Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-19
2003-11-25
Huang, Evelyn Mei (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S127000
Reexamination Certificate
active
06653477
ABSTRACT:
FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel compounds which are used in the pharmaceutical industry as intermediates for the production of medicaments.
1. Prior Art
The international patent applications WO98/42707 and WO 98/54188 disclose tricyclic imidazopyridine derivatives having a very specific substitution pattern, which should be suitable for the treatment of gastric and intestinal disorders.
2. Description of the Invention
The invention relates to compounds which can be used as important intermediates for the preparation of the compounds mentioned in the prior art and further compounds having a similar basic structure.
The invention thus relates in a first aspect to compounds of the formula 1
in which
R1 is hydrogen, methyl, formyl or hydroxymethyl and
R2 is hydrogen, halogen, carboxyl, —CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical —CO—NR3R4, where
R3 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
R4 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
R3 and R4 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidine or morpholino radical,
and their salts.
Halogen within the meaning of the invention is bromine, chlorine or fluorine.
1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl radical, isobutyl radical, sec-butyl radical, tert-butyl radical, propyl radical, isopropyl radical, ethyl radical and the methyl radical.
1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the buto radical, isobutoxy radical, sec-butoxy radical, tert-butoxy radical, propoxy radical, isopropoxy radical and preferably the ethoxy radical and methoxy radical.
Hydroxy-1-4C-alkyl represents abovementioned 1-4C-alkyl radicals which are substituted by a hydro group. Examples which may be mentioned are the hydroxymethyl radical, the 2-hydroxyethyl radical and the 3-hydroxypropyl radical.
1-4C-Alkoxy-1-4C-alkyl represents 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 radical, the methoxyethyl radical and the butoxyethyl radical.
1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkyl represents one of the abovementioned 1-4C-alkoxy-1-4C-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 represents one of the abovementioned 1-4C-alkyl radicals which is substituted by a fluoro-1-4C-alkoxy radical. Fluoro-1-4C-alkoxy in this case represents one of the above mentioned 1-4C-alkoxy radicals which is completely or partly substituted by fluorine. Examples of 1-4 alkoxy which is completely or partly substituted by fluorine, which may be mentioned, are the 1,1,1,3,3,3-hexafluoro-2-propoxy radical, the 2-trifluoromethyl-2-propoxy radical, the 1,1,1-trifluoropropoxy radical, the perfluoro-tert-butoxy radical, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy radical, the 4,4,4-trifluoro-1-butoxy radical, the 2,2,3,3,3-pentafluoropropoxy radical, the perfluoroethoxy radical the 1,2,2-trifluoroethoxy radical, in particular the 1,1,2,2-tetrafluoroethoxy radical, the 2,2,2-trifluoryl ethoxy radical, the trifluoromethoxy radical and preferably the difluoromethoxy radical.
1-7C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl radical, isoheptyl radical (5-methylhexyl radical), hexyl radical, isohexyl radical (4-methylpentyl radical), neohexyl radical (3,3-dimethylbutyl radical), pentyl radical, isopentyl radical (3-methylbutyl radical), neopentyl radical (2,2-dimethylpropyl radical), butyl radical, isobutyl radical, sec-butyl radical, tert-butyl radical, propyl radical, isopropyl radical, ethyl radical and the methyl radical.
Suitable salts of compounds of the formula I are especially all acid addition salts. Particular mention may be made of the salts of the inorganic and organic acids customarily used. Those which are suit able are water-soluble and water-insoluble acid addition salts with acids such as 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 toluene-sulfonic 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.
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 1, and also all solvates and in particular all hydrates of the salts of the compounds of the formula 1.
Compounds of the formula 1 to be emphasized are those in which
R1 is methyl,
R2 is hydrogen, fluorine, chlorine, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxymethyl, methoxyethoxymethyl, difluoromethoxymethyl or the radical —CO—NR3R4, where
R3 is hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl or 2-methoxyethyl and
R4 is hydrogen, methyl or ethyl,
and their salts.
Preferred compounds of the formula 1 are those in which
R1 is methyl,
R2 is hydrogen, fluorine, chlorine, methoxycarbonyl, ethoxycarbonyl, hydroxymethyl or methoxymethyl,
and their salts.
The compounds according to the invention can be prepared, for example, according to the following reaction scheme.
The reaction to give the compound 2 is carried out in a manner which is known per se to the person skilled in the art. The reaction of 2 to give 3 can be carried out in various ways, for example using the Heck reaction (with Pd(II), carbon monoxide and ethanol) or by metallation in the 6-position (with lithium or magnesium) and subsequent Grignard reaction. The metallation also offers the possibility of introducing other desired groups R2 in position 6, for example fluorine, chlorine or the carboxyl group The debenzylation/reduction of the compound 3 is likewise carried out in a manner known per se, for example using hydrogen/Pd(0). If compounds where R2═—CO—NR3R4 are desired, an appropriate derivatization can be carried out in a manner known per se (conversion of an ester into an amide) at the stage of compound 3 or after the debenzylation/reduction.
The following examples serve to illustrate the invention in greater detail without restricting it. Likewise further compounds of the formula 1 whose preparation is not described explicitly can be prepared in an analogous manner or in a manner familiar per se to the person skilled in the art using customary process techniques. The abbreviation min stands for minute(s) and h for hour(s).
REFERENCES:
patent: WO 98/42707 (1998-10-01), None
patent: WO 98/54188 (1998-12-01), None
Hafenbradl D et al. Angewandte Chemie, International Edition in English, (1996), 35(5), 545-7.
Buhr Wilm
Senn-Bilfinger Jörg
Zimmermann Peter
Altana Pharma AG
Huang Evelyn Mei
Juneau Tood L.
Nath Gary M.
Nath & Associates PLLC
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