Piperazino-derivatives and their use as pde4 inhibitor
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Abstract
The compounds of formula I, in which R1, R2, R3, A, X, s and R9 have the meanings as given in the description are novel effecfive PDE4 inhibitors.
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Citations
14 Claims
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1.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
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2. Compounds of formula I according to claim 1 in which
R1 and R2 are both hydrogen or together form an additional bond, R3 represents a benzene derivative of formula (a) or (b) wherein R4 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine, R5 is 14C-alkoxy, R6 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine, R7 is methyl and R8 is hydrogen, or wherein R7 and R8 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofurane or tetrahydropyran ring, A is a bond or methylene (— - CH2—
),R9 is —
C(O)R10, —
(CH2)m—
C(O)R11, —
(CH2)nR12, Aryl, Hetaryl, phenylprop-1-en-3-yl or 1-methylpiperidin-4-yl,R10 hydrogen, 1-4C-alkyl, —
OR13, furanyl, indolyl, pyridyl or pyridyl substituted by R18 and/or R19,R11 is —
N(R14)R15,R12 is —
N(R14)R15, tetrahydrofuranyl or pyridinyl,R13 is 1-4C-alkyl, R14 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, R15 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or R14 and R15 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring, Aryl is phenyl, pyridyl, pyrimidinyl, phenyl substituted by R16 and/or R17, pyridyl substituted by R18 and/or R19, R16 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R17 is halogen or 14C-alkyl, R18 Is halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R19 is halogen or 1-4C-alkyl, Hetaryl is indol-4-yl, 2-methyl-quinolin-4-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl, 3-phenyl-1,2,4-thiadiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl, n is an integer from 1 to 4, m is an integer from 1 to 4, s is 1, X is —
C(O) or —
S(O)2—
,and the salts of these compounds.
- CH2—
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3. Compounds of formula I according to claim 1 in which
R1 and R2 together form an additional bond, R3 represents a benzene derivative of formula (a) or (b) wherein R4 is methoxy or ethoxy, R5 is methoxy or ethoxy, R6 is methoxy, R7 is methyl and R8 is hydrogen, or wherein R7 and R8 together and with inclusion of the two carbon atoms, to which they are bonded, form a cyclopentane or cyclohexan ring, A is a bond or methylene (— - CH2—
),R9 is phenyl, pyrid-2-yl, pyrid-4-yl, pyrimidin-2-yl, 3-dimethylaminopropyl, 2-dimethylaminoethyl, dimethylaminocarbonylmethyl, furan-2-yl-methanoyl, fonmyl, ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin-4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-morpholin-4-yl-2-oxo-ethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 1 H-indol-4-yl, tetrahydrofuran-2-ylmethyl, 2-(pyrrolidin-1-yl)-ethyl, pyridin-4-ylmethyl, 2-methyl-quinolin-4-yl, 1-methyl-piperidin-4-yl, 5-trifluoromethyl-pyridin-2-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 3-o-tolyl-1,2,4-thiadiazol-5-yl or (E)-3-phenylallyl, s is1, X is —
C(O)—
or —
S(O)2—
,and the salts of these compounds.
- CH2—
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4. Compounds of formula I according to claim 1 in which
R1 and R2 together form an additional bond, R3 represents a benzene derivative of formula (a) or (b) wherein R4 is methoxy or ethoxy, R5 is methoxy or ethoxy, R6 is methoxy, R7 is methyl and R8 is hydrogen, A is a bond, R9 is phenyl, pyrid-2-yl, pyrid4-yl, 3-dimethylaminopropyl, 2-dimethylaminoethyl, dimethylaminocarbonylmethyl, furan-2-yl-methanoyl, formyl, ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin-4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-morpholin-4-yl-2-oxo-ethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 1H-indol-4-yl, tetrahydrofuran-2-ylmethyl, 2-(pyrrolidin-1-yl)ethyl, pyridin-4-ylmethyl, 2-methyl-quinolin-4-yl, 1-methyl-piperidin-4-yl, 5-trifluoromethyl-pyridin-2-yl, 5chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 3-o-tolyl-1,2,4-thiadiazol-5-yl or (E)-3-phenylallyl, s is 1, X is — - C(O)—
,and the salts of these compounds.
