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WO2002006238A1 - 6-phenylphenanthridines a substitution cycloalkyle ou cycloalkylmethyle - Google Patents

6-phenylphenanthridines a substitution cycloalkyle ou cycloalkylmethyle Download PDF

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Publication number
WO2002006238A1
WO2002006238A1 PCT/EP2001/007817 EP0107817W WO0206238A1 WO 2002006238 A1 WO2002006238 A1 WO 2002006238A1 EP 0107817 W EP0107817 W EP 0107817W WO 0206238 A1 WO0206238 A1 WO 0206238A1
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Prior art keywords
alkyl
hydrogen
alkoxy
cycloalkyl
aryl
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PCT/EP2001/007817
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English (en)
Inventor
Beate Gutterer
Daniela Bundschuh
Dieter Flockerzi
Gerhard Grundler
Armin Hatzelmann
Hans-Peter Kley
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Altana Pharma Ag
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Priority to AU2001267589A priority Critical patent/AU2001267589A1/en
Publication of WO2002006238A1 publication Critical patent/WO2002006238A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/10—Aza-phenanthrenes
    • C07D221/12—Phenanthridines

Definitions

  • the invention relates to novel 6-phenylphenanthridines, which are used in the pharmaceutical industry for the production of medicaments.
  • the invention thus relates to compounds of the formula I,
  • R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloaIkylmethoxy or completely or predominantly fluorine-substituted 1-4C-aIkoxy,
  • R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloaIkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy, or in which
  • R1 and R2 together are a 1-2C-alkylenedioxy group
  • R3 is hydrogen or 1-4C-alkyl
  • R31 is hydrogen or 1-4C-alkyl, or in which
  • R3 and R31 together are a 1-4C-alkylene group
  • R4 is hydrogen or 1-4C-alkyl
  • R5 is hydrogen
  • R51 is hydrogen, or in which
  • R6 is 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl
  • R7 is hydrogen, hydroxyl, halogen, cyano, nitro, amino, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, trifluoromethyl, 1-4C-alkoxy, completely or predominantly fluorine- substituted 1-4C-alkoxy, phenyl, phenyl-1-4C-alkyl, 0-R8, S-R9, C(O)-R10, CH 2 -R11 , S(0) 2 -aryl, 0-S(0) 2 -R12, C(0)-OR14, C(0)-N(R15)R16, N(R17)R18, pyrrolidinyl, pyrrolidin-1- yI-2-one, pyrrolidin-1-yl-2,5-dione, piperidin-1-yl, piperidin-1-yl-2-one, piperidin-1-yl-2,6-dione, S(0) 2 -R19 or S(0) 2 -N
  • R8 is 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, 1 -4C-alkoxy-1 -4C-alkyl, aryl or phenyl-1 -4C-alkyl,
  • R9 is hydrogen, 1-4C-alkyl, 1-4C-alkylcarbonyl, arylcarbonyl, trifluoromethyl, difluoromethyl, tri- chloromethyl or phenyl,
  • R10 is 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyI, 1 -pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, 4-morpholinyl or aryl,
  • R11 is hydroxyl, halogen, cyano, carboxyl, 1-4C-alkoxy, phenoxy, 1-4C-alkoxycarbonyl, aminocar- bonyl, mono- or di-1-4C-alkylaminocarbonyl, N(R15)R16 or 1-4C-alkylcarbony!amino, and
  • R12 is 1-4C-alkyl, amino, mono- or di-1-4C-alkylamino or aryl,
  • Aryl is phenyl, pyridyl or R13-substituted phenyl, where
  • R13 is hydroxyl, halogen, carboxyl, nitro, amino, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-aIkoxycarbonyl, 1-4C-alkylcarbonylamino, 1-4C-alkylcarbonyloxy or aminocarbonyl,
  • 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,
  • R16 is hydrogen, 1-4C-alkyl, 3-7C-cycloaIkyl, 3-7C-cycloalkylmethyl or aryl, or where R15 and R16 together and including the nitrogen atom to which they both are bonded, are a 1 -pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazin-1-yl, 1 -hexahydroazepinyl or 4-morpholinyl radical,
  • R17 is hydrogen, 1-4C-aIkyl, S(0) 2 -R19 or S(0) 2 -aryl,
  • R18 is 1-4C-alkyl, 1-4C-alkylcarbonyI, 3-7C-cycloalkylcarbonyl, 3-7C-cycloalkylmethylcarbonyl or S(0) 2 -R19 or S(0) 2 -aryl, and
  • R19 is 1-4C-alkyl
  • R20 is hydrogen, hydroxyl, halogen, nitro, amino, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl- methyl, trifluoromethyl, , 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, CH 2 -R10, carboxyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-aIkylcarbonylamino or aminocarbonyl, and the salts, the N-oxides and the salts of the N-oxides of these compounds.
