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Definitions

• the invention relates to novel piperidine-derivatives, which are used in the pharmaceutical industry for the production of pharmaceutical compositions.
• R1 and R2 represent independently from one another hydrogen or 1-4C-alkyl, or R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form a group selected from
• R3 represents a phenyl derivative of formulae (a) or (b) wherein
• 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 Aryl1, Aryl2 substituted by R10 and R11, —(CH 2 ) n , —C(O)—R12, —C(O)—(CH 2 ) m —R13, —(CH 2 ) p —R14 or —Y—(CH 2 ) q -Z-(CH 2 ) r —R16,
• Aryl1 is naphthyl, pyrazinyl, pyridazinyl, pyrimidin-4-yl, pyrimidin-5yl, quinazolinyl, quinoxalinyl, cinnolinyl, quinolyl, isoquinolyl, phthalazinyl, indanyl, indolyl, isoindolyl, indazolyl, chromanyl, isochromanyl, purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl or thiophenyl,
• Aryl2 is naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, quinolyl, isoquinolyl, phthalazinyl, indanyl, indolyl, isoindolyl, indazolyl, chromanyl, isochromanyl, purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl or thiophenyl,
• R10 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- 1-4 C-alkylamino, aminocarbonyl 1-4C-alkylcarbonylamino or mono-or di-1-4C-alkylaminocarbonyl,
• R11 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy
• R12 is 4H-benzo[1,4]oxazin-3-one-6-yl, Aryl2 or Aryl2 substituted by R10 and R11,
• R13 is 1-4C-alkoxy, phenoxy, napthalenoxy or 2-oxo-1,2-dihydro-quinolin-6-yloxy,
• R14 is Aryl 3, Aryl2 substituted by R10 and R11, phenyl substituted by R15,
• R16 is hydrogen, hydroxyl, 1-4C-alkoxy, hydroxy-2-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, mono- or di-1-4C-dialkylamino, 1-4C-alkoxycarbonyl, amino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonylamino or —N(H)—C(O)—N(R18)R19,
• Y represents a bond or —C(O)—
• Z represents a bond, —O—, —C(O)—, —C(O)—N(H)—, —N(H)—C(O)—, —N(R17)-, —S— or —S(O) 2 —,
• R17 is hydrogen or 1-4C-alkyl
• R18 and R19 are independent from each other hydrogen or 1-4C-alkyl, or R18 and R19 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl-, 1-hexahydroazepino- or a 1-piperazinyl-ring,
• n is an integer from 1 to 4,
• n 1 to 4
• p is an integer from 1 to 4,
• q is an integer from 1 to 4,
• r is an integer from 1 to 4,
• the invention relates to the use of compounds of formula 1 in which R1 and R2 represent independently from one another hydrogen or 1-4C-alkyl, or R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form a group selected from
• R3 represents a phenyl derivative of formulae (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
• 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 Aryl1, Aryl2 substituted by R10 and R11, —(CH 2 ) n —C(O)—R12, —C(O)—(CH 2 ) m —R13, —(CH 2 )—R14 or —Y—(CH 2 ) q -Z-(CH 2 ) r —R16,
• Aryl1 is naphthyl, pyrazinyl, pyridazinyl, pyrimidin-4-yl, pyrimidin-5-yl, quinazolinyl, quinoxalinyl, cinnolinyl, quinolyl, isoquinolyl, phthalazinyl, indanyl, indolyl, isoindolyl, indazolyl, chromanyl, isochromanyl, purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl or thiophenyl,
• Aryl2 is naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, quinolyl, isoquinolyl, phthalazinyl, indanyl, indolyl, isoindolyl, indazolyl, chromanyl, isochromanyl, purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl or thiophenyl,
• R10 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-alkylaminocarbonyl,
• R11 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy
• R12 is 4H-benzo[1,4]oxazin-3-one-6-yl, Aryl2 or Aryl2 substituted by R10 and R11,
• R13 is 1-4C-alkoxy, phenoxy, napthalenoxy or 2-oxo-1,2-dihydro-quinolin-6-yloxy,
• R14 is Aryl 3, Aryl2 substituted by R10 and R11, phenyl substituted by R15,
• R16 is hydrogen, hydroxyl, 1-4C-alkoxy, hydroxy-2-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, mono- or di-1-4C-dialkylamino, 1-4C-alkoxycarbonyl, amino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonylamino or —N(H)—C(O)—N(R18)R19,
• Y represents a bond or —C(O)—
• Z represents a bond, —O—, —C(O)—, —C(O)—N(H)—, —N(H)—C(O)—, —N(R17)—, —S— or —S(O) 2 —,
• R17 is hydrogen or 1-4C-alkyl
• R18 and R19 are independent from each other hydrogen or 1-4C-alkyl, or R18 and R19 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl-, 1-hexahydroazepino- or a 1-piperazinyl-ring,
• n is an integer from 1 to 4,
• n 1 to 4
• p is an integer from 1 to 4,
• q is an integer from 1 to 4,
• r is an integer from 1 to 4,
• 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, isopropoxy, 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), pentyloxy, 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 cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
• 3-7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy or cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
• 3-5C-Cycloalkoxy 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, tetrahydropyran and the tetrahydrothiophen ring may be mentioned the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahydropyran and the tetrahydrothiophen ring.
