Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-06-05
2000-04-11
Mach, D. Margaret
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514212, 514415, 514568, 540593, 546165, 548507, 562405, 562442, C07D22316, C07D21500, C07D20910, C07D22900
Patent
active
060488727
DESCRIPTION:
BRIEF SUMMARY
This application is filed pursuant to 35 U.S.C. .sctn.371 as a United States National Phase Application of International Application No. PCT/EP96/05469 filed Dec. 6, 1996 which claims priority from GB 9525177.3 filed Dec. 8, 1995.
This invention relates to a new class of chemical compounds and to their use in medicine. In particular, the invention concerns novel phenethanolamine derivatives, methods for their preparation, pharmaceutical compositions containing them and their use as agonists at atypical beta-adrenoceptors (also known as beta-3-adrenoceptors). Such receptors have been described for example by J R S Arch et. al., Nature, 309, 163-165 (1984); C Wilson et. al., Eur. J. Pharmacol., 100, 309-319 (1984); L J Emorine et. al., Science, 245, 1118-1121 (1989); and A. Bianchetti et. al. Br. J. Pharmacol., 100, 831-839 (1990). Phenethanolamine derivatives having activity at atypical beta-adrenoceptors are disclosed in, for example, European Patent Applications EP-A-0455006 and EP-A-0543662.
Atypical beta-adrenoceptors belong to the family of adrenoceptors which mediate the physiological actions of the hormones adrenaline and noradrenaline. Sub-types of the adrenoceptors, .alpha..sub.1 -, .alpha..sub.2 -, .beta..sub.1 -, .beta..sub.2 - and .beta..sub.3 -(atypical) can be identified on the basis of their pharmacological properties and physiological effects. Chemical agents which stimulate or block these receptors (but not .beta..sub.3) are widely used in clinical medicine. More recently, emphasis has been placed upon specific receptor selectivity in order to reduce side effects caused, in part, by interactions with other receptors.
Atypical beta-adrenoceptors are known to occur in adipose tissue and the gastrointestinal tract.
Atypical beta-adrenoceptor agonists have been found to be particularly useful as thermogenic anti-obesity agents and as anti-diabetic agents. Compounds having atypical beta-adrenoceptor agonist activity have also been described as being useful in the treatment of hyperglycaemia, as animal growth promoters, as blood platelet aggregation inhibitors, as positive inotropic agents and as antiatherosclerotic agents, and as being useful in the treatment of glaucoma.
We have now found a novel class of phenylethanolamine derivatives which act as agonists at atypical beta-adrenoceptors. GB 9525177.3, which is the priority document for the present application, describes the syntheses of the compounds of the invention. WO95/33724, which was unpublished at the priority date of the present application, describes the syntheses of compounds which are also of use as agonists at atypical beta-adrenoceptors.
The invention therefore provides, in a first aspect, compounds of formula (I): ##STR1## wherein
R.sup.1 represents an aryl group optionally substituted by one or more substituents selected from halogen, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, cyano, hydroxymethyl and trifluoromethyl;
R.sup.2 represents hydrogen or C.sub.1-6 alkyl;
R.sup.3 represents a group A ##STR2## where the ring is substituted by one to four further substituents selected from C.sub.1-6 alkyl, halogen, trifluoromethyl, and C.sub.1-6 alkoxy;
or R.sup.3 represents a group B ##STR3## where the aromatic ring is optionally substituted by up to three further substituents selected from C.sub.1-6 alkyl, halogen, trifluoromethyl, and C.sub.1-6 alkoxy;
R.sup.4 represents hydrogen, or C.sub.1-6 alkyl;
R.sup.5 represents ZCH.sub.2 CO.sub.2 H wherein Z represents a bond, or O;
Y represents (CH.sub.2).sub.n where n is 1-3;
Referring to the general formula (I), alkyl includes both straight and branched chain saturated hydrocarbon groups. Similarly, alkoxy includes both straight and branched chain groups.
Referring to the general formula (I), aryl includes monocyclic or bicyclic aromatic carbocyclic groups such as phenyl and naphthyl.
Preferably R.sup.1 represents phenyl optionally substituted by one, two or three substituents selected from halogen, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, cyano, hydroxymethyl and trifluor
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Foxton Michael Walter
Green Richard Howard
Brink Robert H.
Glaxo Wellcome Inc.
Mach D. Margaret
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