Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-15
2002-08-20
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, C546S065000, C546S081000
Reexamination Certificate
active
06436952
ABSTRACT:
This application is the 371 of PCT/EP99/06139, filed on Aug. 21, 1999.
FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel benzonaphthyridine N-oxides which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
DE-A 21 23 328 and U.S. Pat. 3,899,494 describe substituted benzonaphthyridines which are distinguished by marked inhibition of blood platelet aggregation. International Applications WO 91/17991 and WO 98/121208 disclose 6-phenylbenzonaphthyridines for the treatment of inflammatory airway disorders.
DESCRIPTION OF THE INVENTION
It has now been found that the following compounds of the formula I which are described in greater detail and differ from the compounds of WO 91/17991 and WO 98/21208, in particular, by the substitution on the 6-phenyl ring and the presence of an N-oxide in the 2-position, have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula I
in which
R1 is 1-4C-alkyl,
R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which completely or predominantly substituted by fluorine,
R3 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which completely or predominantly substituted by fluorine,
or in which
R2 and R3 together are a 1-2C-alkylenedioxy group,
R4 is a phenyl radical which is substituted by R5, where
R5 is a tetrazol-5-yl radical which is substituted by a radical R6, where
R6 is hydrogen, 1-10C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-4C-alkyl,
where
Ar is a phenyl radical which is unsubstituted or substituted by R7 and/or R8, and
R7 and R8 independently of one another are 1-4C-alkyl or 1-4C-alkoxy, and to 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.
As 1-4C-Alkoxy which is completely or predominantly substituted by fluorine, the 2,2,3,3,3-penta-fluoropropoxy, 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, for example, may be mentioned.
1-2C-Alkylenedioxy represents, for example, the methylenedioxy (—O—CH
2
—O—) or the ethylenedioxy radical (—O—CH
2
—CH
2
—O—).
1-10C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 10 carbon atoms. Examples which may be mentioned are the decyl, nonyl, octyl, 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 or cycloheptyl radical. The 5-7C-cycloalkyl radicals cyclopentyl, cyclohexyl and cycloheptyl may preferably be mentioned.
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 cyclohexyl-methyl radicals.
Ar-1-4C-alkyl is 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.
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 particularly mentioned. 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-hydroxylbenzoyl)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-hydroxyl-2-naphthoic acid, where the acids are employed in salt preparation—depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired—in an equimolar quantitative ratio or one differing therefrom.
On the other hand—for example in the case of 1H- or 2H-tetrazol-5-yl substitution—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 can be obtained first, for example, as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by methods known to the person skilled in the art.
It is known to the person skilled in the art that the compounds according to the invention and their salts, if they are isolated, for example, in crystalline form, can contain various amounts of solvents. The invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates in particular all hydrates of the salts of the compounds of the formula I.
Compounds of the formula I to be emphasized are those in which
R1 is 1-2C-alkyl,
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R3 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
or in which
R2 and R3 together are a 1-2C-alkylenedioxy group,
R4 is a phenyl radical which is substituted by R5, where
R5 is a tetrazol-5-yl radical which is substituted by a radical R6, where
R6 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 R7 and/or R8, and
R7 and R8 independently of one another are 1-4C-alkyl or 1-4C-alkoxy,
and the salts of these compounds.
Compounds of the formula I particularly to be emphasized are those in which
R1 is methyl,
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R3 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R4 is a phenyl radical which is substituted by R5, where
R5 is a tetrazol-5-yl radical which is substituted by a radical R6, where
R6 is hydrogen, 1-7C-alkyl, 5-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-2C-alkyl,
where
Ar is a phenyl radical which is unsubstituted or substituted by R7, and
R7 is 1-2C-alkyl or 1-2C-alkoxy,
and the salts of these compounds.
Preferred compounds of the formula I are those in which
R1 is methyl,
R2 is 1-4C-alkoxy,
R3 is 1-4C-alkoxy,
R4 is a phenyl radical which is substituted by R5, where
R5 is a tetrazol-5-y
Byk Gulden Lomberg Chemische Fabrik - GmbH
Huang Evelyn Mei
Jacobson & Holman PLLC
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