  • 1-4C-Alkyl represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably the ethyl and methyl radicals.
  • 1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.
  • 3-7C-CycIoalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cyclo- heptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
  • 3-7C-Cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cy- clohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
  • fluorine-substituted 1-4C-alkoxy for example, the 2,2,3,3,3-penta- fluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy, in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy radicals may be mentioned.
  • "Predominantly" in this connection means that more than half of the hydrogen atoms of the 1-4C-alkoxy radical are replaced by fluorine atoms.
  • 1-2C-Alkylenedioxy represents, for example, the methylenedioxy [-0-CH 2 -0-] and the ethylenedioxy [-0-CH 2 -CH 2 -0-] radicals.
  • R3 and R31 together have the meaning 1-4C-alkylene
  • the positions 1 and 4 in compounds of the formula I are linked to one another by a 1-4C-alkylene bridge, 1-4C-alkylene representing straight-chain or branched alkylene radicals having 1 to 4 carbon atoms.
  • 1-4C-alkylene representing straight-chain or branched alkylene radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the radicals methylene [-CH 2 -], ethylene [-CH 2 -CH 2 -], trimethylene [-CH 2 -CH 2 -CH 2 -], 1 ,2-dimethylethyIene [-CH(CH 3 )-CH(CH 3 )-] and isopropylidene [-C(CH 3 ) 2 -].
  • 3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
  • 3-7C-Cycloalkylmethyl represents a methyl radical which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals.
  • the 3-5C-cycloalky!methyl radicals cyclopropylmethyl, cyclobutyl- methyl and cyclopentylmethyl may be mentioned.
  • 1-4C-Alkoxy-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the meth- oxymethyl radical, the methoxyethyl radical and the isopropoxyethyl radical.
  • Phenyl-1-4C-alkyl represents one of the abovementioned phenyl-substituted 1-4C-alkyl radicals. Examples which may be mentioned are the phenethyl radical and the benzyl radical.
  • 1-4C-Alkylcarbonyl represents a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-4C-aIkyl radicals.
  • An example which may be mentioned is the acetyl radical.
  • 3-7C-Cycloalkylcarbonyl represents a radical which, in addition to the carbonyl group, contains one of the abovementioned 3-7C-cycloalkyl radicals.
  • An example which may be mentioned is the cyclopentyl- carbonyl radical.
  • 3-7C-CycloalkylmethylcarbonyI represents a radical which, in addition to the carbonyl group, contains one of the abovementioned 3-7C-cycloalkyImethyl radicals.
  • An example which may be mentioned is the cyclopropylmethylcarbony! radical.
  • 1-4C-Alkoxycarbonyl represents 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 ethoxycarbonyl [CH 3 CH 2 0-C(0)-] radicals.
  • 1-4C-Alkylcarbonyloxy represents a carbonyloxy group to which one of the abovementioned 1-4C-alkyl radicals is bonded.
