HK1158075A - Carbostyril derivatives and mood stabilizers for treating mood disorders - Google Patents

Description

Quinolone derivatives and mood stabilizers for the treatment of affective disorders

The present application is a divisional application of the chinese patent application having application number 201010513052.0, application date 2004, 5/19, entitled "quinolone derivative and mood stabilizer for treating affective disorders".

Technical Field

The present invention provides a combination comprising a quinolone derivative and a mood stabilizer as a stabilizer for the dopamine-5-hydroxytryptamine system in a pharmaceutically acceptable carrier. The present invention provides methods of treating affective disorders (mood disorders), such as bipolar disorder with or without psychotic features, mania or mixed episodes (mixed episodes), using the compositions of the invention or by administering the above-described quinolone derivatives and mood stabilising agents alone. The quinolone derivatives of the present invention include, but are not limited to, aripiprazole and its metabolites, such as dehydroaripiprazole. The mood stabilizer includes, but is not limited to, lithium, valproic acid, divalproex sodium, carbamazapine, oxcarbamazapine, zonisamide, lamotrigine, topiramate, gabapentin, levetiracetam, and clonazepam.

Background

For a variety of reasons, the number of people with affective disorders, such as bipolar disorder with or without psychotic features, mania or mixed episodes, is increasing year by year. Tricyclic antidepressants (e.g., imipramine, desipramine, amitriptyline, etc.) for the inhibition of monoamine reuptake have been developed in the 50 s of the 19 th century. They are commonly used to treat patients suffering from affective disorders. However, these drugs have side effects such as the following: dry mouth, blurred eyes, dysuria, constipation, cognitive disorders, etc. due to anticholinergic activity; based on alpha₁Cardiovascular side effects caused by adrenoreceptor antagonist activity, such as orthostatic hypotension, tachycardia and the like; based on histamine-H₁Side effects caused by the activity of receptor antagonists such as sedation, weight gain, etc.

Although affective disorders, including bipolar disorder, mania or mixed episodes with or without psychotic features, are heterogeneous diseases, the causes of such disorders are not fully understood, possibly due to abnormalities in the monoaminergic central nervous system caused by 5-hydroxytryptamine, norepinephrine, and dopamine, abnormalities in various hormones and peptides, and various stressors responsible for depression and various other affective disorders (Kubota Masahau et al: "RINSHOU SEISHIN IGAKU" Vol.29, pp 891-899, (2000)). For the reasons described above, even with mood stabilizer drugs such as lithium, valproic acid, divalproex sodium, carbamazepine, oxcarbamazapine, zonisamide, lamotrigine, topiramate, gabapentin, levetiracetam and clonazepam, these drugs are not always effective in treating all patients.

The new treatment regimen comprises a combination therapy proposed using drugs for the treatment of schizophrenia (antipsychotics) an atypical antipsychotic such as olanzapine (olanzapine) or quetiapine and a mood stabilising drug such as sodium valproate, lithium or divalproex ((arch. gen. psychotherapy, 2002 jan.59: 1): 62-69; J Am ad Child Adolesc psychotherapy 2002 Oct; 41 (10): 1216-23).

In addition, the marketed antipsychotics have a great problem in their safety. For example, clozapine, olanzapine, and quetiapine increase body weight while increasing the risk of diabetes (Newcomer, J.W. (Aoba Anri directed translation): RINSHOU SEISHIN YAKURI "Vol.5, pp 911-925, (2002), Haupt, D.W. and Newcomer, J.W. (Fuji Yasuo and Misawa Fuminari translation): RINSHOU SEISHIN YAKUI" Vol.5, pp 1063-1082, (2002)). Indeed, various urgent safety warnings concerning hyperglycemia, diabetic ketoacidosis and diabetic coma caused by olanzapine and quetiapine have been issued in japan, suggesting that these drugs are liable to cause dose contraindications for diabetic patients and patients with a history of diabetes. Risperidone causes elevated serum prolactin levels at high doses with the appearance of extrapyramidal side effects. Ziprasidone increases the likelihood of severe arrhythmias arising due to cardiac-QTc prolongation. In addition, clozapine causes granulocytopenia and its clinical use is therefore severely limited (van Kammen, d.p. (edited by Murasaki Mitsuroh guide) "rinsho SEISHIN YAKURI" vol.4, pp 483-492, (2001)).

