WO2004018449A1 - Derives de piperidine utilises comme inhibiteurs de la phospodiesterase-4 (pde4) - Google Patents

Derives de piperidine utilises comme inhibiteurs de la phospodiesterase-4 (pde4) Download PDF

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WO2004018449A1
WO2004018449A1 PCT/EP2003/008673 EP0308673W WO2004018449A1 WO 2004018449 A1 WO2004018449 A1 WO 2004018449A1 EP 0308673 W EP0308673 W EP 0308673W WO 2004018449 A1 WO2004018449 A1 WO 2004018449A1
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alkoxy
halogen
hydrogen
alkyl
substituted
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PCT/EP2003/008673
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WO2004018449A8 (fr
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Geert Jan Sterk
Steffen Weinbrenner
Armin Hatzelmann
Johannes Barsig
Degenhard Marx
Hans-Peter Kley
Johannes A. M. Christiaans
Wiro M.P.B. Menge
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Altana Pharma Ag
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Priority to AU2003255376A priority Critical patent/AU2003255376A1/en
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Publication of WO2004018449A8 publication Critical patent/WO2004018449A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to novel pipendine derivatives, which are used in the pharmaceutical industry for the production of pharmaceutical compositions.
  • R1 and R2 are both hydrogen or together form an additional bond
  • R3 represents a phenyl derivative of formulae (a) or (b)
  • R4 is 1 -4C-alkoxy or 1 -4C-aIkoxy 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-aIkyl
  • R8 is hydrogen or 1-4C-alkyl
  • 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,
  • R9 is -S(O) 2 -R10
  • R10 is phenyl substituted by R11 , R12 and R13, phenyl-1-4C-alkyl, phenyl-1-4C-a!kyl substituted in the phenyl moiety by R14, R15 and R16, aryl, aryl substituted by R17, R18 and R19, aryl-1-4C- alkyl, aryl-1-4C-alkyl substituted in the aryl moiety by R17, R18 and R19, naphthalenyl, naphtha- lenyl substituted by R20, R21 and R22, naphthalenyl-1-4C-alkyl substituted by R17, R18 and R19, 4-benzenesulfonyl-thiophene-2-yl, 5-(phenylcarbonylaminomethyl)thiophene-2-yl, 5-(pyridin- 2-yl)thiophen-2-yl or 5-isoxazol-3-yl-thiophen-2-y
  • R11 is 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R12 is hydrogen, halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-aIkylcarbonylamino or mono-or di-1-4C-alkylamino- carbonyl,
  • R13 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy
  • R14 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl, amino, mono-or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkylcarbonylamino or mono- or di-1-4C-alkylaminocar- bonyl,
  • R15 is hydrogen, halogen, amino, nitro, 1-4C-alkyI or 1-4C-alkoxy
  • R16 is hydrogen or halogen
  • R17 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-aIkoxycarbonyl, amino, mono-or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkylcarbonylamino or mono- or di-1-4C-alkylaminocar- bonyl,
  • R18 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy
  • R19 is hydrogen or halogen
  • R20 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl, aminocarbonyl, 1-4C- alkylcarbonylamino or mono-or di-1-4C-alkylaminocarbonyl,
  • R21 is hydrogen, halogen, nitro, 1-4C-alkyl or 1-4C-alkoxy
  • R22 is hydrogen or halogen
  • Aryl is pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, quinolyl, isoqui- nolyl, phthalazinyl, indanyl, indolyl, isoindolyl, indazolyl, chromalyl, isochromanyl, purinyl, pteridi- nyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxa- zolyl, thiazolyl, isothiazolyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl or thiophenyl, and the salts of these compounds.
  • 1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
  • 1-4C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
  • Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned in this context are, for example, the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, iso- propoxy, ethoxy and methoxy radicals.
  • 1-8C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 8 carbon atoms.
  • Alkoxy radicals having 1 to 8 carbon atoms which may be mentioned in this context are, for example, the octyloxy, heptyloxy, isoheptyloxy (5-methylhexyloxy), hexyloxy, isohexyloxy (4-methylpentyloxy), neohexyloxy (3,3-dimethylbutoxy), pentyioxy, isopentyloxy (3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
  • 3-7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cyclo- heptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
  • 3-7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclo- hexylmethoxy or cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
  • 3-5C-CycloaIkoxy stands for cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.