  • An example which may be mentioned is the acetoxy radical [CH 3 C(0)-0-].
  • mono- or di-1-4C-alkylaminocarbonyl radicals contain 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 N-isopropylaminocarbonyl radicals.
  • mono- or di-1-4C-alkylamino radicals contain one or two of the above- mentioned 1-4C-alkyl radicals. Di-1-4C-alkylamino is preferred and here, in particular, dimethyl-, di- ethyl- or diisopropylamino.
  • a 1-4C-alkylcarbonylamino radical which may be mentioned is, for example, the propionylamino radical [C 3 H 7 C(0)NH-] and the acetylamino radical [CH 3 C(0)NH-].
  • R6-, R7- and R20-substituted phenyl radicals which may be mentioned are 3-cyclohexylphenyl, 4-cyclohexylphenyl, 4-cyclopentylphenyl, 3-cyclopentylphenyl, 4-cyclobutylphenyl, 3-cyclobutylphenyl, 4-cyclopropylphenyl, 3-cyclopropylphenyl, 4-cycloheptylmethylphenyl, 4-cyclohexylmethylphenyl, 4-cyclopentylmethylphenyl, 4-cyclobutylmethylphenyI, 3-cyclo- propylmethylphenyl, .
  • Possible salts for compounds of the formula I - depending on substitution - are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids and bases customarily used in pharmacy. Those suitable are, on the one hand, water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, it being possible to employ
  • salts with bases are also suitable.
  • examples of salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, where here too the bases are employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
  • Pharmacologically intolerable salts which can initially be obtained, for example, as process products in 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 according to the invention and their salts when they are isolated, for example, in crystalline form, can contain various amounts of solvents.
  • the invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.
  • R1 is 1-2C-aIkoxy, 3-5C-cycloalkoxy, 3-5C-cycloa!kylmethoxy or completely or predominantly fluorine-substituted 1-2C-aIkoxy,
  • R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,
  • R3 is hydrogen
  • R31 is hydrogen
  • R4 is hydrogen or 1-2C-alkyl
  • R5 is hydrogen
  • R51 is hydrogen, or in which
  • R6 is 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl
  • R7 is hydrogen, hydroxyl, halogen, cyano, nitro, amino, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, trifluoromethyl, 1-4C-alkoxy, completely or predominantly fluorine- substituted 1-4C-alkoxy, phenyl, phenyl-1-4C-alkyl, 0-R8, S-R9, C(O)-R10, CH 2 -R11 , S(0) 2 -aryl, 0-S(0) 2 -R12, C(0)-OR14, C(0)-N(R15)R16, N(R17)R18, pyrrolidinyl, pyrrolidin-1- yl-2-one, S(0) 2 -R19 or S(0) 2 -N(R15)R16, where
  • R8 is 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, 1-4C-alkoxy-1-4C-alkyl, aryl or phenyl-1-4C-alkyl,
  • R9 is hydrogen, 1-4C-alkyl, acetyl, trifluoromethyl, or phenyl,
  • R10 is 1-4C-alkyl, 3-7C-cycIoalkyl, 3-7C-cycloalkyImethyl, 1-piperidinyl, 1-piperazinyl, 4-methyIpiperazinyl, 4-morpholinyl or aryl,
  • R11 is halogen, carboxyl, 1-4C-alkoxy, phenoxy, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbony!, N(R15)R16 or 1-4C-alkylcarbonylamino, and
  • R12 is 1-4C-alkyI, mono- or di-1-4C-alkylamino or aryl
  • Aryl - is phenyl, pyridyl or R13-substituted phenyl, where
  • R13 is halogen, carboxyl, nitro, amino, cyano, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy,
  • R14 is hydrogen or 1-4C-alkyl
  • R15 is hydrogen or 1-4C-alkyl
  • R16 is hydrogen, 1-4C-alkyl or aryl, or where R15 and R16 together and including the nitrogen atom to which they both are bonded, are a 1-piperidyl, 1-piperazinyl, 1-methylpiperazin-4-yI or 4-morpholinyl radical,
  • R1 is hydrogen, 1-4C-alkyl, S(0) 2 -R19 or S(0) 2 -aryl,
  • R18 is 1-4C-alkyl, 1-4C-aIkylcarbonyl, 3-7C-cycloalkyIcarbonyl, 3-7C-cycloalkylmethylcarbonyl, S(0) 2 -R19 or S(0) 2 -aryl, and
  • R19 is 1-4C-alkyl
  • R20 is hydrogen, hydroxyl, halogen, nitro, amino, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl- methyl, trifluoromethyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, 3-7C-cycloaIkoxy, 3-7C-cycloalkylmethoxy, carboxyl, 1-4C-aIkoxycarbonyl or 1 -4C-alkyIcarbonyloxy, and the salts, the N-oxides and the salts of the N-oxides of these compounds.