• 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 O—C(O)—] and the ethoxycarbonyl [CH 3 CH 2 O—C(O)—] radical.
• Hydroxy-2-4C-alkoxy stands for one of the abovementioned 2-4C-alkoxy radicals, which is substituted by hydroxyl.
• An example is the 2-hydroxyethoxy radical [—O—CH 2 —CH 2 —OH].
• 1-4C-Alkoxy-2-4C-alkoxy stands for a 2-4C-alkoxy radical which is substituted one of the abovementioned 1-4C-alkoxy radicals.
• Examples which may be mentioned are the 2-(methoxy)ethoxy [—O—CH 2 —CH 2 —O—CH 3 ] and the 2-(ethoxy)ethoxy radical [—O—CH 2 —CH 2 —O—CH 2 —CH 3 ].
• 1-4C-Alkylcarbonyl is a carbonyl group to which one of the abovementioned 1-4C-alkyl radicals is bonded.
• An example is the acetyl radical [CH 3 C(O)—].
• An 1-4C-Alkylcarbonylamino radical is, for example, the propionylamino [C 3 H 7 C(O)NH—] and the acetylamino radical [CH 3 C(O)NH—].
• Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogen atom, one or two of the abovementioned 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-isopropylaminocarbonyl 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-gluconic 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.
• R1 and R2 represent independently from one another hydrogen or 1-4C-alkyl, or R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form a group selected from
• R3 represents a phenyl derivative of formulae (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
• 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 Aryl1, Aryl2 substituted by R10 and R11, —(CH 2 ) n —C(O)—R12, —C(O)—(CH 2 ) m —R13, —(CH 2 ) p —R14 or —Y—(CH 2 ) q -Z-(CH 2 ) r —R16,
• Aryl1 is naphthyl, pyrazinyl, pyridazinyl, pyrimidin-4-yl, pyrimidin-5-yl, quinazolinyl, quinoxalinyl, cinnolinyl, quinolyl, isoquinolyl, phthalazinyl, indanyl, indolyl, isoindolyl, indazolyl, chromanyl, isochromanyl, purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl or thiophenyl,
• Aryl2 is naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, quinolyl, isoquinolyl, phthalazinyl, indanyl, indolyl, isoindolyl, indazolyl, chromanyl, isochromanyl, purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl or thiophenyl,
• R10 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-alkylaminocarbonyl,
• R11 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy
• R12 is 4H-benzo[1,4]oxazin-3-one-6-yl, Aryl2 or Aryl2 substituted by R10 and R11,
• R13 is 1-4C-alkoxy, phenoxy, napthalenoxy or 2-oxo-1,2-dihydro-quinolin-6-yloxy,
• R14 is Aryl 3, Aryl2 substituted by R10 and R11, phenyl substituted by R15,
• R15 is purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl or thiophenyl,
• R16 is hydrogen, hydroxyl, 1-4C-alkoxy, hydroxy-2-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, mono- or di-1-4C-dialkylamino, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonylamino or —N(H)—C(O)—N(R18)R19,
• Y represents a bond or —C(O)—
• Z represents a bond, —O—, —C(O)—, —C(O)—N(H)—, —N(H)—C(O)—, —N(R17)—, —S— or —S(O) 2 —,
• R17 is hydrogen or 1-4C-alkyl
• R18 and R19 are independent from each other hydrogen or 1-4C-alkyl, or R18 and R19 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl-, 1-hexahydroazepino- or a 1-piperazinyl-ring,
• n is an integer from 1 to 4,
• n 1 to 4
• p is an integer from 1 to 4,
• q is an integer from 1 to 4,
• r is an integer from 1 to 4,
• R1 and R2 represent independently from one another hydrogen or 1-4C-alkyl, or R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form a group selected from
