Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-08-04
1999-04-06
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546133, 514305, 514317, C07D21114, C07D21146, C07D40112, A61K 31445
Patent
active
058920471
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
The present invention relates to a novel process for the preparation of substituted 4-ethyl-piperidines and intermediates for the preparation of same. The substituted 4-ethyl-piperidines prepared according to the invention are useful in therapy as calcium channel blocking agents.
BACKGROUND OF INVENTION AND PRIOR ART
The substituted 4-ethyl-piperidines prepared according to the invention and their activity as calcium channel blocking agents are disclosed in WO-A1-92/02502, WO-A1-93/15052, and Neuropharmacology, Vol. 32, No. 11, p. 1249-1257 (1993). These publications describes several methods for the preparation of the compounds, using piperidines or pyridines as starting materials. It has now been found that substituted 4-ethyl-piperidines can be prepared by a very convenient, high yielding, one pot, two step synthesis, from readily available starting materials.
OBJECTS OF THE INVENTION
It is the object of the present invention to provide a novel method for the preparation of substituted 4-ethyl-piperidines, which is convenient and high yielding, using readily available starting materials. Furthermore, it is an object of the present invention to provide novel intermediates useful for the preparation of substituted 4-ethyl-piperidines.
SUMMARY OF THE INVENTION
In detail the invention, then, comprises inter alia the following:
A process for the preparation of substituted 4-ethyl-piperidines having the formula ##STR2## or a salt thereof wherein wherein the aryl groups may be substituted; cycloalkyl; or cycloalkylalkyl; comprises the step of reacting a quinuclidinium salt of formula ##STR3## wherein R is as defined above and Y is a counter ion, with a compound of the formula HA-(CH.sub.2).sub.m -Ar or a reactive derivative thereof, and thereafter optionally forming a salt thereof; base; ##STR4## wherein R and Y is as defined a bove; provided that when R is alkyl, the alkyl group contains at least three carbon atoms, and Y is not bromide; and ##STR5## wherein R and Y are as defined above, as an intermediate in the preparation of substituted 4-ethyl-piperidines.
To the above formulas the following applies:
Alkyl means a straight or branched chain of from one to eight carbon atoms, including but not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, and heptyl.
Alkenyl and alkynyl means straight or branched chains of from two to eight carbon atoms, with respectively, at least one double dr triple bond, and including but not limited to ethenyl, 1,2- or 2,3 propenyl, 1,2- or 3,4-butenyl, ethynyl, 2,3-propynyl, 2,3- or 3,4-butynyl.
Cycloalkyl means cyclic alkyl of from three to eight carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkylalkyl is cycloalkyl and alkyl as above.
It is to be understood that the (aryl).sub.p akyl, (aryl).sub.p alkenyl and (aryl).sub.p alkynyl and cycloalkylalkyl groups R, are linked to the piperidine nitrogen atom via the alkyl, alkenyl and alkynyl moieties respectively.
Suitable aryl groups include, for example, unsaturated, partially saturated or saturated monocyclic, bicyclic or tricyclic ring systems of up to fifteen carbon atoms, such as, for example, phenyl, naphthyl, tetrahydronaphthyl, fluorene, flurenone, dibenzosuberene, and dibenzosuberenone.
Suitable heteroaryl groups include, for example, unsaturated, partially saturated, or saturated monocyclic, bicyclic or tricyclic ring systems of up to fifteen carbon atoms containing at least one heteroatom, such as pyridyl, thienyl, imidazolyl, quinolinyl, tetrahydroquinolinyl, benzofuranyl. A tricyclyclic ring system most preferably has the structure: ##STR6## wherein Y.sup.1 represents -X(CH.sub.2).sub.r -, X is O, S, or NR (where R is hydrogen or C.sub.1-4 alkyl), Z is --(CH.sub.2).sub.q - or --CH.dbd.CH--, q is 0, 1 or 2 and r is 0 or 1 or is a corresponding dehydro ring system. Examples of tricyclic heteroaryl groups include dibenzofuranyl, dibenzothienyl, carbazole, N-methylcarbazole, acridine and
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Axelsson Oskar
Peters Dan
NeuroSearch A/S
Rotman Alan L.
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