  • 3-5C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy.
  • 1-4C-Alkoxy which is completely or predominantly substituted by fluorine is, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy and in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxy radical, of which the difluoromethoxy radical is preferred.
  • "Predominantly" in this connection means that more than half of the hydrogen atoms of the 1-4C-alkoxy group are replaced by fluorine atoms.
  • spiro-linked 5-, 6- or 7-membered hydrocarbon rings optionally interrupted by an oxygen or sulphur atom
  • the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahydro- pyran and the tetrahydrothiophen ring may be mentioned the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahydro- pyran and the tetrahydrothiophen ring.
  • Halogen within the meaning of the present invention is bromine, chlorine or fluorine.
  • 1-4C-Alkoxycarbonyl is a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxycarbonyl [CH 3 0-C(0) ⁇ ] and the ethoxycar- bonyl [CH 3 CH 2 0-C(0)-] radical.
  • An 1-4C-Alkylcarbonylamino radical is, for example, the propionylamino [C 3 H 7 C(0)NH-] and the ace- tylamino radical [CH 3 C(0)NH-].
  • Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogen atom, one or two of the above- mentioned 1-4C-alkyl radicals.
  • Mono- or Di-1-4C-alkylaminocarbonyl radicals contain in addition to the carbonyl group one of the abovementioned mono- or di-1-4C-alkylamino radicals. Examples which may be mentioned are the N-methyl- the N,N-dimethyl-, the N-ethyl-, the N-propyl-, the N,N-diethyl- and the N-isopropylaminocar- bonyl radical.
  • Phenyl-1-4C-alkyl radicals stand for one of the abovementioned 1-4C-alkyl radicals substituted by an phenyl group. Examples which may be mentioned are the phenylethyl and the benzyl radical.
  • Aryl-1-4C-aIkyl radicals stand for one of the abovementioned 1-4C-aIkyl radicals substituted by an Aryl group. Examples which may be ' mentioned are the pyrid-3-ylmethyl and the pyrid-4-ylmethyl radical.
  • Suitable salts for compounds of the formula 1 are all acid addition salts. Particular mention may be made of the pharmacologically tolerable inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-giuconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonic acid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether a mono- or polybasic acid is concerned and depending on which salt is
  • Pharmacologically intolerable salts which can be obtained, for example, as process products during the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
  • the compounds of the invention as well as their salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula 1 as well as all solvates and in particular all hydrates of the salts of the compounds of formula 1.
  • 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
  • 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,
  • R9 is -S(O) 2 -R10
  • R10 is phenyl substituted by R11 , R12 and R13, phenylethyl, benzyl, benzyl substituted in the phenyl moiety by R14, R15 and R16, aryl, aryl substituted by R17, R18 and R19, arylmethyl, arylmethyl substituted in the aryl moiety by R17, R18 and R19, naphthalenyl, naphthalenyl substituted by
  • R11 is 1 -4C-alkoxy which is completely or predominantly substituted by fluorine
  • R12 is hydrogen, halogen, nitro, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine or 1-4C-alkoxycarbonyl
  • R13 is hydrogen or halogen
  • R14 is halogen, nitro, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine or 1-4C-alkoxycarbonyl
  • R15 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R16 is hydrogen or halogen
  • R17 is halogen, nitro, cyano, 1-4C-alkyl, triflu
  • Preferred compounds of formula 1 are those, in which
  • R3 represents a phenyl derivative of formulae (a) or (b)
  • R4 is 1-2C-alkoxy
  • R5 is 1-4C-alkoxy
  • R6 is 1-2C-alkoxy
  • R7 is methyl
  • R8 is hydrogen
  • R9 is -S(O) 2 -R10
  • R10 is phenyl substituted by R11 , benzyl, aryl, aryl substituted by R17, R18 and R19, naphthalenyl,
  • R11 is 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R17 is halogen, 1 -4C-alkyl, 1 -4C-alkoxy or 1 -4C-alkoxycarbonyl