• R3 represents a phenyl derivative of formulae (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
• R8 is hydrogen
• 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 Aryl1, Aryl2 substituted by R10 and R11, —(CH 2 ) n , —C(O)—R12, —C(O)—(CH 2 ) m —R13, —(CH 2 ) p —R14 or —Y—(CH 2 ) q -Z-(CH 2 ) r —R16,
• Aryl1 is pyrimidin-4-yl, pyrimidin-5-yl, quinazolinyl, quinolyl, isoquinolyl, indolyl, indazolyl, purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl or thiophenyl,
• Aryl2 is pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl, indolyl, indazolyl, purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl or thiophenyl,
• R10 is halogen, nitro, cyano, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino, mono-or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkylcarbonylamino or mono-or di-1-4C-alkylaminocarbonyl,
• R11 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
• R12 is 4H-benzo[1,4]oxazin-3-one-6-yl, Aryl2 or Aryl2 substituted by R10 and R11,
• R13 is phenoxy, napthalenoxy or 2-oxo-1,2-dihydro-quinolin-6-yloxy
• R14 is Aryl 3, Aryl2 substituted by R10 and R11, phenyl substituted by R15,
• Y represents a bond or —C(O)—
• Z represents a bond, —O—, —S— or —S(O) 2 —
• R16 is hydrogen, hydroxyl, 1-4C-alkoxy, hydroxy-2-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy or —N(H)—C(O)—N(R18)R19,
• R18 and R19 are independent from each other hydrogen or 1-4C-alkyl, or R18 and R19 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl- or 1-piperidinyl -ring,
• n is an integer from 1 to 2
• n 1 to 3
• p is an integer from 1 to 2
• q is an integer from 1 to 3
• r is an integer from 1 to 2
• Preferred compounds of formula 1 are those, in which
• R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form a group selected from
• R3 represents a benzene derivative of formulae (a) or (b) wherein
• R4 is 1-2C-alkoxy
• R5 is 1-4C-alkoxy
• R6 is 1-2C-alkoxy
• R7 is methyl
• R8 is hydrogen
• R9 is —(CH 2 ) n —C(O)—R12, —C(O)—(CH 2 ) m —R13, —(CH 2 ) p —R14 or —Y—(CH 2 ) q -Z-(CH 2 ) r —R16,
• R12 is benzofuran-2-yl or 4H-benzo[1,4]oxazin-3-one-6-yl,
• R13 is 2-oxo-1,2-dihydro-quinolin-6-yloxy
• R14 is phenyl substituted by R15
• Y represents a bond or —C(O)—
• Z represents a bond, —O—, —S— or —S(O) 2 —
• R16 is hydrogen, hydroxyl, methoxy, hydroxyethoxy, methoxyethoxy or —N(H)—C(O)—N(R18)R19,
• n 1,
• n 1 to 3
• q is an integer from 1 to 2
• r is an integer from 1 to 2
• Particularly preferred compounds of formula 1 are those in which
• R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form the following group
• R3 represents a phenyl derivative of formula (a) wherein
• R4 is methoxy
• R5 is methoxy
• R9 is 2-(methanesulfonyl)ethanoyl, 2-benzofuran-2-yl-2-oxo-ethyl, 4-benzimidazol-1-ylbenzyl, 2-(4H-benzo[1,4]oxazin-3-one-6-yl)ethanoyl, 3- ⁇ 2-[(1-morpholin-4-yl-methanoyl)-amino]-ethanesulfonyl ⁇ -propionyl, 2-(2-oxo-1,2-dihydroquinolin-6-yloxy)ethanoyl, 4-(2-oxo-1,2-dihydroquinolin-6-yloxy)butanoyl, 2-methoxyethyl, 2-methylsulfanylethyl, 2-methanesulfonylethyl or 2-(2-hydroxy-ethoxy)ethyl,
• R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form a group selected from
• R3 represents a benzene derivative of formula (a) wherein
• R4 is 1-2C-alkoxy
• R5 is 1-2C-alkoxy
• R9 is —CH 2 ) n —C(O)—R12, —C(O)—(CH 2 ) m —R13 or —(CH 2 ) p —R14,
• R12 is benzofuran-2-yl or 4H-benzo[1,4]oxazin-3-one-6-yl,
• R13 is 2-oxo-1,2-dihydro-quinolin-6-yloxy
• R14 is phenyl substituted by R15
• n 1,
• n 1 to 3
