Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-03
2002-05-07
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...
C546S081000, C546S092000
Reexamination Certificate
active
06384047
ABSTRACT:
FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel benzonaphthyridines, a process for their preparation, their use and medicaments containing them. The compounds according to the invention are used in the pharmaceutical industry for the preparation of medicaments.
KNOWN TECHNICAL BACKGROUND
WO91/17991 describes under the title “New sulphonyl compounds” certain benzonaphthyridine derivatives, which are to be suitable for the treatment of airway disorders. In WO93/09780 and in DE-OS 4310050 the use of these benzonaphthyridine derivatives for the treatment of dermatoses, allergic rhinitis and conjunctivitis as well as of nasal polyps is described. For the compound (−)-cis-8,9-Dimethoxy-2-methyl-6-[4-(p-toluenesulfonamido)-phenyl]-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine, which is particularly emphasized in WO91/17991, WO93/09780 and DE 4310050, the WHO has proposed the INN Tolafentrine.
DESCRIPTION OF THE INVENTION
The invention relates to compounds of the formula I
in which
R1 is ethoxy,
R2 is methoxy or ethoxy,
and the salts of these compounds.
The compounds of the formula I are chiral compounds having chiral centers in positions 4a and 10b. The Invention therefore both comprises all conceivable pure diastereomers and pure enantiomers, and their mixtures in any mixing ratio, including the racemates. Preferred compounds of the formula I are those in which the hydrogen atoms in the positions 4a and 10b are cis to one another.
Particularly preferred are the compounds
(−)-cis-8,9-Diethoxy-2-methyl-6-[4-(p-toluenesulfonamido)-phenyl]-1,2,3,4,4a,10b-hexahydro-benzo-[c][1,6]naphthyridine and
(−)-cis-9-Ethoxy-8-methoxy-2-methyl-6-[4-(p-toluenesulfonamido)-phenyl]-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine
and the salts of these compounds.
Suitable salts for compounds of the formula I preferably are all acid addition salts. Particular mention may be made of the pharmacologically tolerable salts with the inorganic and organic acids customarily used in pharmacy. Examples of such suitable salts are 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 a mono- or polybasic acid is concerned and depending on which salt is desired—in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically intolerable salts, which can be obtained, for example, as process products during 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.
The invention further relates to a process for the preparation of the compounds of the formula I, in which R1 and R2 have the meanings indicated above, and their salts.
The process is characterized in that
a) compounds of the formula II
in which R1 and R2 have the abovementioned meanings, are reacted with a reactive derivative of p-toluenesulfonic acid, or in that
b) compounds of the formula III
in which R1 and R2 have the abovementioned meanings, are subjected to a cyclocondensation reaction
and in that, If desired, compounds of the formula I obtained according to a) or b) are then converted Into their salts, or in that, if desired, salts of the compounds of the formula I obtained according to a) or b) are then converted into the free compounds.
The reaction of compounds of the formula II with reactive derivatives of the p-toluenesulfonic acid (for example, a p-toluenesulfonic acid halide, particularly the acid chloride) is carried out in inert solvents in a manner known to the expert for the preparation of sulfonamides. The reaction is preferably carried out in the presence of an auxiliary base, such as for example, triethylamine or pyridine.
The cyclocondensation is carried out in a manner known per se to the person skilled in the art according to Bischler-Napieralski (e.g. as described in J. Chem. Soc., 1956, 4280-4282) in the presence of a suitable condensing agent, such as, for example, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, thionyl chloride or preferably phosphorus oxychloride, in a suitable inert solvent, e.g. in a chlorinated hydrocarbon such as chloroform, or in a cyclic hydrocarbon such as toluene or xylene, or another inert solvent such as acetonitrile, or without a further solvent using an excess of condensing agent, preferably at elevated temperature, in particular at the boiling temperature of the solvent or condensing agent used.
The described methods of preparation can be carried out analogously to the methods described in WO91/17991. The following examples serve to illustrate this.
REFERENCES:
patent: 5346904 (1994-09-01), Flockerzi et al.
patent: 2 123 328 (1971-12-01), None
patent: 43 10 050 (1993-10-01), None
patent: 0 247 971 (1987-12-01), None
patent: 0 163 965 (1996-12-01), None
patent: 91/17991 (1991-11-01), None
patent: 93/09780 (1993-05-01), None
Flockerzi Dieter
Hatzelmann Armin
Byk Gulden Lomberg Chemische Fabrik - GmbH
Jacobson & Holman PLLC
Rotman Alan L.
LandOfFree
Benzonaphthyridine does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Benzonaphthyridine, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzonaphthyridine will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2877725