WO1994016698A1

WO1994016698A1 - Medicaments having central analgesic activity

Info

Publication number: WO1994016698A1
Application number: PCT/EP1994/000204
Authority: WO
Inventors: Rosanna Lodi
Original assignee: Riace Establishment
Priority date: 1993-01-29
Filing date: 1994-01-26
Publication date: 1994-08-04
Also published as: ITMI930140A1; ITMI930140A0; AU5970994A; IT1271350B

Abstract

3,8-Diazabicyclo(3,2,1)-octane derivatives are used for the preparation of medicaments having a central analgesic activity combined with, in comparison to morphine, a lower capacity of inducing withdrawal syndrome and tolerance.

Description

MEDICAMENTS HAVING CENTRAL ANALGESIC ACTIVITY

The present invention refers to the use of 3,8- diazabicyclo(3,2,1)-octane derivatives for the preparation of medicaments having central analgesic activity combined with a capacity of inducing withdrawal syndrome and tolerance which is lower than that of morphine.

More particularly, the invention refers to the use of compounds of formula I

wherein R and R_* , which are different, represent propionyl or p-nitrocynnamyl, for the preparation of analgesic medicaments having substantially the same activity as morphine, without sharing however the tolerance or addiction and withdrawal phenomena typical of this substance. The compounds of formula I have been disclosed as analgesic agents in J. Med. Chem. , 1965, 8., 326.

It has been recently reported (G. Cignarella et al., Pharmacol. Res. Comm. , 1985, J5, 383) that said compounds have i vitro an affinity for μ receptor similar to morphine (Ki ~ 15-30 nM) whereas, in vitro, in the hot plate test on mice, they show an analgesic potency higher than morphine.

It has now been found that the compounds I, even though comparable to morphine on the ground of the data until now published, have surprising properties since they are substantially devoid of withdrawal phenomena and less liable than morphine in inducing tolerance or -.* addiction after chronic treatment.

The term "substantially devoid" means an activity from 3 to 20 times lower than morphine in the jumping test in mice, after chronic administrations three times a day for 7 consecutive days of analgesically

.'-1 equipotent doses.

Tolerance, which for morphine is already statistically significant after administrations repeated for three only consecutive days in mice, occurs for the two compounds of the invention only at the fifth and eleventh day, as reported in the pharmacological tests summarized in the enclosed Figures, wherein:

Figure 1 represents the dose-response curve of compound I wherein R is p-nitro-cynnamyl and R^ is ^■> _' propionyl (DBO-II) in the hot plate test in the mouse: Swiss male albino mice (20-25 g), treated i.p. 30' before the hot plate test (56.6^βC) were used. Each bar represents the mean ± standard error of at least three experiments in which 8 animals per group were used.

Figure 2 represents the dose-response curve, under the same experimental conditions of Figure 1, of compound I wherein R is propionyl and R-. is p- nitrocynnamyl (DBO-17). so - Figure 3 shows the tolerance to compound DBO-11: Swiss male albino mice (20-25 g) acutely or chronically treated i.p. 30' before the hot plate test (56.6^βC) were used. Each bar represents the mean ± standard error of at least two experiments ^•j in which 8 animals per group were used (p<0.05).

Figure 4 and 5 respectively show the tolerance to compound DBO-17 and to morphine, in the same experimental conditions of Figure 3.

Figure 6 refers to the withdrawal syndrome in the

1 ' _' mouse after chronic administration of the compounds I in comparison to morphine. Swiss male albino mice (6 per group, 20-25 g) were used.

Increasing doses of DBO-11 (2.5-10 ng/kg s.c),

DBO 17 (1.25-5 ng/kg s.c), morphine (25-100 ng/kg) were administered three times a day for 7 consecutive days. "Jumping" was induced by naloxone (1 ng/kg i.p.). Each bar represents the number of jumps per group in the 30 min subsequent to the naloxone administration.

/" From the above results, it is evident that compounds I, as such or salified with pharmaceutically acceptable acids, may be advantageously used as active principles of medicaments having central analgesic activity combined with low capacity of inducing tolerance and withdrawal phenomena, i.e. the most serious drawbacks limiting the use of morphine.

The lack of tolerance and withdrawal induction could not be by no means expected according to the available knowledge on opioid receptors μ and δ. r,n For the intended therapeutic uses, the compounds I or their salts will be formulated in suitable pharmaceutical compositions according to usual techniques and methods.

The dosage will of course depend on several -> factors (patient's weight, sex, age and condition) but the posology may generally be from about 5 to about 20 times lower than that usually used for morphine.

The compounds I may be prepared according to the methods disclosed in Pharmacol. Res. Comm. , 1985, 5., J.o 383.

Claims

1. The use of compounds of formula I

wherein R and R₁, which are different, represent 10 propionyl or p-nitrocynnanyl for the preparation of medicaments having central analgesic activity combined with a capacity of inducing withdrawal syndrome and tolerance which is lower than that of morphine.

2. The use according to claim 1 wherein in compound I J O R is propionyl and R^ is p-nitro-cynnamyl.

3. The use according to claim 1 wherein in compound I R is p-nitro-cynnamyl and R_* is propionyl.