• Preferred compounds of formula 1 of embodiment A are those in which
• R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form the following group
• R3 represents a phenyl derivative of formula (a) wherein
• R4 is methoxy
• R5 is methoxy
• R9 is —(CH 2 ) n —C(O)—R12, —C(O)—(CH 2 ) m —R13 or —(CH 2 ) p —R14,
• R12 is benzofuran-2-yl or 4H-benzo[1,4]oxazin-3-one-6-yl,
• R13 is 2-oxo-1,2-dihydro-quinolin-6-yloxy
• R14 is phenyl substituted by R15
• n 1
• n 1 to 3
• R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form a group selected from
• R3 represents a benzene derivative of formula (a) wherein
• R4 is 1-2C-alkoxy
• R5 is 1-2C-alkoxy
• R9 is —Y—(CH 2 ) q -Z-(CH 2 ) r —R16,
• Y represents a bond or —C(O)—
• Z represents a bond, —O—, —S— or —S(O) 2 —
• R16 is hydrogen, hydroxyl or —N(H)—C(O)—N(R18)R19,
• q is an integer from 1 to 2
• r is an integer from 1 to 2
• Preferred compounds of formula 1 of embodiment B are those in which
• R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form the following group
• R3 represents a phenyl derivative of formula (a) wherein
• R4 is methoxy
• R5 is methoxy
• R9 is —Y—(CH 2 ) q -Z-(CH 2 ) r —R16,
• Y represents a bond or —C(O)—
• Z represents a bond, —O—, —S— or —S(O) 2 —
• R16 is hydrogen, hydroxyl or —N(H)—C(O)—N(R18)R19,
• q is an integer from 1 to 2
• r is an integer from 1 to 2
• R1 and R2 represent independently from one another hydrogen or 1-4C-alkyl, or R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form a group selected from
• R3 represents a phenyl derivative of formulae (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
• 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 Aryl1, Aryl2 substituted by R10 and R11, —(CH 2 ) n , —C(O)—R12, —C(O)—(CH 2 ) m —R13, —(CH 2 ) p —R14 or —Y—(CH 2 ) q -Z-(CH 2 ) r —R16,
• Aryl1 is naphthyl, pyrazinyl, pyridazinyl, pyrimidin-4-yl, pyrimidin-5-yl, quinazolinyl, quinoxalinyl, cinnolinyl, quinolyl, isoquinolyl, phthalazinyl, indanyl, indolyl, isoindolyl, indazolyl, chromanyl, isochromanyl, purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl or thiophenyl,
• Aryl2 is naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, quinolyl, isoquinolyl, phthalazinyl, indanyl, indolyl, isoindolyl, indazolyl, chromanyl, isochromanyl, purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl or thiophenyl,
• R10 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-alkylamino-carbonyl,
• R11 is hydrogen, halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy
• R12 is 4H-benzo[1,4]oxazin-3-one-6-yl, Aryl2 or Aryl2 substituted by R10 and R11,
• R13 is 1-4C-alkoxy, phenoxy, napthalenoxy or 2-oxo-1,2-dihydro-quinolin-6-yloxy,
• R14 is Aryl 3, Aryl2 substituted by R10 and R11, phenyl substituted by R15,
• R16 is hydrogen, hydroxyl, 1-4C-alkoxy, hydroxy-24C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, mono- or di-1-4C-dialkylamino, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonylamino or —N(H)—C(O)—N(R18)R19,
• Y represents a bond or —C(O)—
• Z represents a bond, —O—, —C(O)—, —C(O)—N(H)—, —N(H)—C(O)—, —N(R17)-, —S— or —S(O) 2 —,
• R17 is hydrogen or 1-4C-alkyl
• R18 and R19 are independent from each other hydrogen or 1-4C-alkyl, or R18 and R19 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl-, 1-hexahydroazepino- or a 1-piperazinyl-ring,
• n is an integer from 1 to 4,
• n 1 to 4
• p is an integer from 1 to 4,
• q is an integer from 1 to 4,
• r is an integer from 1 to 4,
