Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-09-16
1998-05-12
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514312, 514398, 514 82, 514367, 514376, 514397, 5143051, 546156, 546 23, 5483064, 5483071, 548221, 548169, 5483051, C07D215227, C07D21536, A61K 3147
Patent
active
057507015
DESCRIPTION:
BRIEF SUMMARY
This is a 371 application of PCT/EP95/00794, filed Mar. 3, 1995.
This invention relates to novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine and agriculture.
It has been discovered that a series of novel heterocyclic ethanolamine derivatives have good .beta.-adrenoreceptor agonist activity and in particular show good selectivity for .beta..sub.3 -adrenoreceptors versus .beta..sub.1 - or .beta..sub.2 -adrenoreceptors. These compounds are therefore indicated to have good anti-hyperglycaemic and/or anti-obesity activity coupled with especially good selectivity from cardiac and tremorigenic side effects.
These compounds are also indicated to have potential in the treatment of gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome and also for the treatment of gastrointestinal ulcerations, especially when induced by non-steroidal anti-inflammatory drugs or corticosteroids.
These compounds also have potential as growth promoters for livestock and for decreasing birth mortality rate and increasing the post-natal survival rate in livestock. These compounds may also be of use in increasing the high-density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum and are therefore of potential use in the treatment and/or prophylaxis of atherosclerosis. They are also indicated to be useful for the treatment of hyperinsulinaemia. They are also indicated to be useful for the treatment of depression.
Accordingly the present invention provides a compound of formula (I): ##STR1## or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, ##STR2## in which A.sup.1 represents --CH.dbd.CH.dbd., NH, S or O; A.sup.2 represents an oxo or a thioxo group; A.sup.3 represents H or an alkylcarbonyl group; and A.sup.4 represents hydroxy or NR.sup.s R.sup.t wherein R.sup.s and R.sup.t each independently represents H or alkyl; R.sup.0 and R.sup.1 each independently represents hydrogen or an alkyl group; R.sup.2 represents a moiety of formula (b): ##STR3## wherein R.sup.4 and R.sup.5 each independently represent hydrogen, alkyl, hydroxyalkyl, cycloalkyl or R.sup.4 together with R.sup.5 represents (CH.sub.2).sub.m wherein m is 2, 3 or 4; and with R.sup.2 represents a moiety of formula (c): ##STR4## or an ester or amide thereof, wherein R represents hydrogen, alkyl, hydroxymethyl or a moiety of formula (CH.sub.2).sub.n CO.sub.2 H, wherein n is zero or an integer 1, 2 or 3, or an ester or amide thereof.
Suitably, A.sup.1 is --CH.dbd.CH--.
Suitably, A.sup.2 is oxo.
Suitably, A.sup.3 is H.
Suitably, A.sup.4 is OH, favourably substituted at the 4-position relative to the bond linking X to the CHOH carbon atom.
Suitably R.sup.0 is hydrogen.
Suitably, R.sup.1 is an alkyl group.
When R.sup.1 is alkyl, it is favourably a C.sub.1-6 alkyl group, especially a methyl group.
Suitably, R.sup.2 together with R.sup.3 represents a moiety of formula (c).
The compounds of formula (I) have two or more asymmetric carbon atoms, for example those marked with asterisks in the formula. These compounds may therefore exist in different stereoisomeric forms. The present invention encompasses all stereoisomers of the compounds of the general formula (I) whether free from other isomers, or admixed with other isomers in any proportion, such as mixtures of diastereoisomers and racemic mixtures of enantiomers.
Of particular interest are those carbon atoms marked with one (*) or two (**) asterisks in the formula.
Preferably, the asymmetric carbon atom indicated by a single asterisk (*) is in the R-configuration.
Preferably, the asymmetric carbon atom indicated by two asterisks (**) is in the R-configuration.
It should also be mentioned that the carbon atom in moiety (c) marked with three asterisks (***) may also be chiral when
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Milecki, J. et al. J. Med. Chem. vol. 30 No. 9, Sep. 1987, pp. 1563-1566 Carbostyril derivatives haaving a . . .
Beeley Lee James
Dean David Kenneth
Kinzig Charles M.
Lentz Edward T.
Shah Mukund J.
SmithKline Beecham Plc
Wong King Lit
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