Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-05-12
1994-03-29
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D48909, A61K 31485
Patent
active
052986225
DESCRIPTION:
BRIEF SUMMARY
Endogenous opioid peptides are involved in the mediation or modulation of a variety of mammalian physiological processes, many of which are mimicked by opiates or other non-endogenous opioid ligands. Some of the effects that have been investigated are analgesia, tolerance and dependence, appetite, renal function, gastrointestinal motility, gastric secretion, learning and memory, mental illness, epileptic seizures and other neurological disorders, cardiovascular responses, and respiratory depression.
The fact that the effects of endogenous and exogenous opioids are mediated by at least three different types [mu (.mu.), delta (.delta.), kappa (.kappa.)] of opioid receptors raises the possibility that highly selective exogenous opioid agonist or antagonist ligands might have therapeutic applications. See W. R. Martin, Pharmacol. Rev., 35, 283 (1983). Thus, if a ligand acts at a single opioid receptor type or subtype, the potential side effects mediated through other opioid receptor types can be minimized or eliminated.
The prototypical opioid antagonists, naloxone and naltrexone, are used primarily as pharmacologic research tools and for the reversal of toxic effects of opioids in case of overdose. Since these antagonists act at multiple opioid receptors, their applications in other therapeutic areas or as pharmacologic tools appear to be limited. However, naltrexone recently was reported to reduce the incidence of relapse in recovering alcoholics by J. R. Volpicelli et al., Opioids, Bulimia and Alcohol Abuse and Alcoholism, L. D. Reid, ed., Springer-Verlag (1990) at pages 195-214. Naloxone has been reported to suppress ethanol but not water intake in a rat model of alcoholism. J. C. Froehlich et al., Pharm. Biochem. Behav., 35, 385 (1990).
Some progress has been made in the development of highly selective opioid antagonists. For example, Portoghese et al. (U.S. Pat. No. 4,816,586) disclose certain opiate analogs which possess high selectivity and potency at delta receptors. Minimal involvement was observed at mu and kappa opioid receptors. One of the highly selective analogs disclosed in U.S. Pat. No. 4,816,586 has been named "naltrindole" or "NTI," and has the formula (1): ##STR1## See P. S. Portoghese et al., J. Med. Chem., 31, 281 (1988).
It has recently been reported that suppression of ethanol ingestion may be mediated by the delta opioid receptor type. For example, the .delta. antagonist, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174864), strongly inhibits ethanol drinking, but has a very short duration of action, which may limit its clinical utility. See J. C. Froehlich et al., Psychopharmacol., 103, 467 (1991). Using NTI as an antagonist, M. Sofuoglu et al., J. Pharmacol. Exp. Ther., 257, 676 (1991) determined that the antinociceptive activity of two delta receptor agonist enkephalin analogs, DSLET and DPDPE, may be mediated by two discrete delta opioid receptor subtypes. It has also been suggested that development of addiction and/or tolerance to opiates may be inhibited by delta-opioid receptor antagonists, and that opioid-type delta-opioid receptor antagonists may be useful as immunosuppressive agents. Likewise, compounds which are selective at mu receptors may be useful as analgesics which do not exhibit the potentially harmful side effects of less-selective analgesics such as morphine.
Therefore, a continuing need exists for compounds which are opioid receptor-selective, i.e., which can act as agonists or antagonists with specificity at the delta, mu or kappa opioid receptor, or at one of the subtypes of these receptors.
SUMMARY OF THE INVENTION
The present invention is directed to biologically active compounds of the formulas (I) and (II): ##STR2## R.sup.1 is (C.sub.1 -C.sub.5)alkyl, C.sub.3 -C.sub.6 (cycloalkyl)alkyl, C.sub.5 -C.sub.7 (cycloalkenyl)alkyl, (C.sub.6 -C.sub.12)aryl, (C.sub.6 -C.sub.12)aralkyl, trans(C.sub.4 -C.sub.5)alkenyl, allyl or furan-2-ylalkyl, R.sup.2 is H, OH or O.sub.2 C(C.sub.1 -C.sub.5)alkyl; R.sup.3 is H, (C.sub.6 -C.sub.10)aralkyl, (C.sub.1 -C.sub.5)alkyl or (C.sub.
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Moe Scott T.
Ohkawa Shigenori
Portoghese Philip S.
Berch Mark L.
Regents of the University of Minnesota
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