Tricylic delta 3-piperidines as pharmaceuticals

Details Tricylic delta 3-piperidines as pharmaceuticals Tricylic delta 3-piperidines as pharmaceuticals

2001-03-30

2002-03-05

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S080000, C546S089000, C544S333000, C514S269000

Reexamination Certificate

active

06352999

ABSTRACT:

The present invention concerns tricyclic &Dgr;3-piperidines having central &agr;
2
-adrenoceptor antagonist activity. It further relates to their preparation, compositions comprising them and their use as a medicine.
Central &agr;
2
-adrenoceptor antagonists are known to increase noradrenaline release by blocking presynaptic &agr;
2
-receptors which exert an inhibiting control over the release of the neurotransmitter. By increasing the noradrenaline concentrations, &agr;
2
-antagonists can be used clinically for the treatment or prophylaxis of depression, cognitive disturbances, Parkinson's disease, diabetes mellitus, sexual dysfunction and impotence, elevated intraocular pressure, and diseases related to disturbed enterokinesia, since all these conditions are associated with a deficiency of noradrenaline in the central or peripheral nervous system.
The compounds of the present invention are novel and have a specific and selective binding affinity for the different known subtypes of the &agr;
2
-adrenoceptors, i.e. the &agr;
2A
, &agr;
2B
and &agr;
2C
-adrenoceptor.
The present invention concerns the compounds of formula
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
Alk is C
1-6
alkanediyl;
n is 1 or 2;
X is —O—, —S—, —S(═O)— or —S(═O)
2
—;
each R
1
is independently hydrogen, halogen, C
1-6
alkyl, nitro, hydroxy or C
1-4
alkyloxy;
D is a radical of formula
wherein
each m independently is 0, 1 or 2;
each Y independently represents —CH
2
—, —O—, —S— or —NR
3
—;
R
2
and R
3
each independently are hydrogen or C
1-6
alkyl; and
each R
4
independently represents halo or C
1-6
alkyl.
As used in the foregoing definitions the term halogen is generic to fluoro, chloro, bromo and iodo. The term C
1-4
alkyl defines straight and branched saturated hydro-carbons, having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl and the like. The term C
1-6
alkyl is meant to include C
1-4
alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, hexyl and the like. The term C
1-5
alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 1 to 5 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl and the like. C
1-6
alkanediyl is meant to include C
1-5
alkanediyl and the higher homologue thereof having 6 carbon atoms such as, for example, 1,6-hexanediyl and the like.
The addition salts as mentioned herein are meant to comprise the therapeutically active addition salt forms which the compounds of formula (I) are able to form with appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The pharmaceutically acceptable addition salts as mentioned hereinabove are also meant to comprise the therapeutically active non-toxic base, in particular, a metal or amine addition salt forms which the compounds of formula (I) are able to form. Said salts can conveniently be obtained by treating the compounds of formula (I) containing acidic hydrogen atoms with appropriate organic and inorganic bases such as, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) are able to form and said solvates are meant to be included within the scope of the present invention. Examples of such solvates are, e.g. the hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
The term stereochemically isomeric forms as used herein defines all the possible isomeric forms in which the compounds of formula (I) may occur. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term compounds of formula (I) is meant to include also the N-oxide forms, the pharmaceutically acceptable addition salts and all stereoisomeric forms.
Suitably, D is a radical of formula (a), (b), (c), (d), (e), (f) or (g) wherein
m is 0; each Y independently represents —CH
2
—, —O—, —S— or —NR
3
—; and R
2
and R
3
each independently are hydrogen or C
1-6
alkyl.
As used hereinafter, when the position of the R
1
substituent is referred to, the following numbering is used:
An interesting group of compounds are those compounds of formula (I) wherein n is 1 and R
1
is hydrogen, chloro, fluoro, methyl, methoxy or nitro, in particular R
1
is hydrogen, chloro, methyl or methoxy. Also interesting are those compounds of formula (I) wherein n is 2 and both R
1
are methoxy.
In case R
1
is other than hydrogen, then R
1
is suitably connected to the tricyclic ring system in the 6 or 7 position.
Another interesting group of compounds are those compounds of formula (I) wherein Alk is methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl or 1,5-pentanediyl, in particular methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, more in particular 1,2-ethanediyl.
Still another interesting group of compounds are those compounds of formula (I) wherein D is a radical of formula (a), (b), (c), (e), (f), (g), (h), (i) or (j), more in particular, (a), (c), (j), (h), (i) or (j).
Compounds of formula (I) wherein D is other than (a) and other than (b) are also of particular interest.
Particular compounds are those compounds of formula (I) wherein X is —O— or —S—, more in particular, —O—.
Other particular compounds are those compounds of formula (I) wherein Y is —O— or —S—.
Preferred compounds are those compounds of formula (I) wherein n is 1, R
1
is hydrogen, chloro, methyl or methoxy, and X is —O— or —S—.
Most preferred compounds are those compounds depicted below or their N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof:
The compounds of formula (I) can generally be prepared by N-alkylating an intermediate of formula (II) with an alkylating reagent of formula (III) following the procedure described in EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255. In particular, the N-alkylation may be performed in a reaction-inert solvent such as, for example, methyl isobutyl keton, N,N-dimethylformamide or N,N-dimethylacetamide, in the presence of a base such as, for example, triethylamine, sodium carbonate or sodiumbicarbonate, and optionally in the presence of a catalyst such as, for example, potassium iodide.
Under similar reaction conditions, compounds of formula (I) wherein D is a radical of formula (h), said compounds being represented by formula (I-h), may be prepared by reacting an intermediate of formula (VII) with an intermediate of formula (VIII).
In intermediate (III) and intermediate (VIII), W
1
represents an appropriate

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