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WO2003020707A1 - Optical isomers of an iloperidone metabolite - Google Patents

Optical isomers of an iloperidone metabolite Download PDF

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Publication number
WO2003020707A1
WO2003020707A1 PCT/EP2002/009700 EP0209700W WO03020707A1 WO 2003020707 A1 WO2003020707 A1 WO 2003020707A1 EP 0209700 W EP0209700 W EP 0209700W WO 03020707 A1 WO03020707 A1 WO 03020707A1
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acid addition
compound
free base
addition salt
salt form
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PCT/EP2002/009700
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French (fr)
Inventor
Dominique Grimler
Hans O. Kalkman
Hequn Yin
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Novartis Ag
Novartis Pharma Gmbh
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Priority to AT02767454T priority Critical patent/ATE518845T1/en
Priority to US10/488,128 priority patent/US20050020632A1/en
Priority to JP2003524978A priority patent/JP2005504783A/en
Priority to DK02767454.8T priority patent/DK1425272T3/en
Priority to EP02767454A priority patent/EP1425272B1/en
Publication of WO2003020707A1 publication Critical patent/WO2003020707A1/en
Priority to HK04109446.7A priority patent/HK1066536A1/en
Priority to US12/403,755 priority patent/US7977356B2/en
Priority to US13/661,609 priority patent/US20130296366A1/en

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    • 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 lloperidone, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
  • the invention relates to optical isomers of the metabolite P-88-8991 of lloperidone.
  • lloperidone 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 lloperidone in human plasma, having the formula A
  • 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 lloperidone.
  • 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 lloperidone.
  • the invention provides the enantiomers (R)-P-88-8991 and (S)-P-88-8991 of formulae I and II
  • the invention provides a process for the production of the compounds of formulae I and II, comprising the reduction of lloperidone of formula III
  • 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 ⁇ and ⁇ 2o receptors (pKi 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 (pKi 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
  • 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)
  • Neurology (AREA)
  • Biomedical Technology (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)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)

Abstract

The invention provides compounds of formulae (I) and (II), their preparation and their use as pharmaceuticals.

Description

Optical isomers of an lloperidone metabolite
The present invention relates to novel isomers of a metabolite of lloperidone, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
More particularly, the invention relates to optical isomers of the metabolite P-88-8991 of lloperidone.
lloperidone 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 lloperidone in human plasma, having the formula A
Figure imgf000002_0001
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 lloperidone.
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 lloperidone.
In the first aspect, the invention provides the enantiomers (R)-P-88-8991 and (S)-P-88-8991 of formulae I and II
Figure imgf000003_0001
Figure imgf000003_0002
in free base or acid addition salt form.
In a further aspect, the invention provides a process for the production of the compounds of formulae I and II, comprising the reduction of lloperidone of formula III
Figure imgf000003_0003
with an optically active boran complex of formula IV
Figure imgf000003_0004
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
Figure imgf000004_0001
whereas the compound (R)-1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1- yl]propoxy}-3-methoxy-phenyl)-ethanol of formula ll 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
Figure imgf000004_0002
The reactions can be effected according to conventional methods, e.g. as described in the Examples.
Working up the reaction mixtures and purification of the compounds thus obtained may be carried out in accordance to known procedures.
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
Figure imgf000005_0001
according to known procedures, e.g. as described in the Examples.
The starting materials of formulae Va and Vb are known.
The compounds of formulae I and II and their pharmaceutically acceptable acid addition salts, hereinafter referred to as agents of the invention, exhibit valuable pharmacological properties when tested in vitro and in animals, and are therefore useful as pharmaceuticals.
In particular the agents of the invention display high affinity for adrenergic αι and α2o receptors (pKi 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 HT2A and 5 HT6 receptors (pKi 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 D2 family (pK| 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 D2 and noradrenergic 2c receptors is tested in cell-lines using luciferase reporter gene assays based on 2 -,nd messenger responses.
In vivo, 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). In this test, 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). In this test, 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.
For the above-mentioned indications, 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.
The 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.
Examples for 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.
In accordance with the foregoing, 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 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.
Moreover the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of psychotic disorders.
In still a further aspect 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 following examples illustrate the invention.
Example 1
(S)-1-(4-(3-r4-(6-Fluoro-benzofd1isoxazol-3-vπ-piperidin-1-vπ-propoxy)-3-methoxy-phenvπ- ethanol
56.36 g of boran complex of (3aR, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2- c][1 ,3,2]oxazaborole (1 equivalent) is dissolved under nitrogen in methylenchloride, and the solution is cooled to 0°C. A 1M solution of 1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)- piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanone (iloperidone; 1 equivalent) in methylenchloride is added via a dropping funnel over 90 minutes while the internal temperature is maintained at 0°C ± 2°C. After the addition is complete, the mixture is stirred at 0°C for 20 hours. The reaction mixture is then poured into precooled methanol (0-5°C) during 1 hour. The solution is warmed to room temperature and stirred until the H2 evolution ceases. The solution is concentrated by distillation and the residue dried in vacuum, treated with methanol and stirred for about 1 hour at 50°C and an additional hour at 0CC. The product is isolated by filtration and dried under reduced pressure for 3 hours at 50°C. The title compound is obtained (white crystals).
[α]D 20- 19.3° (c=1 in chloroform) Mp: 138.2 - 138.8°C
The boran complex used as starting material can be obtained as follows:
200 ml of a solution of (3aR, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2- c][1,3,2]oxazaborole (1M in toluene) is stirred at room temperature under nitrogen. 1.2 equivalent borane-dimethylsulfide complex is added with a syringe. The solution is stirred for 2 further hours at room temperature. The borane complex is then crystallised by addition of 4 vol dry hexane and cooling to -12°C for 1.5 hour. The product is isolated by filtration in a sintered glass funnel and dried in vacuum at 40°C. The boran complex is obtained /white crystals). Example 2
(R)-1-(4-(3-r4-(6-Fluoro-benzord1isoxazol-3-vπ-piperidin-1-vn-propoxy)-3-methoxy-phenlvπ- ethanol
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.
[α]D 20 = + 18.4° (c=1 in chloroform) Mp: 137.9 - 138.3°C

