Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-26
1997-06-03
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 86, A61K 3144, C07D47104
Patent
active
056355130
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/EP93/02014 filed on Dec. 29, 1993.
This invention relates to a novel salt of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl] -1H-pyrido[4,3-b]indol-1-one, to solvates of this salt, to pharmaceutical compositions containing it and to its use in medicine.
6-Fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]- 1H-pyrido[4,3-b]indol-1-one, which may be represented by the formula (I) ##STR2## and its physiologically acceptable salts and solvates are described in European Patent Application publication No. 0353983. The compound of formula (I) is a potent and selective antagonist of 5-hydroxytryptamine (5-HT) at 5-HT.sub.3 receptors and is useful in the treatment of, for example, emesis (i.e. nausea and vomiting), irritable bowel syndrome and gastrointestinal dysfunction such as dyspepsia. Physiologically acceptable salts of the compounds of formula (I) specifically disclosed in European Patent Application publication No. 0353983 are the maleate, benzoate and hydrochloride salts.
We have now found, surprisingly, that a novel salt of the compound of formula (I), and solvates, particularly hydrates of this salt, more particularly its dihydrate, is advantageous for the preparation of pharmaceutical compositions by virtue of its solubility and stability.
The present invention therefore provides in a first aspect 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl] -1H-pyrido-[4,3-b]indol-1-one methanesulphonate and physiologically acceptable solvates thereof.
Preferred solvates of the methanesulphonate salt of the compound of formula (I) are hydrates, in particular the dihydrate.
The preferred compound of the invention is 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl] -1H-pyrido[4,3-b]indol-1-one methanesulphonate dihydrate.
The potent and selective antagonism of 5-HT at 5-HT.sub.3 receptors by the compound of formula (I) has been demonstrated by its ability to inhibit 3-(5-methyl-1H-imidazol-4-yl)-1-[1-(methyl-t.sub.3)-1H-indol-3-yl]-1-propa none binding in rat entorhinal cortex homogenates (following the general procedure described by G. Kilpatrick et al. in Nature, 1987, 330, 746).
In view of its 5-HT.sub.3 antagonist activity, 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4yl)methyl]- 1H-pyrido[4,3-b]indol-1-one methanesulphonate or a physiologically acceptable solvate is useful in the treatment of conditions ameliorated by antagonism of 5-HT at 5-HT.sub.3 receptors, such as emesis (i.e. nausea and vomiting), particularly that associated with cancer chemotherapy and radiotherapy, that occurring post operatively, and also that induced by opioids; cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease), and vascular dementia (including multi-infarct dementia), as well as dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment; psychotic disorders, such as schizophrenia and mania; anxiety disorders, including panic disorder, agoraphobia, social phobia, simple phobia, obsessive compulsive disorders, post traumatic stress disorder, mixed anxiety and depression, and generalized anxiety disorder; irritable bowel syndrome; gastric stasis; symptoms of gastrointestinal dysfunction such as occur with dyspepsia, peptic ulcer, reflux oesophagitis and flatulence; migraine; obesity and conditions such as bulimia; pain; dependency on drugs and substances of abuse; and depression.
There is also provided as a further aspect of the invention 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1 H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one methanesulphonate or a physiologically acceptable solvate
REFERENCES:
patent: 5183820 (1993-02-01), Coates
Hartley Peter L.
Roberts Tony G.
Whitesell Leonard G.
Glaxo Group Limited
Huang Evelyn
Ivy C. Warren
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