  • R18 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R19 is hydrogen or halogen
  • Aryl is pyridinyl, quinolyl, isoquinolyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl,
  • Particularly preferred compounds of formula 1 are those in which R1 and R2 together form an additional bond, R3 represents a phenyl derivative of formula (a)
  • R4 is methoxy
  • R5 is methoxy
  • R9 is naphthalene-1-sulfonyl, phenylmethanesulfonyl, 5-chloro-1 ,3-dimethyl-1 H-pyrazole-4-sulfonyl, quinolin-8-sulfonyl, thiophene-2-sulfonyl, 3,5-dimethyl-isoxazole-4-suifonyl, 5-chloro-thiophene-2- sulfonyl, 2-trifluoromethoxybenzene-2-sulfonyl, 3-methoxy-4-methoxycarbonyl-thiophene-2-sul- fonyl, 4-benzenesuifonyl-thiophene-2-sulfonyl, 5-(phenylcarbonylaminomethyl)thiophene-2-sul- fonyl, 5-isoxazol-3-yl-thiophene-2-sulfonyl, 4,5-dichloro-
  • 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
  • R8 is hydrogen or 1-4C-alkyl
  • 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,
  • R9 is -S(O) 2 -R10
  • R10 is phenyl substituted by R11 , R12 and R13, phenyl-1-4C-alkyl, phenyl-1-4C-alkyl substituted in the phenyl moiety by R14, R15 and R16, aryl, aryl substituted by R17, R18 and R19, aryl-1-4C- alkyl, aryl-1-4C-alkyl substituted in the aryl moiety by R17, R18 and R19, naphthalenyl, naphthalenyl substituted by R20, R21 and R22, naphthalenyl- 1-4C-alkyl substituted by R17, R18 and R19, 4-benzenesulfonyl-thiophene-2-yl, 5-(phenylcarbonylaminomethyl)thiophene-2-yl or 5-isoxa- zol-3-yl-thiophen-2-yl,
  • R11 is 1 -4C-alkoxy which is completely or predominantly substituted by fluorine
  • R12 is hydrogen, halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl, 1-4C-a!kylcarbonylamino or mono-or di-1-4C-alkylamino- carbonyl,
  • R13 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy
  • R14 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1 -4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl, amino, mono-or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkylcarbonylamino or mono- or di-1-4C-alkylaminocar- bonyl,
  • R15 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy
  • R16 is hydrogen or halogen
  • R17 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-aIkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl, amino, mono-or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkylcarbonylamino or mono- or di-1-4C-alkylaminocar- bonyl, R18 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy, R19 is hydrogen or halogen, R20 is halogen, nitro, cyano, carboxyl, 1-4C-aIkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl, aminocarbonyl, 1-4C- alkylcarbonylamino or mono-
  • 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
  • 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
  • R9 is -S(O) 2 -R10
  • R10 is phenyl substituted by R11 , R12 and R13, phenylethyl, benzyl, benzyl substituted in the phenyl moiety by R14, R15 and R16, aryl, aryl substituted by R17, R18 and R19, arylmethyl, arylmethyl substituted in the aryl moiety by R17, R18 and R19, naphthalenyl, naphthalenyl substituted by R20, R21 and R22, naphthalenylmethyl substituted in the naphthalenyl moiety by R17, R18 and R19, 4-benzenesul
  • R11 is 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R12 is hydrogen, halogen, nitro, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine or 1-4C-alkoxycarbonyl,
  • R13 is hydrogen or halogen
  • R14 is halogen, nitro, cyano, 1-4C-alkyI, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine or 1-4C-alkoxycarbonyl,
  • R15 is hydrogen, halogen, 1 -4C-alkyl or 1 -4C-alkoxy
  • R16 is hydrogen or halogen
  • R17 is halogen, nitro, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1 -4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl,
  • R18 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R19 is hydrogen or halogen
  • R20 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine or 1 -4C-alkoxycarbonyl,
  • R21 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R22 is hydrogen or halogen
  • Aryl is pyridinyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl, indolyl, indazolyl, purinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazo- lyl, pyrrolyl, pyrazolyl, furanyl or thiophenyl, and the salts of these compounds.
