IL30721A - Analgesia and sleep producing preparations containing a lower alkyl ester of 4-imidazoleacetic acid - Google Patents

Description

30721/2 Analgesia and sleep producing preparation containing a lower alkyl ester of 4-imidaz- oleacetic acid am OP HOPE MEDICAX CENTER C:28959 - la - 30721/2 This invention relates to pharmaceutical preparations having an analgesic or hypnotic effect.

A wide variety of therapeutic agents are known which have the property of inducing analgesia at lower concentrations, and sleep at higher concentrations, when administered to warm-blooded animals. Kost of the known and used substances suffer from one or more disadvantages, among which may be mentioned habituation, tendency toward addiction, and side effects such as allergenic manifestations, inducing of blood dyscrasias, and the like. It is apparent that in spite of the large amount of effort that has been expended in the past on the development of agents of this type, much room for improvement still remains.

It has been discovered in accordance with this invention, that both analgesia and sleep can be induced in warm-blooded animals b administering them relatively small amounts of lower alkyl esters of 4-imidazoleacetic acid, as explained in detail hereinbelow. In general, the 4-lmidaz-oleacetic acid ester may be injected or administered orally. In the case of small test animals such as mice, intraperitoneal injection is suitable; and in the case of larger animals, sue ss rats, guinea pigs, and even larger animals, the administrative route may be oral as well as by parenteral injection.

I general, from 0.1 to 1,0 millimols of the ester per kilogram weight of animal gives analgesia and from about 1 to 5 millimols per kilogram produces sleep, these dosage ranges being for injection, with approximately twice as much - 2 - 30721/2 When Injection is the chosen route, the 4-imidaz-oleacetic acid ester may be solution, preferably aqueous, and preferably in physiologic saline; and when administered orally, depending on the animal concerned, it may likewise be in solution form or in tablet or capsule or like form as a dry substance, and mixed if desired with the usual excipients. 4-Imidazoleacetlc acid has a carboxyl group which forms eaters much after the manner of acetic acid itself with lower alkyl alechols, wherein by lower alkyl is to he understood methyl, ethyl, propyl, butyl* It also has a basic nitrogen atoa in the imidazole ring which forms acid salts in the usual fashion, for example, with hydrochloric acid, sulfuric acid acetic acid, and the like, The esters may be conveniently dissolved in water, or indeed in physiologic saline solution, and the pH adjusted as desired. Por oral use, the selected ester (or mixtures of two or more esters) may be mixed with a pharmacologically acceptable carrier, such as distilled water? glycerol; alcohol; sugar syrup; starch; powdered sugar; gum arabic; and others usual in the pharmaceutical art.

The specific advantages of utilizing these lower alkyl esters of 4-imidazoleacetic acid, as contrasted with the acid itself or simple salts thereof, reside, first, in a faster onset of the therapeutic effects, viz., analgesia and sleep; second, more prolonged duration of these; and third, effectiveness at a lower dosage level. In other words, the esters are in general more effective on a weight-for-weight basis as compared with 4-imidazoleacetic acid. It is - 3 - 30721/2 believed that this results from the conversion of the carboxyl radical, which in 4-lmidazoleacetlc acid itself at pH values within the physiological range exists as a carboxyl ion, to a carboxyl ester, which of course is not ionized. It is believed that this transformation to an essentially non-ionic compound facilitates transport across cell membranes, and in particular, the blood-brain barrier. in orderjto show the effectiveness of the esters in accordance with the invention, and at the same time to indicate their superiority over the unesterified acid, several sets of five mice each were injected peritonially with various esters of 4-imidazoleacetic acid, and also with 4-imidazoleacetic acid itself. Drowsiness and/or sleep induced in the animals was recorded, with the following results: A. Methyl ester of 4-imidazoleacetic acid: mice 3 millimols/kg body weight 6-25 minutes required before sleep attained. 2 mice slept ½ hours 3 mice slept more than 6 hours (were asleep at 5 p.m.).

No fatalities. jt l. Isopropyl ester of 4-imidazoleacetic acid: mice 1.5 millimols/kg body weight 3 mice required 40-45 minutes to attain sleep.

These same 3 mice slept 1.0-1.5-3.0 hours respectively. 2 mice did not sleep at all but were drowsy. o fatalities. - 4 * 30721/2 B-2. Iaopropyl eater of 4-imidazoleacetic acid: mice 0.75 millimols/kg body weight All became drowsy 1 hour after injection.

All remained that way for 1 hour and then recovered, and became very active.

Ko fatalities.

C. 4-Imidazoleacetic acid 3 millimols/&g body weight mice Intraperitoneal injections -25 minutes required before sleep attained.

All 5 mice slept an average of 4 hours.

I5o fatalities.

It will be observed that in the caee of the methyl ester, sleep set in in some of the mice as early as six minutes after the injection, as compared to a minimum time of 20 minutes for 4-imidazoleacetic acid.

In the case of the isopropyl ester, the effectiveness was so much greater on a weight basis that it was possible to reduce the dosage to one-half of that required by the methyl esterm and still induce drowsiness in "two of the mice and sleep in three.

It should be remarked that inasmuch as sedation and tranquilization go hand-in-hand with analgesia and soporifi- the cation,/4-imldasoleacetic acid ester may be used at lower dosage levels where the former effects are the principal ones sought, than for achieving full-scale deep sleep. t ' ' -v r· - 5 - 30721/2

Claims (5)

1. Pharmaceutical preparations having an analgesic or hypnotic effect in mammals, comprising, as an active ingredient, a lower-alkyl ester of 4-lmidazoleacetic acid.

2. Pharmaceutical preparations according to Claim 1, wherein the alkyl moiety of the ester is a methyl, propyl, isopropyl, butyl, isobutyl or terbutyl group.

3· Pharmaceutical preparations according to Claims 1 or 2, for use as analgesics, containing about 0.1 to 1.0 mlllimol per kg of body weight of the mammal for injection, and about 0.2 to 2.0 millimols for oral administration.

4. Pharmaceutical preparations according to Claims 1 or 2, for use as hypnotics, containing about 1 to 5 millimols per kg of body weight of the mammal for infection, and about 2 to 10 millimols for oral administration.

5. A process of inducing analgesia and/or sleep in mammals, not being humans, which comprises administering to them an effective dose of an active agent as set out in Claims 1 or 2. For the Applicants RC/rb