Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-21
2001-02-13
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S198000
Reexamination Certificate
active
06187793
ABSTRACT:
The present invention relates to 7-[3-[4-(6-fluorobenzo [d]isoxazol-3-yl)piperidin-1-yl]propoxy]-chromen-4-one derivatives having the general formula (I):
wherein R is hydrogen, CHO, CH
2
OR
2
or COOH; R
1
is hydrogen or CH
2
OH; and R
2
is alkyl having 1 to 4 carbon atoms with the proviso that one of substituents R and R
1
should be hydrogen, as well as their pharmaceutically acceptable addition salts.
The compoounds of the present invention are new and are obtained by reacting 2 (or 3)-substituted 7-(3-halopropoxy)-4H-1-benzopyran-4-one of general formula (II), wherein R and R
1
is as defined for (I) and X is a halogen selected preferably between chlorine or bromine, with 6-fluoro-3-(4-piperidinyl)-benzo[d]isoxazole (III), according to Scheme 1, in the presence of a base selected between an alkali or earth-alkali metal carbonate or bicarbonate 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.
Alternatively, the compounds (I, R:CHO, R
1
:H) and (I, R:CH
2
OR
2
, R
1
:H) can also be obtained from 7-[3-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidin-1-yl]propoxy]-3-(hydroxymethyl)-chromen-4-one (Spanish Patent Application No. 9600323) by oxidation or by alkylation, respectively. The oxidation is conducted conveniently with oxalyl chloride and dimethyl sulfoxide in a halogenated solvent, preferably dichloromethane. The alkylation is conducted conveniently with the corresponding alcohol R
2
—OH (IV), wherein R
2
is as defined for (I), in an acid medium and at the boiling temperature of the mixture. From the new compounds of general formula (I), their salts may be obtained by adding respective acids according to conventional methods of Organic Chemistry.
Spanish Patent Applications No. 9500737 and 9600323 describe chromene derivatives with neuroleptic and anxiolytic action.
The properties of the compounds of the present invention are different from those of the compounds disclosed in the aforesaid patents. In fact, the applicants have found out that the compounds of the general formula (I) exhibit, in addition to a potent action on D
2
and 5-HT2A receptors which is of their own as antipsychotic agents, an important action on histamine H
1
receptors. In contrast, a H
1
-antihistamic action has not been previously reported for any of the compounds of the preceding patents.
Specific binding to D
2
, 5-HT
2A
and H
1
receptors was tested as follows:
D
2
receptors: A 2-nM solution of radioactive spiperone ([
3
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° 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
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.
5HT
2A
receptors: A 0.5 nM solution of radioactive ketanserin ([
3
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° 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
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
1
receptors: Testing for activity was performed by incubation of guinea-pig cerebellum membranes, in the presence or absence of test compounds, in a 1 nM solution of [
3
H]-pyrilamine as a specific marker at 25° C. for 60 minutes. The bound radioactivity was separated by filtration (Whatman GF/B) in a Brandel Harvester. The amount of receptor-bound radioactivity present in the filters was determined using a Packard 1800TR counter. The specific binding was established with a 1 &mgr;M concentration of triprolidine.
The biochemical results expressed as IC
50
in molar concentrations are presented comparatively to the compound of Example 2′ in Spanish Patent Application No. 9600323 and to standard haloperidol in Table 1 for D
2
and
5
-HT2A receptors, and comparatively to the compound of Example 2′ in Spanish Patent Application No. 9600323 and to standard promethazine in Table 2 for H
1
receptors.
TABLE 1
Compound
D
2
5-HT
2A
Example 1
1.31 × 10
−8
2.11 × 10
−9
Example 2
1.28 × 10
−8
5.94 × 10
−10
Ex. 2′ (ES 9600323)
1.72 × 10
−8
3.08 × 10
−9
Haloperidol
1.37 × 10
−8
1.04 × 10
−7
From the data of Table 1 it can be concluded that the compounds of Examples 1 and 2 of the present invention are more potent as ligands of D
2
and 5-HT
2
A receptors than the compound of Example 2′ of Spanish Patent Application No. 9600323. The ratio D
2
/5-HT
2
A shows that all the compounds are superior to standard haloperidol, which results in a lower risk of extrapyramidal effects.
TABLE 2
Compound
H
1
Example 3
3.39 × 10
−10
Example 6
1.01 × 10
−9
Ex. 2′ (ES 9600323)
1.20 × 10
−9
Promethazine
8.93 × 10
−10
Similarly, from the data of Table 2 it can be concluded that the compounds of Examples 3 and 6 of the present invention are more potent as ligands of H
1
receptors than the compounds of Example 2′ in the Spanish Patent Application No. 9600323 and of the same order as promethazine. In addition, the potency of the compound of Example 3 is greater than that of standard promethazine.
The compounds of the present invention were compared with the compound of Example 2′ of Spanish Patent Application No. 9600323 in Animal Pharmacology by the inhibition test of apomorphine-induced climbing behaviour (P.Protais et al: “Psychopharmacology”, 50, 1-6, 1976). For the practical performance of this experiment, male Swiss mice weighing 22-24 g were used. One week prior to experiment, animals were kept in our facilities at a temperature of 20-22° C. and 12/12 h light-dark cycle, and had free access to food and water. Two hours prior to experiment, the animals were placed in individual cages without access to food.
Animals were administered orally with test drug or 0.25% agar at time 0. After 60 minutes, apomorphine was subcutaneously injected at a dose of 1 mg/kg, and after further 70 minutes the animal's behaviour was assessed. Two additional assessments were performed at 10-min intervals.
For assessment, each animal was placed on the bottom of a small upright box (11×7 0.5×4.5 cm). The walls of the box were made of translucent methacrylate except one of the lateral surfaces (7.5 cm wide) which was a 3-mm wire mesh. The position of the animal was scored for 2 minutes according to the following criteria: 0=four paws on the floor; 1=three paws on the floor; 2=two paws on the floor; 3=one paw on the floor; and 4=four paws holding the wire mesh. If an animal keeps several positions within the 2-min observation, the seconds elapsed in each position will be recorded. Finally, mean scoring was calculated. The cataleptic activity of the compounds by the oral route was simultaneously
Bolos Jordi
Castello Josep M.
Foguet Rafael
Ortiz José A.
Sacristan Aurelio
Birch, Stewart, Birch & Kolasch LLP
Ferrer Internacional S.A.
Reamer James H.
LandOfFree
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