Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-12
2003-03-18
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S287000, C514S289000, C514S290000, C514S291000, C546S109000, C546S108000, C546S065000, C546S074000, C546S101000
Reexamination Certificate
active
06534518
ABSTRACT:
FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel polysubstituted 6-phenylphenanthridines, 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 6-phenylphenanthridines described in greater detail below, which differ from the previously known 6-phenylphenanthridines by a different substitution pattern on the 6-phenyl ring, have surprising and particularly advantageous properties.
The invention thus relates to 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 a phenyl radical substituted by R7, R19 and R20,
R7 is hydroxyl, halogen, cyano, nitro, amino, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, phenyl, phenyl-1-4C-alkyl, C(O)—OR8, C(O)-N(R9)R10, N(R14)R15, S(O)
2
—R16 or S(O)
2
—N(R17)R18,
R8 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,
R9 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, and
R10 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, pyridyl, R11-substituted pyridyl, or aryl,
or where R9 and R10, together and including the nitrogen atom to which both are bonded, are a 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazin-1-yl, 1-hexahydroazepinyl or 4-morpholinyl radical,
R11 is halogen, nitro, carboxyl, 1-C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkyl, trifluoromethyl or completely or predominantly fluorine-substituted 1-4C-alkoxy,
aryl is phenyl or R12- and/or R13-substituted phenyl, where
R12 is hydroxyl, halogen, 1-4C-alkyl or 1-4C-alkoxy,
R13 is hydroxyl, halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonylamino, amino, mono- or di-1-4-C-alkylamino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl or completely or predominantly fluorine-substituted 1-4C-alkoxy,
R14 is hydrogen, 1-4C-alkyl, S(O)
2
—R16 or S(O)
2
-aryl,
R15 is 1-4C-alkyl, 1-4C-alkylcarbonyl, S(O)
2
—R16 or S(O)
2
-aryl,
R16 is 1-4C-alkyl,
R17 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,
R18 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or aryl,
or where R17 and R18, together and including the nitrogen atom to which both are bonded, are a 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazin-1-yl, 1-hexahydroazepinyl or 4-morpholinyl radical,
R19 is hydroxyl, halogen, nitro, cyano, amino, mono- or di-1-4C-alkylamino, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonylamino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, and
R20 is hydroxyl, halogen, nitro, 1-4C-alkoxy, 1-4C-alkyl or 1-4C-alkylcarbonyloxy,
or in which
R6 is an R21- and R22-substituted phenyl radical and
R21 and R22 have the same meaning and are selected from the group consisting of trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, carboxyl, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl and completely or predominantly fluorine-substituted 1-4C-alkoxy,
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-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 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
—], 1,2dimethylethylene [—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 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.
Phenyl-1-4C-alkyl represents one of the abovementioned, phenyl-substituted 1-4C-alkyl radicals. Examples which may be mentioned are the phenethyl and the benzyl radicals.
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. Preferably, the 3-5C-cycloalkylmethyl radicals cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl may be mentioned.
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
O—C(O)—] and the ethoxycarbonyl [CH
3
CH
2
O—C(O)—] 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(O)—O—].
In addition to the nitrogen atom, mono- or di-1-4C-alkylamino radicals contain one or two of the abovementioned 1-4C-alkyl radicals. Di-1-4C-alkylamino is preferred and here, in particular, dimethyl-, diethyl- or diisopropylamino.
In addition to the carbonyl group, 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.
As a 1-4C-Alkylcarbonylamino radical, for example, the propionylamino [C
3
H
7
C(O)NH—] and the acetylamino
Altana Pharma AG
Goldberg Joshua B.
Huang Evelyn Mei
Juneau Todd L.
Nath Gary M.
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