Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-03-03
2000-11-28
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514426, 546223, 548557, A61K 31445, C07D21158
Patent
active
061536261
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
The present application claims priority to international application PCT/SE97/02051, filed on Dec. 9, 1997 and also to Swedish application 9604786-5, filed on Dec. 20, 1996.
FIELD OF THE INVENTION
The present invention is related to novel nitrogen ring compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful 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 .delta. 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. ligands.
Thus, the problem underlying the present invention was to find new analgesics having improved 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.
The problem mentioned above has been solved by developing novel compounds which possess a piperidine ring, which may be a 5-membered, a 6-membered or a 7-membered nitrogen ring, as will be described below.
OUTLINE OF THE INVENTION
The novel compounds according to the present invention are defined by the general formula (I) ##STR2## wherein m is 0 or 1; and cycloalkyl is C.sub.3 -C.sub.6 cycloalkyl; ##STR3## where G is a hydroaromatic or a heteroaromatic group having 5 or 6 atoms, and where the heteroatoms are selected from O, S and N; and ##STR4## and wherein n=0 or 1; C.sub.6 -C.sub.10 aryl; or heteroaryl having from 5 to 10 atoms selected from any of C, S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents independently selected from any of hydrogen, CH.sub.3, (CH.sub.2).sub.p CF.sub.3, halogen, CONR.sup.5 R.sup.4, COOR.sup.5, COR.sup.5, (CH.sub.2).sub.p NR.sup.5 R.sup.4, (CH.sub.2).sub.p CH.sub.3 (CH.sub.2).sub.p SOR.sup.5 R.sup.4, (CH.sub.2).sub.p SO.sub.2 R.sup.5, and (CH.sub.2).sub.p SO.sub.2 NR.sup.5, wherein R.sup.4 and R.sup.5 is each and independently as defined for R.sup.1 above and p is 0, 1 or 2; alkyl)heteroaryl, the heteroaryl moieties having from 5 to 10 atoms selected from any of C, S, N and O, and where the aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents independently selected from any of hydrogen, CH.sub.3, CONR.sup.5 R.sup.4, COOR.sup.5, COR.sup.5, (CH.sub.2).sub.q NR.sup.5 R.sup.4, (CH.sub.2).sub.q CH.sub.3 (CH.sub.2).sub.q SOR.sup.5 R.sup.4, (CH.sub.2).sub.q SO.sub.2 R.sup.5, (CH.sub.2).sub.q SO.sub.2 NR.sup.5, and (CH.sub.2).sub.q OR.sup.4, wherei
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Pelcman Benjamin
Roberts Edward
Astra Pharma Inc.
Chang Ceila
Sanzo Michael A.
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