Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-08-22
1999-03-23
Daus, Donald G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 35, 546 44, 546 45, A61K 31445
Patent
active
058860010
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention is related to novel .delta. opioid receptor agonists as well as to their pharmaceutically acceptable salts, a process for their preparation and their use in the manufacture of pharmaceutical preparations.
BACKGROUND OF THE INVENTION
Three major types of opioid receptors, .mu., .kappa. and .delta., are known and characterized. The identification of different opioid receptors has lead to efforts to develop specific ligands for these receptors. These ligands are known to be useful for at least two purposes: receptors, and
Analgesic drugs having specificity for an individual opioid receptor type have been demonstrated to have fewer side effects (e.g. respiratory depression, constipation, dependence), and in cases in which tolerance to one drug has developed, a second drug with different opioid receptor specificity may be effective. For example the successful substitution of DADLE (intrathecal application), a partially .delta.-selective analgesic peptide, for morphine in a human cancer patient with morphine tolerance has been demonstrated (E. S. Krames et al., Pain, Vol. 24:205-209, 1986). Evidence that a .delta.-selective agonist could be a potent analgesic with less tolerance and dependence liability was presented by Frederickson et al. (Science, Vol. 211:603-605, 1981). The peptide, hundred fold more potent than morphine in the hot-plate test for analgesia after i. c. v. (intracerebral ventricular) administration. Naloxone precipitation of withdrawal after chronic administration of metkephamid and morphine in rats showed that metkephamid-treated animals exhibited fewer withdrawal symptoms than those given morphine, scoring only a little above the saline control group. Meltkephamid produced substantially less respiratory depression than morphine. (DPDPE) produces potent analgesic effects while showing little if any respiratory depression (C. N. May, Br.J. Pharmacol., Vol.98:903-913, 1989). DPDPE was found not to produce gastrointestinal side effects (e.g. constipation) (T. F.Burks, Life Sci., Vol.43:2177-2181, 1988). Since it is desireable that analgesics are stable against peptidases and are capable of entering the CNS easily, non-peptide analgesics are much more valuable.
PRIOR ART
Recently a non-peptide, .delta.-selective opioid agonist, BW373U86--a piperazine derivative, has been disclosed. BW 373U86 is reported to be a potent analgesic which does not produce physical dependence (P. H. K. Lee et al., J.Pharmacol.Exp.Ther., Vol. 267:983-987, 1993).
An undesired side effect of this compound is that it produces convulsions in animals. The convulsions were antagonized by the .delta.-selective opioid antagonist naltrindole.
OUTLINE OF THE INVENTION
The present invention provides novel analgesic compounds of the formula I ##STR2## wherein R.sub.1 represents C.sub.1 -C.sub.6 alkyl or hydrogen; -C.sub.6 alkenyloxy; C.sub.7 -C.sub.16 arylalkyloxy wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkyloxy is C.sub.1 -C.sub.6 alkyloxy; C.sub.7 -C.sub.16 arylalkenyloxy wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkenyloxy is C.sub.1 -C.sub.6 alkenyloxy; C.sub.1 -C.sub.6 alkanoxyloxy, C.sub.1 -C.sub.6 alkenoyloxy, C.sub.7 -C.sub.16 arylalkanoyloxy wherein the aryl is C.sub.6 -C.sub.10 aryl, and the alkanoyloxy is C.sub.1 -C.sub.6 alkanoyloxy; alkenyl; C.sub.7 -C.sub.16 arylalkyl wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkyl is C.sub.1 -C.sub.6 alkyl; C.sub.7 -C.sub.16 arylalkenyl wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkenyl is C.sub.1 -C.sub.6 alkenyl; hydroxy(C.sub.1 -C.sub.6)alkyl; alkoxyalkyl wherein the alkoxy is C.sub.1 -C.sub.6 alkoxy and the alkyl is C.sub.1 -C.sub.6 alkyl; CO.sub.2 H; CO.sub.2 (C.sub.1 -C.sub.6 alkyl); arylalkyloxy wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkyloxy is C.sub.1 -C.sub.6 akyloxy; C.sub.1 -C.sub.6 alkenyloxy; C.sub.1 -C.sub.6 alkanoyloxy; C.sub.7 -C.sub.16 arylalkanoyloxy wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkanoyloxy is C.sub.1 -C.sub.6 alkanoyloxy; alkyloxyalkoxy whe
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Burks et al., "Regulation of Gastrointestinal Function by Multiple Opioid Receptors," Life Sci. 43:2177-2181 (1988).
Frederickson et al., "Metkephamid, a Systemically Active Analog of Methionine Enkephalin with Potent Opioid .delta.-Receptor Activity," Science 211:603-605 (1981).
Krames et al., "Intrathecal D-Ala.sup.2 -D-Leu.sup.5 -enkephalin (DADL) Restores Analgesia in a Patient Analgetically Tolerant to Intrathecal Morphine Sulfate," Pain 24:205-209 (1986).
Astra AB
Daus Donald G.
Sanzo Michael A.
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