U.S. patent application number 13/661609 was filed with the patent office on 2013-11-07 for optical isomers of an iloperidone metabolite.
This patent application is currently assigned to NOVARTIS AG. The applicant listed for this patent is Dominique Grimler, Hans O. Kalkman, Hequn Yin. Invention is credited to Dominique Grimler, Hans O. Kalkman, Hequn Yin.
Application Number | 20130296366 13/661609 |
Document ID | / |
Family ID | 23228843 |
Filed Date | 2013-11-07 |
United States Patent
Application |
20130296366 |
Kind Code |
A1 |
Grimler; Dominique ; et
al. |
November 7, 2013 |
OPTICAL ISOMERS OF AN ILOPERIDONE METABOLITE
Abstract
The present invention relates to novel isomers of a metabolite
of Iloperidone, their preparation, their use as pharmaceuticals and
pharmaceutical compositions containing them.
Inventors: |
Grimler; Dominique;
(Hirsingue, FR) ; Kalkman; Hans O.; (Muttenz,
CH) ; Yin; Hequn; (Basking Ridge, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Grimler; Dominique
Kalkman; Hans O.
Yin; Hequn |
Hirsingue
Muttenz
Basking Ridge |
NJ |
FR
CH
US |
|
|
Assignee: |
NOVARTIS AG
|
Family ID: |
23228843 |
Appl. No.: |
13/661609 |
Filed: |
October 26, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13096015 |
Apr 28, 2011 |
8314129 |
|
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13661609 |
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|
12403755 |
Mar 13, 2009 |
7977356 |
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13096015 |
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10488128 |
Sep 16, 2004 |
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12403755 |
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Current U.S.
Class: |
514/321 ;
546/197 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 413/04 20130101; A61P 25/18 20180101; A61P 25/00 20180101 |
Class at
Publication: |
514/321 ;
546/197 |
International
Class: |
C07D 413/04 20060101
C07D413/04 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 30, 2002 |
EP |
PCT/EP02/09700 |
Claims
1. A pharmaceutical composition comprising
(S)-1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]propoxy}-3-
-methoxy-phenyl]-ethanol or a pharmaceutically acceptable salt
thereof and a pharmaceutical carrier or diluent.
2. A method for treating a psychotic disorder in a human subject in
need of such treatment, the method comprising administering to the
subject a therapeutically effective amount of
(S)-1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]propoxy}-3-
-methoxy-phenyl]-ethanol or a pharmaceutically acceptable salt
thereof.
3. The method of claim 2, wherein the psychotic disorder is
schizophrenia or bipolar disorder.
4. A process for the production of the compound of Formula II:
##STR00008## or a pharmaceutically acceptable salt thereof;
comprising reduction of iloperidone of formula III: ##STR00009##
with an optically active boran complex of formula compound of
Formula IV: ##STR00010## and recovering the resulting compound or a
pharmaceutically acceptable salt thereof.
5. The process of claim 4, further comprising production of the
compound of Formula IV: ##STR00011## by reacting a compound of
Formula V: ##STR00012## with borane-dimethylsulfide complex.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending U.S. patent
application Ser. No. 12/403,755, filed 13 Mar. 2009, which in turn
is a continuation of U.S. patent application Ser. No. 10/488,128,
filed 16 Sep. 2004, each of which is hereby incorporated
herein.
[0002] The present invention relates to novel isomers of a
metabolite of iloperidone, their preparation, their use as
pharmaceuticals and pharmaceutical compositions containing
them.
[0003] More particularly, the invention relates to optical isomers
of the metabolite P88-8991 of iloperidone.
[0004] 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).
[0005] P-88-8991 is a major circulating metabolite of iloperidone
in human plasma, having the formula A
##STR00001##
[0006] See for example Mutlib A E 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.
[0007] 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.
[0008] In the first aspect, the invention provides the enantiomers
(R)-P-88-8991 and (S)-P-88-8991 of formulae I and II
##STR00002##
in free base or acid addition salt form.