  • R1 is 1-2C-alkoxy
  • R2 is 1-2C-alkoxy
  • R3, R31 , R4, R5 and R51 are hydrogen
  • R6 is 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl
  • R7 is hydrogen or 1-4C-alkyl
  • R20 is hydrogen or 1-4C-alkyl, and the salts, the N-oxides and the salts of the N-oxides of these compounds.
  • Preferred compounds of the formula I are those in which
  • R1 is methoxy
  • R2 is methoxy
  • R3, R31 , R4, R5 and R51 are hydrogen
  • R6 is 3-7C-cycloalkyl
  • R7 is hydrogen
  • R20 is hydrogen, and the salts, the N-oxides and the salts of the N-oxides of these compounds.
  • the compounds of the formula I are chiral compounds having chiral centers in positions 4a and 10b and, depending on the meaning of the substituents R3, R31 , R4, R5 and R51 , further chiral centers in the positions 1 , 2, 3 and 4.
  • the invention therefore comprises all conceivable pure diastereomers and pure enantiomers and their mixtures in any mixing ratio, including the racemates.
  • the compounds of the formula I are preferred in which the hydrogen atoms in positions 4a and 10b are cis to one another.
  • the pure cis enantiomers are particularly preferred.
  • the enantiomers can be separated in a manner known per se (for example by preparation and separation of appropriate diastereoisomeric compounds).
  • an enantiomer separation is carried out at the stage of the starting compounds of the formula IV
  • racemic compounds of the formula IV for example by means of salt formation of the racemic compounds of the formula IV with optically active carboxylic acids.
  • optically active carboxylic acids examples which may be mentioned in this connection are the enantiomeric forms of mandelic acid, tartaric acid, O.O'-dibenzoyltartaric acid, camphoric acid, quinic acid, glutamic acid, malic acid, camphorsulfonic acid, 3-bromocamphorsulfonic acid, ⁇ -methoxyphenylacetic acid, ⁇ -methoxy- ⁇ -trifluoromethylphenylacetic acid and 2-phenylpropionic acid.
  • enantiomeri- cally pure starting compounds of the formula IV can also be prepared via asymmetric syntheses.
  • R1 , R2, R3, R31 , R4, R5, R51 , R6, R7 and R20 have the meanings indicated above, and, if desired, then converting the compounds of the formula I obtained into their salts, or, if desired, then converting salts of the compounds of the formula I obtained into the free compounds.
  • R7 and/or R11 and/or R13 and/or R20 are an ester group
  • the corresponding acids can be obtained by acidic or alkaline hydrolysis, or the corresponding amides can be prepared by reaction with suitably substituted amines;
  • R13 and/or R20 is a 1-4C-alkylcarbonyloxy group, the corresponding hydroxy compounds can be obtained by acidic or alkaline hydrolysis;
  • the compounds of the formula I can be converted, if desired, into their N-oxides, for example with the aid of hydrogen peroxide in methanol or with the aid of m-chloroperoxybenzoic acid in di- chloromethane.
