Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-04-17
1998-11-17
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514364, 514408, 514422, 514428, 5462764, 548131, 548143, 548517, 548527, 548568, 564162, 564163, 564169, 564182, 564193, 564199, 564210, A61K 3140, C07D20712, C07C23313, C07C23331
Patent
active
058377204
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/IB95/00374 filed May 18, 1995.
TECHNICAL FIELD
This invention relates to novel carboxamide compounds and their pharmaceutically acceptable salts, and to pharmaceutical compositions containing them. These compounds and compositions are useful as analgesic, antiinflammatory, diuretic or neuroprotective agents 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 discovery 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.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula: ##STR2## and its pharmaceutically acceptable salt, wherein R is hydrogen or hydroxy; from halo, C.sub.1-4 alkyl and C.sub.1-4 alkoxy; three substituents selected from halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy and methoxycarbonyl; mono-, di- or tri-halomethyl; cyano; COR.sup.1, CH.dbd.NOR.sup.2, OR.sup.2, SR.sup.2, CH.sub.2 CN, CH.sub.2 OR.sup.2, CH.sub.2 SR.sup.2, CH.sub.2 S(O)R.sup.2, CH.sub.2 S(O).sub.2 R.sup.2, CH.sub.2 (R.sup.2)R.sup.3, CH.sub.2 N(R.sup.2)R.sup.3, CH.sub.2 NR.sup.2 OH, CH.sub.2 N(COR.sup.2)OH, CH.sub.2 NR.sup.2 COR.sup.3, CH.sub.2 NR.sup.2 S(O).sub.2 R.sup.3 or CH.sub.2 OCOR.sup.2, wherein R.sup.1 is hydrogen, hydroxy, amino, NHOH, NHOCH.sub.3, pyridylamino, NHN(CH.sub.3).sub.2, C.sub.1-4 alkoxy, benzyloxy, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.1-4 alkyl or C.sub.1-4 alkylthio; and R.sup.2 and R.sup.3 are each hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or C.sub.7-11 phenylalkyl; and or benzothienyl; phenyl, naphtyl, furyl, thienyl, pyridyl, thiazolyl, benzofuryl or benzothienyl, substituted with one to three substituents selected from halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, amino, hydroxy, nitro, trifluoromethyl and mesyl. ##STR3## wherein R, Ar and X are as already defined. These compounds can be used as intermediates to prepare the compounds of formula (I).
The carboxamide compounds of the present invention of formula (I) exhibit significant agonist activity toward opioid kappa receptor and are thus useful as analgesic, antiinflammatory, diuretic and neuroprotective agents, in mammals, especially man.
Accordingly, the present invention also provides a pharmaceutical composition useful as an analgesic, antiinflammatory, diuretic or neuroprotective agent, in a mammal, especially man, which comprises a therapeutically effective amount of the carboxamide compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
DETAILED DISCLOSURE OF THE INVENTION
In this specification, the term "heterocyclic" means a monocyclic or bicyclic hydrocarbon group which has one or more hetero atoms in the ring, preferably has 4 to 10 carbon atoms and 1 to 3 heteroatoms, including piperidino, morpholino, thiamorpholino, pyrrol
REFERENCES:
patent: 5232978 (1993-08-01), Gottschlich et al.
"2-(3,4-Dichlo Use of Conformational Analysis in the Development of a Novel Series of Potent Opioid k Agonists," Costello et al., J. Med. Chem. 1991 (Jan.), 34(1), 181-189.
"Structure/Activity Studies Related to etamides:A Novel Series of Potent and Selective k-Opioid Agonists," Barlow et al., J. Med. Chem. 1991 (Nov.), 34(11), 3149-3158.
Ginsburg Paul H.
Oswecki Jane C.
Pfizer Inc.
Richardson Peter C.
Richter Johann
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