Dihydrobenzofurans

Details Dihydrobenzofurans Dihydrobenzofurans

2000-08-03

2002-04-30

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S230000, C544S237000

Reexamination Certificate

active

06380196

ABSTRACT:

FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel compounds which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
International Patent Applications WO91/12251 and WO93/07146 describe phthalazinones having bronchodilating and antiasthmatic properties. International Patent Application WO94/12461 describes 3-aryl-pyridazin-6-one derivatives as selective PDE4 inhibitors. European Patent Application EP 0722936 describes fused pyridazine compounds with cGMP-PDE inhibiting activity. In J. Med. Chem. 1993, 4052-4060 Yamaguchi et al. describe phthalazinones having thromboxane A
2
synthetase inhibitory and bronchodilatory activities.
DESCRIPTION OF THE INVENTION
It has been found that the phthalazinones described in greater detail below, which differ from the previously published compounds by a different substitution pattern have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula I
in which
R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is 1-4C-alkyl and
R3 is hydrogen or 1-4C-alkyl,
or wherein
R2 and R3 together and with inclusion of the two carbon atoms, to which they are bonded, form a spirolinked 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen or sulphur atom,
Het represents a heterocycle having the meaning
wherein
R4 is R5, —C
m
H
2m
—R6 or —C
p
H
2p
—Y—Ar
R5 is hydrogen, 1-8C-alkyl, 3-10C-cycloalkyl, 3-7C-cycloalkylmethyl, 7-10C-polycycloalkyl an unsubstituted phenyl or pyridyl radical or a phenyl radical substituted by R51 and/or R52, in which
R51 is 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, cyano, nitro, halogen, hydroxyl, amino, mono- or di-1-4C-alkylamino, imidazolyl or tetrazolyl, and
R52 is 1-4C-alkyl, 1-4C-alkoxy, nitro or halogen,
R6 is hydroxyl, halogen, nitro, cyano, carboxyl, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkyl-amino, aminocarbonyl or mono- or di-1-4C-alkylaminocarbonyl,
Y is O (oxygen), S (sulphur) or a covalent bond,
Ar is an unsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, isoquinolyl, quinolyl, purinyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, coumarinyl, imidazolyl, pyrazolyl, oxazolyl or pyrrolyl radical or a phenyl radical substituted by R7 and/or R8, in which
R7 is hydroxyl, halogen, nitro, cyano, 1-4C-alkyl, 1-4C-alkoxy, carboxyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino, imidazolyl or tetrazolyl,
R8 is halogen, nitro, 1-4C-alkyl or 1-4C-alkoxy,
m is an integer from 1 to 4,
p 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, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
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.
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.
According to the invention, the group Het is represented by a heterocycle having the meaning a, b or c, of which the heterocycles having the meaning a or b are preferred.
Possible groups —C
p
H
2p
—, —C
m
H
2m
— are straight chain or branched groups. Examples which may be mentioned are the butylene, isobutylene, sec-butylene, tert-butylene, propylene, isopropylene, ethylene and the methylene group.
1-8C-Alkyl is a straight-chain or branched alkyl radical having 1 to 8 carbon atoms. Examples are the octyl, isooctyl (6-methylheptyl), 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 radicals.
3-10C-Cycloalkyl stands, for example, for cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
3-7C-Cycloalkylmethyl stands for a methyl radical, which is substituted by one of the above-mentioned 3-7C-cycloalkyl radicals.
7-10C-polycycloalkyl stands for 7-10C-bicycloalkyl or 7-10C-tricycloalkyl groups, such as for example, bornyl, norbornyl or adamantyl.
Halogen within the meaning of the present invention is bromine, chlorine and fluorine.
1-4C-Alkoxycarbonyl is a carbonyl group to which one of the above-mentioned 1-4C-alkoxy radicals is bonded. Examples are the methoxycarbonyl [CH
3
O—C(O)—] and the ethoxycarbonyl [CH
3
CH
2
O—C(O)—] radical.
Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogen atom, one or two of the above-mentioned 1-4C-alkyl radicals. Preferred are the di-1-4C-alkylamino radicals, especially the dimethylamino, the diethylamino and the diisopropylamino radical.
Mono- or Di-1-4C-alkylaminocarbonyl radicals contain in addition to the carbonyl group one of the above-mentioned mono- or di-1-4C-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-isopropylamino-carbonyl radical.
An 1-4C-Alkylcarbonylamino radical is, for example, the propionylamino [C
3
H
7
C(O)NH—] and the acetylamino radical [CH
3
C(O)NH—].
Carboxy-1-4C-alkyl radical are, for example, the carboxymethyl (—CH
2
COOH) and the carboxyethyl (—CH
2
CH
2
COOH) radicals.
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 salts with the 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, megiumine 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

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