Phenanthridine-N-oxides

Details Phenanthridine-N-oxides Phenanthridine-N-oxides

2002-06-18

2003-10-07

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S109000, C546S065000, C514S287000

Reexamination Certificate

active

06630483

ABSTRACT:

FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel phenanthridine-N-oxides, which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
Chem. Ber. 1939, 72, 675-677, J. Chem. Soc., 1956, 4280-4283 and J. Chem. Soc. (C), 1971, 1805 describe the synthesis of 6-phenylphenanthridines. The International Applications WO 97/28131 and WO 97/35854 describe 6-phenyl- and 6-pyridylphenanthridines as PDE4 inhibitors.
DESCRIPTION OF THE INVENTION
It has now been found that the novel N-oxides of substituted 6-phenylphenanthridines described in greater detail below have surprising and particularly advantageous properties.
The invention thus relates to the N-oxides of the compounds of the formula I,
in which
R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 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
R5 and R51 together represent an additional bond,
R6 is an R7- and R8-substituted phenyl radical, where
R7 is hydroxyl, halogen, cyano, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylcarbonyloxy, trifluoromethyl, phenyl, phenyl-14C-alkyl, nitro, amino, completely or predominantly fluorine-substituted 1-4C-alkoxy, SO
2
—R70 or N(R71)R72, where
R70 is 1-4C-alkyl,
R71 is hydrogen, 1-4C-alkyl, SO
2
—R9 or SO
2
—R10 and
R72 is 1-4C-alkyl, 1-4C-alkylcarbonyl or SO
2
—R10,
R8 is hydrogen, hydroxy, halogen, 1-4C-alkoxy or 1-4C-alkyl
 and where
R9 and R10 independently of one another are 1-4C-alkyl, phenyl, phenyl-1-4C-alkyl or phenyl which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of nitro, 1-4C-alkyl, halogen, 1-4C-alkylcarbonylamino, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, cyano, phenyl, naphthyl, trifluoromethyl or 1-4C-alkoxycarbonyl,
 and the salts of these N-oxides.
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-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
3-7C-Cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
As completely or predominantly fluorine-substituted 1-4C-alkoxy, for example, the 2,2,3,3,3-pentafluoropropoxy, 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 are replaced by fluorine atoms.
1-2C-Alkylenedioxy represents, for example, the methylenedioxy [—O—CH
2
—O—] and the ethylenedioxy [—O—CH
2
—CH
2
—O—] radicals.
If R3 and R31 together have the meaning 1-4C-alkylene, the positions 1 and 4 in the N-oxides of the 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. 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-dimethylethylene [—CH(CH
3
)—CH(CH
3
)—] and isopropylidene [—C(CH
3
)
2
—].
If R5 and R51 together are an additional bond, then the carbon atoms in positions 2 and 3 in the N-oxides of the compounds of the formula I are linked to one another via a double bond.
Halogen within the meaning of the invention is bromine, chlorine or fluorine.
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(O)—O—].
Phenyl-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by a phenyl radical. Examples which may be mentioned are the benzyl radical and the phenethyl radical.
1-4C-Alkylcarbonyl represents a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-4C-alkyl radicals. An example which may be mentioned is the acetyl radical.
1-4C-Alkylcarbonylamino represents an amino radical which is substituted by one of the abovementioned 1-4C-alkylcarbonyl radicals. An example which may be mentioned is the acetylamino radical [CH
3
C(O)—NH—].
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 radical [CH
3
O—C(O)—] and the ethoxycarbonyl radical [CH
3
CH
2
O—C(O)—].
Exemplary R7- and R8-substituted phenyl radicals which may be mentioned are the radicals 4-acetamidophenyl, 3-acetamidophenyl, 4-acetoxyphenyl, 3-aminophenyl, 4-aminophenyl, 2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2-chloro-4-nitrophenyl, 4-diethylamino-2-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-chloro-5-nitrophenyl, 4-chloro-3-nitrophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dibromophenyl, 2-cyanophenyl, 3-cyanophenyl, 4cyanophenyl, 4-diethylaminophenyl, 4-dimethylaminophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2-fluoro-5-nitrophenyl, 2-hydroxyphenyl, 3-hydroxy-phenyl, 3,4-dichlorophenyl, 4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 2-hydroxy-4-methoxyphenyl, 2,4-dihydroxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2-dimethylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chloro-6-methylphenyl, 4-methyl-3-nitrophenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,3-dimethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 3,4-dinitrophenyl, 3,5-dinitrophenyl, 2,6-dinitrophenyl, 4-ethoxyphenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-(p-nitrophenylsulfonamido)phenyl, 3-(p-toluenesulfonamido)phenyl, 4-(p-toluenesulfonamido)phenyl, 4-(4ethylphenylsulfonamido)phenyl, 4-bis(p-toluenesulfonyl)aminophenyl, 4-bis(p-nitrophenylsulfonyl)aminophenyl, 3-(p-nitrophenylsulfonamido)phenyl, (N-acetyl-4-p-toluenesulfonamido)phenyl, 4-(benzylsulfonamido)phenyl, 3-(benzylsulfonamido)phenyl, 4-(methylsulfonamido)phenyl, 3-(methylsulfonamido)phenyl, 4-(N-methylmethylsulfonamido)phenyl, 3-(N-methylmethylsulfonamido)phenyl, 4-(3,4-dichlorophenylsulfonamido)phenyl, 3-(3,4-dichlorophenylsulfonamido)phenyl, 4-(3-nitrophenylsulfonamido)phenyl, 3-(3-nitrophenylsulfonamido)phenyl, 4-(4-bromophenyisulfonamido)phenyl, 3-(4-bromophenyisulfonamido)phenyl, 4-(3-bromophenylsulfonamido)phenyl, 3-(3-bromophenylsulfonamido)phenyl, 4-(3-fluorophenylsulfonamido)phenyl, 3-(3-fluorophenylsulfonamido)phenyl, 4-(4-fluorophenylsulfonamido)phenyl, 3-(4-fluorophenylsulfonamido)phenyl, 4-(4-chlorophenyisulfonamido)phenyl, 3-(4-chlorophenylsulfonamido)phenyl, 4-(3-chlorophenylsulfonamido)phenyl, 3-(3-c

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