Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-08
2002-11-26
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S296000
Reexamination Certificate
active
06486162
ABSTRACT:
The invention relates to the fumaric acid salt of 2-{3-[4-(2-t-butyl-6-trifluoromethyl-4-pyrimidinyl)-1-piperazinyl]propylthio}-4-pyrimidinol and to a pharmaceutical composition comprising this compound. This compound has valuable therapeutic properties and is particularly useful for treating disorders which respond to dopamine D
3
ligands.
WO 96/02519 describes said compound in the form of the free base of the formula
which is likewise useful for treating disorders which respond to dopamine D
3
ligands. However, a salt of this compound is not disclosed.
It has now been found, surprisingly, that the acid addition salt of this compound with fumaric acid has particular advantages.
The present invention therefore relates to the fumaric acid salt of 2-{3-[4-(2-t-butyl-6-trifluoromethyl-4-pyrimidinyl)-1-piperazinyl]propylthio}-4-pyrimidinol and to a pharmaceutical composition comprising this compound.
The present invention also relates to tautomeric forms (pyridone structure) as well as solvates and hydrates of the fumaric acid salt.
The fumaric acid salt has very good affinity and high selectivity for the D
3
receptor, i.e. it is a selective dopamine D
3
receptor ligand which acts regioselectively in the limbic system. It has a selectivity, K
i
D
2
/K
i
D
3
of 120 (cf. WO 96/02519). The compound is therefore useful for treating disorders which respond to dopamine D
3
ligands, eg. for treating disorders of the central nervous system, in particular schizophrenia, depressions, neuroses and psychoses. It is additionally useful for treating sleep disturbances and nausea and as antihistamine. Solubility tests of the substances showed a substantially higher solubility of the salt in water compared to that of the free base. Thus, resorption is significantly enhanced when the substance is administered orally and especially parenterally.
Furthermore, the fumarate is more soluble in polar solvents such as C
1
-C
6
-alkanols than the free base. Because of the altered solubility characteristics, it can also be purified more simply while avoiding physiologically unacceptable solvents. Additionally, the fumaric acid salt of 2-{3-[4-(2-t-butyl-6-trifluoromethyl-4-pyrimidinyl)-1-piperazinyl]propylthio}-4-pyrimidinol exhibits a higher stability against oxidative processes than 2-{3-[4-(2-t-butyl-6-trifluoromethyl-4-pyrimidinyl)-1-piperazinyl]propylthio}-4-pyrimidinol.
The free base can be prepared by the general processes described in WO 96/02519, preferably by process (ii). The fumarate is obtainable by reacting the free base with fumaric acid in a suitable solvent such as C
1
-C
6
-alkanols, in particular methanol, ethanol, n-propanol, isopropanol and n-butanol, a mixture of water and one of the said alcohols, or an ester such as ethyl acetate. An elevated temperature will generally be used so that the required fumarate crystallizes out on cooling and can be isolated in a straightforward manner. The fumaric acid is generally added in equimolar amounts or with a slight excess of up to about 10%. The fumarate produced in this way already has high purity. It can also be additionally purified by stirring in or recrystallization from a suitable solvent, e.g. water, one of the abovementioned alkanols, esters or mixtures thereof.
For treating the abovementioned disorders, the novel compound is administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional way. Oral administration is preferred.
The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active substance is about 10 to 1000 mg per patient and day on oral administration and about 1 to 500 mg per patient and day on parenteral administration.
The invention also relates to pharmaceutical compositions comprising the novel compound. These compositions are in the form of the usual solid or liquid pharmaceutical forms, for example as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions or sprays. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain from 1 to 99% by weight of active substance.
REFERENCES:
patent: WO 96/02519 (1996-02-01), None
Lammers et al., Molecular Psychiatry,5, pp. 378-388 (2000).*
Reynolds et al.,Drugs, vol. 51, p. 7-11, 1996.
Blank Stefan
Höger Thomas
Koser Stefan
Schaefer Bernd
Starck Dorothea
Abbott Laboratories
Bernhardt Emily
Keil & Weinkauf
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