Phthalazinone PDE III/IV inhibitors

Details Phthalazinone PDE III/IV inhibitors Phthalazinone PDE III/IV inhibitors

2000-09-13

2001-07-03

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S248000, C544S008000, C544S237000

Reexamination Certificate

active

06255303

ABSTRACT:

FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel Phthalazinones, which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
International Patent Application WO91/12251 describes phthalazinones having bronchodilating and thromboxane A2 synthetase inhibiting properties. In the Intemational Patent Application W094/12461 and in the European Patent Application EP 0 763 534 3-aryl-pyridazin-6-one respectively arylalkyl-diazinone derivatives are described as selective PDE4 inhibitors.
DESCRIPTION OF THE INVENTION
It has now been found that the phthalazinones, which are described in greater details below, have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula I
in which
R1 is hydroxyl, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is hydroxyl, halogen, 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R3 and R4 are both hydrogen or together form an additional bond,
and in which either
X is a covalent bond and
Y is a covalent bond,
or
X is —C
n
H
2n
— and
Y is O (oxygen), S (sulfur), carboxylate (—C(O)—O—), carboxamido (—C(O)NH—) or sulfonamido (—S(O)
2
—NH—),
or
X is phenylene and
Y is carboxylate (—C(O)O—), carboxamido (—C(O)NH—) or sulfonamido (—S(O)
2
NH—),
R5 represents a radical of formula (a)
 wherein
A is S (sulphur) or —CH(R51)—,
R51 is hydrogen or 1-4C-alkyl,
R52 is hydrogen or 1-4C-alkyl, or wherein
R51 and R52 together form an additional bond,
n is an Integer from 1 to 4,
and the salts of these compounds.
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, iso-butoxy, sec-butoxy, tert-butoxy, propoxy and in particular the isopropoxy, ethoxy and methoxy radicals.
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.
Halogen within the meaning of the present invention is bromine, chlorine and fluorine.
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-methylpentyloxy), neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy (3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy and in particular the isopropoxy, ethoxy and methoxy radicals.
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.
Possible radicals —C
n
H
2n
— are straight chain or branched radicals. Examples which may be mentioned are the butylene, isobutylene, sec-butylene, tert-butylene, propylene, isopropylene, ethylene and the methylene radical.
Suitable 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 tolerable inorganic and organic acids and bases 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, 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.
On the other hand, salts with bases are—depending on substitution—also suitable. As examples of salts with bases are mentioned the lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, meglumine or guanidinium salts, here, too, the bases being employed in salt preparation 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.
Compounds of the formula I to be emphasized are those in which
R1 is hydroxyl, 1-4C-alkoxy, or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is hydroxyl, halogen, 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R3 and R4 are both hydrogen or together form an additional bond,
and in which either
X is a covalent bond and
Y is a covalent bond
or
X is —C
n
H
2n
— and
Y is O (oxygen), carboxamido (—C(O)NH—) or sulfonamido (—S(O)
2
NH—),
or
X is phenylene and
Y is carboxamido (—C(O)NH—) or sulfonamido (—S(O)
2
NH—),
R5 represents a radical of the formula (a)
 wherein
A is S (sulphur) or —CH(R51)—,
R51 is hydrogen or 1-2C-alkyl,
R52 is hydrogen or 1-2C-alkyl, or wherein
R51 and R52 together form an additional bond,
n is an integer from 1 to 4,
and the salts of these compounds.
Compounds of the formula I which are particulary to be emphasized are those in which
R1 is methoxy, ethoxy or difluoromethoxy,
R2 is chlorine, methoxy, ethoxy, difluoromethoxy or cyclopentyloxy,
R3 and R4 are both hydrogen or together form an additional bond,
and in which either
X is a covalent bond and
Y is a covalent bond
or
X is —C
n
H
2n
— and
Y is O (oxygen) or carboxamido (—C(O)NH—)
or
X is phenylene and
Y is carboxamido (—C(O)NH—),
R5 represents a radical of formula (a)
 wherein
A is S (sulphur) or —CH(R51)—,
R51 is hydrogen,
R52 is methyl, or wherein
R51 and R52 together form an additional bond,
n is an integer from 1 to 4,
and the salts of these compounds.
One embodiment of the particulary to be emphasized compounds of the formula I are those in which
R1 is methoxy or difluoromethoxy,
R2 is methoxy, difluoromethoxy or cyclopentyloxy,
R3 and R4 are both hydrogen or together form an additional bond,
and in which either
X is a covalent bond and
Y is a covalent bond
or
X is —C
n
H
2n
— and
Y is O (oxygen) or carboxamido (—C(O)NH—)
or
X is phenylene and
Y is carboxamido (—C(O)NH—),
R5 represents a radical of formula (a)
&ems

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