[0009] In a further aspect, the invention provides a process for
the production of the compounds of formulae I and II, comprising
the reduction of iloperidone of formula III
##STR00003##
with an optically active boran complex of formula IV
##STR00004##
[0010] 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]oxazab-
orole of formula IVa
##STR00005##
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 II is obtained using the boran
complex of
(3aS,7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazabo-
role of formula IVb
##STR00006##
[0011] The reactions can be effected according to conventional
methods, e.g. as described in the Examples.
[0012] Working up the reaction mixtures and purification of the
compounds thus obtained may be carried out in accordance to known
procedures.
[0013] 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.
[0014] The boran complexes used as starting materials can be
produced from the corresponding compounds of formula Va and Vb
##STR00007##
according to known procedures, e.g. as described in the
Examples.
[0015] The starting materials of formulae Va and Vb are known.
[0016] 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.
[0017] In particular the agents of the invention display high
affinity for adrenergic .alpha..sub.1 and .alpha..sub.2c receptors
(pK.sub.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 5HT.sub.2A and 5HT.sub.6 receptors (pK.sub.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.sub.2 family (pK.sub.i 7.4 to 7.6 for the compound of
formula I and 7.4 to 7.8 for the compound of formula II).
[0018] Receptor affinity is determined with standard radioligand
binding techniques, using human recombinant receptors and native
rat brain receptors. Blockade of dopamine D.sub.2 and noradrenergic
.alpha..sub.2c receptors is tested in cell-lines using luciferase
reporter gene assays based on 2nd messenger responses.
[0019] 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.
[0020] 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.
[0021] The phencyclidine-induced hyperlocomotion test is performed
according to a rat adaptation of the method described by Gleason S
D and Shannon H E 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.
[0022] The agents of the invention are therefore useful for the
treatment of psychotic disorders such as schizophrenia and bipolar
disorders.
[0023] 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.
[0024] 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.
[0025] 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.
[0026] Examples for compositions comprising an agent of the
invention include, e.g. a solid dispersion, an aqueous solution,
e.g. containing a solubllising 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.
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] The following examples illustrate the invention.
EXAMPLE 1
(S)-1-[4-{3-[4-(6-fluoro-benzo(d)isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-
-methoxv-phenyl]-ethanol
[0033] 56.36 g of boran complex of (3aR,
7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2c][1,3,2]oxazaborole
(1 equivalent) is dissolved under nitrogen in methylenchloride, and
the solution is cooled to 0.degree. C. A 1M solution of
1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)piperidin-1-yl]-propoxy}-3-met-
hoxy-phenyl)-ethanone (Iloperidone; 1 equivalent) in
methylenchloride is added via a dropping funnel over 90 minutes
while the internal temperature is maintained at 0.degree.
C..+-.2.degree. C. After the addition is complete, the mixture is
stirred at 0.degree. C. for 20 hours. The reaction mixture is then
poured into precooled methanol (0-5.degree. C.) during 1 hour. The
solution is warmed to room temperature and stirred until the
H.sub.2 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.degree. C. and an additional
hour at 0.degree. C. The product is isolated by filtration and
dried under reduced pressure for 3 hours at 50.degree. C. The title
compound is obtained (white crystals).
[0034] [.alpha.].sub.D.sup.20-19.3.degree. (c=1 in chloroform)
[0035] Mp: 138.2-138.8.degree. C.
[0036] The boran complex used as starting material can be obtained
as follows:
[0037] 200 mL of a solution of (3aR,
7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2c][1,3,2]oxazaborole
(1 M 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.degree. C. for 1.5 hour. The product is
isolated by filtration in a sintered glass funnel and dried in
vacuum at 40.degree. C. The boran complex is obtained (white
crystals).
EXAMPLE 2
(R)-1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-
-methoxy-phenlyl)-ethanol
[0038] 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.
[0039] [.alpha.].sub.D.sup.20=+18.4.degree. (c=1 in chloroform)
[0040] Mp: 137.9-138.3.degree. C.
* * * * *