Benzisoxazoles and phenones as &agr;2-antagonists

Details Benzisoxazoles and phenones as &agr;2-antagonists Benzisoxazoles and phenones as &agr;2-antagonists

2001-07-26

2003-06-10

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, C546S085000, C546S089000, C514S292000

Reexamination Certificate

active

06576640

ABSTRACT:

The present invention concerns benzisoxazoles and phenones 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.
WO98/45297, published on Oct. 15, 1998, 1,2,3,4-tetrahydro-benzofuro-[3,2-c]pyridine derivatives having central &agr;
2
-adrenoceptor antagonist activity.
1-(4-fluorophenyl)-4-(1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-1-butanone derivatives are disclosed in Kimura et al. [Arch. Int. Pharmacodyn. Ther. (1971), 190(1), 124-134], Nagai et al. [Chem. Parm. Bull. (1979), 27(8), 1922-1926], Harbert et al. [J. Med. Chem. (1980), 23(6), 635-643 & Mol. Pharmacol. (1980), 17(1), 38-42], Wong et al. [Can. Eur. J. Pharmacol. (1981), 73(2-3), 163-173], Ismaiel et al. [Med. Chem. Res. (1996), 6(3), 197-211], WO 95/07075, WO 94/10989, WO 94/08040, JP 47,029,395, DE 2,514,084, ZA 6,705,178, U.S. Pat. Nos. 3,382,250, 4,001,263, 4,224,329 and 5,508,306
4-(3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl)-1-(4-fluorophenyl)-1-butanone derivatives are disclosed in Aksanova et al. [Khim. Farm. Zh. (1975), 9(1), 7-9] as central nervous system blocking agents.
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. When compared to the closest art compounds, the present compounds unexpectedly show an improvement in dissociation between binding affinity for the &agr;
2A
-adrenoceptor and the dopamine D
2
receptor which is particularly useful when treating depression.
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
5-12
alkanediyl;
n is 1 or 2;
p is 1 and q is 2; or
p is 2 and q is 1;
X is —O—, —S—, —S(═O)—, —S(═O)
2
— or NR
2
;
each R
1
is independently hydrogen, halogen, C
1-6
alkyl, nitro, hydroxy or C
1-4
alkyl-oxy;
R
2
is hydrogen, C
1-6
alkyl, aryl or C
1-6
alkyl substituted with aryl;
aryl is phenyl or phenyl substituted with a halogen or C
1-6
alkyl;
D is a radical of formula
 wherein
m is 1 or 2;
each R
3
independently is hydrogen, C
1-4
alkyl, C
1-4
alkyloxy or halo.
As used in the foregoing definitions the term halogen is generic to fluoro, chloro, bromo and iodo. The term C
1-4
alkyl as a group or part of a group 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-methyl-propyl 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
6-12
alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 5 to 12 carbon atoms such as, for example, 1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyl and the like. The term C
5-12
alkanediyl is meant to include C
6-12
alkanediyl and the lower homologue having 5 carbon atoms such as, for example, 1,5-pentanediyl 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, &rgr;-toluenesulfonic, cyclamic, salicylic, &rgr;-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.
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 or 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 1,5-pentanediyl.
Still another interesting group of compounds are those compounds of formula (I) wherein D is a radical of formula (a) and R
3
is fluoro, bromo, methoxy, methyl or hydrogen, in particular, fluoro.
Compounds of formula (I) wherein D is a radical of formula (b) are also of particular interest.
Particular compounds are those compounds of formula (I) wherein X is O, S or NH.
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 pr

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