Benzoxazoles with PDE-inhibiting activity

Details Benzoxazoles with PDE-inhibiting activity Benzoxazoles with PDE-inhibiting activity

2001-01-03

2002-04-23

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S321000, C514S375000, C540S524000, C546S198000, C548S217000, C548S224000

Reexamination Certificate

active

06376485

ABSTRACT:

FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel benzoxazoles which are employed in the pharmaceutical industry for the preparation of medicaments.
1. Known Technical Background
International Patent Application WO 96/11917 describes substituted benzoxazoles as cyclic nucleotide phosphodiesterase inhibitors of type 4. U.S. Pat. No. 4,405,633 and European Patent Application EP-A-127 066 propose substituted benzoxazoles as agents for the prevention and treatment of asthma.
2. Description of the Invention
It has now been found that the benzoxazoles described below in greater detail, which differ from the previously published compounds by a different type of substitution, have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula I
in which
R1 is 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
R2 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or 1-4C-alkoxy-1-4C-alkyl,
R3 is hydrogen, hydroxyl, nitro, cyano, ethynyl, carboxyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,
A is B, —CH(R4)—, >C═O or >C═N—R5, where
B is oxygen (—O—), imino (—NH—), sulfinyl (—S(O)—), sulfonyl (—S(O)
2
—) or carbonylimino (—C(O)NH—) and
R4 is hydroxyl, carboxyl, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, hydroxyaminocarbonyl (—C(O)NHOH) or 1-4C-alkoxyaminocarbonyl,
R5 is hydroxyl or 1-4C-alkylcarbonyloxy,
and the salts of these compounds.
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-methylpenty), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
1-6C-Alkoxy represents a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Alkoxy radicals having 1 to 6 carbon atoms which may be mentioned are, for example, the hexyloxy, isohexyloxy (4-methylpentyloxy), neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy (3-methylbutoxy), neopentyioxy (2,2-dimethylpropoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
3-7C-Cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexyl-methoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
Completely or predominantly fluorine-substituted 1-4C-alkoxy which may be mentioned are, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy and the 1,2,2-trifluoroethoxy radicals, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy radicals.
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 preferably be mentioned.
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 and the methoxyetnyl radicals and the butoxyethyl radical.
1-4C-Alkoxycarbonyl represents a carbonyl group to which is bonded one of the abovementioned 1C-alkoxy radicals. Examples which may be mentioned are the methoxycarbonyl (CH
3
O—C(O)—) and the ethoxycarbonyl (CH
3
CH
2
O—C(O)—) radicals.
In addition to the carbonyl group, mono- or di-14C-alkylaminocarbonyl radicals contain one of the abovementioned mono- or di-14C-alkylamino radicals. Examples which may be mentioned are the N-methyl, the N,N-dimethyl, the N-ethyl, the N-propyl, the N,N-diethyl and the N-isopropylaminocarbonyl radicals.
A 1-4C-alkylaminocarbonyl radical which may be mentioned is, for example, the methoxyaminocarbonyl radical (—C(O)NHOCH
3
).
1-4C-Alkylcarbonyloxy represents a carbonyloxy group to which is bonded one of the abovementioned 1-4C-alkyl radicals. An example which may be mentioned is the acetoxy radical (CH
3
C(O)—O—).
Suitable 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 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, the acids being 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.
On the other hand, salts with bases are also suitable. Examples of salts which 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.
Pharmacologically intolerable salts which can initially be obtained as process products, for example in 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.
It is known to the person skilled in the art that the compounds according to the invention and also their salts, when they are isolated, for example, in crystalline form, can contain various amounts of solvents. The invention therefore also includes all solvates and in particular all hydrates of the compounds of the formula I, and also 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
R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-4C-alkyl, 3-5C-cycloalkyl, 3-5C-cycloalkylmethyl or 1-2C-alkoxy-1-2C-alkyl,
R3 is hydroxyl, cyano, carboxyl, 1-2C-alkoxy or 1-2C-alkoxycarbonyl,
A is B, —CH(R4)—, >C═O or >C═N—R5, where
B is oxygen (—O—), sulfinyl (—S(O)—), sulfonyl (—S(O)
2
—) or carbonylimino (—C(O)NH—) and
R4 is hydroxyl, carboxyl, 14C-alkoxycarbonyl or aminocarbonyl,
R5 is hydroxyl or 1-4C-alkylcarbonyloxy,
and the salts of these compounds.
Compounds of the formula I particularly to be emphasized are those in which
R1 is 1-4C-alkoxy,
R2 is 1-4C-alkyl or 3-5C-cycloalkyl,
R3 is hydroxyl, cyano or methoxy,
A is B, —CH(R4)— or >C═O, where
B is oxygen (—O—) or sulfonyl (—S(O)
2
—),
R4 is hydroxyl, carboxyl, methoxycarbonyl or aminocarbonyl,
and the salts of these compounds.
One embodiment of the particularly preferred compounds of the formula I are those in which
R1 is 1-4C-alkoxy,
R2 is 1-4C-alkyl or 3-5C-cycloalkyl,
R3 is hydroxyl, cyano or methoxy,
A is B or —CH(R4)—, where
B is oxygen (—O—) or sulfonyl (—S(O)
2
—),
R4 is carboxyl, methoxycarbonyl or aminocarbonyl,
and the salts of these compounds.
Preferred compounds of the formula I are those in which
R1 is 1-4C-alkoxy,
R2 is 1-4C-alk

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