acid can be prepared by esterification of 3-nitrophenyl bo- ronic acid and L-tartaric acid in the presence of a dehydrating agent such as calcium hydride, preferably at temperatures of 60-800C.
Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure di- astereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent. As chiral auxiliary agents, for example, chiral acids, such as (+)- or (-)-tartaric acid, (+)- or (-)-malic acid, (+)- or (-)- mandelic acid, (+)- or (-)-lactic acid or (+)- or (-)-camphersulfonic acid, can be used to separate enantiomeric bases and chiral bases, such as (+)- or (-)-brucine, (+)- or (-)-quinidine or (+)- or (-)- quinine, can be used to separate enantiomeric acids via formation of diastereomeric salts. Furthermore, diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids, such as (+)- or (-)-lactic acid or (+)- or (-)-mandelic acid, or chiral alcohols, such as (+)- or (-)-1- phenylethanol, respectively, as chiral auxiliary agents. Additionally, diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures. Alternatively, enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.
As will be appreciated by persons skilled in the art, the invention is not limited to the particular embodiments described herein, but covers all modifications of said embodiments that are within the spirit and scope of the invention as defined by the appended claims. All patents, patent applications, publications, test methods and other materials cited herein are incorporated by reference in their entireties.
The following examples illustrate the invention in greater detail, without restricting it. Further com- pounds according to the invention, of which the preparation is not explicitly described, can be prepared in an analogous way.
The compounds which are mentioned in the examples, the salts thereof, N-oxides of the compounds and the salts thereof and stereoisomers of the compounds, salts, N-oxides of the com- pounds and N-oxides of the salts thereof represent preferred embodiments of the invention.
Examples
1H nmr spectra are recorded on a Bruker DPX200 (1H 200 MHz), a Bruker Avance (1H 300 MHz) or a Bruker AV400 (1H 400 MHz) spectrometer. Spectra are calibrated on tetramethylsilane (TMS) as internal standard (0.00 ppm for 1H). Chemical shifts are given in ppm (δ) relative to TMS, multiplicities are indicated by s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), m (multi- plet) and b (broadened). Coupling constants, J, are reported in Hz. Data are reported in the form δ = chemical shift (multiplicity, (coupling constant(s) if appropriate), integral in fold of 1 H). Mass spectra are recorded on a LCQ classic or an LCQ advantage ion trap mass spectrometer from Thermofinnigan, using combined liquid chromatography / mass spectroscopy methodology. Samples are dissolved in acetonitrile and chromatographed on a Survey HPLC from Thermofinni- gan, using a reversed phase column (Merck LiChroCART 75-4, 60 RP-B) as stationary phase and a gradient of aqueous buffer (20 mM ammoniumacetate / formic acid, pH 4) and methanol as mobile phase at a flow of 0.8 ml/min, and ionized by electrospray ionization (ESI), positive mode. Data are reported in the form MS (ionized particle found) = m/z. In that context, the molecule is abbreviated by M. For compounds containing bromine, both isotopic forms are reported, for compounds containing chlorine and all other elements, only the major isotopes are reported.
Melting points, mp., are measured on a Bϋchi B-540 or a Bϋchi B-541 instrument and are uncor- rected.
The following abbreviations are used: min: minutes, h: hour(s), DCM: dichloromethane, DCE: di- chloroethane, THF: tetrahydrofuran, mp.: melting point, RT: room temperature (20 to 250C), tic: thin layer chromatography, MS: mass spectrometry, 1H-NMR: 1H nuclear magnetic resonance spectroscopy.
Reactions are performed in dry (water free) solvents and under air atmosphere unless otherwise noted. Glassware is heated to 15O0C in a vacuum of 10~1 mbar for 5 min prior to use, unless otherwise noted. Furthermore, reactions and single processes, such as dissolutions, additions, filtering, extractions or chromatography, are performed at room temperature and under air atmosphere unless otherwise noted.
Reactions using microwave radiation are performed using Biotage Initiator Sixty (0 - 300 W) and Biotage Emry's Optimizer (0 - 300 W) instruments. The temperatures and times indicated for these reactions refer to the input data using the user interface of these instruments. The reaction mixtures are stirred in closed (sealed) reaction vials for the indicated time at the indicated internal temperature, the microwave radiation power is controlled by the internal temperature. Heating and cooling phase are not considered. Purchased chemicals and solvents are used without further purification. Column chromatography is performed using silica gel 60 (0.040 - 0.063 mm), pH 6.5 - 7.5, from Merck KGaA or amino modified silica gel Bulk Isolute® Sorbent Flash NH2 60 (0.040 - 0.070 mm) from International Sorbent Technology Ltd. If pressure (max. 0.3 bar) is applied to increase the flow of the mobile phase the chromatography is referred to as flash chromatography. Preparative HPLC purification is performed on a customary instrument from Gilson using a re- versed phase column (C18, Phenomenex, Gemini, 75x30 mm, 5μm) as stationary phase and an acetonitrile / water gradient as mobile phase at a flow of 40 ml/min.
Starting Compounds
A1. 2-(1 H-lndol-3-yl)-cyclopentane-1 ,3-dione
Step 1 : 2-(1-Acetyl-1 H-indol-S-yO-S-hydroxycyclopent^-enone. 1-Acetyl-1 ,2-dihydro-indol-3-one (7.0 g) is suspended in acetic acid (80 ml) and 1 ,3-cyclopentane-dione (3.92 g) is added. The reaction mixture is stirred for 20 min and triethylamine (5.56 ml) is added. The mixture is partitioned into 4 microwave vials and each portion is heated for 2 h at 1850C in the microwave. The reaction mixtures are recombined and concentrated in vacuo. The residue is treated with 2M methanolic hydrochloride solution (20 ml) and further methanol (5 ml) is added, until complete dissolution occurred. The solution is again concentrated in vacuo and the crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate). The product is crystallized from ether / ethyl acetate 9:1 (v/v) to give 6.8 g (66%) of 2-(1-acetyl-1/-/-indol-3-yl)-3-hydroxycyclopent-2-enone.
1H-NMR (200 MHz, CDCI3); δ = 2.31 (s, 3H), 2.55-2.82 (m, 5H), 7.19-7.59 (m, 4H), 8.43 (d, J = 7.5 Hz, 1 H).
Step 2: 2-(1 H-lndol-3-yl)-cyclopentane-1 ,3-dione. 2-(1-Acetyl-1 H-indol-3-yl)-3-hydroxycyclopent-2- enone (4.17 g) is dissolved in aqueous 1 N NaOH solution (53.1 ml) and stirred for 17 h. The reac- tion mixture is diluted with dichloromethane (200 ml) and acidified with 2M aqueous HCI solution (pH 6.5). The organic layer is separated and the aqueous layer is extracted thoroughly with dichloromethane / isopropanol 9:1 (v/v). The combined organic layers are dried and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient ethyl acetate / n-hexane 1 :1 (v/v) to ethyl acetate) to give 1.19 g (34%) of the title compound. 1H-NMR (200 MHz, d6-DMSO); δ = 2.55 (s, 4H), 6.82-7.11 (m, 2H), 7.34 (d, J = 7.3 Hz, 1 H), 7.51 (d, J = 2.5 Hz, 1 H), 7.75 (d, J = 7.9 Hz, 1 H).
