Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1995-05-15
2001-08-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06271239
ABSTRACT:
BACKGROUND OF THE INVENTION
The use of aldehyde dehydrogenase (ALDH) inhibitors is one pharmacotherapeutic approach which has been employed for the treatment of alcohol (ethanol) abuse and alcoholism. Examples of these types of compounds presently used clinically are disulfiram (tetraethylthiuram disulfide) (Antabuse®), and carbimide (citrated calcium carbimide, cyanamide (Temposil®)). Disulfiram is used through-out the world, whereas calcium carbimide has not been approved by the FDA for use in the United States.
The rationale for the use of ALDH inhibitors such as disulfiram for the treatment of alcoholism is that they block the metabolism of ethanol. Thus, after ethanol ingestion, inhibitors of liver mitochondrial low Km ALDH cause an increase in the formation of acetaldehyde. Clinically, this leads to tachycardia, hypotension, nausea, and other adverse symptoms that are referred to as the disulfiram-ethanol reaction (DER). Although disulfiram is widely used in the treatment of alcoholism, its use is not without controversy. A number of reports have questioned disulfiram's toxicity and its ability to produce a DER that is effective to deter ethanol ingestion.
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 application 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:
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 established &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.
Therefore, a continuing need exists for compounds which are &dgr; opioid receptor-selective. Delta opioid receptor antagonists are needed to develop pharmacological approaches to the treatment of alcohol dependence. More specifically, a need exists for an effective method to deter ethanol ingestion by humans using specific and potent &dgr; opioid receptor antagonists, which have a duration of action and ability to access the central nervous system which are superior to the peptide-based &dgr; receptor antagonists.
SUMMARY OF THE INVENTION
The present invention is directed to biologically active compounds of the formula I:
wherein R
1
is (C
1
-C
5
)alkyl, C
3
-C
6
(cycloalkyl)alkyl, C
5
-C
7
-(cycloalkenyl)alkyl, aryl, 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
1
-C
5
)alkyl or (C
1
-C
5
)alkylCO; and R
4
and R
5
are individually H, F, Cl, Br, NO
2
, NH
2
, (C
1
-C
5
)alkyl, (C
1
-C
5
)-alkoxy or together are dioxymethylene (—OCH
2
O—) or benzo; and the pharmaceutically acceptable salts thereof.
The present invention also provides a method for blocking delta-opioid receptors in mammalian tissue comprising contacting said receptors in vivo or in vitro with an effective amount of the compound of formula I. Using peptide antagonists of known binding selectivity as standards, it was unexpectedly found that the compounds of the invention are selective for the &egr;
1
subset of delta receptors. 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 opioid receptor antagonists or agonists.
The present invention also can provide a method for suppressing ethanol ingestion by a human comprising administering to said human a pharmaceutical unit dosage form comprising an amount of a compound of the formula I. It is believed that compounds of formula I can decrease ethanol consumption by mammals without decreasing the intake of food or water for prolonged periods of time. Therefore, it is believed that the compounds of formula I will be clinically useful in the treatment of alcoholism, e.g., that they will be effective to decrease remission rates in recovering alcoholics. Also, the compounds of formula I may be co-administered with morphine to block its addictive effects without blocking its analgesic effects.
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, aryl-methyl 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 formula I, the position of the —R
4
and —R
5
groups indicate that they can be either ortho, meta, or para to the ═CH— group, e.g., R
4
and/or R
5
can occupy any available site on the phenyl ring. 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 delta-opioid antagonists include compounds of the formula I, 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, at least one, and most preferably, both of R
4
and R
5
are H. Preferred compounds also result when R
4
is H and R
5
is F, (C
1
-C
5
)alkyl or (C
1
-C
5
)alkoxy. The methylene-dioxy group is preferably a 3,4-methylene-dioxy group.
Since the compounds of the invention are fo
Raymond Richard L.
Regents of the University of Minnesota
Schwegman Lundberg Woessner & Kluth P.A.
LandOfFree
Delta opioid receptor-selective benzylidene-substituted... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Delta opioid receptor-selective benzylidene-substituted..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Delta opioid receptor-selective benzylidene-substituted... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2550914