Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-03-14
1998-04-07
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546198, A61K 31445, C07D40114
Patent
active
057365580
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/EP96/01551 filed on Apr. 11, 1996.
The present invention relates to new 4-(6-fluoro-1,2-benzisoxazolyl)-1-piperidinyl-propoxy-chromen-4-one derivatives having the formula (I): ##STR2## wherein R is hydrogen or alkyl having 1 to 4 carbon atoms optionally substituted by hydroxyl, as well as its pharmaceutically acceptable addition salts.
The compounds of the present invention, namely, piperidin-1-yl!propoxy!-3-methyl-chromen-4-one and ymethyl)-chromen-4-one, are obtained by reacting 7-(3-halopropoxy)-4H-1-benzopyran-4-ones of general formula (II), wherein R is as defined for (I) and X is chlorine or bromine, with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (III), according to Scheme 1, in the presence of a base selected between an alkali or earth-alkali metal carbonate or acid carbonate and a catalytic quantity of potassium iodide. The reaction occurs conveniently under heating and in a nonpolar medium, such as that composed of a solvent selected from N,N-dimethyl-formamide, acetonitrile or the like. From compounds (I), their pharmaceutically acceptable addition salts may be obtained by adding the proper acids according to conventional methods of Organic Chemistry. ##STR3## The starting compounds of the general formula (II) may be obtained by known procedures of Organic Chemistry as described in "J.Med.Chem.", 34, 248-256, 1991 and in previous patents of addition, ES 9401437 and ES 9500163.
Spanish Patent No. 9400581 describes the obtention of and its use as a neuroleptic.
The compounds of formula (I) are different from the compound in Spanish Patent No. 9400581 and are not obvious from the disclosure of such a patent. The compounds of the present invention also show an interesting profile as neuroleptics; the applicants have found out that their therapeutic index is surprisingly higher than that of its preceding one. This provides a larger safety for their therapeutic use and, in addition, a higher affinity to 5HT.sub.1a -receptors, which also makes them to be potentially useful in the treatment of anxiety.
Biochemical assays have revealed that the compounds of formula (I) exhibit an enhanced action on the receptors involved in neuroleptic (D.sub.2 and 5HT.sub.2) and anxiolytic (5HT.sub.1a) actions (B. A. McMillen et al., "Drug Dev. Res.", 1988, 12, 53-62).
Specific binding to D.sub.2, 5HT.sub.2 and, 5HT.sub.1a receptors was tested as follows: H!spiperone), which acts as a specific ligand, was incubated with the membrane corresponding to 20 mg of rat striatum for 20 min at 35.degree. C. buffered at pH 7.4 with Tris.HCl. The non-specific binding was then determined by addition of a micromolar concentration of unlabelled spiperone. IC.sub.50 (inhibitory concentration 50%) was calculated from the inhibition rate of the specific binding obtained by addition of eleven different concentrations of the compounds to be tested. After the incubation was completed, the sample was filtered through a glass fiber filter and then washed three times with Tris.HCl buffer. The amount of receptor-bound radioactivity was retained on the membrane and determined by liquid scintillation counting. H!ketanserin, which acts as a specific ligand, was incubated with the membrane corresponding to 1 mg of rat cortex for 30 min at 35.degree. C. buffered at pH 7.4 with Tris.HCl. Non-specific binding was then determined by addition of 5 micromolar concentration of unlabelled mianserin. IC.sub.50 (inhibitory concentration 50%) was calculated from the inhibition rate of the specific binding obtained by addition of eleven different concentrations of the compounds to be tested. After the incubation was completed, the sample was filtered through a glass fiber filter and then washed three times with Tris.HCl buffer. The amount of receptor-bound radioactivity was retained on the membrane and determined by liquid scintillation counting. H!5-OH-DPAT), which acts as a specific ligand, was incubated with the membrane corresponding to 1 mg of rat cortex for 20 min at 35.degree. C. buffered at pH 7.4 with T
REFERENCES:
patent: 4678787 (1987-07-01), Jaen
patent: 5100902 (1992-03-01), Peglion
McMillen et al., Drug Dev. Res. 12, 53-62 (1988).
Jaen et al., J. Med. Chem. 34, 248-256 (1991).
Anglada Lluis
Bolos Jordi
Castello Josep M.
Foguet Rafael
Ortiz José A.
Ferrer Internacional S.A.
Huang Evelyn
Ivy C. Warren
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