Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to novel isomers of a metabolite of Iloperidone, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
• the invention relates to optical isomers of the metabolite P-88-8991 of Iloperidone.
• Iloperidone is an atypical antipsychotic developed for the treatment of schizophrenia, having functional affinity for noradrenergic, dopaminergic and serotoninergic receptors. See for example Richelson E. and Souder T., Life Sciences, 68:29-39 (2000).
• P-88-8991 is a major circulating metabolite of Iloperidone in human plasma, having the formula A See for example Mutlib AE et al., Drug Metab. Dispos; 23(9):951-964 (1995). P-88-8991 has been shown to have plasma levels in human about 1.5 fold higher than the parent drug. It is roughly as active as Iloperidone.
• P-88-8991 consists of a mixture of two enantiomers which have never been disclosed in the literature. It has now surprisingly been found that humans produce only one enantiomer stereospecifically following administration of Iloperidone.
• the invention provides the enantiomers (R)-P-88-8991 and (S)-P-88-8991 of formulae I and II in free base or acid addition salt form.
• the invention provides a process for the production of the compounds of formulae I and II, comprising the reduction of Iloperidone of formula III with an optically active boran complex of formula IV
• the compound (S)-1-(4- ⁇ 3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy ⁇ -3-methoxy-phenyl)-ethanol of formula I is obtained using the boran complex of (3aR, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole of formula IVa
• the compound (R)-1-(4- ⁇ 3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]propoxy ⁇ -3-methoxy-phenyl)-ethanol of formula II is obtained using the boran complex of (3aS,7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole of formula IVb
• the reactions can be effected according to conventional methods, e.g. as described in the Examples.
• Acid addition salts may be produced from the free bases in known manner, and vice-versa.
• Suitable acid addition salts for use in accordance with the present invention include for example the hydrochloride.
• the boran complexes used as starting materials can be produced from the corresponding compounds of formula Va and Vb according to known procedures, e.g. as described in the Examples.
• agents of the invention exhibit valuable pharmacological properties when tested in vitro and in animals, and are therefore useful as pharmaceuticals.
• the agents of the invention display high affinity for adrenergic ⁇ 1 and ⁇ 2c receptors (pK I 8.9 and 7.8 respectively, for the compound of formula I, and 9.2 and 7.7 respectively, for the compound of formula II), high affinity for 5 HT 2A and 5 HT 6 receptors (pK I 8.9 and 8.1 respectively, for the compound of formula I, and 8.9 and 7.8 respectively, for the compound of formula II) and moderate affinity for the D 2 family (pK I 7.4 to 7.6 for the compound of formula I and 7.4 to 7.8 for the compound of formula II).
• Receptor affinity is determined with standard radioligand binding techniques, using human recombinant receptors and native rat brain receptors. Blockade of dopamine D 2 and noradrenergic ⁇ 2c receptors is tested in cell-lines using luciferase reporter gene assays based on 2 nd messenger responses.
• the agents of the invention exhibit antipsychotic activity, as assessed in standard tests such as the amphetamine-induced hypermotility and the phencyclidine-induced hyperlocomotion tests.
• the amphetamine-induced hypermotility test is performed according to the method described by Arnt J in Eur. J. Pharmacol. 283, 55-62 (1995).
• the agents of the invention significantly inhibit the amphetamine-induced locomotion of the animals at doses of about 0.01 to about 10 mg/kg s.c.
• the phencyclidine-induced hyperlocomotion test is performed according to a rat adaptation of the method described by Gleason SD and Shannon HE in Psychopharmacol. 129, 79-84 (1997).
• the agents of the invention significantly block the phencyclidine-induced hyperlocomotion of the rats at doses of about 0.01 to about 10 mg/kg s.c.
• the agents of the invention are therefore useful for the treatment of psychotic disorders such as schizophrenia and bipolar disorders.
• the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 500, preferably from about 0.5 to about 100 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 1 to about 500, preferably from about 1 to about 300 mg of an agent of the invention, conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
• the agent of the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.
• agents of the invention may alternatively be administered e.g. topically in the form of a cream, gel or the like, or by inhalation, e.g. in dry powder form.
• compositions comprising an agent of the invention include, e.g. a solid dispersion, an aqueous solution, e.g. containing a solubilising agent, a microemulsion and a suspension of an agent of the invention.
• the composition may be buffered to a pH in the range of e.g. from 3.5 to 9.5, by a suitable buffer.
• the agents of the invention can be administered either alone or in combination with other pharmaceutical agents effective in the treatment of psychotic disorders such as schizophrenia or bipolar disorders.
• the present invention thus provides a combination comprising a therapeutically effective amount of an agent of the invention and a second drug substance, for simultaneous or sequential administration.
• the present invention also provides an agent of the invention, for use as a pharmaceutical, e.g. for the treatment of psychotic disorders.
• the present invention furthermore provides a pharmaceutical composition
• a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent.
• Such compositions may be manufactured in conventional manner.
• Unit dosage forms contain, for example, from about 0.25 to about 150, preferably from 0.25 to about 25 mg of a compound according to the invention.
• the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of psychotic disorders.
• the present invention provides a method for the treatment of psychotic disorders, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention.
• the boran complex used as starting material can be obtained as follows:
• This compound is produced in analogy to Example 1, using boran complex of (3aS, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Psychiatry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Hydrogenated Pyridines (AREA)
• Cosmetics (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

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• 2002
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