  • R3 represents a phenyl derivative of formulae (a) or (b)
  • R4 is 1-2C-alkoxy
  • R5 is 1-4C-alkoxy
  • R6 is 1-2C-alkoxy
  • R7 is methyl
  • R8 is hydrogen
  • R9 is -S(O) 2 -R10
  • R10 is phenyl substituted by R11 , benzyl, aryl, aryl substituted by R17, R18 and R19, naphthalenyl,
  • R11 is 1 -4C-alkoxy which is completely or predominantly substituted by fluorine
  • R17 is halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl
  • R18 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R19 is hydrogen or halogen
  • Aryl is pyridinyl, quinolyl, isoquinolyl, indolyl, indazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, ben- zimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyi, imidazolyl, pyrrolyl, pyr
  • FIG. 1 Another embodiment (embodiment B) of the compounds of formula 1 are those in which R1 and R2 are both hydrogen or together form an additional bond, R3 represents a phenyl derivative of formulae (a) or (b)
  • 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
  • R8 is hydrogen or 1-4C-alkyl
  • 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, R9 is -S(O) 2 -R10,
  • R10 is phenyl substituted by R11 , R12 and R13,
  • R11 is 1 -4C-alkoxy which is completely or predominantly substituted by fluorine
  • R12 is hydrogen, halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl, 1 -4C-alky!carbony!amino or mono-or di-1-4C-alkylamino- carbonyl,
  • R13 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy, and the salts of these compounds.
  • R4 is 1-2C-alkoxy
  • R5 is 1-4C-alkoxy
  • R9 is -S(O) 2 -R10
  • R10 is phenyl substituted by R11 , R12 and R13,
  • R11 is 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R12 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R13 is hydrogen, and the salts of these compounds.
  • R4 is methoxy
  • R5 is methoxy
  • R9 is -S(O) 2 -R10
  • R10 is phenyl substituted by R11 , R12 and R13
  • R11 is trifluoromethoxy
  • R12 is hydrogen
  • R13 is hydrogen, and the salts of these compounds.
  • a further embodiment (embodiment C) of the compounds of formula 1 are those in which R1 and R2 are both hydrogen or together form an additional bond, R3 represents a phenyl derivative of formulae (a) or (b)
  • 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-cycloalky!methoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R6 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycIoalkylmethoxy, 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,
  • R9 is -S(O) 2 -R10
  • R10 is aryl, aryl substituted by R17, R18 and R19, aryl-1-4C-alkyl, aryl-1-4C-alkyl substituted in the aryl moiety by R17, R18 and R19, 4-benzenesulfonyl-thiophene-2-yl, 5- (phenylcarbonylaminomethyl)thiophene-2-yl, 5-(pyridin-2-yl)thiophen-2-yl or 5-isoxazol-3-yl- thiophen-2-yl,
  • R17 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl, amino, mono-or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkylcarbonylamino or mono- or di-1-4C-alkylaminocar- bonyl,
  • R18 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy
  • R19 is hydrogen or halogen
  • Aryl is pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, quinolyl, isoquinolyl, phthalazinyl, indanyl, indolyl, isoindolyl, indazolyl, chromalyl, isochromanyl, purinyl, pterid- inyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl or thiophenyl, and the salts of these compounds.
  • R4 is 1-2C-alkoxy
  • R5 is 1-4C-alkoxy
  • R9 is -S(O) 2 -R10
  • R10 is aryl, aryl substituted by R17, R18 and R19, 4-benzenesulfonyI-thiophene-2-yl
  • R4 is methoxy
  • R5 is methoxy
  • R9 is -S(O) 2 -R10
  • R10 is aryl, aryl substituted by R17, R18 and R19, 4-benzenesulfonyl-thiophene-2-yl, 5-(phenylcarbonylaminomethyl)thiophene-2-yl, 5-(pyridin-2-yl)thiophen-2-yl or 5-isoxazol-3-yl- thiophen-2-yl,
  • R17 is halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,
  • R18 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R19 is hydrogen
  • Aryl is quinolyl, benzothiophenyl, isoxazolyl, pyrazolyl or thiophenyl, and the salts of these compounds.
  • 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,
  • R9 is -S(O) 2 -R10
  • R10 is phenyl-1-4C-alkyl, phenyl- 1-4C-alkyl substituted in the phenyl moiety by R14, R15 and R16, naphthalenyl, naphthalenyl substituted by R20, R21 and R22 or naphthalenyl-1-4C-alkyl substituted by R17, R18 and R19,
  • R14 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl, amino, mono-or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkylcarbonylamino or mono- or di-1-4C-alkylaminocar- bonyl,
  • R15 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy
  • R16 is hydrogen or halogen
  • R17 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkoxycarbonyl, amino, mono-or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkylcarbony!amino or mono- or di-1-4C-alkylaminocar- bonyl,
  • R18 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy
  • R19 is hydrogen or halogen, and the salts of these compounds.
