Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-23
2002-06-25
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S101000
Reexamination Certificate
active
06410551
ABSTRACT:
FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel 6-[(tetrazol-5-yl)-phenyl]phenanthridines, 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 partial hydrogenated 6-phenylphenanthridines. In the international patent applications WO97/35854 and WO97/28131 partial hydrogenated 6-phenylphenanthridines are described as cyclic nucleotide phosphodiesterase (PDE) inhibitors of type 4.
DESCRIPTION OF THE INVENTION
It has now been found that the novel 6-phenyl-phenanthridines, which are described below in greater detail, which differ from the prior art, in particular, by the substitution 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 are an additional bond,
R6 is a phenyl radical substituted by R7, where
R7 is a tetrazol-5-yl radical substituted by a radical R8, where
R8 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-4C-alkyl, where
Ar is a phenyl radical which is unsubstituted or substituted by R9 and/or R10, and
R9 and R10 independently of one another are halogen, nitro, cyano, 1-4C-alkyl, trifluoromethyl or 1 -4C-alkoxy,
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 b ranched 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 cyclopentyl methoxy 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 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
—), 1,2-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 compounds of the formula I are linked to 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 (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 the cycloheptyl radicals. The 5-7C-cycloalkyl radicals cyclopentyl, cyclohexyl and cycloheptyl may be mentioned as preferred.
3-7C-Cycloalkylmethyl represents a methyl radical which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the cyclopentylmethyl and the cyclohexylmethyl radicals.
Ar-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals, which is substituted by one of the aryl radicals defined above. Examples which may be mentioned are the p-methoxybenzyl, the phenethyl and the benzyl radicals.
Halogen within the meaning of the invention is bromine, chlorine and fluorine.
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, 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, 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—for example if the tetrazol-5-yl radical R7 is substituted by R8=H— 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 solvates 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 and R51 together are an additional bond,
R6 is a phenyl radical substituted by R7, where
R7 is a tetrazol-5-yl radical substituted by a radical R8, where
R8 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-4C-alkyl, where
Ar is a ph
Byk Gulden Lomberg Chemische Fabrik - GmbH
Robinson Binta
Rotman Alan L.
LandOfFree
Tetrazole derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Tetrazole derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tetrazole derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2915916