Phenanthridines

Details Phenanthridines Phenanthridines

1998-07-31

2001-02-20

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S291000, C546S065000, C546S109000

Reexamination Certificate

active

06191138

ABSTRACT:

FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel 6-phenylphenanthridines which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
The synthesis of 6-phenylphenanthridines is described in Chem. Ber. 1939, 72, 675-677, J. Chem. Soc., 1956, 4280-4283 and J. Chem. Soc. (C), 1971, 1805-1808.
DESCRIPTION OF THE INVENTION
It has now been found that the novel phenanthridines described in greater detail below have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula I (see attached formula sheet), in which
R1 is hydroxy, 1-4C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or partially substituted by fluorine,
R2 is hydroxy, 1-4C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or partially substituted by fluorine,
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 are an additional bond,
R6 is a phenyl radical which is substituted by R7, where
R7 is COOR71 or CON(R72)R73 and R71 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl and R72 and R73 independently of one another are each hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,
and the salts of these compounds.
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 radical.
3-7C-cycloalkoxy represents, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, and preferably cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.
3-7C-cycloalkylmethoxy respresents, for example, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, and preferably cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy.
1-4C-alkoxy which is completely or partially substituted by fluorine is, for example, the 1,2,2-trifluoroethoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy and in particular the 2,2,2-trifluoroethoxy and preferably the difluoromethoxy radical.
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 radical.
1-2C-alkylenedioxy represents, for example, the methylenedioxy (—O—CH
2
—O—) and the ethylenedioxy radical (—O—CH
2
—CH
2
—O—).
If R3 and R31 together have the meaning 1-4C-alkylene, positions 1 and 4 in compounds of the formula I are linked with each other by a 1-4C-alkylene bridge, and 1-4C-alkylene represents 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 denote an additional bond, the carbon atoms in positions 2 and 3 of the compounds of the formula I are linked with one another via a double bond.
1-7C-alkyl represents straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (2-methylhexyl), hexyl, isohexyl (2-methylpentyl), neohexyl (2,2-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radical.
3-7C-cycloalkyl represents the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radical. Preference is given to the 3-5C-cycloalkyl radicals, cyclopropyl, cyclobutyl and cyclopentyl.
3-7C-cycloalkylmethyl represents a methyl radical which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. Preference is given to the 3-5C-cycloalkylmethyl radicals, cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl.
The substituent R7 may be attached to any suitable position on the phenyl ring. Particular preference is given to the substituent R7 attached in position 4 of the phenyl ring.
Examples of R7-substituted phenyl radicals which may be mentioned are 4-carboxyphenyl, 3-carboxyphenyl, 4-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 2-methoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 4-(N-methylaminocarbonyl)phenyl, 3-(N-methylaminocarbonyl)phenyl, 4-(N,N-dimethylaminocarbonyl)phenyl, 4-carbamoylphenyl and 3-carbamoylphenyl.
Compounds of the formula I to be emphasized are those in which
R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxy or 1-2C-alkoxy which is completely or partially substituted by fluorine,
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxy or 1-2C-alkoxy which is completely or partially substituted by fluorine,
R3 is hydrogen,
R31 is hydrogen,
or in which
R3 and R31 together are a 1-2C-alkylene group,
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen,
R51 is hydrogen,
or in which
R5 and R51 together are an additional bond,
R6 is a phenyl radical which is substituted by R7, where
R7 is COOR71 or CON(R72)R73 and R71 is hydrogen, 1-7C-alkyl or 3-7C-cycloalkylmethyl and R72 and R73 independently of one another are each hydrogen or 1-7C-alkyl,
and the salts of these compounds.
Compounds of the formula I which are particularly to be emphasized are those in which
R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy or 1-2C-alkoxy which is completely or partially substituted by fluorine,
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy or 1-2C-alkoxy which is completely or partially substituted by fluorine,
R3 is hydrogen,
R31 is hydrogen,
or in which
R3 and R31 together are a 1-2C-alkylene group,
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen,
R51 is hydrogen,
or in which
R5 and R51 together are an additional bond,
R6 is a phenyl radical which is substituted by R7, where
R7 is COOR71 or CON(R72)R73 and R71 is hydrogen, 1-7C-alkyl or 3-7C-cycloalkylmethyl and R72 and R73 independently of one another are each hydrogen or 1-4C-alkyl,
and the salts of these compounds.
Preferred compounds of the formula I are those in which
R1 is methoxy, ethoxy or difluoromethoxy,
R2 is methoxy, ethoxy or difluoromethoxy,
R3 and R31 are each hydrogen,
R4 is hydrogen,
R5 and R51 are each hydrogen,
R6 is a phenyl radical which is substituted by R7, where
R7 is COOR71 or CON(R72)R73 and R71 is hydrogen or 1-4C-alkyl, R72 is hydrogen and R73 is 1-4C-alkyl,
and the salts of these compounds.
An embodiment of the preferred compounds of the formula I are those in which
R1 is methoxy or ethoxy,
R2 is methoxy, ethoxy or difluoromethoxy,
R3 and R31 are each hydrogen,
R4 is hydrogen,
R5 and R51 are each hydrogen,
R6 is a phenyl radical which is substituted by R7, where
R7 is COOR71 and R71 is hydrogen or 1-4C-alkyl,
and the salts of these compounds.
Suitable salts of compounds of the formula I—depending on substitution—are all acid addition salts or all salts with bases. The pharmacologically tolerable salts of the inorganic and organic acids and bases customarily used in pharmacy may be mentioned particularly. 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, the acids being employ

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