Claims

1. (R)-1 -(4-{3-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1 -yl]-propoxy}-3-methoxy- phenyl)-ethanol of formula I
Figure imgf000010_0001
in free base or acid addition salt form.
2. (S)-1 -(4-{3-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1 -yl]-propoxy}-3-methoxy- phenyl)-ethanol of formula II
Figure imgf000010_0002
in free base or acid addition salt form.
3. A process for the production of the compounds of formulae I and II according to claims 1 and 2, and their salts, comprising the reduction of lloperidone of formula III
Figure imgf000010_0003
with an optically active boran complex of formula IV
Figure imgf000011_0001
and recovering the resulting compound in free base or acid addition salt form.
4. A compound of claim 1 or 2 in free base or pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical.
5. A compound of claim 1 or 2 in free base or pharmaceutically acceptable acid addition salt form, for use in the treatment of psychotic disorders.
6. A pharmaceutical composition comprising a compound of claim 1 or 2 in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
7. The use of a compound of claiml or 2 in free base or pharmaceutically acceptable acid addition salt form, as a pharmaceutical for the treatment of psychotic disorders.
8. The use of a compound of claim 1 or 2 in free base or pharmaceutically acceptable acid addition salt form, for the manufacture of a medicament for the treatment of psychotic disorders.
9. 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 a compound of claim 1 or 2 in free base or pharmaceutically acceptable acid addition salt form.
0. A combination comprising a therapeutically effective amount of a compound of claim 1 or 2 in free base of pharmaceutically acceptable acid addition salt form, and a second drug substance, for simulataneous or sequential administration.
PCT/EP2002/009700 2001-08-31 2002-08-30 Optical isomers of an iloperidone metabolite WO2003020707A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
AT02767454T ATE518845T1 (en) 2001-08-31 2002-08-30 OPTICAL ISOMERS OF AN ILOPERIDONE METABOLITE
US10/488,128 US20050020632A1 (en) 2001-08-31 2002-08-30 Optical isomers of an iloperidone metabolite
JP2003524978A JP2005504783A (en) 2001-08-31 2002-08-30 Optical isomers of iloperidone metabolites
DK02767454.8T DK1425272T3 (en) 2001-08-31 2002-08-30 Optical isomers of an iloperidone metabolite
EP02767454A EP1425272B1 (en) 2001-08-31 2002-08-30 Optical isomers of an iloperidone metabolite
HK04109446.7A HK1066536A1 (en) 2001-08-31 2004-11-30 Optical isomers of an iloperidone metabolite
US12/403,755 US7977356B2 (en) 2001-08-31 2009-03-13 Optical isomers of an Iloperidone metabolite
US13/661,609 US20130296366A1 (en) 2001-08-31 2012-10-26 Optical isomers of an iloperidone metabolite