• R1 and R2 represent independently from one another hydrogen or 1-4C-alkyl, or R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form a group selected from
• R3 represents a phenyl derivative of formulae (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
• R8 is hydrogen
• R7 and R8 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cydopentane, cyclohexane, tetrahydrofurane or tetrahydropyran ring,
• R9 is Aryl1, Aryl2 substituted by R10 and R11, —CH 2 ) n —C(O)—R12, —C(O)—(CH 2 ) m —R13, —(CH 2 ) p —R14 or —Y—(CH 2 ) q -Z-(CH 2 ) r —R16,
• Aryl1 is pyrimidin-4-yl, pyrimidin-5-yl, quinazolinyl, quinolyl, isoquinolyl, indolyl, indazolyl, purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl or thiophenyl,
• Aryl2 is pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl, indolyl, indazolyl, purinyl, pteridinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl or thiophenyl,
• R10 is halogen, nitro, cyano, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino, mono-or di-1-4C-alkylamino, aminocarbonyl, 1-4C-alkylcarbonylamino or mono-or di-1-4C-alkylaminocarbonyl,
• R11 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
• R12 is 4H-benzo[1,4]oxazin-3-one-6-yl, Aryl2 or Aryl2 substituted by R10 and R11,
• R13 is phenoxy, napthalenoxy or 2-oxo-1,2-dihydro-quinolin-6-yloxy
• R14 is Aryl 3, Aryl2 substituted by R10 and R11, phenyl substituted by R15,
• Y represents a bond or —C(O)—
• Z represents a bond, —O—, —S— or —S(O) 2 —
• R16 is hydrogen, hydroxyl, 1-4C-alkoxy, hydroxy-2-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or —N(H)—C(O)—N(R18)R19,
• R18 and R19 are independent from each other hydrogen or 1-4C-alkyl, or R18 and R19 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl- or 1-piperidinyl -ring,
• n is an integer from 1 to 2
• n 1 to 3
• p is an integer from 1 to 2
• q is an integer from 1 to 3
• r is an integer from 1 to 2
• R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form a group selected from
• R3 represents a benzene derivative of formulae (a) or (b) wherein
• R4 is 1-2C-alkoxy
• R5 is 1-4C-alkoxy
• R6 is 1-2C-alkoxy
• R7 is methyl
• R8 is hydrogen
• R9 is —-(CH 2 ) n —C(O)—R12, —C(O)—(CH 2 ) m —R13, —(CH 2 ) p —R14 or —Y—(CH 2 ) q -Z-(CH 2 ) r —R16,
• R12 is benzofuran-2-yl or 4H-benzo[1,4]oxazin-3-one-6-yl,
• R13 is 2-oxo-1,2-dihydro-quinolin-6-yloxy
• R14 is phenyl substituted by R15
• Y represents a bond or —(O)—
• Z represents a bond, —O—, —S— or —S(O) 2 —
• R16 is hydrogen, hydroxyl, methoxy, hydroxyethoxy, methoxyethoxy or —N(H)—C(O)—N(R18)R19,
• n 1,
• n 1 to 3
• q is an integer from 1 to 3
• r is an integer from 1 to 2
• Preferred compounds of formula 1 of embodiment C are those in which
• R1 and R2 together and with inclusion of the two carbon atoms, to which they are bonded, form the following group
• R3 represents a phenyl derivative of formula (a) wherein
• R4 is methoxy
• R5 is methoxy
• R9 is 2-(methanesulfonyl)ethanoyl, 2-benzofuran-2-yl-2-oxo-ethyl, 4-benzimidazol-1-ylbenzyl, 2-benzo[1,4]oxazin-3-one-6-yl)ethanoyl, 2-(2-oxo-1,2-dihydroquinolin-6-yloxy)ethanoyl, 4-(1,2-dihydroquinolin-6-yloxy)butanoyl, 2-methoxyethyl, 2-methylsulfanylethyl, 2-methanesulfonylethyl or 2-(2-hydroxy-ethoxy)ethyl,
• 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.
• a further special embodiment of the compounds of the present invention include those compounds of formula 1 in which R1 and R2 are hydrogen, R3 represents a phenyl derivative of formula (a) and R4 and R5 have the meaning methoxy.