  • the person skilled in the art is familiar on the basis of his/her expert knowledge with the reaction conditions which are specifically necessary for carrying out the N-oxidation.
  • cyclocondensation is carried out in a manner known per se to the person skilled in the art according to Bischler-Napieralski (e.g. as described in J. Chem. Soc, 1956, 4280-4282) in the presence of a suitable condensing agent, such as polyphosphoric acid, phosphorus pentachloride, phosphorus pen- toxide or preferably phosphorus oxychloride, in a suitable inert solvent, e.g.
  • a chlorinated hydrocarbon such as chloroform
  • a cyclic hydrocarbon such as toluene or xylene
  • another inert solvent such as acetonitrile
  • an excess of condensing agent preferably at elevated temperature, in particular at the boiling temperature of the solvent or condensing agent used.
  • R6, R7 and R20 have the meanings indicated above and X is a suitable leaving group, preferably a chlorine atom.
  • acylation or benzoylation is carried out as described in the following examples or as in J. Chem. Soc. (C), 1971 , 1805-1808.
  • azodicarboxylic acid derivatives e.g. diethyl azodicarboxylate
  • uronium salts e.g. 0-(benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate] and N,N'-carbonyldiimidazole.
  • This alternative preparation process is particularly suitable for the preparation of compounds of the formula II in which the substituents R7 and/or R20 are amino and/or hydroxyl.
  • Compounds of the formula III and compounds of the formula IV are either known or can be prepared in a known manner.
  • the compounds of the formula IV can be prepared, for example, from compounds of the formula V,
  • R1 , R2, R3, R31 , R4, R5 and R51 have the abovementioned meanings, by reduction of the nitro group.
  • the reduction can be carried out, for example, by catalytic hydrogenation, e.g. in the presence of Ra- ney nickel, in a lower alcohol such as methanol or ethanol at room temperature and under normal or elevated pressure.
  • a catalytic amount of an acid such as, for example, hydrochloric acid
  • the reduction is carried out using metals such as zinc or iron with organic acids such as acetic acid or mineral acids such as hydrochloric acid.
  • the compounds of the formula IV in which R1 , R2, R3, R31 and R4 have the meanings indicated above and R5 and R51 together represent an additional bond can be prepared from the corresponding compounds of the formula V by selective reduction of the nitro group in a manner known to the person skilled in the art, for example in the presence of Raney nickel in a lower alcohol as solvent using hydra- zine hydrate as a hydrogen donor.
  • the compounds of the formula V in which R1 , R2, R3, R31 and R4 have the meanings indicated above and R5 and R51 are hydrogen, are either known or can be prepared from corresponding compounds of the formula V in which R5 and R51 together are an additional bond.
  • the reaction can be carried out in a manner known to the person skilled in the art, preferably by hydrogenation in the presence of a catalyst, such as, for example, palladium on active carbon, e.g. as described in J. Chem. Soc. (C), 1971, 1805-1808.
  • a catalyst such as, for example, palladium on active carbon, e.g. as described in J. Chem. Soc. (C), 1971, 1805-1808.
  • the compounds of the formula V, in which R5 and R51 together are an additional bond are either known or can be obtained by the reaction of compounds of the formula VI,
  • R3, R31 and R4 have the meanings mentioned above.
  • the cycloaddition is in this case carried out in a manner known to the person skilled in the art according to Diels-Alder, e.g. as described in J. Amer. Chem. Soc. 1957, 79, 6559 or in J. Org. Chem. 1952, 17, 581 or as described in the following examples.
  • the compounds of the formulae VI and VII are either known or can be prepared in a known manner.
  • the compounds of the formula VI can be prepared, for example, in a manner known to the person skilled in the art from corresponding compounds of the formula VIII as described, for example, in J. Chem. Soc. 1951 , 2524 or in J. Org. Chem. 1944, 9, 170 or as described in the following examples.