A2. 2-(1 H-lndol-3-yl)cyclopentanone Step 1 : 2-(1 H-lndol-3-yl)cyclopentanol. Indole (7.0 g) is dissolved in dry THF (25 ml) and isopropyl magnesium chloride (2M in THF, 30.0 ml) is added dropwise at O0C. The mixture is stirred at room temperature for 1 h and a solution of cyclopentene oxide (5.2 ml) in dry THF (20 ml) is added dropwise. The reaction mixture is stirred for 42 h at room temperature. After that, saturated sodium hydrogencarbonate solution (100 ml) is added, the precipitate is filtered off, washed thoroughly with ethyl acetate and the phases of the combined filtrate are separated. The aqueous phase is extracted with ethyl acetate (2 x 100 ml), the combined organic phases are washed with 1 M sodium carbonate solution (1 x 300 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient dichloromethane to dichloromethane / ethyl acetate 1 :1 (v/v)) to give rise to 3.8 g (32%) of 2-(1 H-indol-3- yl)cyclopentanol.
Step 2: 2-(1 H-lndol-3-yl)cyclopentanone. Dimethylsulfoxide (3.1 ml) is dissolved in dry dichloromethane (40 ml), the solution is cooled to -750C and trifluoroacetic anhydride (4.5 ml) is added drop-wise at a rate, that internal temperature does not exceed -7O0C. After 15 min stirring at -7O0C, a solution of 2-(1 H-indol-3-yl)cyclopentanol (3.8 g) in dry THF (25 ml) was added drop-wise. The mixture is stirred for 1 h at -7O0C. Triethyl amine (12.1 ml) is added and the temperature is raised to room temperature within 18 h. Distilled water (25 ml) is then added, after phase separation the aqueous phase is extracted with dichloromethane (3 x 40 ml), the combined organic extracts are washed with distilled water (1 x 100 ml), dried (magnesium sulfate) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient dichloro- methane to dichloromethane / ethyl acetate 9:1 (v/v)) to give 1.20 g (32%) of the title compound.
Final Compounds
1. 5-Benzyl-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one
Step 1 : 5-Benzylidene-2,3,5,6-tetrahydro-1 H-cyclopenta[b]indeno[1 ,2-d]pyran-1-one. 2-(1 H-lndol- 3-yl)-cyclopentane-1 ,3-dione (example A1 ) (533 mg) and phenyl acetic acid anhydride (6.36 g) are suspended in nitromethane (16 ml). The resulting slurry is treated with 70% (v/v) aqueous HCIO4 solution (215 μl, 3 portions, every 10 minutes) and stirred for one additional hour at room tempera- ture. The reaction mixture is diluted with dichloromethane (20 ml) and saturated aqueous sodium hydrogencarbonate solution (10 ml). The organic layer is separated and the aqueous layer is extracted again with dichloromethane (2 x 10 ml). The combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash column chromatography (silica gel, eluting with gradient n-hexane / ethyl acetate) to give rise to 5-benzylidene-2,3,5,6-tetrahydro- 1 H-cyclopenta[b]indeno[1 ,2-d]pyran-1-one (330 mg, 42%), which is used in the next step without further purification.
Step 2: 5-Benzyl-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one. 5-Benzylidene-2,3,5,6- tetrahydro-1 H-cyclopenta[b]indeno[1 ,2-d]pyran-1-one (330 mg) is suspended in acetonitrile (21 ml) and treated with 25% (w/v) aqueous ammonia solution (21 ml). The reaction mixture is heated in two portions in a sealed vial for 25 min at 13O0C using microwave radiation. The mixture is extracted with dichloromethane (3 x 20 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / n-hexane 5:95 to 1 :1 (v/v)) to give 73 mg (22%, 2 steps) of the title compound. 1H-NMR (200 MHz, d6-DMSO); δ = 2.72-2.89 (m, 2H), 3.20-3.38 (m, 2H), 4.58 (s, 2H), 7.10-7.48 (m, 6H), 7.56-7.72 (m, 2H), 8.91 (d, J = 8.1 Hz, 1 H), 12.12 (s, 1 H). MS (MH+ found) = 313.3
The following compound is obtained by using the procedure of example 1 analogously.
2. 5-(4-Methoxybenzyl)-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one
Starting compounds: 2-(1 H-lndol-3-yl)-cyclopentane-1 ,3-dione (example A1 ) and 4-methoxyphenyl acetic acid anhydride; yield: 22% (2 steps)
1H-NMR (200 MHz, CDCI3); δ = 2.82-2.98 (m, 2H), 3.37-3.51 (m, 1 H), 3.78 (s, 3H), 4.56 (s, 2H), 6.81-6.94 (m, 2H), 7.19-7.43 (m, 4H), 7.48-7.61 (m, 1 H), 8.02 (s, 1 H), 9.07 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 343.2
3. 5-(3-Fluoro-4-methoxy-benzyl)-3,6-dihydro-2H-4,6-diaza-cyclopenta[c]fluoren-1-one
2-(1 H-lndol-3-yl)-cyclopentane-1 ,3-dione (example A1 ) (1.10 g) is suspended in dichloroethane (5 ml) and a 1 M zinc(ll) chloride solution in ether (15 ml) and 3-fluoro-4-methoxy-phenylacetyl- chloride (2.0 g) is added. The mixture is heated in a sealed vial for 8 min at 8O0C using microwave radiation. After cooling, a 7N ammonia solution in methanol (7 ml) is added and the mixture is again heated in a sealed vial for 30 min at 16O0C using microwave radiation. After cooling, the mixture is filtered, the precipitate washed with ethyl acetate (25 ml), the combined filtrate washed with 2M ammonia (3 x 50 ml) and saturated sodium chloride solution (1 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with dichloromethane / ethyl acetate 3:1 (v/v)) and crystallized from diethyl ether to yield 0.24 g (13%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 2.73-2.88 (m, 2H), 3.21-3.39 (m, 2H), 3.77 (s, 3H), 4.51 (s, 2H), 7.06 (t, J = 8.9 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 1 H), 7.21-7.36 (m, 2H), 7.59-7.71 (m, 2H), 8.90 (d, J = 8.0 Hz, 1 H), 12.09 (s, 1 H). MS (MH+ found) = 361.2 4. δ-tS.δ-Difluoro^-methoxy-benzy^-S.Θ-dihydro^H^.Θ-diaza-cyclopentaEcJfluoren-i- one
3,5-Difluoro-4-methoxyphenylacetic acid (2.0 g) is stirred with trifluoroacetic anhydride (1.4 ml) at room temperature. After 15 min the solution is diluted with dichloroethane (3 ml) and added to a cooled (O0C) solution of 2-(1/-/-indol-3-yl)-cyclopentane-1 ,3-dione (example A1 ) (1.1 g) in dichloroethane (7 ml) and a 1 M zinc(ll) chloride solution in ether (7.5 ml). The mixture is stirred at room temperature for 1 h. A 7N ammonia solution in methanol (5.0 ml) is added drop by drop and the mixture is stirred at 8O0C for 17 h. The mixture is cooled to RT and ethyl acetate (25 ml) and 2M aqueous ammonia (20 ml) are added. The organic layer is separated, dried (MgSO4) and concen- trated in vacuo. The product is crystallized from warm methanol. Crystals are filtered and dried in vacuo to yield 136 mg (7%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 2.74-2.83 (m, 2H), 3.21-3.35 (m, 2H), 3.85 (s, 3H), 4.54 (s, 2H), 7.12-7.24 (m, 2H), 7.24-7.35 (m, 1 H), 7.59-7.71 (m, 2H), 9.08 (d, J = 8.0 Hz, 1 H), 12.09 (s, 1 H). MS (MH+ found) = 379.3 mp.: 219°C (decomp.)