  • R4 is 1-2C-alkoxy
  • R5 is 1-4C-alkoxy
  • R9 is -S(O) 2 -R10
  • R10 is benzyl, benzyl substituted in the phenyl moiety by R14, R15 and R16, naphthalenyl or naphthalenyl substituted by R20, R21 and R22,
  • R14 is halogen, 1-4C-aIkyl or 1-4C-alkoxy
  • R15 is hydrogen, halogen, 1-4C-alkyl or 1-4C-aIkoxy
  • R16 is hydrogen
  • R20 is halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R21 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R22 is hydrogen, and the salts of these compounds.
  • R4 is methoxy
  • R5 is methoxy
  • R9 is -S(O) 2 -R10
  • R10 is benzyl or naphthalenyl, and the salts of these compounds.
  • a special embodiment of the compounds of the present invention include those compounds of formula 1 in which R3 represents a phenyl derivative of formula (a).
  • Another special embodiment of the compounds of the present invention include those compounds of formula 1 in which R3 represents a phenyl derivative of formula (a) and R4 and R5 have the meaning methoxy.
  • Still another special embodiment of the compounds of the present invention include those compounds of formula 1 in which R1 and R2 together form an additional bond, R3 represents a phenyl derivative of formula (a) and R4 and R5 have the meaning methoxy.
  • the compounds of formula 1 are chiral compounds. Chiral centers exist in the compounds of formula 1 in the positions 4a and 8a.
  • R3 represents a phenyl derivative of formula (b) there is one further chiral center in the dihydrofuran-ring, if the substituents -R7 and -CH 2 R8 are not identical.
  • preferred are in this connection those compounds, in which the substituents -R7 and -CH 2 R8 are identical or together and with inclusion of the two carbon atoms to which they are bonded form a spiro- connected 5-, 6- or 7-membered hydrocarbon ring.
  • the invention includes all conceivable pure diastereomers and pure enantiomers of the compounds of formula 1 , as well as all mixtures thereof independent from the ratio, including the race- mates.
  • Preferred are those compounds of formula 1, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated.
  • Particular preferred in this connection are those compounds, 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. Racemates can be split up into the corresponding enantiomers by methods known by a person skilled in the art.
  • racemic mixtures are separated into two diastereomers during the preparation with the help of an optical active separation agent on the stage of the cyclohexane- carboxylic acids or the 1 ,2,3,6-tetrahydrobenzoic acids (for example, starting compounds A7, A8 and A9).
  • an optical active separation agent on the stage of the cyclohexane- carboxylic acids or the 1 ,2,3,6-tetrahydrobenzoic acids (for example, starting compounds A7, A8 and A9).
  • the compounds according to the invention can be prepared, for example, as described in Reaction scheme 1.
  • Reaction scheme 1 shows that the compounds of formula 1 can be, for example, prepared starting from 4-oxo-piperidine-1 -carboxylic acid tert-butyl ester which is reacted in a first reaction step with tert- butylcarbazate to give 4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1 -carboxylic acid tert-butyl ester (starting compound A6).
  • Compound A6 is reduced with, for example, the boran tetrahydrofurane com- plex to give 4-(N'-tert-Butoxycarbonyl-hydrazino)-piperidine-1 -carboxylic acid tert-butyl ester (starting compound A5).
  • Treatment of compound A5 with concentrated hydrochloric acid results in the formation of piperidin-4-yl-hydrazine dihydrochloride (starting compound A4).
  • the substances according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallising 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.
  • Salts are obtained by dissolving the free compound in a suitable solvent (for example a ketone like acetone, methylethylketone, or methylisobutylketone, an ether, like diethyl ether, tetrahydrofuran or diox- ane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol, such as ethanol, isopropanol) which contains the desired acid, or to which the desired acid is then added.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basification into the free compounds which, in turn, can be converted into salts. In this manner, pharmacologically non- tolerable salts can be converted into pharmacologically tolerable salts.
  • MS atmospheric pressure chemical ionization mass spectrometry (APCI-MS).
  • h stands for hour(s), RT for room temperature and calc. for calculated.
  • Detection was carried out by UV at 220 nm.
  • the compounds according to the invention have useful pharmacological properties which make them industrially utilizable.
