Compounds with analgesic effect

Details Compounds with analgesic effect Compounds with analgesic effect

1997-04-24

2000-10-10

Bernhardt, Emily

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

51425305, 51425306, 51425401, 51425406, 51425411, 514331, 514326, 514314, 544396, 544397, 544363, 544372, 544371, 544373, 544376, 544377, 544379, 546198, 546196, 546234, A61K 31495, C07D24104, C07D40110, C07D40506

Patent

active

061302228

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention is related to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are used in therapy, and in particular for the treatment of pain.


BACKGROUND AND PRIOR ART

The .delta. receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the .delta. receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the 67 receptor have also been shown to possess immunomodulatory activities.
The identification of at least three different populations of opioid receptors (.mu., .delta. and .kappa.) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid .delta. ligands are peptidic in nature and are unsuitable for administration by systemic routes. Some non-peptidic .delta. antagonists have been available for some time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269. for review). These compounds, e.g. naltrindole, suffer from rather poor (i.e., <10-fold) selectivity for the .delta. receptor vs .mu. receptor binding and exhibit no analgesic activity, a fact which underscores the need for the development of highly selective non-peptidic .delta. agonists.
Recently, a non-peptidic .delta. agonist, BW 373U86, was described by Chang et al., 1993, J. Pharmacol. Exp. Ther., 267: 852-857., as the first .delta.-selective non-peptide with analgesic activity, however, it shows significant affinity for the .mu. receptor.
Thus, the problem underlying the present invention was to find new analgesics having excellent analgesic effects, but also with an improved side-effect profile over current .mu. agonists and potential oral efficacy.
Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically.
In WO 93/15062 and WO 95/045051, some diarylmethylpiperazine and diarylmethylpiperidine compounds, including BW 373U86, are disclosed, but these prior art compounds are structurally distinct from the compounds according to the present invention.
The problem mentioned above has been solved by developing novel piperazine and piperidine compounds, as will be described below.


OUTLINE OF THE INVENTION

The novel compounds according to the present invention are defined by the formula (I) ##STR2## wherein G is a carbon atom or a nitrogen atom; NH.sub.2 or --COCH.sub.3 ; ##STR3## wherein the phenyl ring of each A substituent may be optionally and independently substituted by 1 or 2 substituents selected from hydrogen, CH.sub.3, (CH.sub.2).sub.0 CF.sub.3, halogen, CONR.sup.7 R.sup.8 , CO.sub.2 R.sup.7, COR.sup.7, (CH.sub.2).sub.o NR.sup.7 R.sup.8, (CH.sub.2).sub.o CH.sub.3 (CH.sub.2).sub.o SOR.sup.7, (CH.sub.2).sub.o SO.sub.2 R.sup.7 and (CH.sub.2).sub.o SO.sub.2 NR.sup.7 R.sup.8 wherein o is 0, 1, or 2, and R.sup.7 and R.sup.8 are as defined below;
R.sup.1 is selected from hydrogen; a branched or straight C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, --CO(C.sub.1 -C.sub.6 alkyl); (C.sub.1 -C.sub.6 alkyl)-B wherein B is as defined below; C.sub.3 -C.sub.8 cycloalkyl, C.sub.4 -C.sub.8 (alkyl-cycloalkyl) wherein alkyl is C.sub.1 -C.sub.2 alkyl and cycloalkyl is C.sub.3 -C.sub.6 cycloalkyl; C.sub.6 -C.sub.10 aryl; and heteroaryl having from 5-10 atoms selected from any of C, S, N and O; and whereby the C.sub.6 -C.sub.10 aryl and the heteroaryl may optionally be substituted by 1 or 2 substituents selected from hydrogen, CH.sub.3, (CH.sub.2).sub.o CF.sub.3, h

REFERENCES:
patent: 3940386 (1976-02-01), Szabo et al.
patent: 5681830 (1997-10-01), Chang et al.
patent: 5807858 (1998-09-01), Chang et al.
Calderon et al., J. Med. Chem. 37, pp. 2125-2128, 1994.
Bilsky et al., Regulatory Peptides, 54 pp. 25-26, 1994.
Bilsky et al. J. Pharmacology 273, pp. 1-567, 1995.
Chemical Abstracts, vol. 124, No. 8843 fu JP 07,138230 (May 30, 1995), Kuki et al.
Chang, et al., "A Novel, Potent and Selective Nonpeptidic Delta Opioid Receptor Agonist BW373U86," J. Pharmacol. and Exper. Ther. 267:852-857 (1993).
Takemori, et al., "Selective Naatrexone-Derived Opiod Receptor antagonist, " Annu. Rev. Pharmaco. Toxico. 32-51:239-269 (1992).
English language abstract of document DE2431178, WPI accession number 74-81010V/197447, Dialog file 351.
English language abstract of document DE2900810, WPI accession number 80-53516C/198031.Dialog file 351.
English language absract of document FR9212163, WPI accession number 94-146424/199418, Dialog file 351.

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