The following compound is obtained by using the procedure of example 4 analogously.
5. δ-tS-Fluoro^-methoxy-benzy^-I^.S.Θ-tetrahydro^.θ-diaza-cyclopentaEcJfluorene Starting compounds: 2-(1 H-lndol-3-yl)-cyclopentanone (example A2) and 3-fluoro-4-methoxy- phenylacetic acid; yield: 5%.
1 H-NMR (400 MHz, d6-DMSO); δ = 2.14-2.29 (m, 2H), 3.00 (t, J = 7.6 Hz, 2H), 3.26-3.40 (m, 2H), 3.75 (s, 3H), 4.34 (s, 2H), 7.03 (t, J = 8.7 Hz, 1 H), 7.09-7.15 (m, 1 H), 7.16-7.26 (m, 2H), 7.52 (t, J = 7.1 Hz, 1 H), 7.58 (d, J = 8.1 Hz, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 11.46 (s, 1 H). MS (MH+ found) = 347.3 mp.: 182-1830C
6. Benzyl-1 ,2,3,6-tetrahydrocyclopenta[5,6]pyrido[3,4-b]indol-1 -ol
5-Benzyl-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one (example 1 ) (35 mg) is dissolved in methanol (5 ml) and sodium borohydride (8.5 mg) is added. The reaction mixture is stirred for 2 h and additional sodium borohydride (6 mg) is added. The mixture is stirred for additional 2 h, until the reaction is finished by tic analysis. Dichloromethane (10 ml) and saturated aqueous sodium hydrogencarbonate solution (10 ml) are added, the organic layer is separated and the aqueous layer is extracted again with dichloromethane (20 ml). The combined organic layers are dried (MgSO4) and concentrated in vacuo to give 20 mg (57%) of the title compound.
1H-NMR (200 MHz, d6-DMSO); δ = 1.89-2.11 (m, 1 H), 2.40-2.69 (m, 1 H), 2.73-2.99 (m, 1 H), 3.01- 3.23 (m, 1 H), 4.43 (s, 2H), 5.38 (d, J = 7.7 Hz, 1 H), 5.53-5.71 (m, 1 H), 7.06-7.41 (m, 6H), 7.42-7.63 (m, 2H), 8.34 (d, J = 7.9 Hz, 1 H), 11.55 (s, 1 H). MS (MH+ found) = 315.3 The following compound is obtained by using the procedure of example 6 analogously.
7. 5-(4-Methoxybenzyl)-1 ,2,3,6-tetrahydrocyclopenta[5,6]pyrido[3,4-b]indol-1 -ol Starting compound: 5-(4-Methoxybenzyl)-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one (example 2); yield: 99%.
1H-NMR (200 MHz, d6-DMSO); δ = 1.89-2.11 (m, 1 H), 2.42-2.66 (m, 1 H), 2.76-3.00 (m, 1 H), 3.02- 3.25 (m, 1 H), 3.67 (s, 3H), 4.35 (s, 2H), 5.37 (d, J = 7.7 Hz, 1 H), 5.53-5.71 (m, 1 H), 6.81 (d, J = 8.7 Hz, 2H), 7.11-7.36 (m, 3H), 7.42-7.62 (m, 2H), 8.33 (d, J = 7.9 Hz, 1 H), 1 1.50 (s, 1 H). MS (MH+ found) = 345.2
8. 5-(3-Fluoro-4-methoxy-benzyl)-1 ,2,3,6-tetrahydro-4,6-diaza-cyclopenta[c]fluoren-1 -ol
5-(3-Fluoro-4-methoxy-benzyl)-3,6-dihydro-2H-4,6-diaza-cyclopenta[c]fluoren-1-one (example 3) (150 mg) is suspended in methanol (5 ml) and sodium borohydride (76 mg) is added in 6 portions within 5 min. The mixture is stirred for 2 h at room temperature. The reaction is finished by tic analysis and distilled water (2 ml) is added. The mixture is stirred over night at room temperature. The product precipitates, is filtered off and dried in vacuo to give 100 mg (66%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 1.92-2.09 (m, 1 H), 2.47-2.62 (m, 1 H), 2.80-2.96 (m, 1 H), 3.05- 3.20 (m, 1 H), 3.75 (s, 3H), 4.33 (d, AB, J = 14.3 Hz, 1 H), 4.38 (d, AB, J = 14.3 Hz, 1 H), 5.39 (bs, 1 H), 5.54-5.68 (m, 1 H), 7.04 (t, J = 8.8 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 1 H), 7.16-7.26 (m, 2H), 7.51 (t, J = 7.1 Hz, 1 H), 7.58 (d, J = 8.2 Hz, 1 H), 8.34 (d, J = 7.9 Hz, 1 H), 11.50 (bs, 1 H). MS (MH+ found) = 363.3 mp.: 120-126 0C
9. (SJ-S-β-Fluoro^-methoxy-benzyO-I^.S.δ-tetrahydro-^δ-diaza-cyclopentatclfluoren- 1-ol
3-Nitrophenylboronic acid (0.62 g), D-tartaric acid (0.56 g) and calcium hydride (0.30 g) are suspended in THF (10 ml) and heated under reflux for 2 h. The suspension is cooled and filtered under nitrogen atmosphere. 5-(3-Fluoro-4-methoxy-benzyl)-3,6-dihydro-2H-4,6-diaza- cyclopenta[c]fluoren-1-one (example 3) (0.45 g) is dissolved in the filtrate and sodium borohydride (0.14 g) is added in 6 portions at O0C. After the last addition, stirring is continued for 90 min at room temperature. Methanol (5 ml) is added slowly (hydrogen evolution) and the mixture is stirred for 30 min at room temperature. Next, 2M hydrochloric acid (5 ml) is added (pH = 1 ) and stirring is contin- ued for 1 h. The mixture is basified with 2M NaOH (pH = 12), water (25 ml) is added and the mixture is extracted with dichloromethane (3 x 50 ml). The combined organic layers are washed with water (100 ml), dried (MgSO4) and concentrated in vacuo. The product is crystallized from ether to give 0.27 g (50%) of the title compound as colorless crystals. 1H-NMR (400 MHz, d6-DMSO); δ = 1.92-2.08 (m, 1 H), 2.44-2.61 (m, 1 H), 2.71-2.93 (m, 1 H), 3.08- 3.20 (m, 1 H), 3.75 (s, 3H), 4.33 (d, AB, J = 14.3 Hz, 1 H), 4.38 (d, AB, J = 14.3 Hz, 1 H), 5.38 (d, J = 7.6 Hz, 1 H), 5.58-5.69 (m, 1 H), 7.04 (t, J = 8.8 Hz, 1 H), 7.12 (d, J = 8.6 Hz, 1 H), 7.16-7.26 (m, 2H), 7.51 (t, J = 7.0 Hz, 1 H), 7.58 (d, J = 8.2 Hz, 1 H), 8.34 (d, J = 7.9 Hz, 1 H), 1 1.51 (s, 1 H). MS (MH+ found) = 363.3 mp.: 127-131 0C ee > 95% [by 1H NMR using 1.5 eq. quinine as chiral resolution agent] assignment of absolute configuration by analogy
10. 5-(4-Methoxybenzyl)-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one 4-oxide
5-(4-Methoxybenzyl)-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one (example 2) (685 mg) is suspended in dichloromethane (10 ml) and solid sodium hydrogencarbonate (336 mg) is added followed by dry 3-chloro-perbenzoic acid (690 mg). The mixture is stirred at room temperature for 2 h. After that, dichloromethane (40 ml) and saturated sodium hydrogencarbonate solution (150 ml) is added. After phase separation, the aqueous phase is filtered off and the precipitate is washed subsequently with saturated sodium chloride solution (20 ml), distilled water (25 ml), diethyl ether (25 ml) and dried in high vacuum to give 523 mg (73%) of the title compound. 1H-NMR (200 MHz, DMSO); δ = 2.74-2.92 (m, 2H), 3.08-3.52 (m, 2H), 3.67 (s, 3H), 4.63 (s, 2H), 6.81 (d, J = 8.7 Hz, 2H), 7.28 (t, J = 7.1 Hz, 1 H), 7.42 (d, J = 8.6 Hz, 2H), 7.55 (t, J = 7.1 Hz, 1 H), 7.66 (d, J = 8.1 Hz, 1 H), 8.75 (d, J = 8.0 Hz, 1 H), 12.48 (bs, 1 H). MS (MH+ found) = 359.2
11. 5-(4-Methoxybenzyl)-1 ,2,3,6-tetrahydrocyclopenta[5,6]pyrido[3,4-b]indol-1 -ol 4-oxide
5-(4-Methoxybenzyl)-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one 4-oxide (example 10) (505 mg) is suspended in methanol (50 ml) and sodium borohydride (160 mg) is added. The mixture is stirred for 4 h at room temperature. After that, the precipitate is filtered and washed with methanol (10 ml). It is crystallized from ether / isopropanol 10:1 (v/v) to give 323 mg (63%) of the title compound.