  • selective cyclic nucleotide phosphodiesterase (PDE) inhibitors specifically of type 4
  • they are suitable on the one hand as bronchial therapeutics (for the treatment of airway obstructions on account of their dilating action but also on account of their respiratory rate- or respiratory drive-increasing action) and for the removal of erectile dysfunction on account of their vascular dilating action, but on the other hand especially for the treatment of disorders, in particular of an inflammatory nature, e.g.
  • the compounds according to the invention are distinguished by a low toxicity, a good enteral absorption (high bioavailability), a large therapeutic breadth and the absence of significant side effects.
  • the compounds according to the invention can be employed in human and veterinary medicine as therapeutics, where they can be used, for example, for the treatment and prophylaxis of the following illnesses: acute and chronic (in particular inflammatory and allergen-induced) airway disorders of varying origin (bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD); dermatoses (especially of proliferative, inflammatory and allergic type) such as psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and widespread pyodermias, endogenous and exogenous acne, acne rosacea and other prolife
  • the compounds of the invention are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alz- heimer's disease), memory impairment associated with Parkinson's disease or multiinfarct dementia; and also illnesses of the central nervous system, such as depressions or arteriosclerotic dementia.
  • cerebral metabolic inhibition such as cerebral senility, senile dementia (Alz- heimer's disease), memory impairment associated with Parkinson's disease or multiinfarct dementia
  • illnesses of the central nervous system such as depressions or arteriosclerotic dementia.
  • the invention further relates to a method for the treatment of mammals, including humans, which are suffering from one of the above mentioned illnesses.
  • the method is characterized in that a therapeutically active and pharmacologically effective and tolerable amount of one or more of the compounds according to the invention is administered to the ill mammal.
  • the invention further relates to the compounds according to the invention for use in the treatment and/or prophylaxis of illnesses, especially the illnesses mentioned.
  • the invention also relates to the use of the compounds according to the invention for the production of pharmaceutical compositions which are employed for the treatment and/or prophylaxis of the illnesses mentioned.
  • the invention furthermore relates to pharmaceutical compositions for the treatment and/or prophylaxis of the illnesses mentioned, which contain one or more of the compounds according to the invention.
  • the invention relates to an article of manufacture, which comprises packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective for antagonizing the effects of the cyclic nucleotide phosphodiesterase of type 4 (PDE4), ameliorating the symptoms of an PDE4-mediated disorder, and wherein the packaging material comprises a label or package insert which indicates that the pharmaceutical agent is useful for preventing or treating PDE4-mediated disorders, and wherein said pharmaceutical agent comprises one or more compounds of formula 1 according to the invention.
  • the packaging material, label and package insert otherwise parallel or resemble what is generally regarded as standard packaging material, labels and package inserts for pharmaceuticals having related utilities.
  • compositions are prepared by processes which are known per se and familiar to the person skilled in the art.
  • the compounds according to the invention are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries and/or excipients, e.g. in the form of tablets, coated tablets, capsules, cap- lets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, the active compound content advantageously being between 0.1 and 95% and where, by the appropriate choice of the auxiliaries and/or excipients, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active compound and/or to the desired onset of action can be achieved.
  • suitable pharmaceutical auxiliaries and/or excipients e.g. in the form of tablets, coated tablets, capsules, cap- lets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, the active compound content advantageously being
  • auxiliaries or excipients which are suitable for the desired pharmaceutical formulations on account of his/her expert knowledge.
  • gel for- mers, ointment bases and other active compound excipients for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers, colorants, complexing agents or permeation promoters, can be used.
  • compositions according to the invention may be performed in any of the generally accepted modes of administration available in the art.
  • suitable modes of administration include intravenous, oral, nasal, parenteral, topical, transdermal and rectal delivery. Oral delivery is preferred.
  • the compounds according to the invention are preferably also administered by inhalation in the form of an aerosol; the aerosol particles of solid, liquid or mixed composition preferably having a diameter of 0.5 to 10 ⁇ m, advantageously of 2 to 6 ⁇ m.
  • Aerosol generation can be carried out, for example, by pressure-driven jet atomizers or ultrasonic atomizers, but advantageously by propellant-driven metered aerosols or propellant-free administration of micronized active compounds from inhalation capsules.
