Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-12-02
2000-10-03
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
51421108, 51421111, 540553, 540556, A61K 31495, C07D48718
Patent
active
061273627
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP 98/02252 filed Apr. 4, 1998.
The present invention relates to 9,10-diazatricyclo[4.2.1.1.sup.2,5 ]decane and 2,7-diazatricyclo[4,4,0,0.sup.3,8 ]decane derivatives having analgesic activity.
WO 95/23152 and WO 94/16698 disclose 3,8-diazabicyclo[3.2.1]octane derivatives having central analgesic activity, wherein the two nitrogen atoms are respectively substituted with acyl groups and aryl or heteroaryl-acrylic groups. Said compounds proved to be particularly active as central analgesics and are characterized by satisfactory tolerability and poor or no induction of addiction and tolerance.
Now it has been found that analogues of two novel tricyclic systems, characterized by two endoethylenic bridges on the piperazine ring, have an even higher analgesic activity.
The compounds of the invention have the following general formulae: ##STR2## in which R.sub.1 and R.sub.2 are both hydrogen or are different from each other, and are selected from hydrogen; C.sub.1 -C.sub.8 alkyl; C.sub.2 -C.sub.10 acyl; an Ar group wherein Ar is optionally substituted phenyl, optionally substituted naphthyl, an heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur having 5 to 7 ring atoms, optionally benzofused and optionally substituted at the benzene ring; a group of formula --CH.sub.2 --CH.dbd.CH--Ar wherein Ar is as defined above.
Examples of Ar groups can be represented by the following formulae ##STR3## wherein X, Y and Z, which are the same or different, are selected from N, NH, S, O, .dbd.(CH).sub.n or --(CH.sub.2).sub.n -- wherein n=0-2 and R is hydrogen or a substituent selected from halogen atoms, nitro, amino, methoxy, ethoxy, C.sub.1 -C.sub.6 alkylamino or C.sub.1 -C.sub.8 acylamino groups.
Preferably, R.sub.1 is a C.sub.2 -C.sub.10 acyl group and R.sub.2 is an Ar group or --CH.sub.2 --CH.dbd.CH--Ar as defined above.
A C.sub.2 -C.sub.10 acyl group is preferably acetyl, propionyl or butyryl, more preferably propionyl.
R.sub.2 is preferably a group of formula --CH.sub.2 --CH.dbd.CH--Ar
The compounds of formulae I and Ib can be prepared according to the following schemes: ##STR4##
In the schemes reported above, X is a reactive group suitable for the desired N-alkylation or N-acylation reaction, for example a halogen atom, a mesyl, tosyl, acyl chloride, anhydride group and the like.
The process according to the invention comprises the reaction of 5,6-epoxycyclooctene III, easily obtainable from commercially available 1,5-cyclooctadiene II, with benzylamine in dichloromethane, in the presence of ytterbium (III) trifluoromethanesulfonate, to give aminoalcohol IV.
The alcohol group is then transformed into the corresponding sulphate ester which is refluxed in concentrated sodium hydroxide to yield aziridine V. The latter is treated with sodium azide and ammonium chloride with heating in ethanol and water to yield amino-azide VI, which is transformed into the compounds VIIa and VIIb by addition of bromine. The dibromo derivatives cannot be isolated as an intramolecular condensation occurs.
The compounds VIIa and VIIb are separated by chromatography according to conventional techniques.
The compounds VIIa and VIIb can then be converted into compounds of formula VIIIa or VIIIb, respectively, by treatment with triphenylphosphine in tetrahydrofuran and subsequent addition of water.
Conventional N-alkylation or N-acylation reactions, in suitable sequence, allow then to prepare the desired compounds.
The compounds of formula Ia and Ib have affinity to opioid receptors, evaluated according to the method described by Wood et al., Neuropharmacology, 1981, 20, 1219, which is up to 5-fold higher than that of the compounds described in WO 95/23152 and WO 94/16698.
The compounds of the invention, optionally in the form of pharmaceutically acceptable salts, can conventionally be formulated in pharmaceutical compositions suitable for the oral, parenteral or rectal administration. The daily dosage will, of course, depend on a number of factors, but it will generally range
REFERENCES:
Mascal et al. Tetrahedron Letters, 37(1) 131-4, only Abs is provided, 1996.
Cignarella Giorgio
Vianello Paola
Neuroscienze S.C.A.R.L.
Shah Mukund J.
Sripada Pavanaram K
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