- C(O)—
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5. Compounds of formula I according to claim 1 in which
R1 and R2 together form an additional bond, R3 represents a benzene derivative of formula (b) wherein R6 is methoxy, R7 is methyl and R8 is hydrogen, A is methylene (— - CH2—
),R9 is pyrimidin-2-yl, 3-dimethylaminopropyl or 2-(morpholin-4-yl)ethyl, s is 1, X is —
C(O)—
,and the salts of these compounds.
- CH2—
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6. Compounds of formula I according to claim 1 in which
R1 and R2 are both hydrogen or together form an additional bond, R3 represents a benzene derivative of formula (a) or (b) wherein R4 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine, R5 is 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine, R6 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine, R7 is 1-4C-alkyl and R8 is hydrogen or 1-4C-alkyl, or wherein R7 and R8 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen or sulphur atom, A is a bond, R9 is — - C(O)R10, —
(CH2)m—
C(O)R11, —
(CH2)nR12, Aryl, Hetaryl, phenylprop-1-en-3-yl or 1-methyl-piperidin-4-yl,R10 hydrogen, 1-4C-alky, —
OR13, furanyl, indolyl, phenyl, pyridyl, phenyl substituted by R16 and/or R17 or pyridyl substituted by R18 and/or R19,R11 is —
N(R14)R15,R12 is —
N(R14)R15, tetrahydrofuranyl or pyridinyl,R13 is 1-4C-alkyl, R14 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, R15 is hydrogen or 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or R14 and R15 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholiny-, 1-pyrrolidiny-, 1-piperidinyl- or 1-hexahydroazepinyl-ring, Aryl is phenyl, pyridyl, phenyl substituted by R16 and/or R17, pyridyl substituted by R18 and/or R19, R16 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R17 is halogen or 1 4C-alkyl, R18 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R19 is halogen or 1-4C-alkyl, Hetaryl is indol4-yl, 2-methyl-quinolin4-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin4-yl or 3-phenyl-1,2,4-thiadiazol-5-yl, n is an integer from 1 to 4, m is an integer from 1 to 4, s is an integer from 1 to 2, X is —
C(O)—
or —
S(O)2—
,and the salts of these compounds.
- C(O)R10, —
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7. Compounds of formula I according to claim 1 in which
R1 and R2 are both hydrogen or together form an additional bond, R3 represents a benzene derivative of formula (a) or (b) wherein R4 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine, R5 is 1-4C-alkoxy, R6 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine, R7 is methyl and R8 is hydrogen, or wherein R7 and R8 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofurane or tetrahydropyran ring, A is a bond, R9 is — - C(O)R10, —
(CH2)m—
C(O)R11, —
(CH2)nR12, Aryl, Hetaryl, phenylprop-1-en-3-yl or 1-methyl-piperidin-4-yl,R10 hydrogen, 1-4C-alkyl, —
OR13, furanyl, indolyl, pyridyl or pyridyl substituted by R18 and/or R19,R11 is —
N(R14)R15,R12 is —
N(R14)R15, tetrahydrofuranyl or pyridinyl,R13 is 1-4C-alkyl, R14 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, R15 is hydrogen or 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or R14 and R15 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring, Aryl is phenyl, pyridyl, phenyl substituted by R16 and/or R17, pyridyl substituted by R18 and/or R19, R16 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R17 is halogen or 1-4C-alkyl, R18 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R19 is halogen or 1-4C-alkyl, Hetaryl is indol-4-yl, 2-methyl-quinolin-4-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl or 3-phenyl-1,2,4-thiadiazol-5-yl, n is an integer from 1 to 4, m is an integer from 1 to 4, s is 1, X is —
C(O)—
or —
S(O)2—
,and the salts of these compounds.
