Diaryldiamine derivatives and their use as delta opiod (ANT)-ago

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

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514423, 514427, 514619, 514620, 514648, 548566, 564167, 564370, 564433, 560 43, C07D20700, C07D20708, C07C21100, C07C 4590

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059228873

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BRIEF SUMMARY
This application is a .sctn.371 of PCT/EP96/02152 filed May 20, 1996.
This invention is concerned with novel diaryldiamine 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). Evidences exist 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).
Substituted diaryldiamines as intermediates for the synthesis of dibenzodiazepines, useful as antihistaminic and antianaphylaptic agents, Hunziker et al., Helv. Chim. Acta, 46,2337, (1963)!. diaryldiamines which are said to be inhibitors of TPA-induced mouse ear edema WO 93/15062 (The Wellcome Foundation Limited) discloses diphenylpiperazine derivatives which are said to be agonists at all three opiate receptors.
We have now discovered a novel class of diaryldiamine 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, epilepsy and, more 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): ##STR3## in which, R.sub.1 and R.sub.2, which can be the same or different, are each 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.3-6 alkenyl, C.sub.3-5 alkenyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C.sub.3-7 alkyl ring which may be interrupted by an oxygen. linear or branched C.sub.1-6 alkyl preferably methyl, or R.sub.4 is oxygen forming with the carbon atom to which is attached a C.dbd.O group; mercapto, alkylthio, preferably methylthio; or a para or meta --C(Z)-R.sub.8 group, in which Z is oxygen or sulphur, wherein R.sub.9 and R.sub.10, which may be the same or different, are hydrogen, straight 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 together form a C.sub.4 alkyl ring, ##STR4## group in which R.sub.11 and R.sub.12 which may be the same or different are hydrogen, straight 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 and Z is as defined above; and, preferably chlorine.
Examples of R.sub.1 and R.sub.2 are methyl, ethyl, cyclopropylmethyl, allyl or together with the N, pyrrolidino. R.sub.4 is .dbd.O. CON(Me)Et, CON(Me)i--Pr, CONEt.sub.2, CON(i--Pr).sub.2, CONEt(i--Pr), CON(--CH.sub.2 --).sub.4, NHCOi--Pr, NH.sub.2, bromine, phenyl.
A first group of preferred compound of formula (I) are those in which each of R3 and R4 is hydrogen or C1-6 alkyl, preferably methyl or ethyl, and R.sub.1, R.sub.2, R.sub.5, R.sub.6 and R.sub.7 are as defined above.
A second preferred group of compounds of formula (I) are those in which R.sub.5 is an hydroxy or C1-3 alkoxy group, R.sub.1, R.sub.2, R.sub.6 and R.sub.7 are as defined above for formula (I) and each of R.sub.3 and R.sub.4 is hydrogen or C1-6 al

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King, et al., "New Potential Chemotherapeutic Agents Part III", (1946), Journal of the Chemical Society, pp. 5-10 (1946).

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