  • R1 and R2 have the meanings indicated above, are either known or can be prepared in a manner known to the person skilled in the art, as described, for example, in Ber. Dtsch. Chem. Ges. 1925, 58, 203.
  • the isolation and purification of the substances according to the invention is carried out in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on suitable support material.
  • Salts are obtained by dissolving the free compound in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • the salts are obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by alkalization or by acidification into the free compounds, which in turn can be converted into salts. In this way, pharmacologically intolerable salts can be converted into pharmacologically tolerable salts.
  • m.p stands for melting point
  • h for hour(s)
  • RT room temperature
  • EF for empirical formula
  • MW for molecular weight
  • calc. for calculated
  • fnd. for found.
  • (+/-)-cis-1 ,2-dimethoxy-4-(2-nitrocyclohexyl)benzene and 120 g of zinc powder or granules are suspended in 1300 ml of ethanol. 220 ml of acetic acid are added dropwise at boiling heat. The precipitate is filtered off with suction and washed with ethanol, and the filtrate is concentrated under reduced pressure. The residue is taken up in hydrochloric acid and extracted with toluene. The aqueous phase is rendered alkaline using 50% strength sodium hydroxide solution, the precipitate is filtered off with suction and the filtrate is extracted with toluene. The organic phase is dried using sodium sulfate and concentrated. 98 g of the title compound are obtained as a crystallizing oil.
  • (+/-)-cis-1 ,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene are dissolved in 450 ml of methanol, treated with 2 ml of cone, hydrochloric acid and hydrogenated after addition of 500 mg of 10% strength Pd/C.
  • the reaction mixture is filtered and the filtrate is concentrated. M.p.: 84-86.5°C. D1.
  • the compounds according to the invention have valuable pharmacological properties which make them commercially utilizable.
  • selective cyclic nucleotide phosphodiesterase (PDE) inhibitors namely of type 4
  • they are suitable on the one hand as bronchial therapeutics (for the treatment of airway obstructions on account of their dilating but also on account of their respiratory rate- or respiratory drive- increasing action) and for the elimination of erectile dysfunction on account of the vasodilating action, but on the other hand especially for the treatment of disorders, in particular of inflammatory nature, e.g.
  • the compounds according to the invention are distinguished here by low toxicity, good en- teral 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 and 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 various origins (bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD); dermatoses (especially of proliferative, inflammatory and allergic type) such as, for example, psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and wide-area pyodermias, endogenous and exogenous acne, acne rosacea
  • disorders of the arthritis type rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions
  • disorders of the immune system AIDS, multiple sclerosis
  • graft-versus-host reactions transplant rejection reactions
  • symptoms of shock [septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome and ARDS (adult respiratory distress syndrome)]
  • generalized inflammations in the gastrointestinal area Crohn's disease and ulcerative colitis
  • PDE inhibitors such as, for example, cardiac insufficiency
  • the compounds according to the invention can be employed for the treatment of diabetes insipidus and disorders in connection with disturbances of brain metabolism, such as, for example, cerebral senility, senile dementia (Alzheimer's dementia), multiin- farct dementia or alternatively disorders of the CNS, such as, for example, depressions or arterioscle- rotic dementia.
  • brain metabolism such as, for example, cerebral senility, senile dementia (Alzheimer's dementia), multiin- farct dementia or alternatively disorders of the CNS, such as, for example, depressions or arterioscle- rotic dementia.
  • the invention further relates to the compounds according to the invention for use in the treatment of mammals, including man, which are suffering from one of the abovementioned illnesses.
  • the process comprises administering to the sick mammal a therapeutically efficacious and pharmacologically tolerable amount of one or more of the compounds according to the invention.
  • the invention further relates to the compounds according to the invention for use in the treatment and/or prophylaxis of illnesses, in particular the illnesses mentioned.
