Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-09-16
1999-11-30
MacMillan, Keith D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514399, 514400, A61K 31415
Patent
active
059943840
DESCRIPTION:
BRIEF SUMMARY
The invention is related to the use of the levo-enantiomers of certain imidazole derivatives in the prevention or treatment of conditions associated with overexpression or hypersensitization of adrenergic .alpha.-2 receptors as well as in the diagnosis of such conditions. The invention is also related to pharmaceutical compositions containing such imidazole derivatives.
The imidazole derivatives used in the invention are either the levo-enantiomers of the compounds of formula I ##STR1## wherein R.sub.1 is C.sub.1 -C.sub.2 -alkyl and R.sub.2 to R.sub.4 are each the same or different and are independently hydrogen, C.sub.1 -C.sub.2 -alkyl, OH, OCH.sub.3, halogen, C.sub.1 -C.sub.2 -hydroxyalkyl, carboxy, cyano, CHO, COOCH.sub.3, COOCH.sub.2 CH.sub.3, CONH.sub.2, C.dbd.NHNH.sub.2, C.dbd.NHNHCH(C.sub.6 H.sub.6)CH.sub.3 or physiologically acceptable esters or salts thereof with the proviso that more than one of the substituents R.sub.2 to R.sub.4 are not at the same time C.dbd.NHNHCH(C.sub.6 H.sub.6)CH.sub.3.
Preferred compounds are those in which R.sub.1 is methyl and R.sub.2, R.sub.3 and R.sub.4 are each independently hydrogen, C.sub.1 -C.sub.2 -alkyl, hydroxy, C.sub.1 -C.sub.2 -hydroxyalkyl or CONH.sub.2. The levo-enantiomer of medetomidine is particularly preferred.
The preparation of the imidazole derivatives of formula I in general has been described, for example, in EP 72 615 B1, EP 269599 B1, EP 341231 B1 and in EP 626372 A1. The corresponding levo-enantiomers may be prepared, e.g. using optically active acids as described in EP 300652 B1.
Although some of the derivatives of formula I are known from the literature (mostly as a component of the corresponding racemic mixture), it is believed that their use as a medicament or as a diagnostic agent in a form such that the presence of the corresponding dextro enantiomer is limited to insignificant amounts i.e. as an impurity has never been disclosed.
It has now been surprisingly observed that the levo-enantiomers of the imidazole derivative of the formula I are true inverse agonists of adrenergic .alpha.-2 receptors. This means that the compounds of the invention may be used in the prevention or treatment of conditions associated with overexpression or hypersensitization of adrenergic .alpha.-2 receptors.
With the development of sensitive test systems detection of inverse agonism has become possible, making it necessary to reclassify many pharmacological agents (Bond, R. A. et al., 1995, Nature, 374, 272). An inverse agonist appears to destabilize receptor-G protein coupling or to bind selectively to the inactivated form of the receptor (or both). In systems where there is considerable formation of the activated receptor system (constitutively activated receptors i.e. receptors which are active in the absense of an agonist) compounds with inverse agonist properties will alter the equilibrium between active and inactive receptors, increasing the number of receptors in inactivated form. This, in turn, results in the reduction of the number of receptors which are actively participating in the signal transduction (inverse agonism, which can also be called as negative antagonism). In bried, an inverse agonist is a drug that by binding to receptors reduces their fraction in active conformation (Jenkins, D. H., et al., 1995, Pharmacol. Rev., 47, 255).
Inverse agonists may be particularly important in disease states and in pathogenesis which result from mutations in constitutively activated receptors. Inverse agonists, therefore, represent an important and specific therapeutic approach for such disease states.
Previously inverse agonists have been found in the family of antagonists (Bond et al., 1995 and Wang-Ni T. et al., 1994, Molecular Pharmacology, 45, 524). However, antagonist type of inverse agonists besides negating constitutive receptor activity also eliminate endogenous agonist tone in all tissues which is not desired in targeted drug therapy.
A true inverse agonis, like a compound of the invention reduces receptor activation state and, therefore, represent
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.ANG.kerman Karl E. O.
Cockcroft Victor
Jansson Christian
Kukkonen Jyrki
Savola Juha-Matti
MacMillan Keith D.
Orion Corporation
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