Novel amido-substituted hydroxy-6-phenylphenanthridines and their use as pde4 inhibtors
Compounds of the formula I in which the substituents have the definitions provided in the specification, are novel, effective PDE4 inhibitors.
1 . A compound of formula I,
in which
R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy,
R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy,
or in which
R1 and R2 together are a 1-2C-alkylenedioxy group,
R3 is hydrogen or 1-4C-alkyl,
R31 is hydrogen or 1-4C-alkyl,
either, in a first embodiment (embodiment a),
R4 is —O—R41, in which
R41 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkyl, 1-7C-alkylcarbonyl, or completely or predominantly fluorine-substituted 1-4C-alkyl, and
R5 is hydrogen or 1-4C-alkyl,
or, in a second embodiment (embodiment b),
R4 is hydrogen or 1-4C-alkyl, and
R5 is —O—R51, in which
R51 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkyl, 1-7C-alkylcarbonyl, or completely or predominantly fluorine-substituted 1-4C-alkyl,
R6 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,
either,
in a first aspect (aspect 1),
R7 is —N(R8)R9, in which
R8 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl,
R9 is hydrogen, 1-4C-alkyl, mono- or di-1-4C-alkoxy-2-4C-alkyl, hydroxy-2-4C-alkyl, mono- or di-1-4C-alkoxycarbonyl-1-4C-alkyl, Har1, pyridinyl-1-4C-alkyl, 3-7C-cycloalkyl, or 2-4C-alkyl substituted by —NR(93)R94, in which
Har1 is optionally substituted by R91 and/or R92, and is a 5- to 10-membered monocyclic or fused bicyclic unsaturated heteroaryl radical comprising 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, in which
R91 is 1-4C-alkyl or 1-4C-alkoxy,
R92 is 1-4C-alkyl or 1-4C-alkoxy,
R93 is hydrogen or 1-4C-alkyl,
R94 is hydrogen or 1-4C-alkyl,
or R93 and R94 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het1, in which
Het1 is optionally substituted by R931, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R93 and R94 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R931 is 1-4C-alkyl,
or R8 and R9 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het2, in which
Het2 is optionally substituted by R10, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R8 and R9 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R10 is 1-4C-alkyl, —C(O)R11, pyridyl, 2-4C-alkyl substituted by —NR(14)R15, or 1-4C-alkyl substituted by —C(O)N(R16)R17, in which
R11 is 1-4C-alkyl substituted by —NR(12)R13, in which
R12 is hydrogen or 1-4C-alkyl,
R13 is hydrogen or 1-4C-alkyl,
or R12 and R13 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het3, in which
Het3 is optionally substituted by R121, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R12 and R13 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R121 is 1-4C-alkyl,
R14 is hydrogen or 1-4C-alkyl,
R15 is hydrogen or 1-4C-alkyl,
or R14 and R15 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het4, in which
Het4 is optionally substituted by R141, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R14 and R15 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R141 is 1-4C-alkyl,
R16 is hydrogen, 1-4C-alkyl or pyridyl,
R17 is hydrogen or 1-4C-alkyl,
or R16 and R17 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het5, in which
Het5 is optionally substituted by R161, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R16 and R17 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R141 is 1-4C-alkyl,
or,
in a second aspect (aspect 2),
R7 is —NH—N(R18)R19, in which
R18 is hydrogen,
R19 is —C(O)R20, or R21-substituted phenyl, in which
R20 is Har2, Het6, or Aryl-1-4C-alkyl, in which
Har2 is optionally substituted by R201 and/or R202, and is a 5- to 10-membered monocyclic or fused bicyclic unsaturated heteroaryl radical comprising 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, in which
R201 is 1-4C-alkyl or 1-4C-alkoxy,
R202 is 1-4C-alkyl or 1-4C-alkoxy,
Het6 is optionally substituted by R203 and/or R204, and is a monocyclic 3- to 7-membered saturated heterocyclic ring radical comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, in which
