Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-04
2004-02-24
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...
C514S233200, C546S082000, C546S083000, C546S065000, C544S126000
Reexamination Certificate
active
06696461
ABSTRACT:
FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel compounds which are used in the pharmaceutical industry as active compounds for preparing medicaments.
PRIOR ART
U.S. Pat. No. 4,468,400 describes tricyclic imidazo[1,2-a]pyridines having different ring systems fused to the imidazopyridine skeleton, which compounds are said to be suitable for treating peptic ulcer disorders. The international Patent Application WO95/27714 describes certain 8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridines having gastric acid secretion-inhibiting properties. The international Patent Applications WO98/42707 and WO98/54188 disclose tricyclic imidazopyridine derivatives having a very particular substitution pattern, which compounds are likewise said to be suitable for treating gastroin-testinal disorders.
DESCRIPTION OF THE INVENTION
The invention provides compounds of the formula 1
in which
R1 is methyl or hydroxymethyl,
one of the substituents R2a and R2b is hydrogen and the other is hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methoxyethoxy or methoxypropoxy,
one of the substituents R3a and R3b is hydrogen and the other is hydrogen, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methoxyethoxy or methoxypropoxy,
R4 is halogen, carboxyl, —CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical —CO—NR5R6,
where
R5 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
R6 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R5 and R6 together with the nitrogen atom to which both are attached are a pyrrolidino, piperidino or morpholino radical,
X is O (oxygen) or NH,
and their salts,
except for those compounds in which R4 is chlorine or bromine if R2a or R2b is hydroxyl and simultaneously one of the substituents R3a and R3b is hydrogen and the other is hydrogen or hydroxyl.
For the purposes of the invention, halogen is bromine, chlorine or fluorine.
1-4C-Alkyl denotes straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
1-4C-Alkoxy denotes 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.
Hydroxy-1-4C-alkyl denotes the abovementioned 1-4C-alkyl radicals substituted by a hydroxyl group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl radical.
1-4C-Alkoxy-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the methoxymethyl, the methoxyethyl and the butoxyethyl radical.
1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkyl denotes one of the abovementioned 1-4C-alkoxy-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxy radicals. An example which may be mentioned is the methoxyethoxymethyl radical.
Fluoro-1-4C-alkoxy-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by a fluoro-1-4C-alkoxy radical. Here, fluoro-1-4C-alkoxy denotes one of the 1-4C-alkoxy radicals which is fully or partly fluorine-substituted. Examples of fully or partly fluorine-substituted 1-4C-alkoxy which may be mentioned are the 1,1,1,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy and the trifluoromethoxy and preferably the difluoromethoxy radical.
1-7C-Alkyl denotes 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.
Suitable salts of compounds of the formula 1 are in particular all acid addition salts. Particular mention may be made of the pharmacologically acceptable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable 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 the salt preparation in an equimolar ratio or a ratio differing therefrom, depending on whether the acid is a mono- or polybasic acid and on which salt is desired.
Pharmacologically unacceptable salts, which can be initially obtained, for example, as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into the pharmacologically acceptable salts by processes 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 can, for example when they are isolated in crystalline form, comprise varying amounts of solvents. The invention therefore also embraces all solvates and, in particular, all hydrates of the compounds of the formula 1, and all solvates and, in particular, all hydrates of the salts of the compounds of the formula 1.
The compounds of the formula 1 have at least two chiral centers. The invention provides all feasible stereoisomers in any mixing ratio, including the pure enantiomers which are the preferred subject matter of the invention.
One embodiment (embodiment a) of the invention are compounds of the formula 1, in which R4 is halogen.
A further embodiment (embodiment b) of the invention are compounds of the formula 1 in which R4 is carboxyl, —CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical —CO—NR5R6.
Emphasis is given to compounds of the formula 1*
in which
R1 is methyl or hydroxymethyl,
one of the substituents R2a and R2b is hydrogen and the other is hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methoxyethoxy or methoxypropoxy,
one of the substituents R3a and R3b is hydrogen and the other is hydrogen, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methoxyethoxy or methoxypropoxy,
R4 is halogen, carboxyl, —CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4 C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical —CO—NR5R6,
where
R5 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
R6 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R5 and R6 together with the nitrogen atom to which both are attached are a pyrrolidino, piperidino or morpholino radical,
X is O (oxygen) or NH,
and its salts,
except for those compounds in which R4 is chlorine or bromine if R2a is hydrogen and R2b is hydroxyl and simultaneously R3a is hydrogen or hydroxyl and R3b is hydrogen.
Compounds of embodiment a of the invention which are to be emphasized are those of the formula 1* in which R4 is halogen.
Compounds of embodiment b of the invention which are to be emphasized are those of the formula 1* in which R4 is carboxyl, —CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the rad
Buhr Wilm
Huber Reinhard
Senn-Bilfinger Jörg
Sturm Ernst
Altana Pharma AG
Huang Evelyn Mei
Juneau Todd L.
McGee Sheldon M.
Nath Gary M.
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