Opioid receptor antagonist compounds

Details Opioid receptor antagonist compounds Opioid receptor antagonist compounds

1995-08-22

2000-10-24

Huang, Evelyn Mei

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546 35, 546 37, 546 44, 546 45, A61K 31485, C07D48909, C07D49118

Patent

active

061368172

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention is related to novel .delta. opioid receptor antagonists 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

Opiod antagonists have been indispensable as tools in opioid research. For example, the chief criterion for the classification of an agonist effect as being opioid receptor mediated is the ability of known opioid antagonists naloxone or naltrexone to reversibly antagonize this effect in a competitive fashion. The usefulness of naloxone and naltrexone for this purpose stems from the fact that they are universal opioid antagonists; that is, they are capable of antagonizing the agonist effects mediated by multiple opioid receptor types.
Since it is now firmly established that there are a minimum of three opioid receptor types (.mu., .kappa. and .delta.), it has become increasingly evident that selective opioid antagonists are valuable pharmacological tools for identifying receptor types involved in the interaction with opioid agonists. One of the major advantages of selective opioid antagonists over selective agonists is their utility in probing the interaction of endogenous opioid peptides and new opioid agonists with opioid receptor types. Moreover, since it is sometimes not easy to distinguish among .mu., .kappa. and .delta. opioid receptor mediated agonist effects if the pharmacological endpoints are identical (e.g. antinociception or inhibition of a smooth muscle preparation by agonists), selective antagonists clearly have wider utility as tools than selective agonists.
The general utility of selective antagonists as pharmacological tools depends upon the correlation of in vitro and in vivo acitivity. This can be accomplished more easily with non-peptide ligands because they generally can penetrate the blood-brain barrier and therefore can be administered peripherally in vivo. Also, they are less subject to metabolism than are peptides.
In addition to their uses as pharmacological tools, selective, non-peptide opioid antagonists have been described as having potential clinical applications in the treatment of a variety of disorders where endogenous opioids play a modulatory role. These include for instance disorders of food intake, shock, constipation, mental disorders, CNS injury, alcoholism, and immune function (immune stimulation or suppression) (P. S. Portoghese et al., J. Med. Chem., Vol 34: 1757-1762, 1991).
Non-peptide, competitive, .delta.-selective opioid antagonists have been found recently. The prototypes are: cyprodime for .mu. (H. Schmidhammer et al., J. Med. Chem., Vol. 32:418-421, 1989; H. Schmidhammer et al., J. Med. Chem., Vol. 33: 1200-1206, 1990), norbinaltorphimine for .kappa. (P. S. Portoghese et al., J. Med. Chem., Vol. 30:238-239, 1987), and naltrindole for .delta. opioid receptors (P. S. Portoghese et al., J. Med. Chem., Vol. 31:281-282, 1988).
These compounds (cyprodime, norbinaltorphinine and naltrindole) are being used as pharmacological tools. They have been tritium labelled and can be used as receptor selective ligands in opioid receptor binding studies to sort out the affinities of new ligands to different receptors and to determine whether a compound is selective to a special receptor.
An object of the present invention was to find new, highly selective .delta. opioid receptor antagonists with high potency. Another object was to find highly selective .delta. opioid receptor antagonists with high immunosuppressive potency. The high selectivity for .delta. opioid receptors would repress adverse side effects caused by the interaction with other receptors. Still another object was to find compounds which have a brain-cell protecting effect. The problem with the .delta. opiod receptor antagonists known from the prior art is that they are not highly selective.


PRIOR ART

Certain opioid agonists represented by morphine, which act on .mu. receptors, are known to exhibit immunosuppressive effects. The

REFERENCES:
patent: 4816586 (1989-03-01), Portoghese
patent: 5223507 (1993-06-01), Dappen et al.
patent: 5225417 (1993-07-01), Dappen et al.
Portoghese, et al., "Design of Peptidomimetic .delta. Opioid Receptor Antagonists Using the Message-Address Concept," J. Med. Chem. 33:1714-1720 (1990).
Portoghese, et al., "Opioid Agonist and Antagonist Activities of Morphindoles Related to Naltrindole," J. Med. Chem. 35:4325-4329 (1992).
Dialog abstract of Japanese counterpart of WO94/07896 (listed above as document AL1), Derwent World Patents Index accession no. 94-135494/199416.
Dialog abstract of Japanese patent JP 4-3342529 (listed on p. 1 as document AN1), Derwent World Patents Index accession No. 93-14047/199302).
International Search Report for Swedish appl. 9401728-2 (priority appl. of PCT/SE95/00503).
Hiroshi et al., "Preparation of Naloxyindole Derivatives as .delta.-Opioid Antagonists," Chemical Abstracts 119:1096-1097, abstr. # 95503d (1993).
Portoghese et al., "Bimorphinans as Highly Selective, Potent .kappa. Opioid Receptor Antagonists," J. Med. Chem. 30:238-239 (1987).
Portoghese et al., "Application of the Message-Address Concept in the Design of Highly Potent and Selective Non-Peptide .delta. Opioid Receptor Antagonists," J. Med. Chem. 31:281-282 (1988).
Portoghese, "An Approach to the Design of Receptor-Type-Selective Non-Peptide Antagonists of Peptidergic Receptors: .delta. Opioid Antagonists," J. Med. Chem. 34:1757-1762 (1991).
Schmidhammer et al., "Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 2..sup.1 (-)-N-(Cyclopropylmethyl)-4, 14-dimethoxymorphinan-6-one, a Selective .mu. Opioid Receptor Antagonist," J. Med. Chem. 32:418-421 (1989).
Schmidhammer et al., "Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 3..sup.1 Extensive Study on Cyprodime-Related Compounds," J. Med. Chem. 33:1200-1206 (1990).

Affiliated with

Also associated with

Rating

Opioid receptor antagonist compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Opioid receptor antagonist compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Opioid receptor antagonist compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1964301