Pharmaceutical compositions containing 4-substituted imidazoles

Details Pharmaceutical compositions containing 4-substituted imidazoles Pharmaceutical compositions containing 4-substituted imidazoles

1993-11-12

1995-11-07

Phelan, D. Gabrielle

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

514396, 514944, 514937, 514969, A61F 1302

Patent

active

054646286

DESCRIPTION:

BRIEF SUMMARY
This invention relates to the use of certain known therapeutically active imidazoles substituted in the 4-position for use in the manufacture of pharmaceutical preparations for transdermal administration. Such transdermal preparations are also within the scope of the invention.
The therapeutically active 4-substituted imidazoles have the general formula ##STR2## where R.sub.1, R.sub.2 and R.sub.3 which can be the same or different are H, CH.sub.3, C.sub.2 H.sub.5 or Cl; X is CH.dbd.CH or (CH.sub.2).sub.n where n is 1 to 3 or X is --C(OR.sub.5)H-- where R.sub.5 is methyl or ethyl; and R.sub.4 is hydrogen or a straight alkyl of 1 to 4 carbon atoms.
Members of formula (I) and (II) are well known potent and selective .alpha..sub.2 -adrenoceptor active agents. Compounds of formula (I) are .alpha..sub.2 -adrenoceptor agonists while compounds of formula (II) are .alpha..sub.2 -adrenoceptor antagonists. Based on these pharmacological features the compounds are useful in a wide field of therapy. Compounds of formula (I) are disclosed e.g. in the European Patent Publications 24829, 34473, 34474, and 72615 and compounds of formula (II) are described in EP 198492. EP 24829 discloses various members of formula (I) having X being CH.sub.2 or --C(OR.sub.5)H-- as active antihypertensive, antiulcer, diuretic, tranquilizing, sedative, analgesic and anti-inflammatory agents. One member, 4-(2,3-dimethylbenzyl)-1H-imidazole, the generic name of which is detomidine, is commercially used as a veterinary sedative injection preparation to be used in the treatment of big animals, especially horses. EP 34473 discloses componds of formula (I) where X is (CH.sub.2).sub.n and n is greater than 1 as valuable agents for the treatment of hypertension. EP 34474 discloses compounds of formula (I) where X is CH.dbd.CH as valuble antihypertensive, antithrombotic, antifungal and antimicrobial agents. EP 72615 describes i.a. compounds of formula (I) where X is --C(CH.sub.3)H-- as useful antihypertensive agents. One member, 4-[.alpha.-methyl-2,3-dimethylbenzyl-1H-imidazole the generic name of which is medetomidine, has further been disclosed in U.S. Pat. No. 4,783,477 and has been commercialized as a veterinary sedative-analgesic injection preparation for small animals. EP 183492 discloses members of formula (II) as useful .alpha..sub.2 -adrenoceptor antagonists. Atipamezole, which is the compound of formula (II) where R.sub.4 is ethyl, is described in said patent to be useful for the reversal of detomidine. The compound is also marketed as an injection preparation for this purpose, especially as a reversal for medetomidine. EP 183492 suggests moreover a great many uses of the compounds of formula (II) e.g. antidiabetic, antidepressive and antiasthmatic uses.
In many therapeutic uses a steady, uniform administration of the active agent is desirable. Many compounds, especially those of formula (II) are known to have a rather poor bioavailability due to extensive initial metabolism of the drug. These compounds would not therefore be suitable for oral administration. In many fields of therapy injections are, however, not convenient. Transdermal administration is one alternative in such cases as it combines the convenience of oral administration and the high bioavailability of injections.
The present invention relates to transdermal administration of compounds of formula (I) and (II) as well as suitable preparation therefore.
Only a minor part of commercially available therapeutically active substances is suitable for transdermal administration due to many different pharmacokinetic and pharmacological reasons. One of the most limiting factors is, however, the physicochemical properties of the therapeutically active substance itself. For a compound to be able to penetrate the skin it must have both lipophilic (fat soluble) and hydrophilic (water soluble) properties in a suitable proportion. Such a suitable ratio between the lipophilic and hydrophilic properties is not very common for drug substances. The ability of a drug to penetrate through the ski

REFERENCES:
patent: 5124157 (1992-06-01), Colley

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