Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-05-26
1996-11-05
McKane, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514415, 548468, 548504, A61K 3140, C07D20708
Patent
active
055718337
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB92/01089 filed Jun. 17, 1992.
The present invention relates to known and novel tryptamine analogues, processes and intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular for the treatment and/or prophylaxis of disorders characterised by excessive vasodilatation, such as migraine and portal hypertension.
Migraine is a non-lethal disease suffered by one in ten individuals. The main symptom is headache; other symptoms include vomiting and photophobia. Currently, the most widely used treatment for migraine involves administration of ergotamine, dihydroergotamine or methysergide. All these drugs are inter alia agonists of 5HT.sub.1 -like receptors but also have other actions; treatment with them is associated with a number of adverse side effects. In addition, some patients experience a "withdrawal headache" following the cessation of treatment with an ergot product, such as ergotamine, causing them to repeat the treatment and resulting in a form of addiction. More recently a variety of tryptamine derivatives have been proposed for potential use in the treatment of migraine.
Portal hypertension, which is commonly associated with cirrhosis of the liver is characterised by increased portal venous blood flow, (which is caused by dilatation of mesenteric arterioles), and increased portal vascular resistance. A serious complication of this condition is rupture of oesophageal varices or paraesophageal collaterals, which develop to reduce portal pressure.
Japanese Published Application No. J58-83671 (Mitsui Toatsu Chem Inc) describes a process for preparing compounds of the formula: ##STR1## wherein R.sub.1-10 represent hydrogen, halogen, hydroxyl, alkoxy, cyano, acyl, aryl or alkyl; and R.sub.7 and R.sub.8 or R.sub.9 and R.sub.10 may be linked by a saturated or unsaturated carbon chain. In the compounds specifically exemplified R.sup.3, R.sup.5 and R.sup.6 are hydrogen and R.sup.4 is hydrogen or methoxy. The compounds are said to have physiological activity, but no specific utility is described.
PCT Application WO 90/05721 describes a class of .alpha.-amino-indole-3-acetic acids which are said to be useful as antidiabetic, antiobesity and anti-atherosclerotic agents. The compounds are represented by the general formula: ##STR2## and the values of R-R.sub.6 may be chosen from many possibilities. Thus R, R.sub.1, R.sub.3 and R.sub.4 may be inter alia hydrogen; R.sub.6 is inter alia hydrogen or alkyl; R.sub.2 is inter alia alkyl; R.sub.5 is inter alia hydrogen, halogen, hydroxy, alkoxy, nitro, CN or CF.sub.3 ; a is 1-4 and n is 0 or 1. All the compounds specifically disclosed are derivatives of indole-3-acetic acid or tryptophan.
The compound 3-(2-aminoethyl)-4-chloro-5-hydroxyindole is described as a putative intermediate in the oxidation of 5-hydroxytryptamine (Wrona and Dryhurst, J. Org. Chem 1987, 52, 2817-2825. 4-Methyl-5-hydroxytryptamine and its actions at `D` and `M` receptors are described by Richardson et al, Nature, 316(6024), 126-131, 1985.
We have now surprisingly found that certain 4,5-substituted tryptamines not specifically disclosed in J 58-83671 or WO 90/05721 are agonists at 5-HT.sub.1 -like and/or 5-HT.sub.2 receptors and are expected to have utility in the treatment of conditions where such agonists are indicated, such as the treatment or prophylaxis of migraine or the treatment of portal hypertension. In this specification the term agonist also includes partial agonists.
The present invention therefore provides, in a first aspect, the use of a compound of structure (I): ##STR3## in which R.sup.1 is hydrogen, hydroxy, C.sub.1-4 alkoxy, halo C.sub.1-4 alkoxy, C.sub.3-7 cycloalkyl-C.sub.1-4 alkoxy, aryloxy or arylC.sub.1-4 alkoxy; C.sub.1-4 alkyl or together with the nitrogen atom to which they are attached form a ring; the manufacture of a medicament for the treatment of conditions where a 5-HT.sub.1 -like or 5-HT.sub.2 agonist is indicated, in particular the treatment and prophylaxis of migrain
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CA 81:105166j Synthesis . . . 2-(2-aminopropyl) indoles. Bhat et al., p. 497, 1974.
CA83:147449a Synthesis . . . indoles. Bhat et al., p. 497, 1975.
CA85:21176g Synthesis . . . agent. Hiremath et al., p. 675, 1976.
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Patent Abstracts of Japan C-179 7175 3 Mar. 83.
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Comp Biochem Physiol C, vol. 69C, No. 2, 1981, 359-366, Landau et al.
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J. Org. Chem. vol. 52, No. 13, 26 Jun. 1987, 2817-2825. Wrona M Z & Dryhurst G.
Kaumann Alberto J.
Kruse Lawrence I.
Young Rodney C.
King William T.
Lentz Edward T.
McKane Joseph
SmithKline Beecham Plc
Stein-Fernandez Nora
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