Substituted hydroisoquinoline derivatives and their use as pharm

Details Substituted hydroisoquinoline derivatives and their use as pharm Substituted hydroisoquinoline derivatives and their use as pharm

1998-05-29

1999-10-19

Mach, D M

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

546144, 546150, 546151, C07D21700, C07D21710

Patent

active

059689498

DESCRIPTION:

BRIEF SUMMARY
The present invention is concerned with novel substituted hydroisoquinoline derivatives, processes for their preparation and their use in medicine.
The presence of at least three populations of opioid receptors (mu, delta and kappa) is now well established and documented and all three appear to be present in the central and peripheral nervous system of many species including man (Lord J. A. H. et al., Nature 1977, 267, 495).
Activation of all three opioid receptor subtypes can lead to antinociception in animal models. In particular, studies with peptidic delta agonists have indicated that activation of the delta receptor produces antinociception in rodents, primates and can induce clinical analgesia in man (D. E. Moulin et al. Pain, 1985, 23, 213). Evidence exists that suggest a lesser propensity of delta agonists to cause the usual side-effects associated with mu and kappa activation (Galligan et al, J. Pharm. Exp. Ther., 1984, 229, 641).
Hydroisoquinoline derivatives used both as opioid analgesics and as antagonists of pharmacological effects induced by narcotic and psychotomimetic drugs, have already been disclosed (U.S. Pat. No. 273,806, U.S. Pat. No. 4,419,517, Du Pont de Nemours; J. Med. Chem., 1988, 31, 555, Zimmermann, D. M. et al.; J. Med. Chem., 1992, 35, 48, Duncan, B. J. et al.)
A structural characteristic of the compounds disclosed in the documents mentioned above is the presence of a 4a-arylhydroisoquinoline framework optionally substituted with oxygen and/or lower alkyl or lower alkylidene groups. These compounds exert their pharmacological action via a predominant interaction with the mu and kappa opioid receptors.
Hydroisoquinoline derivatives having selectivity for the delta opioid receptor have already been described. All the known derivatives are characterised by an aromatic heterocycle system condensed with the hydroisoquinoline ring. For example, indolo octahydroisoquinoline derivatives are disclosed in EP-A-0,485,636 (Toray Ind.), JP-A-4,368,384 (Toray Ind.), whereas quinolino and quinoxalino octahydroisoquinoline derivatives are disclosed in JP-A-6,275,288 (Toray Ind.). In WO 93/01186 (Dr. Lo Zambeletti), indolo, benzofuro or quinolino octahydroisoquinoline derivatives are disclosed.
We have now discovered a novel class of 4a-arylhydroisoquinoline derivatives substituted with an additional aryl, aralkyl or aralkenyl group which are potent and selective delta opioid agonists and antagonists which may therefore be of potential therapeutic utility as analgesics, immunosuppressants to prevent rejection in organ transplant and skin graft, anti-allergic and anti-inflammatory agents, brain cell protectants, agents for treating drug and alcohol abuse, gastritis, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness, epilepsy and, in general, agents for those pathological conditions which, customarily, can be treated with agonists and antagonists of the delta opioid receptor.
According to the present invention, there is provided a compound, or a solvate or salt thereof of formula (I): ##STR2## in which,
R.sub.1 is hydrogen, linear or branched C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkenyl, C.sub.4-6 cycloalkylalkyl, C.sub.3-5 alkenyl, aryl, aralkyl or furan-2 or 3-yl alkyl or (CH.sub.2).sub.m COR wherein m is 1 to 5 and R represents hydroxy, OC.sub.1-5 alkyl, OC.sub.3-6 alkenyl, aryl or aralkyl or R.sub.1 is a group A-B wherein A represents C.sub.1-10 alkylene and B represents substituted or unsubstituted aryl or heteroaryl;
R.sub.2 is hydrogen, hydroxy or C.sub.1-5 alkoxy, preferably methoxy, halogen, nitro, NR.sub.7 R.sub.8, SR.sub.7, where R.sub.7 and R.sub.8, which may be the same or different, are each hydrogen, linear or branched C.sub.1-6 alkyl, aryl, aralkyl, or COR.sub.1 preferably acetyl;
R.sub.3 and R.sub.4, which can be the same or different, are each hydrogen, hydroxy, C.sub.1-3 alkoxy, preferably methoxy, haloalkyl, preferably trifluoromethyl, halogen, SH, C.sub.1-4 -alkylthio, NHR.sub.7, NR.sub.7 R.sub.8, NHCOR.sub.7, NHSO.sub.2 R.sub.7, wher

REFERENCES:
patent: 4077954 (1978-03-01), Ripka
patent: 4150135 (1979-04-01), Ripka
Judd et al., Journal of Medicinal Chemistry, 35(1), pp. 48-56 (1992).

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