1H-NMR (200 MHz, DMSO); δ = 1.88-2.1 1 (m, 1 H), 2.40-2.70 (m, 1 H), 2.75-3.01 (m, 1 H), 3.02-3.26 (m, 1 H), 3.67 (s, 2H), 5.56-5.77 (m, 2H), 6.80 (d, J = 8.6 Hz, 2H), 7.21 (t, J = 7.0 Hz, 1 H), 7.33 (d, J = 8.6 Hz, 2H), 7.40-7.61 (m, 2H), 8.24 (d, J = 7.8 Hz, 1 H), 1 1.70 (s, 1 H). MS (MH+ found) = 361.3 Commercial utility
The compounds, salts thereof, N-oxides of the compounds and the salts thereof, and the stereoisomers of the compounds, the salts, the N-oxides of the compounds and the N-oxides of the salts thereof according to the invention are hereinafter referred to as the compounds of the invention. In particular, the compounds of the invention are pharmaceutically acceptable.
The compounds of the invention have valuable pharmaceutical properties which make them commercially utilizable. In particular, as type 5 phosphodiesterase (PDE5) inhibitors, they are able to influence the physiological and pathophysiological function of various cells, e.g., but not limited to, smooth muscle cells, fibroblasts, myofibroblasts and platelets, which are involved in a great variety of physiological and pathophysiological mechanisms. In particular, the PDE5 inhibiting compounds of the invention can effect relaxation of the vasculature, thus increasing blood flow, improve the spatial balance between blood perfusion and ventilation within the lung ("re-matching" effect) thereby reducing the amount of so-called low V/Q-areas [areas within the lung with high perfusion (Q) but no or reduced ventilation (V)] and high V/Q-areas (areas within the lung with low perfusion but high ventilation), induce neurogenesis, inhibit platelet function, such as aggregation, adhesion and mediator release and, thus, have an anti-inflammatory effect. The compounds of the invention are distinguished by valuable and desirable properties, such as, for example, high efficacy, high selectivity, low toxicity, superior bioavailability in general (e.g. good enteral absorption), superior therapeutic window, superior pharmacokinetics (e.g. half-life), absence of significant side effects, and further beneficial effects related with their therapeutic and pharmaceutical suitability.
Accordingly, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by inhibition of the type 5 phosphodiesterase. In particular, the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, such as, but not limited to, male erectile dysfunction, premature ejaculation, Peyronie's disease; acute and chronic airway diseases, such as, but not limited to, COPD (chronic obstructive pulmonary disease), bronchitis, emphysema, pulmonary vascular remodeling, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, cystic fibrosis, bronchiectasis, bronchiolitis obliterans, connective tissue diseases, sarcoidosis, kyphoscoliosis, pneumoconiosis, amyotrophic lateral sclerosis, thoracoplasty, extrinsic allergic alveolitis; inflammatory diseases, such as, but not limited to, vasculature inflammation, acute respiratory distress syndrome, mesangial glomerulonephritis, chronic inflammatory bowel disease, disseminated intravascular inflammation, allergic vasculitis, dermatoses (e.g., but not limited to, psoriasis, toxic and allergic contact eczema, atopic eczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, fol- licular and widespread pyodermias, endogenous and exogenous acne, acne rosacea), disorders of the arthritis type (e.g., but not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis), disorders of the immune system [e.g., but not limited to, AIDS (acquired immunodeficiency syndrome), multiple sclerosis], graft versus host reaction, allograft rejections, shock [e.g., but not Mm- ited to, septic shock, endotoxin shock, gram-negative sepsis shock, toxic shock syndrome and
ARDS (adult respiratory distress syndrome)], gastrointestinal inflammations (e.g., but not limited to, Crohn's disease and ulcerative colitis); disorders which are based on allergic and/or chronic, immunological false reactions (e.g., but not limited to, allergic rhinitis, allergic sinusitis, chronic rhinitis, chronic sinusitis, allergic conjunctivitis, nasal polyps); pain, such as, but not limited to, inflammatory pain; right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia; ischaemic diseases, such as, but not limited to, diabetes mellitus, stroke, coronary artery disease, angina (including, but not limited to, vasospastic angina), myocardial infarction, peripheral artery disease, cerebrovascular obstruction, sleep apnea, macular ischaemia, arterial and venous occlusion, congestive heart failure; diabetic gastroparesis and diseases with symptoms of gastroparesis; diseases or conditions in which it is desirable to suppress platelet function, for example, but not limited to, after stent implantations (e.g., but not limited to, coronary stenting), after bypass opera- tions, in pulmonary hypertension, thrombotic diseases, post-angioplasty stenosis, coronary artery disease, infarction (e.g., but not limited to, myocardial infarction), instable angina pectoris, stroke, and arterial and venous occlusion diseases (e.g., but not limited to, claudicatio intermittens); diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, such as, but not limited to, arteriosclerotic dementia, multi-infarct demen- tia, cerebral senility; diseases which are based on neuronal damage or degradation, such as but not limited to, stroke, spinal cord injury, brain injury, morbus parkinson, amyotrophic lateral sclerosis, morbus alzheimer, amyloidosis, prion diseases and neuropathy; peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia (Alzheimer's disease), Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia; portal hypertension, liver cirrhosis, toxic liver damage (e.g., but not limited to, alcohol-induced liver damage), hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins (e.g., but without limitation, due to tumors), arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis (bilharziosis), sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders (e.g., but not limited to, chronic myeloid leukemia, osteomyelofibrosis), lymphatic systemic diseases, collagenosis (e.g., but not limited to, systemic lupus erythematodes, sclerodermia), morbus Osier (congenital arterio- venous malformations, inter alia in the liver), nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis; benign prostatic hyperplasia; overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction; insufficient brain skills, such as but not limited to, verbal attainment, attention, concentration, deductive thinking, central auditory processing, cognition, learning, vigilance, apprehension and reagibility.
