Substituted 6-alkylphenanthridines

Details Substituted 6-alkylphenanthridines Substituted 6-alkylphenanthridines

2000-01-24

2001-04-10

Aulakh, Charansit S. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S108000, C546S065000, C514S287000

Reexamination Certificate

active

06214839

ABSTRACT:

FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel 6-alkylphenanthridines which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
German Patent Application DE 11 99 773 describes the preparation of 6-methyl-8,9-methylenedioxy-1,2,3,4,4a,5,6,10b-octahydrophenanthridine, which should have analgesic, antiinflammatory and anti-pyretic properties. In the Indian Journal of Chemistry 7, 1969, 674-677 the preparation of ethyl 1,2,3,4,4a,10a-hexahydrophenanthridine-6-butyrate is described.
DESCRIPTION OF THE INVENTION
It has now been found that the novel 6-alkylphenanthridines which are described below in greater detail 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 are an additional bond,
A is 1-6C-alkylene or 5-7C-cycloalkylene,
R6 is COOR61 or CON(R62)R63, where
R61 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl and
R62 and R63 independently of one another are hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,
and the salts 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.
Completely or predominantly fluorine-substituted 1-4C-alkoxy which may be mentioned are, 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 trifluoromethoxy, the 2,2,2-trifluoroethoxy and, preferably, the difluoromethoxy radicals. “Predominantly” in this connection means that more than half of the hydrogen atoms are substituted by fluorine atoms.
1-2C-Alkylenedioxy represents, for example, the methylenedioxy (—O—CH
2
—O—) and the ethylenedioxy radicals (—O—CH
2
—CH
2
—O—).
If R3 and R31 together have the meaning 1-4C-alkylene, the positions 1 to 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
—), 1,2-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 the positions 2 and 3 in compounds of the formula I are linked to one another via a double bond.
1-6C-Alkylene represents straight-chain or branched 1-6C-alkylene radicals, for example the methylene (—CH
2
—), ethylene (—CH
2
—CH
2
—), trimethylene (—CH
2
—CH
2
—CH
2
—), tetramethylene (—CH
2
—CH
2
—CH
2
—CH
2
—), 1,2-dimethyl-ethylene [—CH(CH
3
)—CH(CH
3
)—], 1,1-dimethylethylene [—C(CH
3
)
2
—CH
2
—], 2,2-dimethylethylene [—CH
2
—C(CH
3
)
2
—], isopropylidene [—C(CH
3
)
2
—], 1-methylethylene [—CH(CH
3
)—CH
2
—], pentamethylene (—CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—) and the hexamethylene radicals (—CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—).
5-7C-Cycloalkylene represents cycloalkylene radicals having 5 to 7 carbon atoms. Cyclohexylene radicals are preferred, where, for example, the 1,3- and the 1,4-cyclohexylene radicals may be mentioned.
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 (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert butyl, propyl, isopropyl, ethyl and methyl radicals.
3-7C-Cycloalkyl represents the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals.
3-7C-Cycloalkylmethyl represents a methyl radical which is substituded by one of the abovementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the cyclopentylmethyl and the cyclohexylmethyl radicals.
Suitable 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 which are 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, sulfosalicyclic 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, where the acids are employed in salt preparation—depending on whether it is a mono- or polybasic acid and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
On the other hand, 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 may be obtained initially as process products, for example 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.
According to expert's knowledge 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 I as well as all solvents and in particular all hydrates of the salts of the compounds of formula I.
Compounds of the formula I to be emphasized are those in which
R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy.
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy.
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 is R51 together are an additional bond,
A is 1-6C-alkylene or 5-7C-cycloalkylene,
R6 is COOR61 or CON(R62)R63, where
R61 is hydrogen, 1-7C-alkyl or 3-7C-cycloalkylmethyl and
R62 and R63 independently of one anoth

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