Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-05-05
1995-01-31
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514397, 514402, 546273, 546278, 5483121, A61K 31415, A61K 3147, C07D40104, C07D40304
Patent
active
053859197
DESCRIPTION:
BRIEF SUMMARY
This invention relates to indole derivatives, their non-toxic salts, processes for their preparation and pharmaceutical compositions of the derivatives or their salts for use in the treatment of diabetes.
Type 2 or maturity onset diabetes is characterised by raised plasma glucose levels in the fasting state and also by glucose intolerance following the ingestion of carbohydrate. Although postprandial elevations in plasma glucose are associated with deficient insulin secretion, plasma insulin levels appear to be in the normal range during fasting conditions. This latter observation is however misleading since when resting plasma insulin levels are related to the prevailing hyperglycaemia they are inappropriately low. Although the underlying cause of Type 2 diabetes is controversial there is now increasing evidence that the primary lesion is a defective insulin secretory process (Cerasi and Luft, Diabetes (1967) 16, 615; O'Rahilly et al, Lancet (1986), 360) which is exacerbated by a reduction in the efficacy of insulin (reduced insulin sensitivity). In normal subjects insulin regulates hepatic glucose production and defects in either the release or efficacy of insulin lead to an increased glucose production by the liver. The hyperglycaemic state is further enhanced by peripheral insulin insensitivity (insulin resistance) which leads to a reduction in the uptake of glucose by muscles. Although it is now generally accepted that reduced beta-cell function is the primary defect in Type 2 diabetes, there is no doubt that insulin resistance is a feature of the disease, particularly in obese patients, and some workers maintain that insulin insensitivity is the more constant feature of the disease (Reaven, Diabetes Care, (1982) 7 (suppl 1), 17).
The most commonly used first line hypoglycaemic agents are the sulphonylureas. These compounds have a complex mechanism of action which, despite extensive studies, is not fully understood. In the short term sulphonylureas stimulate first phase insulin release i.e. release of preformed insulin from beta-cells. Although sulphonylureas are the most commonly used agents in Type 2 diabetes there are inherent limitations to their utility. An important drawback of these compounds is that their major effect is expressed at basal or low blood glucose concentrations with postprandial changes being unaffected.
U.S. Pat. No. 4,659,731 discloses and claims dihydroindoles of the formula ##STR2## in which X is halogen, (C.sub.1-4)alkoxy, (C.sub.1-4)alkyl or allyloxy or, when and (C.sub.1-4)alkyl, (C.sub.3-6)alkenyl, benzyl which is unsubstituted or substituted by one or more halogen, methyl, methoxy and methylenedioxy substituents, or substituted phenyl of formula --C.sub.5 H.sub.4 --Y in which Y is hydrogen, halogen, linear or branched (C.sub.1-6)alkyl or linear or branched (C.sub.1-6)alkoxy and salts thereof with pharmaceutically acceptable acid.
The compounds of formula A are said to be powerful .alpha..sub.2 -adrenoreceptor antagonists which can be used for the treatment of depression (either alone or in combination with a product which inhibits neuronal uptake mechanisms), the treatment of hypotension, the treatment of postoperative paralytic ileum, the treatment of asthma and obesity, the treatment of diabetes and the treatment of impotence.
The patent does not include test data for any specific compound. Included among the compounds described is a compound of formula B in which X is hydrogen and R is phenyl i.e. the compound: ##STR3## isolated as the fumarate salt mp 212.5.degree.-215.degree. C.
In some of our earlier work, J. Med. Chem. 1988, 31, 944 there is described the synthesis and pharmacological evaluation, particularly as .alpha..sub.2 -adrenoreceptor antagonists, of a series of substituted 2-imidazolinylindolines of formula C ##STR4## Included amongst the compounds of formula C prepared and tested was the earlier mentioned compound of formula 8 isolated as the hydrochloride salt mp 208.degree.-209.degree. C. This compound was found to be 0.5 times as potent as idazoxan as
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Chapleo Christopher B.
Fagan Gay P.
Higel Floyd D.
Reckitt & Colman Products Limited
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