R203 is 1-4C-alkyl,
R204 is 1-4C-alkyl,
Aryl is R205- and/or R206-substituted phenyl,
R205 is 1-4C-alkoxy,
R206 is 1-4C-alkoxy,
R21 is aminosulphonyl,
or R18 and R19 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het7, in which
Het7 is optionally substituted by R181, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R18 and R19 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R181 is 1-4C-alkyl,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
2 . A compound of formula I according to claim 1 in which
R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
either, in a first embodiment (embodiment a),
R4 is —O—R41, in which
R41 is hydrogen or 1-4C-alkylcarbonyl, and
R5 is hydrogen,
or, in a second embodiment (embodiment b),
R4 is hydrogen, and
R5 is —O—R51, in which
R51 is hydrogen or 1-4C-alkylcarbonyl,
R6 is hydrogen,
either,
in a first aspect (aspect 1),
R7 is —N(R8)R9, in which
R8 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl,
R9 is hydrogen, 1-4C-alkyl, mono- or di-1-4C-alkoxy-2-4C-alkyl, hydroxy-2-4C-alkyl, mono- or di-1-4C-alkoxycarbonyl-1-4C-alkyl, Har1, pyridinyl-1-4C-alkyl, 3-7C-cycloalkyl, or 2-4C-alkyl substituted by —NR(93)R94, in which
Har1 is optionally substituted by R91 and/or R92, and is a 5- to 10-membered monocyclic or fused bicyclic unsaturated heteroaryl radical comprising 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, in which
R91 is 1-4C-alkyl or 1-4C-alkoxy,
R92 is 1-4C-alkyl or 1-4C-alkoxy,
R93 is hydrogen or 1-4C-alkyl,
R94 is hydrogen or 1-4C-alkyl,
or R93 and R94 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het1, in which
Het1 is optionally substituted by R931, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R93 and R94 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R931 is 1-4C-alkyl,
or R8 and R9 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het2, in which
Het2 is optionally substituted by R10, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R8 and R9 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R10 is 1-4C-alkyl, —C(O)R11, pyridyl, 2-4C-alkyl substituted by —NR(14)R15, or 1-4C-alkyl substituted by —C(O)N(R16)R17, in which
R11is 1-4C-alkyl substituted by —NR(12)R13, in which
R12 is hydrogen or 1-4C-alkyl,
R13 is hydrogen or 1-4C-alkyl,
or R12 and R13 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het3, in which
Het3 is optionally substituted by R121, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R12 and R13 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R121 is 1-4C-alkyl,
R14 is hydrogen or 1-4C-alkyl,
R15 is hydrogen or 1-4C-alkyl,
or R14 and R15 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het4, in which
Het4 is optionally substituted by R141, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R14 and R15 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R141 is 1-4C-alkyl,
R16 is hydrogen, 1-4C-alkyl or pyridyl,
R17 is hydrogen or 1-4C-alkyl,
or R16 and R17 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het5, in which
Het5 is optionally substituted by R161, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R16 and R17 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R141 is 1-4C-alkyl,
or,
in a second aspect (aspect 2),
R7 is —NH—N(R18)R19, in which
R18 is hydrogen,
R19 is —C(O)R20, or R21-substituted phenyl, in which
R20 is Har2, Het6, or Aryl-1-4C-alkyl, in which
Har2 is optionally substituted by R201 and/or R202, and is a 5- to 10-membered monocyclic or fused bicyclic unsaturated heteroaryl radical comprising 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, in which
R201 is 1-4C-alkyl or 1-4C-alkoxy,
R202 is 1-4C-alkyl or 1-4C-alkoxy,
Het6 is optionally substituted by R203 and/or R204, and is a monocyclic 3- to 7-membered saturated heterocyclic ring radical comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, in which
R203 is 1-4C-alkyl,
R204 is 1-4C-alkyl,
Aryl is R205- and/or R206-substituted phenyl,
R205 is 1-4C-alkoxy,
R206 is 1-4C-alkoxy,
R21 is aminosulphonyl,