• Still a further special embodiment of the compounds of the present invention include those compounds of formula 1 in which R1 and R2 together and with inclusion of the two carbon atoms to which they are bonded form the following group
• R3 represents a phenyl derivative of formula (a) and R4 and R5 have the meaning methoxy.
• the compounds of formula 1 are chiral compounds with—depending on the meaning of R3—a chiral center in the phenyl derivative of formula b, if the substituents —R7 and —CH 2 R8 are not identical. However, preferred are those compounds, in which the substituents —R7 and —CH 2 R8 are identical or together and with inclusion of the 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, as well as all mixtures thereof independent from the ratio, including the racemates.
• (4a,8a)-cis-Racemates can be split up into the corresponding enantiomers by methods known by a person skilled in the art.
• the 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 A1 and A2).
• 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 complex 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).
• R9 represents —Y—(CH 2 ) q -Z-(CH 2 ) r —R16.
• 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 dioxane, 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.
• RT stands for room temperature
• h hour(s)
• min for minute(s)
• M. p. for melting point
• a mixture of 10 mmol of starting compound A1, 12 mmol of methanesulfonyl-acetic acid and 10 mmol of triethylamine in 50 ml of dichloromethane is stirred for 60 min after which 20 mmol of (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride is added.
• the resulting mixture is stirred for 18 h at RT and then successively washed with diluted hydrochloric acid and aqueous sodium carbonate. After drying over magnesium sulfate, the solvent is evaporated and the residue crystallised from methanol. M. p. 169-170° C.
• Morpholine-4-carboxylic acid [2-(3- ⁇ 4-[(4aS,8aR)-4-(3,4-dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl ⁇ )-3-oxo-propane-1-sulfonyl)-ethyl]-amide
• a mixture of 10 mmol of starting compound A1, 10 mmol of N-[2-(2-Bromo-ethoxy)-ethyl]-phthalimide and 20 mmol of potassium carbonate in 50 ml of dimethylformamide is stirred at RT. After about 18 h, the mixture is poured into water and this mixture is extracted with diethyl ether. The ether extract is dried over magnesium sulfate and evaporated. The residue is dissolved in ethanol and to this solution, 40 mmol of hydrazine hydrate is added. The resulting mixture is refluxed for 20 h and subsequently evaporated. The residue is partitioned between ethyl acetate and aqueous sodium carbonate. The organic layer is dried over magnesium sulfate and to this solution, a saturated solution of hydrochloric acid in diethyl ether is added. The precipitate is filtered off and dried. M. p. 86-89° C.
• a mixture of 10 mmol of starting compound A1, 13 mmol of 1-chloro-2-methoxy-ethane and 20 mmol of potassium carbonate in 50 ml of dimethylformamide is stirred at RT. After about 18 h, the mixture is poured into water and this mixture is extracted with diethyl ether. The ether extract is dried over magnesium sulfate and evaporated. The residue is purified by chromatography (elution with a mixture of ethyl acetate and methanol, 2:1). After evaporating the eluens, the residue is dissolved in ethanol. To this a solution, a saturated solution of hydrochloric acid in diethyl ether is added. The precipitate is filtered off and dried. M. p. 87-90° C.
• a mixture of 50 mmol of starting compound A4, 50 mmol of starting compound A13 and 100 mmol of triethylamine in 100 ml of 1-propanol is refluxed for 18 h and subsequently evaporated.
• the residue is partitioned between dichloromethane and aqueous sodium carbonate.
• the dichloromethane solution is dried over magnesium sulfate.
• Addition of a saturated solution of hydrochloric acid in diethyl ether causes precipitation of the title compound. M. p. 91-95° C.
• 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 (Alzheimer'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 (Alzheimer'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, caplets, 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, caplets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, the active compound content advantageously being between
• auxiliaries or excipients which are suitable for the desired pharmaceutical formulations on account of his/her expert knowledge.
• solvents 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 customarily 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 immunocompetent cells.
• the PDE4 isoenzyme is broadly expressed in cells involved in the initiation and propagation of inflammatory diseases (H Tenor and C Schudt, in “Phosphodiesterase Inhibitors”, 21-40, “The 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 (J E 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 luminol-enhanced chemiluminescence, or the synthesis of tumor necrosis factors in monocytes, macrophages 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 luminol-enhanced chemiluminescence, or the synthesis of tumor nec
• 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 MgCl 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 HCl 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 nucleoUdes hydrolyzed did not exceed 30% of the original substrate concentration.
• the lC 50 -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.

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