- C(O)R10, —
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8. Compounds of formula I according to claim 1 in which
R1 and R2 together form an additional bond, R3 represents a benzene derivative of formula (a) or (b) wherein R4 is methoxy or ethoxy, R5 is methoxy or ethoxy, R6 is methoxy, R7 is methyl and R8 is hydrogen, or wherein R7 and R8 together and with inclusion of the two carbon atoms, to which they are bonded, form a cyclopentane or cyclohexan ring, A is a bond, R9 is phenyl, pyrid-2-yl, dimethylaminopropyl, dimethylaminoethyl, furan-2-yl-methanoyl, formyl, ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, indol-4-yl, tetrahydrofuran-2-ylmethyl, 2-(pyrrolidin-1-yl)ethyl, pyridin-4-ylmethyl, 2-methyl-quinolin-4-yl, 1-methyl-piperidin-yl, 5-trifluoromethyl-pyridin-2-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl, 3-phenyl-1,2,4-thiadiazol-5-yl or phenylprop-1-en-3-yl, s is 1, X is — - C(O)—
or —
S(O)2—
,and the salts of these compounds.
- C(O)—
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9. Compounds of formula I according to claim 1 in which
R1 and R2 together form an additional bond, R3 represents a benzene derivative of formula (a) or (b) wherein R4 is methoxy or ethoxy, R5 is methoxy or ethoxy, R6 is methoxy, R7 is methyl and R8 is hydrogen, A is a bond, R9 is phenyl, pyrid-2-yl, dimethylaminoethyl, dimethylaminopropyl, furan-2-yl-methanoyl, formyl, ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin-4-yl, 2-(morpholin-4-yl)ethyl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl, 3-phenyl-1,2,4-thiadiazol-5-yl or phenylprop-1-en-3-yl, s is 1, X is — - C(O)—
or —
S(O)2—
,and the salts of these compounds.
- C(O)—
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10. Compounds of formula I according to one of the claims 1 to 8 in which the hydrogen atoms in the positions 4a and 8a are cis-configurated.
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11. Compounds of formula I according to one of the claims 1 to 8 in which the absolute configuration (according to the rules of Cahn, Ingold and Prelog) is S in the position 4a and R in the position 8a.
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12. Compounds of formula I according to claim 1 for the treatment of diseases.
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13. Medicaments containing one or more compounds of formula I according to claim 1 together with the usual pharmaceutical auxiliaries and/or carrier materials.
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14. Use of compounds of formula I according to claim 1 for the preparation of medicaments for the treatment of airway disorders.
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2. Compounds of formula I according to claim 1 in which
Specification
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Current AssigneeAtlanta Pharma AG
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Original AssigneeAtlanta Pharma AG
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InventorsSchmidt, Beate, Sterk, Geert Jan, Grundler, Gerhard
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/218
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CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 1/04 for ulcers, gastritis or re...A61P 11/00 Drugs for disorders of the ...A61P 11/02 Nasal agents, e.g. deconges...A61P 11/06 AntiasthmaticsA61P 11/08 BronchodilatorsA61P 13/04 for urolithiasisA61P 15/10 for impotenceA61P 17/00 Drugs for dermatological di...A61P 17/04 AntipruriticsA61P 17/06 AntipsoriaticsA61P 17/08 AntiseborrheicsA61P 17/10 Anti-acne agentsA61P 17/14 for baldness or alopeciaA61P 17/16 Emollients or protectives, ...A61P 19/02 for joint disorders, e.g. a...A61P 25/16 Anti-Parkinson drugsA61P 25/24 AntidepressantsA61P 25/28 for treating neurodegenerat...A61P 27/14 Decongestants or antiallergicsA61P 29/00 : Non-central analgesic, anti...A61P 31/04 : Antibacterial agentsA61P 31/18 : for HIVA61P 37/02 : ImmunomodulatorsA61P 37/06 : Immunosuppressants, e.g. dr...A61P 37/08 : Antiallergic agents antiast...A61P 43/00 : Drugs for specific purposes...A61P 7/12 : Antidiuretics, e.g. drugs f...A61P 9/04 : Inotropic agents, i.e. stim...C07D 237/32 : with oxygen atoms directly ...C07D 401/04 : directly linked by a ring-m...C07D 401/14 : containing three or more he...C07D 403/04 : directly linked by a ring-m...C07D 405/04 : directly linked by a ring-m...C07D 413/14 : containing three or more he...C07D 417/04 : directly linked by a ring-m...