Benzimidazoles and benzoxazoles

Details Benzimidazoles and benzoxazoles Benzimidazoles and benzoxazoles

2000-11-01

2001-09-25

Higel, Floyd D. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S218000, C548S305100, C548S304400, C514S375000, C514S232500, C544S178000

Reexamination Certificate

active

06294564

ABSTRACT:

FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel benzimidazoles and -oxazoles which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
The international application WO94/12461 describes, inter alia, 2-(substituted phenyl)-benzimidazoles as selective inhibitors of phosphodiesterase type 4. The international application WO96/11917 discloses 2-(substituted phenyl)-benzoxazoles as selective PDE4 inhibitors.
DESCRIPTION OF THE INVENTION
It has now been found that the novel compounds of the general formula I described in greater detail below have surprising and particularly advantageous properties. Thus, the invention provides compounds of the formula I
in which
Y is O (oxygen) or NH,
R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
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 attached, are a spiro-linked 5-, 6- or 7-membered hydrocarbon ring which, if desired, is interrupted by an oxygen atom,
R4 is C(O)R5, C(O)R6, —C
n
H
2n
—C(O)R5 or —C
n
H
2n
—C(O)R6, where
R5 is hydroxyl, 1-7C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, H
2
N—C
m
H
2m
—O— or R51 (R52)N—C
p
H
2p
—O—, where
R51 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl and
R52 is 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or where
R51 and R52, together and including the nitrogen atom to which both are attached, are a 5-, 6- or 7-membered hydrocarbon ring which, if desired, is additionally interrupted by a group —N(R7)— or an oxygen atom,
R6 is N(R61)R62, where R61 and R62 independently of one another are hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,
R7 is hydrogen or 1-4C-alkyl,
m is2,3or 4,
n is1,2,3or 4,
p is1,2,3or 4,
and 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, ethyl and methyl 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, 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 radical.
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 radical.
3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cyclo-heptyloxy, 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 completely or predominantly fluorine-substituted 1-4C-alkoxy, for example, the 2,2,3,3,3-penta-fluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy radical may be mentioned.
Examples of spiro-linked 5-, 6- or 7-membered hydrocarbon rings which, if desired, are interrupted by an oxygen atom are, for example, the cyclopentane, cyclohexane, cyclopentane, tetrahydrofuran and tetrahydropyran ring.
Suitable radicals —C
n
H
2n
— and —C
p
H
2p
— are straight-chain or branched radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butylene, isobutylene, propylene, isopropylene, ethylene, 1-methylmethylene and methylene radical.
Suitable radicals —C
m
H
2m
— are straight-chain or branched radicals having 2 to 4 carbon atoms. Examples which may be mentioned are the butylene, isobutylene, propylene, isopropylene, ethylene and 1-methylmethylene radical.
1-7C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyloxy, isoheptyloxy (5-methylhexyloxy), hexyloxy, isohexyloxy (4-methylpentyloxy), neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy (3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy and preferably the isopropoxy, ethoxy and methoxy radical.
Examples for the grouping R51(R52)N— in which R51 and R52, together and including the nitrogen atom to which both are attached, are a 5-, 6- or 7-membered hydrocarbon ring which, if desired, is additionally interrupted by a group —N(R7)— or an oxygen atom which may mentioned are the 4-methyl-1-piperazinyl, 1-piperazinyl, 1-pyrrolidinyl, 1-piperidyl, 1-hexahydroazepinyl and the 4-morpholinyl radical.
3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
3-7C-Cycloalkylmethyl represents a methyl radical which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. The 3-5C-cycloalkylmethyl radicals cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl may be mentioned as being preferred.
Possible salts for 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 acceptable 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 acids such a s, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonic acid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, it being possible to employ the acids 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, salts with bases are also suitable. Examples of salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminium, 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 unacceptable 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 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, when 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 I to be emphasized are those in which
Y is O (oxygen) or NH,
R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 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 attached, are a spiro-linked cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,

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