In a further embodiment, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by inhibition of the type 5 phosphodiesterase. In particular, the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and insufficient brain skills.
In this respect, the term "pulmonary hypertension" in particular embraces - pulmonary arterial hypertension including primary pulmonary hypertension (e.g. sporadic or familial) and pulmonary arterial hypertension related, for example, but without limitation, to collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, human immunodeficiency virus infection, drugs or toxins (e.g., but not limited to, anorexigens), persistent pulmonary hypertension of the newborn; pulmonary venous hypertension due to, for example, but without limitation, left-sided atrial or ventricular heart disease, left-sided valvular heart disease, extrinsic compression of central pulmonary veins (e.g. fibrosing mediastinitis, adenopathy in relation to tumors), pulmonary veno- occlusive disease; - pulmonary hypertension associated with disorders of the respiratory system or hypoxemia including, for example, but without limitation, chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia; pulmonary hypertension caused by chronic thrombotic or embolic diseases including thromboembolic obstruction of proximal pulmonary arteries and obstruction of distal pulmonary arteries, such as pulmonary embolism (due to thrombus, tumor, ova, parasites, or foreign material), in situ thrombosis and sickle-cell disease, in particular chronic thromboembolic pulmonary hypertension (CTEPH); pulmonary hypertension caused by disorders directly affecting the pulmonary vasculature including inflammatory disorders (e.g., but not limited to, schistosomiasis, sarcoidosis) and pulmonary capillary hemangiomatosis.
Preferably, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepa- titis and liver fibrosis.
Furthermore, the invention further relates to the compounds of the invention for use in the treat- ment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
The invention also relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition inhibiting the type 5 phosphodiesterase, in particular a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase, preferably, a pharmaceutical composition for the treatment or prophylaxis of the diseases exemplified above.
In particular, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, such as, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease. Furthermore, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, such as, but not limited to, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Furthermore, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis.
The invention further relates to a method of treating or preventing a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
In particular, the invention relates to a method of treating or preventing one of the above mentioned diseases comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
Especially, the invention relates to a method of treating or preventing a disease which is alleviated by inhibition of the type 5 phosphodiesterase comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
The invention relates to a method of treating or preventing male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and insufficient brain skills.
Preferably, the invention relates to a method of treating or preventing an acute or chronic airway disease, for example, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
Furthermore, the invention preferably relates to a method of treating or preventing an acute or chronic airway disease, for example, but not limited to, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
Furthermore, the invention preferably relates to a method of treating or preventing portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
In the above methods, the patient is preferably a mammal, more preferably a human. Furthermore, in the above methods, at least one of the compounds of the invention can be used. Preferably, one or two of the compounds of the invention are used, more preferably, one of the compounds of the invention is used.
In a particularly preferred embodiment of the invention, the above methods of treating or preventing one of the above mentioned diseases comprise administering to a patient in need thereof a therapeutically effective amount of one compound of the examples according to the present invention.
The invention furthermore relates to a pharmaceutical composition which comprises at least one of the compounds of the invention together with at least one pharmaceutically acceptable auxiliary.
The invention additionally relates to a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, in particular for the treatment or prophylaxis of pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
The invention further relates to a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, in particular for the treatment or prophylaxis of pulmonary hyper- tension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Preferably, the pharmaceutical composition comprises one or two of the compounds of the invention. More preferably, the pharmaceutical composition comprises one of the compounds of the invention.
In a particularly preferred embodiment of the invention, the pharmaceutical composition comprises a compound of the examples according to the present invention together with at least one pharmaceutically acceptable auxiliary.
The invention additionally relates to a pharmaceutical composition comprising at least one of the compounds of the invention, at least one pharmaceutically acceptable auxiliary and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta- mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta- blockers, type 4 phosphodiesterase inhibitors, antidepressants, antibiotics, anticoagulants, diuretics and digitalis glycosides.
In this respect, the therapeutic agent includes the corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics in form of the free compounds, the pharmaceutically acceptable salts thereof, the pharmaceutically acceptable derivatives thereof (e.g., but not limited to, ester derivatives), the solvates thereof and the stereoisomers of the compounds, salts, derivatives and solvates.
Examples of corticosteroids include without limitation budesonide, fluticasone such as fluticasone propionate, beclometasone such as beclometasone dipropionate, triamcinolone such as triamcinolone acetonide, and ciclesonide. Examples of anticholinergics include without limitation in- dacaterol, tiotropium such as tiotropium bromide, and ipratropium such as ipratropium bromide. Examples of beta-mimetics include without limitation formoterol such as formoterol fumarate, and salmeterol such as salmeterol xinafoate. Examples of lung surfactants include without limitation lusupultide, poractant alfa, sinapultide, beractant, bovactant, colfosceril auch as colfosceril palmi- tate, surfactant-TA, and calfactant. Examples of endothelin antagonists include without limitation bosentan, ambrisentan and sitaxsentan such as sitaxsentan sodium. Examples of prostacyclins include without limitation iloprost such as iloprost tromethamine, epoprostenol such as epopros- tenol sodium and treprostinil such as treprostinil sodium. Examples of calcium channel blockers include without limitation amlodipine such as amlodipine besylate and amlodipine maleate, nifedipine, diltiazem such as diltiazem hydrochloride, verapamil such as verapamil hydrochloride, and felodipine. Examples of beta-blockers include without limitation bisoprolol such as bisoprolol fumarate, nebivolol, metoprolol such as metoprolol succinate and metoprolol tartrate, carvedilol, at- enolol and nadolol. Examples of type 4 phosphodiesterase inhibitors include without limitation ro- flumilast, roflumilast N-oxide, cilomilast, tetomilast and oglemilast. Examples of antidepressants include without limitation bupropion such as bupropion hydrochloride. Examples of antibiotics include without limitation amoxicillin, ampicillin, levofloxacin, clarithromycin, ciprofloxacin such as ciprofloxacin hydrochloride, telithromycin and azithromycin. Examples of anticoagulants include without limitation clopidogrel, enoxaparin, cilostazol, nadroparin, warfarin and abciximab. Examples of diuretics include without limitation furosemide, bumetanide and torsemide. Examples of digitalis glycosides include without limitation digoxin and digitoxin.
