Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-04-24
1999-11-09
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142328, 514281, 544125, 546 39, 546 40, 546 43, 546 44, A61K 3144, A61K 31535, C07D47122, C07D49122
Patent
active
059815400
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with novel morphinoid compounds, 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).
U.S. Pat. No. 5,223,507 and U.S. Pat. No. 5,225,417 (G. D. Searle & Co.) disclose bicycle-condensed morphinoid compounds which are said to be delta opioid agonists having therapeutic utility as analgesics agents.
WO 94/07896 (Toray Ind. Inc.) discloses indole-condensed morphinoid compounds useful as immunosuppressants, anti-allergic and anti-inflammatory agents.
We have now discovered a novel class of substituted monoheterocycle-condensed morphinoid derivatives 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 protectant, agents for treating drug and alcohol abuse, gastritis, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy and, in general, for the treatment of 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.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, C.sub.1-5 alkoxy, OC.sub.3-6 alkenyl or alkylaryl 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: halogen, nitro, NR.sub.8 R.sub.9, SR.sub.8, where R.sub.8 and R.sub.9, which may be the same or different are each hydrogen, C.sub.1-6 alkyl, COR.sub.1 preferably acetyl. halogen, SR.sub.8, preferably hydrogen, nitro, NHR.sub.10, NR.sub.10 R.sub.11, NHCOR.sub.10, NHSO.sub.2 R.sub.10, where R.sub.10 and R.sub.11, which may be the same or different, are each hydrogen or C.sub.1-6 alkyl, preferably methyl; independently hydrogen, hydroxy, C.sub.1-5 alkoxy, preferably methoxy, or together may form an oxy group (--O--). R.sub.6 is a group ##STR3## in which R.sub.3 has the same meaning described above, there being up to three R.sub.3 in the phenyl ring, or R.sub.6 is a group C(Z)R.sub.12, in which Z is oxygen or sulphur. R.sub.12 is C.sub.1-18 alkyl, C.sub.1-18 alkoxy or NR.sub.13 R.sub.14, where R.sub.13 and R.sub.14, which may be the same or different, are hydrogen, linear or branched C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.4-6 cycloalkylalkyl, C.sub.3-6 alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring or may form together a C.sub.3-6 alkyl ring which may be interrupted by an oxygen or a nitrogen. ##STR4## in which R.sub.3 has the same meaning described above; n is 0 or 1; R.sub.6 - or R.sub.7 -substituted carbon atom; and when n=1, then X and Y are both N, or N and CH.
When R.sub.1 is aryl, it is preferably phenyl and when it is aralkyl, it is preferably phenyl-C.sub.1-6 alkyl.
Examples of R.sub.1 are methyl, ethyl, propyl, allyl and cyclopropylmethyl.
Examples of R.sub.2 are hydrogen and hydroxy.
Ex
REFERENCES:
patent: 5223507 (1993-06-01), Dappen et al.
patent: 5225417 (1993-07-01), Dappen et al.
Portoghese et al. (I) Jour. Med. Chem vol. 31 pp. 281-282, 1988.
Portoghese et al (II) Jour. Med. Chem. vol. 31 pp. 1344-1347, 1988.
Dondid et al Chem Abstr vol. 127 Entry 162011 abstracting WO 97 25331, 1997.
Goerlitzer et al., Archiv Der Pharmazie, vol. 325, No. 10, pp. 629-636 (1992).
Dondio Giulio
Ronzoni Silvano
Coleman Brenda
King William T.
Kinzig Charles M.
Raymond Richard L.
Simon Soma G.
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