Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-11-20
1999-05-18
Lambkin, Deborah C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
5462827, 546153, 514320, 514337, 514312, 514456, 549404, C07D401/00;401/04
Patent
active
059051566
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel 2,2-dialkyl- and 2,2-dialkyl-3,4-dihydro-3-hydroxy-2H-1-benzopyrans, and salts, esters and N-oxides thereof, and to processes for their production, as well as to their use as pharmaceuticals and pharmaceutical compositions comprising them.
More particularly the present invention provides in its broadest aspect:
1) A 2,2-di(C.sub.1-5 alkyl)- or trans-2,2-di(C.sub.1-5 alkyl)-3,4-dihydro-3-hydroxy-4-carboxamido-6-(N-arylsulfonamido)-2H-1-benz opyran; or an N-oxide thereof; or a physiologically-hydrolysable and -acceptable ester of such a benzopyran or N-oxide; or acid addition or quarternary ammonium salt of such a benzopyran, N-oxide or ester.
Alkyl groups and moieties of compounds as defined under 1) above may be branched or straight chain. Suitable arylsulfonamido moieties include sulfonamido which is N-substituted with aryl, or N,N-di-substituted with aryl and C.sub.1-5 alkyl, or N,N-disubstituted with aryl and C.sub.2-5 alkylene linked to the aryl to form a bicyclic structure, e.g., a tetrahydroquinolinyl moiety. The term "aryl" includes mono- or bicyclic aromatic groups optionally containing one or more nitrogen atoms, e.g., phenyl, napthyl or pyridyl, which may be optionally substituted, e.g., with up to three substituents, e.g., selected from halogen, C.sub.1-5 alkyl, (halo).sub.1-3 -C.sub.1-5 alkyl, or C.sub.1-5 alkoxy, especially phenyl, fluorophenyl, trifluoromethylphenyl, methoxyphenyl, or pyridyl.
As hereinafter described, compounds of the present invention, e.g. as defined under 1 above, have potassium (K.sup.+) channel opening activity Function and Therapeutic Potential", ed. N. S. Cook, Ellis Horwood, Chichester (1990), p.p. 181-255!. Benzopyran derivatives which are carboxamido-substituted at the 4-position, having K.sup.+ -channel opening activity are extensively described in the art and comprise a substantial and recognisable compound class. The 4-carboxamido moiety in the compounds of the invention may comprise any of those known and described in the art in relation to K.sup.+ -channel opening benzopyrans including N-substituted, for example cyclic, carboxamido moieties. Preferred carboxamido moieties in relation to the compounds of the invention are those of the formula --N(R.sub.9)--COR.sub.10 as defined below.
As will be appreciated, the benzopyran nucleus of compounds defined under 1 may bear substituents in addition to those specifically defined. In particular they may, for example, be 7-C.sub.1-5 alkyl substituted, especially 7-methyl substituted, e.g. as hereinafter indicated in relation to formula I.
In accordance with the present invention 2,2-di(C.sub.1-5 alkyl)-3,4-dihydro-3-hydroxy-4-carboxamido-6-(N-arylsulfonamido)-2H-1-benz opyrans and/or -oxides, esters, and salts thereof as defined under 1 above are preferred. The 3-hydroxy group and the 4-carboxamido moiety in such compounds are disposed in the trans-configuration as specified under 1. For this compound group (3S,4R)-enantiomers will generally be preferred, whether in pure or substantially pure form or in isomeric, e.g. racemic, mixture as hereinafter described in relation to compounds of formula I.
In a more specific aspect the present invention provides:
2) A compound of formula I ##STR1## wherein R.sub.1 is aryl, R.sub.1, hydrogen and R.sub.10 is phenyl or pyridyl, or formula --(CH.sub.2).sub.n -- or ##STR2## in which n is an integer of from 3 to 5 inclusive and m is 1 or 2, R.sub.4 is hydrogen and R.sub.5 is hydroxy in the trans position with respect to R.sub.3, or R.sub.4 and R.sub.5 together represent an additional bond as indicated by the dotted line, N-oxide, or acid addition or quarternary ammonium salt of such a compound, N-oxide or ester.
Alkyl groups as R.sub.2, R.sub.6, R.sub.7 and R.sub.8 may be branched or straight chain. R.sub.6 and R.sub.7 are both preferably methyl. R.sub.8 is preferably hydrogen or methyl, most preferably hydrogen.
In a preferred group of compounds of formula I, R.sub.1 is phenyl, fluorophenyl, trifluoromethylphenyl, methoxyphenyl, or pyridyl; and/
REFERENCES:
patent: 5236935 (1993-08-01), Yoo et al.
patent: 5300511 (1994-04-01), Yoo et al.
patent: 5310753 (1994-05-01), Englert et al.
Lambkin Deborah C.
Loeschorn Carol A.
Novartis AG
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