or R18 and R19 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het7, in which
Het7 is optionally substituted by R181, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R18 and R19 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R181 is 1-4C-alkyl,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
3 . A compound of formula I according to claim 1 in which
R1 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is —O—R41, in which
R41 is hydrogen or 1-4C-alkylcarbonyl,
R5 is hydrogen,
R6 is hydrogen,
either,
in a first aspect (aspect 1),
R7 is —N(R8)R9, in which
R8 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl,
R9 is hydrogen, 1-4C-alkyl, mono- or di-1-4C-alkoxy-2-4C-alkyl, hydroxy-2-4C-alkyl, mono- or di-1-4C-alkoxycarbonyl-1-4C-alkyl, Har1, pyridinyl-1-4C-alkyl, 3-7C-cycloalkyl, or 2-4C-alkyl substituted by —NR(93)R94, in which
either
Har1 is optionally substituted by R91 and/or R92, and is a 9- or 10-membered fused bicyclic unsaturated heteroaryl radical comprising 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, in which
R91 is 1-4C-alkyl,
R92 is 1-4C-alkyl,
or
Har1 is optionally substituted by R91 and/or R92, and is a 6-membered monocyclic unsaturated heteroaryl radical comprising one or two nitrogen atoms, in which
R91 is 1-4C-alkoxy,
R92 is 1-4C-alkoxy,
R93 is hydrogen or 1-4C-alkyl,
R94 is hydrogen or 1-4C-alkyl,
or R93 and R94 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het1, in which
Het1 is optionally substituted by R931, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R93 and R94 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R931 is 1-4C-alkyl,
or R8 and R9 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het2, in which
Het2 is optionally substituted by R10, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R8 and R9 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R10 is 1-4C-alkyl, —C(O)R11, pyridyl, 2-4C-alkyl substituted by —NR(14)R15, or 1-4C-alkyl substituted by —C(O)N(R16)R17, in which
R11is 1-4C-alkyl substituted by —NR(12)R13, in which
R12 is hydrogen or 1-4C-alkyl,
R13 is hydrogen or 1-4C-alkyl,
or R12 and R13 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het3, in which
Het3 is optionally substituted by R121, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R12 and R13 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R121 is 1-4C-alkyl,
R14 is hydrogen or 1-4C-alkyl,
R15 is hydrogen or 1-4C-alkyl,
or R14 and R15 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het4, in which
Het4 is optionally substituted by R141, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R14 and R15 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R141 is 1-4C-alkyl,
R16 is hydrogen, 1-4C-alkyl or pyridyl,
R17 is hydrogen or 1-4C-alkyl,
or R16 and R17 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het5, in which
Het5 is optionally substituted by R161, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R16 and R17 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R141 is 1-4C-alkyl,
or,
in a second aspect (aspect 2),
R7 is —NH—N(R18)R19, in which
R18 is hydrogen,
R19 is —C(O)R20, or R21-substituted phenyl, in which
R20 is Har2, Het6, or Aryl-1-4C-alkyl, in which
Har2 is a 6-membered monocyclic unsaturated heteroaryl radical comprising one or two nitrogen atoms,
Het6 is optionally substituted by R203 and/or R204, and is a monocyclic 3- to 7-membered saturated heterocyclic ring radical comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, in which
R203 is 1-4C-alkyl,
R204 is 1-4C-alkyl,
Aryl is R205- and/or R206-substituted phenyl,
R205 is 1-4C-alkoxy,
R206 is 1-4C-alkoxy,
R21 is aminosulphonyl,
or R18 and R19 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het7, in which
Het7 is optionally substituted by R181, and is a 3- to 7-membered saturated monocyclic heterocyclic ring radical comprising the nitrogen atom, to which R18 and R19 are bonded, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, in which
R181 is 1-4C-alkyl,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
4 . A compound of formula I according to claim 1 in which