  • the invention likewise relates to the use of the compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the illnesses mentioned.
  • Medicaments for the treatment and/or prophylaxis of the illnesses mentioned which contain one or more of the compounds according to the invention, are furthermore a subject of the invention.
  • a further subject of the invention is a commercial product, consisting of a customary secondary pack, a primary pack containing the medicament (for example an ampoule or a blister pack) and, if desired, a pack insert, the medicament exhibiting antagonistic action against cyclic nucleotide phosphodiesterases of type 4 (PDE4) and leading to the attenuation of the symptoms of illnesses which are connected with cyclic nucleotide phosphodiesterases of type 4, and the suitability of the medicament for the prophylaxis or treatment of illnesses which are connected with cyclic nucleotide phosphodiesterases of type 4 being indicated on the secondary pack or on the pack insert of the commercial product, and the medicament containing one or more compounds of the formula I according to the invention.
  • the secondary pack, the primary pack containing the medicament and the pack insert otherwise comply with what would be regarded as standard to the person skilled in the art for medicaments of this type.
  • the medicaments are prepared by processes which are known per se and familiar to the person skilled in the art.
  • the person skilled in the art is familiar on the basis of his/her expert knowledge with the excipients which are suitable for the desired pharmaceutical formulations.
  • solvents gel-forming agents, ointment bases and other active compound vehicles
  • 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, advantagously 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 used in the form of those medicaments which are suitable for topical application.
  • suitable pharmaceutical formulations which may be mentioned are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.
  • the medicaments according to the invention are prepared by processes known per se. Dosage of the active compounds takes place in the order of magnitude customary for PDE inhibitors. Thus topical application forms (such as, for example, ointments) for the treatment of dermatoses 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 per kilogram 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 cells 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 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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Abstract

L'invention concerne des composés représentés par la formule (I), dans laquelle R1, R2, R31, R4, R5, R51, R6, R7 et R20 sont tels que définis dans la description. Ces composés sont des inhibiteurs de PDEA actifs.
PCT/EP2001/007817 2000-07-14 2001-07-07 6-phenylphenanthridines a substitution cycloalkyle ou cycloalkylmethyle WO2002006238A1 (fr)

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WO2004018431A3 (fr) * 2002-08-17 2004-04-22 Altana Pharma Ag Nouvelles phenanthridines
JP2005539043A (ja) * 2002-08-29 2005-12-22 アルタナ　ファルマ　アクチエンゲゼルシャフト Ｐｄｅ４インヒビターとしての２−ヒドロキシ−６−フェニルフェナントリジン
JP2006508913A (ja) * 2002-08-29 2006-03-16 アルタナ　ファルマ　アクチエンゲゼルシャフト Ｐｄｅ４インヒビターとしての３−ヒドロキシ−６−フェニルフェナントリジン
WO2006095009A1 (fr) * 2005-03-09 2006-09-14 Nycomed Gmbh 6-phenylphenanthridines amido-substituees
