Imidazo- and oxazolopyridines

Details Imidazo- and oxazolopyridines Imidazo- and oxazolopyridines

2000-10-04

2001-10-23

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...

C514S303000, C546S015000, C546S113000, C546S118000

Reexamination Certificate

active

06306867

ABSTRACT:

FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel oxazolo- and imidazopyridines, which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
German Patent Applications DE 23 30 109, DE 25 27 321, DE 26 19 547 and DE 26 33 905 and the U.S. Pat. No. 4,038,396 describe 2-(substituted phenyl)-oxazolo[4,5-b]pyridines, -oxazolo-[4,5-c]pyridines and -oxazolo[5,4-b]pyridines as antiinflammatory, antipyretic and analgesic compounds.
German Patent Application DE 23 61 757 describes 2-(substituted phenyl)-imidazo[4,5-b]pyridines having antihypertensive, positively inotropic, platelet aggregation-inhibiting and bleeding time-prolonging properties.
European Patent Application EP 022 495 describes 2-(substituted phenyl)-imidazo[4,5-b]pyridines as cardiotonic agents and hypertensive agents. European Patent Application EP 072 926 describes 2-(substituted phenyl)-imidazo[4,5-b]- and -[4,5-c]pyridines having positively inotropic properties. European Patent Application EP 079 083 describes 2-phenylimidazo[4,5-c]pyridines having vasodilating, positively inotropic and platelet aggregation-inhibiting properties, which have no inhibitory action on myocardial phosphodiesterase.
PCT Application WO94/12461 describes, inter alia, 2-(substituted phenyl)-imidazopyridines and -oxazolopyridines as selective inhibitors of phosphodiesterase of type 4.
DESCRIPTION OF THE INVENTION
It has now been found that the novel compounds of the general formula I described below in greater detail have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula I
in which
of the group of symbols A, B, D and E, independently of one another, one symbol is N (nitrogen), one symbol is C-X and the remaining two symbols are C-H, where
X is hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkoxy, 1-4C-koxycarbonyl, amino, mono- or di1-4C-alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4alkyl, hydroxysulfonyl, 1-4C-alkylsulfonyl, 1-4C-alkoxy-sulfonyl or sulfamoyl,
Y is O (oxygen) or NH,
R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is hydrogen or 1-4C-alkyl and
R3 is hydrogen or 1-4C-alkyl,
or in which
R2 and R3, together and including the two carbon atoms to which they are bonded, are a spiro-linked 5-, 6- or 7-membered hydrocarbon ring, if desired interrupted by an oxygen atom,
and the salts and the N-oxides of these compounds.
Halogen within the meaning of the invention is fluorine, chlorine, bromine or iodine.
1-4C-Alkyl represents 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-Alkylcarbonyl represents a carbonyl group to which one of the abovementioned 1-4C-alkyl radicals is bonded. An example which may be mentioned is the acetyl radical (CH
3
CO—).
1-4C-Alkylcarbonyloxy radicals contain, in addition to the oxygen atom, one of the abovementioned 1-4C-alkylcarbonyl radicals. An example which may be mentioned is the acetoxy radical (CH
3
CO—).
1-4C-Alkoxy represents a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples, of alkoxy radicals having 1 to 4 carbon atoms which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
1-4C-Alkoxycarbonyl represents a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxycarbonyl radical (CH
3
O—CO—) and the ethoxycarbonyl radical (CH
3
CH
2
O—CO—)
Examples of mono- or di-1-4C-alkylamino radicals which may be mentioned are the methylamino, di-methylamino and diethylamino radicals.
An example of a 1-4C-alkylcarbonylamino radical which may be mentioned is the acetylamino radical (—NH—CO—CH
3
).
Hydroxy-1-4C-alkyl represents abovementioned 1-4C-alkyl radicals which are substituted by a hydroxyl group. Examples which may be mentioned are the hydroxyethyl and the hydroxymethyl radicals.
1-4C-Alkylsulfonyl represents a sulfonyl group to which one of the abovementioned 1-4C-alkyl radicals is bonded. An example which may be mentioned is the methylsulfonyl radical (CH
3
SO
2
—).
1-4C-Alkoxysulfonyl represents a sulfonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxysulfonyl radical (CH
3
SO
2
—) and the ethoxysulfonyl radical (CH
3
CH
2
O—SO
2
—).
3-7C-Cycloalkoxy represents the cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy radicals. The 3-5C-cycloalkoxy radicals cyclopropyloxy, cyclobutyloxy and cyclopentyloxy may preferably be mentioned.
3-7C-Cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy. The 3-5C-cycloalkylmethoxy radicals cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy may preferably be mentioned.
Examples of 1-4C-alkoxy which is completely or predominantly substituted by fluorine are the 2,2,3,3,3-pentafluoropropoxy, perfluoroethoxy, 1,2,2-trifluoroethoxy and in particular the 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy and, preferably, the difluoromethoxy radicals.
A spiro-linked 5-, 6- or 7-membered hydrocarbon ring, if desired interrupted by an oxygen atom, which may be mentioned is the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran or tetrahydropyran ring.
Salts of 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 customarily used in pharmacy. Those suitable are, on the one hand, water-soluble and water-insoluble acid addition salts with adds such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(41-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 involved and depending on which salt is desired—in an equimolar quantitative ratio or one differing therefrom.
On the other hand, 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.
Pharnacologically intolerable salts which can initially be obtained, 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 precesses 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, for example, they are isolated 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 die formula I, and all solvates and 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 from the group of symbols A, B, D and a, independently of one another, one symbol is N (nitrogen), one symbol is C-X and the remaining two symbols are C-H, where
X is hydrogen, hydroxyl, hal

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