In a preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and budesonide, a compound of the invention and fluticasone, a compound of the invention and beclometasone, a compound of the invention and triamcinolone, or a compound of the invention and ciclesonide.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an anticholinergic. In a particularly preferred embodiment, the phar- maceutical composition comprises: a compound of the invention and indacaterol, a compound of the invention and tiotropium, or a compound of the invention and ipratropium.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a beta-mimetic. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and formoterol, or a compound of the invention and salmeterol. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a lung surfactant. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and lusupultide, a compound of the invention and poractant alfa, a compound of the invention and sinapultide, a compound of the invention and beractant, a compound of the invention and bovactant, a compound of the invention and colfosceril, a compound of the invention and surfactant-TA, or a compound of the invention and calfactant. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an endothelin antagonist. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and bosentan, a compound of the invention and ambrisentan, or a compound of the invention and sitaxsentan.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a prostacyclin. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and iloprost, a compound of the invention and epoprostenol, a compound of the invention and triprostinil.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a calcium channel blocker. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and amlodipine, a compound of the invention and nifedipine, a compound of the invention and diltiazem, a compound of the invention and verapamil, or a compound of the invention and felodipine.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a beta-blocker. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and bisoprolol, a compound of the invention and nebivolol, a compound of the invention and metoprolol, a compound of the invention and carvedilol, a compound of the invention and atenolol, or a compound of the invention and nadolol. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a type 4 phosphodiesterase inhibitor. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and roflumilast, a compound of the invention and roflumilast N-oxide, a compound of the invention and cilomilast, a compound of the invention and tetomilast, or a compound of the invention and oglemilast. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an antidepressant. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and bupropion. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an antibiotic. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and amoxicillin, a compound of the invention and ampicillin, a compound of the invention and levofloxacin, a compound of the invention and clarithromycin, a compound of the invention and ciprofloxacin, a compound of the invention and telithromycin, or a compound of the invention and azithromycin. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an anticoagulant. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and clopidogrel, a compound of the invention and enoxaparin, a compound of the invention and cilostazol, a compound of the invention and nadroparin, a compound of the invention and warfarin, or a compound of the invention and abciximab.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a diuretic. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and furosemide, a compound of the invention and bumetanide, or a compound of the invention and torsemide. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a digitalis glycoside. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and digoxin, or a compound of the invention and digitoxin. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid and a beta-mimetic. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention, budesonide and indacaterol, a compound of the invention, budesonide and formoterol, a compound of the invention, budesonide and salmeterol, a compound of the invention, fluticasone and indacaterol, a compound of the invention, fluticasone and formoterol, a compound of the invention, fluticasone and salmeterol, a compound of the invention, beclometasone and indacaterol, a compound of the invention, beclometasone and formoterol, a compound of the invention, beclometasone and salmeterol, a compound of the invention, triamcinolone and indacaterol, a compound of the invention, triamcinolone and formoterol, a compound of the invention, triamcinolone and salmeterol, a compound of the invention, ciclesonide and indacaterol, a compound of the invention, ciclesonide and formoterol, or a compound of the invention, ciclesonide and salmeterol.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid and an anticholinergic. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention, budesonide and tiotropium, a compound of the invention, budesonide and ipratropium, a compound of the invention, fluticasone and tiotropium, a compound of the invention, fluticasone and ipratropium, a compound of the invention, beclometasone and tiotropium, a compound of the invention, beclometasone and ipratropium, a compound of the invention, triamcinolone and tiotropium, a compound of the invention, triamcinolone and ipratropium, a compound of the invention, ciclesonide and tiotropium, or a compound of the invention, ciclesonide and ipratropium.
The above mentioned compound of the invention is preferably a compound according to the examples.
The invention furthermore relates to pharmaceutical compositions according to the invention, as defined above, inhibiting the type 5 phosphodiesterase, especially for the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterase, in particular for the treatment or prophylaxis of the diseases exemplified above.
The invention also encompasses pharmaceutical compositions according to the invention, as defined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
Furthermore, the invention also encompasses pharmaceutical compositions according to the inven- tion, as defined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
The pharmaceutical compositions according to the invention preferably contain the compound or compounds of the invention in a total amount of from 0.1 to 99.9 wt%, more preferably 5 to 95 wt%, in particular 20 to 80 wt%. In case at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mi metics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, anti- depressants and antibiotics is present in the pharmaceutical compositions of the invention, the total amount of said therapeutic agent or therapeutic agents in the pharmaceutical compositions is preferably in the range of from 0.1 to 99.9 wt%, more preferably 5 to 95 wt%, in particular 20 to 80 wt%, under the provision that the total amount of the compound or compounds of the invention and the therapeutic agent or therapeutic agents is less than 100 wt%. Preferably, the at least one com- pound of the invention and the at least one therapeutic agent are present in the pharmaceutical composition in a weight ratio of from 1000 : 1 to 1 : 1000, more preferably 500 : 1 to 1 : 500.
As pharmaceutically acceptable auxiliaries, any auxiliaries known to be suitable for preparing pharmaceutical compositions can be used. Examples thereof include, but are not limited to, sol- vents, excipients, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrating agents, buffers, permeation promoters, polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, flavorings, sweeteners and dyes. In particular, auxiliaries of a type appropriate to the desired formulation and the desired mode of administration are used.
The pharmaceutical compositions can be formulated, for example, into tablets, coated tablets (dra- gees), pills, cachets, capsules (caplets), granules, powders, suppositories, solutions (e.g., but not limited to, sterile solutions), emulsions, suspensions, ointments, creams, lotions, pastes, oils, gels, sprays and patches (e.g., but not limited to, transdermal therapeutic systems). Additionally, the pharmaceutical compositions can be prepared as e.g. liposome delivery systems, systems in which the compound of the invention is coupled to monoclonal antibodies and systems in which the compound of the invention is coupled to polymers (e.g., but not limited to, soluble or biodegradable polymers). In case of pharmaceutical compositions comprising at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, the compound of the invention and the therapeutic agent may be formulated together into the same dosage form (e.g., but not limited to, tablets), separately into the same dosage form (e.g., but not limited to, tablets), or into different dosage forms (without limitation e.g. the compound of the invention may be formulated as tablet and the therapeutic agent may be formulated as powder, solution or suspension).
The pharmaceutical compositions can be manufactured in a manner known to a person skilled in the art, e.g. by dissolving, mixing, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
The selected formulation depends inter alia on the route of administering the pharmaceutical composition. The pharmaceutical compositions of the invention can be administered by any suitable route, for example, by the oral, sublingual, buccal, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, topical, transdermal, intranasal, intraocular, intraperitoneal, intrasternal, intracoronary, transurethral, rectal or vaginal route, by inhalation or by insufflation. Oral administra- tion is preferred.