R1 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is —O—R41, in which
R41 is hydrogen,
R5 is hydrogen,
R6 is hydrogen,
either,
in a first aspect (aspect 1),
R7 is —N(R8)R9, in which
R8 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl,
R9 is 1-4C-alkyl, mono- or di-1-4C-alkoxy-2-4C-alkyl, hydroxy-2-4C-alkyl, mono- or di-1-2C-alkoxycarbonyl-1-4C-alkyl, Har1, pyridinyl-1-4C-alkyl, 3-5C-cycloalkyl, or 2-4C-alkyl substituted by —NR(93)R94, in which
Har1 is 2,6-dimethoxypyridinyl, quinolinyl, 2,3-dimethyl-imidazo[1,2-a]pyridinyl or [1,7]naphthyridinyl,
R93 and R94 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het1, in which
Het1 is morpholinyl,
or R8 and R9 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het2, in which
Het2 is pyrrolidinyl, morpholinyl or 4N—(R10)-piperazinyl, in which
R10 is —C(O)R11, pyridyl, 2-4C-alkyl substituted by —NR(14)R15, or 1-4C-alkyl substituted by C(O)N(R16)R17, in which
R11is 1-4C-alkyl substituted by —NR(12)R13, in which
R12 is 1-4C-alkyl,
R13 is 1-4C-alkyl,
or R12 and R13 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het3, in which
Het3 is morpholinyl,
R14 is 1-4C-alkyl,
R15 is 1-4C-alkyl,
or R14 and R15 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het4, in which
Het4 is morpholinyl,
R16 is 1-4C-alkyl or pyridyl,
R17 is hydrogen or 1-4C-alkyl,
or R16 and R17 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het5, in which
Het5 is pyrrolidinyl or morpholinyl,
or,
in a second aspect (aspect 2),
R7 is —NH—N(R18)R19, in which
R18 is hydrogen,
R19 is —C(O)R20, or R21-substituted phenyl, in which
R20 is pyridinyl, morpholinyl, 1N—(R203)-4N—(R204)-piperazinyl, or Aryl-1-2C-alkyl, in which
R203 is 1-4C-alkyl,
R204 is 1-4C-alkyl,
Aryl is 3,4-dimethoxyphenyl,
R21 is aminosulphonyl,
or R18 and R19 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het7, in which
Het7 is morpholinyl or 4N—(R181)-piperazinyl, in which
R181 is 1-4C-alkyl,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
5 . A compound of formula I according to claim 1 in which
R1 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-2C-alkoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is —O—R41, in which
R41 is hydrogen,
R5 is hydrogen,
R6 is hydrogen,
either,
in a first aspect (aspect 1),
R7 is —N(R8)R9, in which
R8 is hydrogen, methyl, ethyl or 2-methoxyethyl,
R9 is methyl, 2-methoxyethyl, methoxycarbonylmethyl, 1,2-di-(methoxycarbonyl)-ethyl, Har1, 2-pyridinyl-ethyl, cyclopropyl, or 2-3C-alkyl substituted by —NR(93)R94, in which
Har1 is 2,6-dimethoxypyridinyl, quinolinyl, 2,3-dimethyl-imidazo[1,2-a]pyridinyl or [1,7]naphthyridinyl,
R93 and R94 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het1, in which
Het1 is morpholinyl,
or R8 and R9 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het2, in which
Het2 is pyrrolidinyl, morpholinyl or 4N—(R10)-piperazinyl, in which
R10 is pyridyl, ethyl substituted by —NR(14)R15, or methyl substituted by —C(O)N(R16)R17, in which
R14 is methyl,
R15 is methyl,
or R14 and R15 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het4, in which
Het4 is morpholinyl,
R16 is methyl or pyridyl,
R17 is hydrogen or methyl,
or R16 and R17 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het5, in which
Het5 is pyrrolidinyl or morpholinyl,
or,
in a second aspect (aspect 2),
R7 is —NH—N(R18)R19, in which
R18 is hydrogen,
R19 is —C(O)R20, or R21-substituted phenyl, in which
R20 is pyridinyl, or morpholin-4-yl,
R21 is aminosulphonyl,
or R18 and R19 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het7, in which
Het7 is morpholinyl or 4N—(R181)-piperazinyl, in which
R181 is methyl,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
6 . A compound of formula I according to claim 1 comprising one or more of the following:
one of R1 and R2 is methoxy, and the other is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy, and
R3 and R31 are both hydrogen,
R4 is —O—R41, in which
R41 is hydrogen, or 1-4C-alkylcarbonyl and
R5 is hydrogen and
R6 is hydrogen,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
