Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-09-26
1999-09-14
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514 63, 514422, 548406, 548517, 548556, A61K 3141, C07D20712, C07D40512
Patent
active
059523697
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP96/00820 filed Mar. 28, 1996.
TECHNICAL FIELD
This invention relates to novel hydroxamic acid derivatives and their pharmaceutically acceptable salts, and to pharmaceutical compositions containing them. These compounds and compositions are useful as analgesic, antiinflammatory, diuretic, anesthetic or neuroprotective agents, or an agent for treatment of stroke or functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject.
BACKGROUND ART
Opioid analgesics such as morphine are therapeutically useful, but their usage is strictly limited because of their side effects such as drug dependency. Thus, analgesics with high usefulness and reduced tendency to cause drug dependency are desired. Considerable pharmacological and biochemical studies have been carried out to discover the opioid peptides and opioid receptors, and the dicovery of the subtype of opioid receptor such as .mu., .delta., .kappa. at a peripheral nerve in a variety of species, including human, has made a beginning towards creating new analgesics. As it is thought that opioid analgesics such as morphine act as a .mu.receptor agonist, separating the action based on a .kappa.-receptor agonist from the action based on .mu.-receptor agonist has been investigated. Recently .kappa.-selective agonists have been reported from the above viewpoint for example, EMD-60400: A. Barber et al., Naunyn-Schmled. Arch. Pharmacol., 345 (Suppl.): Abst 456. Some of them actually have been studied in clinical trials (Med. Res. Rev., 12, 525 (1992)).
However, even when a selective .kappa.-receptor agonist is employed, use of high doses can give rise to side effects such as sedation. Therefore, it would be desired to provide compounds having better agonist activity toward opioid .kappa.-receptor, and in particular compounds having only low sedative activity.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula: ##STR3## and the salts thereof, wherein
A is hydrogen, hydroxy or OY, wherein Y is a hydroxy prQtecting group;
Ar is phenyl optionally substituted with one or more (preferably up to three) substituents selected from halo, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, CF.sub.3, C.sub.1 -C.sub.4 alkoxy-C.sub.1 -C.sub.4 alkyloxy, and carboxy-C.sub.1 -C.sub.4 alkyloxy;
X is phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophenyl, 1-tetralone-6-yl, C.sub.1 -C.sub.4 alkylenedioxy, pyridyl, furyl and thienyl, these groups optionally being substituted with up to three substituents selected from halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, NO.sub.2, CF.sub.3 and SO.sub.2 CH.sub.3 ; and
R is hydrogen, C.sub.1 -C.sub.4 alkyl or a hydroxy protecting group.
The hydroxamic acid derivatives of the present invention of formula (I), wherein A is hydrogen or hydroxy and R is hydrogen or C.sub.1 -C.sub.4 alkyl, exhibit significant agonist activity toward opioid .kappa.-receptor. Therefore these .kappa. agonists are particularly useful as an analgesic agent in mammals, especially humans. They are also useful as antiinflammatory, diuretic, anesthetic or neuroprotective agents, or an agent for treatment of stroke or functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject.
Accordingly, the present invention also provides a pharmaceutical composition useful as an analgesic, antiinflammatory, diuretic, anesthetic or neuroprotective agent, or an agent for treatment of stroke or functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject, which comprises a therapeutically effective amount of a hydroxamic acid of formula (I), wherein A is hydrogen or hydroxy and R is hydrogen or C.sub.1 -C.sub.4 alkyl, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
The compounds of formula (I), wherein either or both of OY and OR represent a protected hyd
REFERENCES:
patent: 3268539 (1966-08-01), Paramus
J. Pharm. Sciences, vol. 63, No. 12, 1974, pp. 1951-1953, XP002005549, J. L. Lewis et. al.: "Chemistry and Biological Activity of N-Substituted Hydroxylamines".
Appleman Jolene W.
Ginsburg Paul H.
Morris Patricia L.
Pfizer Inc
Richardson Peter C.
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