In case of pharmaceutical compositions comprising at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants, antibiotics, anticoagulants, diuretics and digitalis glycosides, the compound of the invention and the therapeutic agent may be administered by the same route, e.g., without limitation, orally, or by different routes, e.g., without limitation, the compound of the invention can be administered orally and the therapeutic agent can be administered by inhalation or instillation.
Tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are e.g. suitable for oral administration. In particular, said formulations can be adapted so as to represent, for example, an enteric form, an immediate release form, a delayed release form, a repeated dose release form, a prolonged release form or a sustained release form. Said forms can be obtained, for example, by coating tablets, by dividing tablets into several compartments separated by layers disintegrating under different conditions (e.g. pH conditions) or by coupling the compound of the invention to a biodegradable polymer. Administration by inhalation or instillation is preferably made by using an aerosol. The aerosol is a liquid-gaseous dispersion, a solid-gaseous dispersion or a mixed liquid/solid-gaseous dispersion.
The aerosol may be generated by means of aerosol-producing devices such as dry powder inhal- ers (DPIs), pressurized metered dose inhalers (PMDIs) and nebulizers. Depending on the kind of the compound of the invention, and optionally the therapeutic agent, to be administered, the aerosol-producing device can contain the compound and, optionally, the therapeutic agent in form of a powder, a solution or a dispersion. The powder may contain, for example, one or more of the following auxiliaries: carriers, stabilizers and fillers. The solution may contain in addition to the sol- vent, for example, one or more of the following auxiliaries: propellants, solubilizers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and flavorings. The dispersion may contain in addition to the dispersant, for example, one or more of the following auxiliaries: propellants, surfactants, stabilizers, buffers, preservatives and flavorings. Examples of carriers include, but are not limited to, saccharides, e.g. lactose and glucose. Examples of propellants in- elude, but are not limited to, fluorohydrocarbons, e.g. 1 ,1 ,1 ,2-tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
The particle size of the aerosol particles (solid, liquid or solid/liquid particles) is preferably less than 100 μm, more preferably it is in the range of from 0.5 to 10 μm, in particular in the range of from 2 to 6 μm (D50 value, measured by laser diffraction).
Specific aerosol-producing devices which may be used for inhaled administration include, but are not limited to, Cyclohaler®, Diskhaler®, Rotadisk®, Turbohaler®, Autohaler®, Turbohaler®, No- volizer®, Easyhaler®, Aerolizer®, Jethaler®, Diskus®, Ultrahaler® and Mystic® inhalers. The aerosol-producing devices may be combined with spacers or expanders, e.g. Aerochamber®, Nebulator®, Volumatic® and Rondo®, for improving inhalation efficiency.
In case of topical administration, suitable pharmaceutical formulations are, for example, ointments, creams, lotions, pastes, gels, powders, solutions, emulsions, suspensions, oils, sprays and patches (e.g., but not limited to, transdermal therapeutic systems).
For parenteral modes of administration such as, for example, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, intraperitoneal and intrasternal administration, preferably solutions (e.g., but not limited to, sterile solutions, isotonic solutions) are used. They are preferably administered by injection or infusion techniques.
In case of intranasal administration, for example, sprays and solutions to be applied in drop form are preferred formulations. For intraocular administration, solutions to be applied in drop form, gels and ointments are exemplified formulations.
Generally, the pharmaceutical compositions according to the invention can be administered such that the dose of the compound of the invention is in the range customary for type 5 phosphodiesterase inhibitors. In particular, a dose in the range of from 0.01 to 4000 mg of the compound of the invention per day is preferred. In this respect, it is to be noted that the dose is dependent, for example, on the specific compound used, the species treated, age, body weight, general health, sex and diet of the subject treated, mode and time of administration, rate of excretion, severity of the disease to be treated and drug combination. In case the pharmaceutical composition of the invention comprises at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, anticoagulants, diuretics and digitalis glycosides,the same dose ranges apply to the therapeutic agent.
The pharmaceutical compositions according to the invention can be administered in a single dose per day or in multiple subdoses, for example, 2 to 4 doses per day. A single dose unit of the pharmaceutical composition can contain e.g. from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1000 mg, most preferably 1 to 500 mg, of the compound of the invention. In case the pharmaceutical composition of the invention comprises at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, a single dose unit of the pharmaceutical composition can contain e.g. from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1000 mg, most preferably 1 to 500 mg, of the therapeutic agent. Furthermore, the pharmaceutical composition can be adapted to weekly, monthly or even more infrequent administration, for example by using an implant, e.g. a subcutaneous or intramuscular implant, by using the compound of the invention in form of a spar- ingly soluble salt or by using the compound of the invention coupled to a polymer. Administration of the pharmaceutical composition in a single dose per day is preferred.
In case the pharmaceutical composition of the invention comprises at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticos- teroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, administration of the compound of the invention and administration of the therapeutic agent can be made simultaneously or sequentially. In case of sequential administration, the compound of the invention can be administered before or after administration of the therapeutic agent. Biological investigations
Method for measuring inhibition of PDE5 activity:
As a source for human PDE5, platelets were used. For that purpose, 150 ml fresh blood from human donors anticoagulated with citrate [final concentration 0.3% (w/v)] was centrifuged at 200 g for 10 min to obtain the so-called platelet-rich-plasma (PRP) as a supernatant. 1/10 volume of ACD solution (85 mM Na3-citrate, 1 11 mM D-glucose, 71 mM citric acid, pH 4.4) was added to 9/10 volume of PRP. After centrifugation (1 ,400 g, 10 min) the cell pellet was resuspended in 3 ml homogenization buffer (NaCI 140 mM, KCI 3.8 mM, EGTA 1 mM, MgCI2 1mM, Tris-HCI 20 mM, beta-mercaptoethanol 1 mM, pH 8.2) plus protease-inhibitor mix giving rise to the final concentrations of 0.5 mM Pefablock (Roche), 10 μM Leupeptin, 5 μM Trypsininhibitor, 2 mM Benzamidin and 10 μM Pepstatin A. The suspension was sonified and thereafter centrifuged for 15 min at 10,000 g. The resulting supernatant (platelet lysate) was used for enzymatic testings.
PDE5A1 activity is inhibited by the compounds of the invention in a modified SPA (scintillation proximity assay) test, supplied by Amersham Biosciences (see procedural instructions "phosphodiesterase [3H]cAMP SPA enzyme assay, code TRKQ 7090"), carried out in 96-well microtitre plates (MTP's). The test volume is 100 μl and contains 20 mM Tris buffer (pH 7.4), 0.1 mg of BSA (bovine serum albumin)/ml, 5 mM Mg2+, 1 μM motapizone, 10 nM PDE2 inhibitor BAY-60-7550, 0.5 μM cGMP (including about 50,000 cpm of [3H]cGMP as a tracer), 1 μl of the respective compound dilution in dimethylsulfoxide (DMSO) and sufficient PDE5-containing platelet lysat (10,000xg supernatant, see above) to ensure that 10-20 wt% of the cGMP is converted under the said experimental conditions. The final concentration of DMSO in the assay (1 % v/v) does not substantially affect the activity of the PDE investigated. After a preincubation of 5 min at 370C, the reaction was started by adding the substrate (cGMP) and the assay was incubated for a further 15 min; after that, it was stopped by adding SPA beads (50 μl). In accordance with the manufacturer's instructions, the SPA beads had previously been resuspended in water, but were then diluted 1 :3 (v/v) in water; the diluted solution also contains 3 mM 8-methoxymethyl-3-isobutyl- 1-methylxanthine (IBMX) to ensure a complete PDE activity stop. After the beads have been sedimented (> 30 min), the MTP's are analyzed in commercially available luminescence detection devices. The corresponding IC50 values of the compounds for the inhibition of PDE activity are determined from the concentration-effect curves by means of non-linear regression.
