Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-01-29
1993-09-14
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514885, 546 70, C07D47102, A61K 31475
Patent
active
052449041
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION
This invention relates to a compound having an affinity for the delta-opioid receptor. The delta-opioid receptor is concerned in the analgesic, immune, and circulatory (particularly blood pressure) systems. Ligands having high selectively for the receptor are usable as medicines like analgesics, immunosuppressants, immunopotentiating agents, and antihypertensive agents.
BACKGROUND OF THE INVENTION
The delta opioid receptor is possessed of many pharmacological actions as described above. Compounds having high selectively for this receptor promise adoption as analgesics, immunosuppressants, immunopotentiating agents, and antihypertensive agents. Except for peptide type compounds, no ligand of high selectivity for the delta receptor has been discovered until recent years. The peptide type compounds have not easily permitted their own development as the medicines mentioned above because they have the fault that they encounter difficulty in passing the blood-brain barrier with yield easily to in vivo decomposition with peptidase. Thus, agonists and antagonists possessed of high selectivity for the delta receptor are in demand. Recently, Portoghese et al have discovered an antagonist, NTI, possessed of high selectivity for the delta-opioid receptor (P. S. Portoghese et al., J. Med. Chem., Vol. 31, No. 2, 1988). This NTI is an alkaloid and, unlike peptides, is free from the problem of passage through the blood-brain barrier and the problem of decomposition with a peptidase. The NTI, however, is problematic in respect that the cost of its production is high because it is synthesized from naltrexone as a raw material and the naltrexone is difficult to procure because it is synthesized from thebaine which is a narcotic. As regards delta receptor agonists, peptides such as DADLE and DPDPE have been known in the art. Alkaloids of high selectivity remain to be developed.
An object of this invention is to provide a ligand (agonist and antagonist) which has a high affinity and selectivity for the delta receptor promising to manifest the aforementioned pharmacological actions, attains synthesis of its own through a route not using a narcotic as a raw material, passes through the blood-brain barrier, enjoys high stability in resisting a peptidase, and is not excessively expensive.
DISCLOSURE OF THE INVENTION
To accomplish the object described above, this invention is constructed as follows.
To be specific, this invention is directed to an indole derivative represented by the general formula (1): ##STR2## wherein R.sub.1 stands for alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aralkyl having 7 to 14 carbon atoms, trans-alkenyl having 4 or 5 carbon atoms, allyl, furanyl-2-ylalkyl having 1 to 5 carbon atoms, thienyl-2ylalkyl having 1 to 5 carbon atoms, vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, alkanoyl having 1 to 5 carbon atoms, aralkylcarbonyl having 7 to 14 carbon atoms, 2-furoyl, thiophene-2-carbonyl, cycloalkylcarbonyl having 4 to 7 carbon atoms, alkenylcarbonyl having 3 to 8 carbon atoms, or anisoyl, R.sub.2 stands for a hydrogen atoms, alkyl having 1 to 3 carbon atoms, benzyl, or alkanoyl having 1 to 5 carbon atoms, R.sub.3 stands for a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, nitro, or alkyl having 1 to 5 carbon atoms, R.sub.4 stands for a hydrogen atom, alkyl having 1 to 5 carbon atoms, benzyl, or phenyl, and R.sub.5 stands for a hydrogen atom, hydroxy, or alkanoyloxy having 1 to 5 carbon atoms, or a pharmacologically acceptable salt thereof.
As pharmacologically desirable salts, inorganic salts such as hydrochloride, sulfate, hydrobromide, and phosphate, and organic salts such as acetate, lactate, methanesulfonate, p-toluenesulfonate, phthalate, fumarate, maleate, glutarate, and tartrate may be mentioned for example. Of course, these salts are not exclusive examples.
In the general formula (1), R.sub.1 stands for methyl, ethyl, propyl, butyl, pentyl, cyclop
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Endo Takashi
Kawai Koji
Matsumoto Shu
Mizusuna Akira
Nagase Hiroshi
Cintins Marianne M.
Miller Austin R.
Scalzo Catherine
Toray Industries Inc.
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