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US60/316,390 2001-08-31

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EP (2) EP1425272B1 (en)
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AT (1) ATE518845T1 (en)
CY (2) CY1112039T1 (en)
DK (2) DK2305656T3 (en)
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HK (2) HK1066536A1 (en)
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WO2004006886A2 (en) * 2002-07-15 2004-01-22 Novartis Ag Injectable depot formulation comprising crystals of iloperidone
EP1799865A2 (en) * 2004-09-30 2007-06-27 Vanda Pharmaceuticals Inc. Methods for the administration of iloperidone
WO2007137227A1 (en) 2006-05-22 2007-11-29 Vanda Pharmaceuticals, Inc. Treatment for depressive disorders
WO2008121899A2 (en) 2007-03-29 2008-10-09 Vanda Pharmaceuticals Inc. Method of predicting a predisposition to qt prolongation
WO2008128166A1 (en) * 2007-04-13 2008-10-23 Concert Pharmaceuticals Inc. Deuterated derivatives of 4-(6-fluoro-1, 2-benzisoxazol-3-yl) piperidine compounds
US7452888B2 (en) 2002-03-27 2008-11-18 Glaxo Group Limited Quinoline derivatives and their use as 5-ht6 ligands
WO2009076663A1 (en) 2007-12-13 2009-06-18 Vanda Pharmaceuticals Inc. Method and composition for treating an alpha adrenoceptor-mediated condition
WO2010117931A1 (en) 2009-04-06 2010-10-14 Vanda Pharmaceuticals, Inc. Method of treatment based on polymorphisms of the kcnq1 gene
WO2010117937A1 (en) 2009-04-06 2010-10-14 Vanda Pharmaceuticals, Inc. Method of predicting a predisposition to qt prolongation
WO2010117941A1 (en) 2009-04-06 2010-10-14 Vanda Pharmaceuticals, Inc. Method of predicting a predisposition to qt prolongation based on abcc2 gene sequence or product thereof
WO2010117943A1 (en) 2009-04-06 2010-10-14 Vanda Pharmaceuticals, Inc. Method of predicting a predisposition to qt prolongation based on bai3 gene sequence or product thereof
US20110172272A1 (en) * 2003-10-01 2011-07-14 Joachim Nozulak Benzisoxazoles
WO2013138602A1 (en) 2012-03-14 2013-09-19 Vanda Pharmaceuticals Inc. An iloperidone metabolite for use in the treatment of psychiatric disorders
US8652776B2 (en) 2007-09-10 2014-02-18 Vanda Pharmaceuticals, Inc. Prediction of QT prolongation based on SNP genotype
US8815293B2 (en) 2001-10-30 2014-08-26 Novartis Ag Organic compounds
WO2016134049A1 (en) 2015-02-17 2016-08-25 Vanda Pharmaceuticals Inc. Iloperidone for the treatment of schizophrenia
US9446038B2 (en) 2007-12-13 2016-09-20 Vanda Pharmaceuticals, Inc. Method and composition for treating a serotonin receptor-mediated condition
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US9745270B2 (en) 2008-10-28 2017-08-29 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
US9775829B2 (en) 2003-07-22 2017-10-03 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US9808455B2 (en) 2007-12-12 2017-11-07 Axovant Sciences Gmbh Combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline
US10022355B2 (en) 2015-06-12 2018-07-17 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder
US10034859B2 (en) 2015-07-15 2018-07-31 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
EP2331098B1 (en) * 2008-09-10 2018-08-08 Vanda Pharmaceuticals Inc. Methods for the administration of iloperidone
US10059691B2 (en) 2008-04-02 2018-08-28 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
US10570453B2 (en) 2007-03-29 2020-02-25 Vanda Pharmaceuticals Inc. Method of predicting a predisposition to QT prolongation
US11607408B2 (en) 2019-10-15 2023-03-21 Vanda Pharmaceuticals Inc. Method of treatment of schizophrenia
WO2023201182A1 (en) 2022-04-13 2023-10-19 Vanda Pharmaceuticals Inc. Treatment of parkinson's disease and parkinson's disease psychosis
WO2024137439A1 (en) 2022-12-19 2024-06-27 Vanda Pharmaceuticals Inc. Dosage regime of iloperidone for treating bipolar i disorder and schizophrenia

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