Representative inhibitory values determined for the compounds of the invention are given in the following Table:
Figure imgf000046_0001

Claims

Claims:
1. Compound of Formula (I)
Figure imgf000047_0001
wherein n and m are each independently selected from 0, 1 , 2 or 3, with the proviso that n + m is 1 or 3,
wherein
RA01 ancj RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA03RA04; or
RA01 ancj RA02 combine to form an oxo-group;
RA03 ancj RA04 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C(O)H and C(O)-C1.6-alkyl, wherein the C(O)-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA21 and R^22 are each independently selected from the group consisting of hydrogen and C1. β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy, nitro and amino;
RE351 JS se|ectec| from tne group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C-j.β-alkoxy, nitro, amino, -N H-C(O)-C <|_2-alkyl, - NH-C(0)-NH2 and a methoxy group substituted by 2 or 3 fluorine atoms; or
RB41 and RB51 combine to form a group selected from -0-CH2-O-, -0-CH2-CH2- and - CH2-CH2-O-;
RB61 JS selected from the group consisting of hydrogen and halogen;
RB^1 JS selected from the group consisting of hydrogen and halogen;
RB81 JS selected from the group consisting of hydrogen and halogen;
a salt thereof, an N-oxide of the compound or the salt thereof or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
2. Compound according to claim 1 , wherein R^01 and R^02 are each independently selected from the group consisting of hydrogen, hydroxy and NRA03RA04- or RA01 ancj RA02 combine to form an oxo-group, wherein RA03 ancj RA04 are eacn independently selected from the group consisting of hydrogen, C(O)H and C(O)-Ci _6-alkyl, wherein the C(O)-C-] _β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; a salt thereof, an N-oxide of the compound or the salt thereof or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
3. Compound according to claim 1 or 2, wherein one of the substituents R^01 and R^02 js hydrogen and the other substituent is hydroxy or NRA03RA04 or
RA01 ancj RA02 combine to form an oxo-group, wherein RA03 ancj RA04 are eacn independently selected from the group consisting of hydrogen, C(O)H and C(O)-Ci_6-alkyl, wherein the C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; a salt thereof, an N-oxide of the compound or the salt thereof or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
4. Compound according to any one of claims 1 to 3, wherein one of the substituents R^01 and RA02 JS hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the substituents R^01 and R^02 t>ind has the S-configu ration; a salt thereof, an N-oxide of the compound or the salt thereof or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
5. Compound according to any one of claims 1 to 4, wherein R^21 and R^22 J00^n are hydrogen; a salt thereof, an N-oxide of the compound or the salt thereof or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
6. Compound according to any one of claims 1 to 5, wherein m + n is 1 ; a salt thereof, an N-oxide of the compound or the salt thereof or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
7. Compound according to any one of claims 1 to 6, wherein RB^1 js selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy, RB^1 is selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms, or RB41 and RB51 combine to form a group selected from -0-CH2-O-, -0-CH2-CH2- and -CH2-CH2-O-; a salt thereof, an N-oxide of the compound or the salt thereof or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
8. Compound according to any one of claims 1 to 7 selected from the group consisting of 5-Benzyl-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one;
5-(4-Methoxybenzyl)-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one;
5-(3-Fluoro-4-methoxy-benzyl)-3,6-dihydro-2H-4,6-diaza-cyclopenta[c]fluoren-1-one;
5-(3,5-Difluoro-4-methoxy-benzyl)-3,6-dihydro-2H-4,6-diaza-cyclopenta[c]fluoren-1-one;
5-(3-Fluoro-4-methoxy-benzyl)-1 ,2,3,6-tetrahydro-4,6-diaza-cyclopenta[c]fluorine; Benzyl-1 ,2,3,6-tetrahydrocyclopenta[5,6]pyrido[3,4-b]indol-1-ol;
5-(4-methoxybenzyl)-1 ,2,3,6-tetrahydrocyclopenta[5,6]pyrido[3,4-b]indol-1-ol;
5-(3-Fluoro-4-methoxy-benzyl)-1 ,2,3,6-tetrahydro-4,6-diaza-cyclopenta[c]fluoren-1-ol;
(S)-5-(3-Fluoro-4-methoxy-benzyl)-1 ,2,3,6-tetrahydro-4,6-diaza-cyclopenta[c]fluoren-1-ol;
5-(4-Methoxybenzyl)-3,6-dihydrocyclopenta[5,6]pyrido[3,4-b]indol-1(2H)-one 4-oxide; 5-(4-Methoxybenzyl)-1 ,2,3,6-tetrahydrocyclopenta[5,6]pyrido[3,4-b]indol-1-ol 4-oxide; a salt thereof, an N-oxide of the compound or the salt thereof or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
9. Compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 8 for use in the treatment or prophylaxis of diseases.
10. Pharmaceutical composition comprising at least one of the compounds, pharmaceutically acceptable salts thereof, N-oxides of the compounds and the salts thereof and stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof according to any of claims 1 to 8 together with at least one pharmaceutically acceptable auxiliary.
11. Pharmaceutical composition according to claim 10 further comprising at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics.
12. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 8 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase.
13. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 8 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, peri- carditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and insufficient brain skills.
14. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 8 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease.
15. Use according to claim 14, wherein the acute or chronic airway disease is selected from pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
16. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N- oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 8 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis.
17. Method of treating or preventing diseases alleviated by inhibition of the type 5 phosphodi- esterase comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 8.
18. Method of treating or preventing male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Hunt- ington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno- occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and, insufficient brain skills comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 8.
19. Method for treating or preventing an acute or chronic airway disease comprising adminis- tering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 8.
20. Method for treating or preventing an acute or chronic airway disease according to claim 19, in which the acute or chronic airway disease is selected from the group consisting of pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
21. Method of treating or preventing portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 8.
PCT/EP2009/060000 2008-08-05 2009-08-03 5-benzyl-1,2,3,6-tetrahydro-4,6-diaza-cyclopenta[c]fluorene compounds and 5-benzyl-1,2,3,6-tetrahydro-4,6-diaza-cyclohepta[c]fluorene compounds WO2010015587A1 (en)

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Citations (3)

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WO2002064590A2 (en) * 2001-02-12 2002-08-22 Lilly Icos Llc Carboline derivatives
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WO2002064590A2 (en) * 2001-02-12 2002-08-22 Lilly Icos Llc Carboline derivatives
WO2008027182A2 (en) * 2006-08-28 2008-03-06 Medipropharma, Inc. Indoloquinoline compounds as calcium channel blockers
EP1953159A1 (en) * 2007-02-05 2008-08-06 Nycomed GmbH 6-Benzyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds useful as PDE5 inhibitors

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