Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-12
2003-04-08
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S237000
Reexamination Certificate
active
06544993
ABSTRACT:
FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel tetrahydrothiopyran-derivatives, which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
International Patent Applications WO98/31674, WO99/31071, WO99/31090 and WO99/47505 disclose phthalazinone derivatives having selective PDE4 inhibitory properties. In the International Patent Application WO94/12461 and in the European Patent Application EP 0 763 534 3-aryl-pyridazin-6-one and arylalkyl-diazinone derivatives are described as selective PDE4 inhibitors.
DESCRIPTION OF THE INVENTION
It has now been found that the tetrahydrothiopyran-derivatives, which are described in greater details below, have surprising and particularly advantageous properties. The invention thus relates to compounds of formula I
in which
R1 and R2 are both hydrogen or together form an additional bond,
A represents S (sulfur), S(O) (sulfoxide) or S(O)
2
(sulfone),
Ar represents a benzene derivative of formula (a) or (b)
wherein
R3 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R4 is halogen, 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R5 is halogen, 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R6 is 1-4C-alkyl and
R7 is hydrogen or 1-4C-alkyl,
or wherein
R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen or sulphur atom,
and the salts of these compounds, with the proviso, that those compounds of formula I are excluded, in which A represents S (sulfur) and Ar represents a benzene derivative of formula (a) and both of R3 and R4 are other than halogen.
1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
1-4C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned in this context are, for example, the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
1-8C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 8 carbon atoms. Alkoxy radicals having 1 to 8 carbon atoms which may be mentioned in this context are, for example, the octyloxy, heptyloxy, isoheptyloxy (5-methylhexyloxy), hexyloxy, isohexyloxy (4-methylpentynoxy), neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy (3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
Halogen within the meaning of the present invention is bromine, chlorine and fluorine.
3-7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
3-7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy or cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
3-5C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.
3-5C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy.
1-4C-Alkoxy which is completely or predominantly substituted by fluorine is, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy and in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxy radical, of which the difluoromethoxy radical is preferred. “Predominantly” in this connection means that more than half of the hydrogen atoms of the 1-4C-alkoxy group are replaced by fluorine atoms.
As spiro-linked 5-, 6- or 7-membered hydrocarbon rings, optionally interrupted by an oxygen or sulphur atom, may be mentioned the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahydropyran and the tetrahydrothiophen ring.
Suitable salts for compounds of the formula I are all acid addition salts. Particular mention may be made of the pharmacologically tolerable 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, 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, 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.
Pharmacologically intolerable salts, which can be obtained, for example, as process products during 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.
According to expert's knowledge the compounds of the invention as well as their salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula I as well as all solvates and in particular all hydrates of the salts of the compounds of formula I.
One embodiment (embodiment 1) of the invention are compounds of formula I in which
R1 and R2 are both hydrogen or together form an additional bond,
A represents S(O) (sulfoxide) or S(O)
2
(sulfone),
Ar represents a benzene derivative of formula (a) or (b)
wherein
R3 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R4 is halogen, 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R5 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R6 is 1-4C-alkyl and
R7 is hydrogen or 1-4C-alkyl,
or wherein
R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,
and the salts of these compounds.
Compounds of formula I of embodiment 1 which are to be emphasized are those in which
R1 and R2 together form an additional bond,
A represents S(O) (sulfoxide) or S(O)
2
(sulfone),
Ar represents a benzene derivative of formula (a) or (b)
wherein
R3 is 1-2C-alkoxy, or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R4 is halogen, 1-4C-alkoxy or 3-5C-cycloalkoxy,
R5 is 1-2C-alkoxy, or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R6 is methyl,
R7 is hydrogen,
or wherein
R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane or cyclohexane ring,
and the salts of these compounds.
Compounds of formula I of embodiment 1 which are particularly to be emphasized are those in which
R1 and R2 together form an additional bond,
A represents S(O) (sulfoxide) or S(O)
2
(sulfone),
Ar represents a benzene derivative of formula (a) or (b)
wherein
R3 is methoxy or ethoxy,
R4 is chlorine, methoxy, ethoxy or cyclopentyloxy,
R5 is methoxy,
R6 is methyl,
R7 is hydrogen,
or wherein
R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, for
Altana Pharma AG
Juneau Todd L.
Nath Gary M.
Nath & Associates PLLC
Rao Deepak
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