Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-12
2002-11-12
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S287000, C514S289000, C514S290000, C514S248000, C514S249000, C514S259500, C546S108000, C546S109000, C546S065000, C546S074000, C544S237000, C544S353000, C544S283000
Reexamination Certificate
active
06479505
ABSTRACT:
FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel 6-arylphenanthridines, which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
Chem. Ber. 1939, 72, 675-677, J. Chem. Soc., 1956, 4280-4283 and J. Chem. Soc.(C), 1971, 1805 describe the synthesis of 6-phenylphenanthridines. The International Applications WO 97/28131 and WO 97/35854 describe 6-phenyl- and 6-pyridylphenanthridines as PDE4 inhibitors.
DESCRIPTION OF THE INVENTION
It has now been found that the novel phenanthridines substituted in the 6-position by a bi- or tricyclic aryl radical and described in greater detail below have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula 1,
in which
R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
or in which
R1 and R2 together are a 1-2C-alkylenedioxy group,
R3 is hydrogen or 1-4C-alkyl,
R31 is hydrogen or 1-4C-alkyl,
or in which
R3 and R31 together are a 1-4C-alkylene group,
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen,
R51 is hydrogen,
or in which
R5 and R51 together represent an additional bond,
Ar is an unsubstituted or R6- and/or R7-substituted bi- or tricyclic radical of the formula Ia or Ib,
where
G is a 5- or 6-membered ring which optionally can contain up to 3 identical or different heteroatoms selected from the group consisting of O and N,
A is a bond, —CH
2
—, —CH
2
—CH
2
—, —CH
2
—O—, —O—CH
2
—, —C(O)—, —O—, —N(H)—, —N═, —CH═, —CH═CH—, —N═CH— or —CH═N—,
B is a bond, —CH
2
—, —C(O)—, —O—, —N(H)—, —N═, —CH═ or —S(O)
2
—,
R6 is hydroxyl, halogen, carboxyl, nitro, cyano, amino, aminocarbonyl, mono- or di-1-4C-alkylamino, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonylamino or completely or predominantly fluorine-substituted 1-4C-alkoxy, and
R7 is hydroxyl, halogen, nitro, 1-4C-alkyl or 1-4C-alkoxy,
and the salts, the N-oxides and the salts of the N-oxides 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 and preferably the ethyl and methyl radicals.
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 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, 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-pentafluoropropoxy, 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 radicals may be mentioned. “Predominantly” in this connection means that more than half of the hydrogen atoms are replaced by fluorine atoms.
1-2C-Alkylenedioxy represents, for example, the methylenedioxy [—O—CH
2
—O—] and the ethylenedioxy [—O—CH
2
—CH
2
—O—] radicals.
If R3 and R31 together have the meaning 1-4C-alkylene, the positions 1 and 4 in compounds of the formula I are linked to one another by a 1-4C-alkylene bridge, 1-4C-alkylene representing straight-chain or branched alkylene radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the radicals methylene [—CH
2
—], ethylene [—CH
2
—CH
2
—], trimethylene [—CH
2
—CH
2
—CH
2
—], 1,2-dimethylethylene [—CH(CH
3
)—CH(CH
3
)—] and isopropylidene [—C(CH
3
)
2
—].
If R5 and R51 together are an additional bond, then the carbon atoms in positions 2 and 3 in compounds of the formula I are linked to one another via a double bond.
Halogen within the meaning of the invention is bromine, chlorine or fluorine.
In addition to the nitrogen atom, mono- or di-1-4C-alkylamino radicals contain one or two of the above-mentioned 1-4C-alkyl radicals. Di-1-4C-alkylamino is preferred and here, in particular, dimethyl-, diethyl- or diisopropylamino.
In addition to the carbonyl group, mono- or di-14C-alkylaminocarbonyl radicals contain one of the abovementioned 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 N-isopropylaminocarbonyl radicals.
1-4C-Alkylcarbonyloxy represents a carbonyloxy group to which one of the abovementioned 1-4C-alkyl radicals is bonded. An example which may be mentioned is the acetoxy radical [CH
3
C(O)—O—].
1-4C-Alkylcarbonyl represents a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-4C-alkyl radicals. An example which may be mentioned is the acetyl radical.
1-4C-Alkoxycarbonyl represents a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxycarbonyl [CH
3
O—C(O)—] and the ethoxycarbonyl [CH
3
CH
2
O—C(O)—] radicals.
As a 1-4C-Alkylcarbonylamino radical, for example, the propionylamino [C
3
H
7
C(O)NH—] and the acetylamino [CH
3
C(O)NH—] radicals may be mentioned.
Ar represents an unsubstituted or R6- and/or R7-substituted bi- or tricyclic radical of the formula Ia or Ib.
In the aryl radicals Ar of the formula Ia, G represents a 5- or 6-membered ring which optionally can contain up to three identical or different heteroatoms selected from the group consisting of O and N. The ring G can be monounsaturated (double bonding of the fused phenyl ring), polyunsaturated or aromatic. Exemplary aryl radicals Ar of the formula Ia which may be mentioned are indenyl, indanyl, naphthalenyl, indazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, 1H-benzimidazolyl, 1H-benzotriazolyl, benzoxazolyl, benzofuranyl, chromanyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[1,4]dioxinyl and benzo[1,3]dioxolyl. The aryl radicals Ar of the formula Ia can be present in unsubstituted form or can be substituted by R6 and/or R7.
In the aryl radicals Ar of the formula Ib, A represents a bond, —CH
2
—, —CH
2
—CH
2
—, —CH
2
—O—, —O—CH
2
—, —C(O)—, —O—, —N(H)—, —N═, —CH═, —CH═CH—, —N═CH— or —CH═N— and B represents a bond, —CH
2
—, —C(O)—, —O—, —CH═, —N(H)—, —N═ or —S(O)
2
. The ring containing the atoms or groups of atoms A and B is in this case 4-, 5-, 6- or 7-membered. Exemplary aryl radicals Ar of the formula Ib which may be mentioned are biphenylenyl, fluorenyl, phenanthrenyl, anthracenyl, phenanthridinyl, acridinyl, phenazinyl, xanthenyl, 9-oxo-9H-xanthenyl, 9-oxo-9H-thioxanthenyl-10,10-dioxide, fluoren-9-onyl, anthraquinonyl, 5-oxo-5H-dibenz[a,d]cycloheptenyl, 10,11-dihydro5H-dibenzo[a,d]cycloheptenyl, 11-oxo-6,11-dihydrodibenz-[b,e]oxepinyl, 10,11-dihydro-5H-dibenz[b,f]azepinyl, dibenzofuranyl and carbazolyl. The aryl radicals Ar of the formula Ib can be present in unsubstituted form or can be substituted by R6 and/or R7.
The aryl radicals Ar of the formulae Ia and Ib are condensed ring systems which contain at least one benzene ring. If the aryl radicals Ar of the formulae Ia and Ib only contain one benzene ring, the bonding to the phenanthridine radical
Altana Pharma AG
Goldberg Joshua B.
Huang Evelyn Mei
Juneau Todd L.
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