Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-11-06
1999-11-09
Stockton, Laura L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514469, 549396, 549462, A61K 3134, A61K 3135, C07D31104, C07D30779
Patent
active
059815728
DESCRIPTION:
BRIEF SUMMARY
This invention relates to bicyclic compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their medical use.
The invention thus provides compounds of Formula (I) ##STR2## wherein R.sup.1 and R.sup.2 which may be the same or different represent H, C.sub.1-6 alkyl or substituted alkyl or C.sub.3-7 cycloalkyl; or aryl; halogen, C.sub.1-6 alkyl; or substituted aryl; and pharmaceutically acceptable solvates (e.g. hydrates) thereof.
It will be appreciated that in formula (I) hereinabove the substituents R.sup.3 and R.sup.4 may be attached at any available position on the phenyl portion of the bicyclic system. Preferably when n is 0, R.sup.3 and R.sup.4 are substituted in the 5 and/or 7 positions on the phenyl ring.
As used herein, an alkyl group may be a straight chain or branched chain alkyl group. Examples of suitable alkyl groups include C.sub.1-4 alkyl groups, for example methyl, ethyl, n-propyl and isopropyl groups. When optionally substituted, the substituent is one or more fluorine atoms.
A halogen substituent may be fluorine, chlorine, bromine or iodine.
As used herein, the term "aryl" as a group means phenyl, optionally substituted by one or more (eg 1-3) atoms or groups selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxyl, halogen, nitro and trifluoromethyl.
Cycloalkyl groups may be bridged cycloalkyl groups, eg norbornyl or non-bridged cycloalkyl groups, eg cyclopropyl.
Examples of the groups R.sup.3 and R.sup.4 include hydrogen, halogen (e.g. chlorine and/or fluorine) and C.sub.1-3 alkyl (e.g. methyl). methyl).
R.sup.1 may particularly represent hydrogen, C.sub.3-5 alkyl (i.e. methyl, ethyl, n-propyl or i-propyl) or C.sub.3-5 cycloalkyl (e.g. cyclopropyl or cyclobutyl).
A particular group of compounds of the invention are compounds of formula (1a). ##STR3## and pharmaceutically acceptable solvates (e.g. hydrates) thereof, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined hereinabove especially halogen, more especially R.sup.3 and R.sup.4 are chlorine and/or fluorine, especially where R.sup.1 is methyl or cyclopropyl.
Another particular group of compounds of the invention are compounds of formula 1(b) ##STR4## wherein R.sup.1 and R.sup.2 which may be the same or different represent H, C.sub.1-6 alkyl or substituted alkyl, C.sub.3-7 cycloalkyl or aryl; halogen, C.sub.1-6 alkyl or substituted aryl; and pharmaceutically acceptable solvates (e.g. hydrates) thereof.
A further particular group of compounds are compounds of formula 1(c) ##STR5## wherein R.sup.1 and R.sup.2 which may be the same or different represent H, C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; halogen, or C.sub.1-6 alkyl; and pharmaceutically acceptable solvates (e.g. hydrates) thereof.
Particular compounds according to the present invention include -[3-(2,3-dihydro-benzofuran-4-yl)-propyl]-amide, -[3-(5-chloro-2,3-dihydro-benzofuran-4-yl)propyl]amide, -[3-(5-chloro-7-fluoro-2,3-dihydro-benzofuran-4-yl)propyl]-amide, [3-(5-chloro-7-fluoro-benzofuran-4-yl)-propyl]-amide, [3-(2,3-dihydro-5-fluoro-benzofuran-4-yl)propyl]amide.
It is to be understood that the present invention covers all combinations of particular and preferred groups described hereinabove.
References hereinafter to a compound of formula (I) includes the compound and its pharmaceutically acceptable solvates.
The compounds of formula (I) may contain at least one asymmetric carbon atom and may exist as stereoisomers. The compounds of formula (I) thus include the R- and S-isomers and mixtures, for example racemic mixtures, thereof.
The compounds of formula (I) have a high affinity and selectivity for binding to melatonin receptors and have either melatonin agonist or antagonist activity as demonstrated in cloned human ML1 receptors in Chinese hamster ovary cells. Accordingly, the compounds are of use as scientific tools for studying the role of melatonin within biological systems.
The compounds of formula (I) are also of use in the treatment of disorders which arise from a disturbed functioning of systems which are regu
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Ecker et al, "Improved Synthesis and Pharmacologic Activity of the Enantiomers of a New Benzofurance type Antiarrhythmic Compound", Chirality, vol. 6, No. 4, 1994, pp. 329-336.
Ecker et al, "Synthese unde Pharmakodynamische Aktivitat von 2-(3-(2-Phenylethyl) benzofuran-2-yl)-N-propylethanamin", Arch.Pharm. (Weinheim, Ger.), vol. 328, No. 4, 1995, pp. 343-348.
Cooke Jason William Beames
Dolan Simon Charles
Ellis Frank
North Peter Charles
Panchal Terence Aaron
Glaxo Wellcome Inc.
Stockton Laura L.
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