7 . A compound of formula I according to claim 1 comprising one or more of the following:
R1 is methoxy,
R2 is methoxy, ethoxy, difluoromethoxy or 2,2-difluoroethoxy, and
R3 and R31 are both hydrogen,
R4 is —O—R41, in which
R41 is hydrogen, and
R5 is hydrogen,
R6 is hydrogen, and —C(O)R7 is attached in the meta or para position with respect to the binding position in which the phenyl moiety is bonded,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
8 . A compound of formula I according to claim 1 in which
R1 is methoxy,
R2 is methoxy, ethoxy, 2,2-difluoroethoxy, or difluoromethoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is —O—R41, in which
R41 is hydrogen,
R5 is hydrogen,
R6 is hydrogen,
R7 is —N(R8)R9, in which
R8 is hydrogen, methyl, ethyl, or isopropyl,
R9 is methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl,
whereby the radical —C(O)R7 is attached in the meta or para position with respect to the binding position in which the phenyl moiety is bonded
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
9 . A compound of formula I according to claim 1 in which
R1 is methoxy,
R2 is ethoxy, 2,2-difluoroethoxy, or difluoromethoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is —O—R41, in which
R41 is hydrogen,
R5 is hydrogen,
R6 is hydrogen,
R7 is —N(R8)R9, in which
either
R8 is isopropyl, and
R9 is isopropyl,
or
R8 is hydrogen, and
R9 is cyclopropyl or cyclobutyl,
whereby the radical —C(O)R7 is attached in the meta or para position with respect to the binding position in which the phenyl moiety is bonded,
or a salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
10 . A compound of formula I according to claim 1 selected from the group consisting of
4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-N-(2-morpholin-4-yl-ethyl)-benzamide,
4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-N-(3-morpholin-4-yl-propyl)-benzamide,
4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-N-(4-methyl-piperazin-1-yl)-benzamide,
4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-N-morpholin-4-yl-benzamide,
({1-[4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-methanoyl}-methyl-amino)-acetic acid methyl ester,
4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-N-quinolin-3-yl-benzamide,
4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-N-(2-pyridin-2-yl-ethyl)-benzamide,
1-[4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-1-(4-pyridin-2-yl-piperazin-1-yl)-methanone,
1-[4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-1-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-methanone,
N-Ethyl-4-((2RS,4aRS,10bRS)-2-hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-N-(2-methoxyethyl)-benzamide,
N-Cyclopropyl-4-((2RS,4aRS,10bRS)-2-hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-benzamide,
2-(4-{1-[4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-methanoyl}-piperazin-1-yl)-1-pyrrolidin-1-yl-ethanone,
2-(4-{1-[4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-methanoyl}-piperazin-1-yl)-N-pyridin-3-yl-acetamide,
4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-N,N-dimethyl-benzamide,
2-(4-{1-[4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-methanoyl}-piperazin-1-yl)-N-pyridin-2-yl-acetamide,
2-(4-{1-[4-((2R,4aR,10bR)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-methanoyl}-piperazin-1-yl)-N,N-dimethyl-acetamide,
2-(4-{1-[4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-methanoyl}-piperazin-1-yl)-1-morpholin-4-yl-ethanone,
1-[4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-1-(4-pyridin-4-yl-piperazin-1-yl)-methanone,
1-[4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-phenyl]-1-morpholin-4-yl-methanone,
4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-N-(2-pyridin-4-yl-ethyl)-benzamide,
4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-N-(2-pyridin-3-yl-ethyl)-benzamide,
4-((2RS,4aRS,10bRS)-2-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-benzoic acid N′-(1-morpholin-4-yl-methanoyl)-hydrazide,
