Kappa opioid receptor antagonists

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C546S035000

Reexamination Certificate

active

06534514

ABSTRACT:

BACKGROUND OF THE INVENTION
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 (&mgr;), delta (&dgr;), kappa (&kgr;)] 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:
wherein X is NH. See P. S. Portoghese et al.,
J. Med. Chem
., 31, 281 (1988).
Portoghese et al. (U.S. Pat. No. 4,649,200) disclose substituted pyrroles which exhibit selective antagonism at kappa opioid receptors. One such analog is norbinaltrophimine (norBNI), which has the formula:
The selectivities of these prototypical &dgr; and &kgr; opioid receptor antagonists have been attributed to the presence of nonpeptide “address” mimics which bear a functional relationship to key elements in the putative &dgr; and &kgr; addresses of enkephalin and dynorphin, respectively. See, P. S. Portoghese et al.,
Trends Pharmacol. Sci
., 10, 230 (1989). Accordingly, the design of NTI employed a model that envisaged the Phe
4
phenyl group of enkephalin as a critical part of the &dgr; address. See, P. S. Portoghese et al.,
J. Med. Chem
., 33, 1714 (1990). Similarly, the address element conferring selectivity in norBNI has been suggested to be a basic function that mimics the guanidinium moiety of Arg
7
in dymorphin, by P. S. Portoghese et al.,
J. Med. Chem
., 31, 1344 (1988).
It has recently been reported that suppression of ethanol ingestion may be mediated by the delta opioid receptor type. For example, the &dgr; 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 formula (I):
wherein R
1
is (C
1
-C
5
)alkyl, C
3
-C
6
(cycloalkyl)alkyl, C
5
-C
7
-(cycloalkenyl)alkyl, (C
6
-C
12
)aryl, (C
6
-C
12
)aralkyl, trans-(C
4
-C
5
)alkenyl, allyl or furan-2-ylalkyl, R
2
is H, OH or O
2
C(C
1
-C
5
)alkyl; R
3
is H, (C
6
-C
10
)aralkyl, (C
1
-C
5
)alkyl or (C
1
-C
5
)alkylCO; X is O, S or NY, wherein Y is H or (C
1
-C
5
)-alkyl; R
4
is CH
2
(methylene) or C═O (carbonyl), R
5
is CH
2
, C═O or C═NH (imino) and R
6
is (C
1
-C
4
)alkyl or NH(C
1
-C
4
)alkyl, optionally substituted by a non-terminal (C
1
-C
2
)alkyl group or by N(R
7
)(R
8
) wherein R
7
and R
8
are individually H or (C
1
-C
3
)alkyl, with the proviso that one of R
4
or R
5
is CH
2
, and the pharmaceutically acceptable salts thereof.
Using peptide antagonists of known binding selectivity as standards, it was unexpectedly found that the compounds of the invention are selective antagonists at kappa opioid receptors, while exhibiting little or no binding at delta or mu receptors. Thus, the present invention also provides a method for blocking kappa opioid receptors in mammalian tissue comprising contacting said receptors in vivo or in vitro with an effective amount of the compound of formula I, preferably in combination with a pharmaceutically acceptable vehicle. Thus, the compounds of formula I can be used as pharmacological and biochemical probes of opiate receptor structure and function, e.g., to measure the selectivity of other known or suspected opioid receptor antagonists or agonists. Such tissue includes tissue of the central nervous system (CNS), the gut, the cardiovascular system, the lung, the kidney, reproductive tract tissue and the like. Therefore, the compounds of formula I which exhibit kappa receptor antagonist activity may also be therapeutically useful in conditions where selective blockage of kappa receptors is desired. This includes blockage of the appetite response, blockage of paralysis due to spinal trauma and a variety of other physiological activities that may be mediated through kappa receptors.
The alkyl moiety present in the R
1
group which links the cycloalkyl, cycloalkenyl, aryl, or furan-2-yl moiety to the basic nitrogen atom in the compounds of formula I is a lower(alkyl) group, preferably —(CH
2
)
n
—, wherein n is about 1-5, most preferably n is 1, e.g., R
1
is C
3
-C
6
(cycloalkyl)methyl, C
5
-C
7
(cycloalkenyl)-methyl, arylmethyl or furan-2-yl-methyl. Preferred aryl moieties include (C
6
-C
10
)aryl, i.e., phenyl, benzyl, tolyl, napthyl, xylyl, anisyl and the like.
In structure I, a bond designated by a wedged or darkened line indicates one extending above the plane of the R
3
O-substituted phenyl ring. A bond designated by a broken line indicates one extending below the plane of the phenyl ring.
Preferred compounds of the formula I are those wherein R
1
is (C
1
-C
5
)alkyl, C
3
-C
6
(cycloalkyl)alkyl or C
5
-C
7
-(cycloalkenyl)alkyl, preferably wherein R
1
is C
3
-C
6
(cycloalkyl)methyl, and most preferably wherein R
1
is cyclopropylmethyl. R
2
is preferably OH or OAc (O
2
CCH
3
), and R
3
preferably is H. Preferably, X is NH or NCH
3
, most preferably NH. Preferably, R
6
is methyl, ethyl, propyl, butyl or 2-methylbutyl which is unsubstituted or is terminally substituted with N(CH
3
)
2
or N(CH
2
CH
3
)
2
. Preferably, R
4
is CH
2
and R
5
is C═O or C═NH.

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