US7585872B2 (en) 2004-02-18 2009-09-08 Nycomed Gmbh Guanidinyl-substituted hydroxy-6-phenylphenanthridines as effective phosphodiesterase (PDE) 4 inhibitors
US7718668B2 (en) 2005-03-02 2010-05-18 Nycomed Gmbh Salts of 6-heterocycle substituted hexahydrophenanthridine derivatives
US7723391B2 (en) 2007-10-04 2010-05-25 Roche Palo Alto Llc Cyclopropyl aryl amide derivatives and uses thereof
US8003798B2 (en) 2004-03-03 2011-08-23 Nycomed Gmbh Hydroxy-6-heteroarylphenanthridines and their use as PDE4 inhibitors

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Cited By (23)

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Publication number Priority date Publication date Assignee Title
WO2004018431A3 (fr) * 2002-08-17 2004-04-22 Altana Pharma Ag Nouvelles phenanthridines
JP2005539043A (ja) * 2002-08-29 2005-12-22 アルタナ　ファルマ　アクチエンゲゼルシャフト Ｐｄｅ４インヒビターとしての２−ヒドロキシ−６−フェニルフェナントリジン
JP2006508913A (ja) * 2002-08-29 2006-03-16 アルタナ　ファルマ　アクチエンゲゼルシャフト Ｐｄｅ４インヒビターとしての３−ヒドロキシ−６−フェニルフェナントリジン
US7329676B2 (en) 2002-08-29 2008-02-12 Nycomed Gmbh 2-hydroxy-6-phenylphenanthridines as PDE-4 inhibitors
US7423046B2 (en) 2002-08-29 2008-09-09 Nycomed Gmbh 3-hydroxy-6-phenylphenanthridines as pde-4 inhibitors
US7632844B2 (en) 2002-08-29 2009-12-15 Nycomed Gmbh 2-hydroxy-6-phenylphenanthridines as PDE-4 inhibitors
US8202880B2 (en) 2002-08-29 2012-06-19 Nycomed Gmbh 3-hydroxy-6-phenylphenanthridines as PDE4 inhibitors
US8329906B2 (en) 2004-02-18 2012-12-11 Nycomed Gmbh Guanidinyl-substituted hydroxy-6-phenylphenanthridines
US7585872B2 (en) 2004-02-18 2009-09-08 Nycomed Gmbh Guanidinyl-substituted hydroxy-6-phenylphenanthridines as effective phosphodiesterase (PDE) 4 inhibitors
US8003798B2 (en) 2004-03-03 2011-08-23 Nycomed Gmbh Hydroxy-6-heteroarylphenanthridines and their use as PDE4 inhibitors
US8455653B2 (en) 2004-03-03 2013-06-04 Takeda Gmbh Hydroxy-6-heteroarylphenanthridines and their use as PDE4 inhibitors
US9962377B2 (en) 2004-03-03 2018-05-08 Takeda Gmbh Hydroxy-6-heteroarylphenanthridines and their use as PDE4 inhibitors
US8318944B2 (en) 2004-03-03 2012-11-27 Nycomed Gmbh Hydroxy-6-heteroarylphenanthridines and their use as PDE4 inhibitors
US8324391B2 (en) 2004-03-03 2012-12-04 Nycomed Gmbh Hydroxy-6-heteroarylphenanthridines and their use as PDE4 inhibitors
US9387205B2 (en) 2004-03-03 2016-07-12 Takeda Gmbh Hydroxy-6-heteroarylphenanthridines and their use as PDE4 inhibitors
US9149479B2 (en) 2004-03-03 2015-10-06 Takeda Gmbh Hydroxy-6-heteroarylphenanthridines and their use as PDE4 inhibitors
US8883818B2 (en) 2004-03-03 2014-11-11 Takeda Gmbh Hydroxy-6-heteroarylphenanthridines and their use as PDE4 inhibitors
US8754218B2 (en) 2005-03-02 2014-06-17 Takeda Gmbh Salts of 6-heterocycle substituted hexahydrophenanthridine derivatives
US8829189B2 (en) 2005-03-02 2014-09-09 Takeda Gmbh Salts of 6-heterocycle substituted hexahydrophenanthridine derivatives
US8354535B2 (en) 2005-03-02 2013-01-15 Nycomed Gmbh Salts of 6-heterocycle substituted hexahydrophenanthridine derivatives
US7718668B2 (en) 2005-03-02 2010-05-18 Nycomed Gmbh Salts of 6-heterocycle substituted hexahydrophenanthridine derivatives
WO2006095009A1 (fr) * 2005-03-09 2006-09-14 Nycomed Gmbh 6-phenylphenanthridines amido-substituees
US7723391B2 (en) 2007-10-04 2010-05-25 Roche Palo Alto Llc Cyclopropyl aryl amide derivatives and uses thereof

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