N-(2,6-Dimethoxy-pyridin-3-yl)-4-((2RS,4aRS,10bRS)-2-hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-benzamide,
4-[(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-N,N-dimethyl-benzamide,
N-Cyclopropyl-4-[(2RS,4aRS,10bRS)-9-(1,1-difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-benzamide,
4-[(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-N,N-bis-(2-methoxy-ethyl)-benzamide,
4-[(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide,
4-[(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-N-(3-morpholin-4-yl-propyl)-benzamide,
1-{4-[(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-phenyl}-1-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-methanone,
1-{4-[(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-phenyl}-1-(4-pyridin-4-yl-piperazin-1-yl)-methanone,
2-[4-(1-{4-[(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-phenyl}-methanoyl)-piperazin-1-yl]-N-pyridin-2-yl-acetamide,
2-[4-(1-{4-[(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-phenyl}-methanoyl)-piperazin-1-yl]-1-morpholin-4-yl-ethanone,
1-{4-[(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-phenyl}-1-pyrrolidin-1-yl-methanone,
2-[4-(1-{4-[(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-phenyl}-methanoyl)-piperazin-1-yl]-N,N-dimethyl-acetamide,
1-{4-[(2RS,4aRS,10bRS)-9-(1,1-Difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-phenyl}-1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanone,
N-(2,6-Dimethoxy-pyridin-3-yl)-4-((2R,4aR,10bR)-2-hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-benzamide,
N-(2,6-Dimethoxy-pyridin-3-yl)-4-((2S,4aS,10bS)-2-hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-benzamide,
N-Cyclopropyl-4-[(2R,4aR,10bR)-9-(1,1-difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-benzamide,
N-Cyclopropyl-4-[(2S,4aS,10bS)-9-(1,1-difluoro-methoxy)-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl]-benzamide,
N-Cyclopropyl-4-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-benzamide,
N-Cyclobutyl-4-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-benzamide,
4-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-N,N-diisopropyl-benzamide,
N-Cyclopropyl-3-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-benzamide,
N-Cyclobutyl-3-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-benzamide,
3-((2R,4aR,10bR)-9-Ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-N,N-diisopropyl-benzamide,
N-Cyclopropyl-4-((3S,4aR,10bR)-9-ethoxy-3-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-benzamide,
and the enantiomers, salts, N-oxides, salts of the N-oxides and enantiomers thereof.
11 . A compound of formula I according to claim 1 , which have with respect to the positions 4a and 10b the configuration shown in formula I*:
or a salt, N-oxide or salt of an N-oxide thereof.
12 . A compound of formula I according to claim 1 , which have with respect to the positions 2, 4a and 10b the configuration shown in formula Ia*****, or, which have with respect to the positions 3, 4a and 10b the configuration shown in formula Ib*****:
or a salt, N-oxide or salt of an N-oxide thereof.
13 . (canceled)
14 . A pharmaceutical composition comprising one or more compounds of formula I as claimed in claim 1 , or a pharmaceutically acceptable salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof, together with a pharmaceutically acceptable excipient and/or vehicle.
15 .- 16 . (canceled)
17 . A method for treating an illness in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula I as claimed in claim 1 , or a pharmaceutically acceptable salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
18 . A method for treating an airway disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula I as claimed in claim 1 , or a pharmaceutically acceptable salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.
19 . A method for treating a PDE-mediated disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula I as claimed in claim 1 , or a pharmaceutically acceptable salt, enantiomer, N-oxide, salt of an N-oxide or enantiomer thereof.