  • the administration forms additionally contain the required excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
  • propellants e.g. Frigen in the case of metered aerosols
  • surface-active substances e.g. Frigen in the case of metered aerosols
  • emulsifiers emulsifiers
  • stabilizers emulsifiers
  • preservatives e.g., emulsifiers, stabilizers, preservatives
  • flavorings e.g. lactose in the case of powder inhalers
  • fillers e.g. lactose in the case of powder inhalers
  • the compounds according to the invention are in particular administered in the form of those pharmaceutical compositions which are suitable for topical application.
  • suitable pharmaceutical formulations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.
  • compositions according to the invention are prepared by processes known per se.
  • the dosage of the active compounds is carried out in the order of magnitude customary for PDE inhibitors.
  • Topical application forms (such as ointments) for the treatment of dermatoses thus contain the active compounds in a concentration of, for example, 0.1-99%.
  • the dose for administration by inhalation is customarly between 0.1 and 3 mg per day.
  • the customary dose in the case of systemic therapy (p.o. or i.v.) is between 0.03 and 3 mg/kg per day.
  • the second messenger cyclic AMP (cAMP) is well-known for inhibiting inflammatory and immunocom- petent cells.
  • the PDE4 isoenzyme is broadly expressed in ceils involved in the initiation and propagation of inflammatory diseases (H Tenor and C Schudt, in obviouslyPhosphodiesterase Inhibitors", 21-40, sentThe Handbook of Immunopharmacology", Academic Press, 1996), and its inhibition leads to an increase of the intracellular cAMP concentration and thus to the inhibition of cellular activation (JE Souness et al., Immunopharmacology 47: 127-162, 2000).
  • Examples are the superoxide production of neutrophilic (C Schudt et al., Arch Pharmacol 344: 682-690, 1991 ) or eosinophilic (A Hatzelmann et al., Brit J Pharmacol 114: 821-831 , 1995) granulocytes, which can be measured as lu- minol-enhanced chemiluminescence, or the synthesis of tumor necrosis factor- ⁇ in monocytes, macro- phages or dendritic cells (Gantner et al., Brit J Pharmacol 121 : 221-231 , 1997, and Pulmonary Pharmacol Therap 12: 377-386, 1999).
  • neutrophilic C Schudt et al., Arch Pharmacol 344: 682-690, 1991
  • eosinophilic A Hatzelmann et al., Brit J Pharmacol 114: 821-831 , 1995
  • granulocytes which can be measured as lu- minol-enhance
  • PDE4 activity was determined as described by Thompson et al. (Adv Cycl Nucl Res 10: 69-92, 1979) with some modifications (Bauer and Schwabe, Naunyn-Schmiedeberg ' s Arch Pharmacol 311 : 193-198, 1980).
  • the assay mixture contained 20 mM Tris (pH 7.4), 5 mM MgCI 2 , 0.5 ⁇ M cAMP, [ 3 H]cAMP (about 30,000 cpm/assay), the test compound and an aliquot of cytosol from human neutrophils which mainly contains PDE4 activity as described by Schudt et al.
  • the reaction was started by the addition of substrate (cAMP) and the assays were incubated for further 15 min at 37°C. 50 ⁇ l of 0.2 N HCI was added to stop the reaction and the assays were left on ice for about 10 min.
  • the assays were loaded on QAE Sephadex A-25 (1 ml bed volume). The columns were eluted with 2 ml of 30 mM ammonium formiate (pH 6.0) and the eluate was counted for radioactivity.
  • Results were corrected for blank values (measured in the presence of denatured protein) which were below 5 % of total radioactivity.
  • the amount of cyclic nucleotides hydrolyzed did not exceed 30 % of the original substrate concentration.
  • the IC 5 o -values for the compounds according to the invention for the inhibition of the PDE4 activity were determined from the concentration- inhibition curves by nonlinear-regression.
  • the inhibitory values [measured as -loglC 50 (mol/l)] determined for the compounds 1 to 16 (the numbers of the compounds correspond to the numbers of the examples) according to the invention are all about 8.8 or greater.

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Abstract

Ces composés correspondant à la formule (I), formule dans laquelle les substituants sont tels que définis dans le descriptif, sont de nouveaux inhibiteurs efficaces de la PDE4.
PCT/EP2003/008673 2002-08-10 2003-08-06 Derives de piperidine utilises comme inhibiteurs de la phospodiesterase-4 (pde4) WO2004018449A1 (fr)

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