There is therefore a need for a new class of compositions for the treatment of affective disorders, in particular bipolar disorder, mania or mixed episodes with or without psychotic features, which are effective and do not cause the adverse side effects associated with the compounds of the prior art.

Summary of The Invention

The above problems are solved by the present invention which provides a novel class of compositions and methods of using the compositions for the treatment of affective disorders, particularly including but not limited to bipolar disorder I, bipolar disorder II, bipolar disorder with or without psychotic features, and mania, acute mania, bipolar depression or mixed episodes.

The present invention provides a solution to the above problems and demonstrates that affective disorders such as bipolar disorder and mania can be effectively treated by administering to a patient suffering from such conditions a composition comprising in combination at least one carbostyril derivative as a stabilizer of the dopamine-5-hydroxytryptamine system and at least one mood stabilizer in a pharmaceutically acceptable carrier. The presently preferred quinolone derivative as a stabilizer for the dopamine-5-hydroxytryptamine system is aripiprazole or a metabolite thereof. Another preferred quinolone derivative of the present invention as a stabilizer for the dopamine-5-hydroxytryptamine system is a metabolite of aripiprazole, known as dehydroaripiprazole, also known as OPC-14857. Other such metabolites of aripiprazole encompassed by the present invention are shown in figure 8. Preferred metabolites of aripiprazole are shown in figure 8 according to the following code numbers: OPC-14857, DM-1458, DM-1451, DM-1452, DM-1454, and DCPP.

Aripiprazole is a quinolone, also known as 7- {4- [4- (2, 3-dichlorophenyl) -1-piperazinyl]Butoxy } -3, 4-dihydro-2 (1H) -quinolones, useful for the treatment of schizophreniｃA (JP-A-2-191256, U.S. Pat. No. 5,006,528). In addition, aripiprazole is also known as 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl]Butoxy radical]3, 4-dihydroquinolone, Abilify, OPC-14597, OPC-31 and BMS-337039. Aripiprazole has 5-HT_1AReceptor agonistic activity, is a currently available compound for the treatment of depression and intractable depression, such as endogenous depression, major depression, and the like (WO 02/060423a 2; Jordan et al, U.S. patent application 2002/0173513a 1)). Aripiprazole has effects on 5-hydroxytryptamine receptor and dopamine receptorHas agonist activity, and can be used as 5-hydroxytryptamine 5-HT_1AAgonists or partial agonists of receptors and dopamine D₂Agonists or partial agonists of the receptor. Aripiprazole is a dopamine-5-hydroxytryptamine system stabilizer. Metabolites of aripiprazole are included within the scope of the present invention. One metabolite of aripiprazole is known as dehydroaripiprazole. Other such metabolites of aripiprazole within the scope of the present invention are shown in figure 8. Preferred metabolites of aripiprazole are shown in figure 8 according to the following code numbers: OPC-14857, DM-1458, DM-1451, DM-1452, DM-1454, and DCPP.

The at least one mood stabilizer for use in the present invention includes, but is not limited to, the following: lithium, valproic acid, divalproex sodium, carbamazapine, oxcarbamazapine, zonisamide, lamotrigine, topiramate, gabapentin, levetiracetam and clonazepam.

The novel compositions of the present invention comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity and at least one mood stabilizer in admixture with a pharmaceutically acceptable carrier may be incorporated in a dosage form, such as a pill. Alternatively, the carbostyril derivative having the stabilizer activity of the dopamine-5-hydroxytryptamine system and at least one mood stabilizer can be each mixed with a pharmaceutically acceptable carrier in separate dosage forms. These compositions are administered to a patient suffering from a mood disorder, such as bipolar disorder or mania, in an amount and in a regimen effective to treat the mood disorder.

It is therefore an object of the present invention to provide a composition useful for the treatment of affective disorders.

It is an object of the present invention to provide a composition useful for the treatment of affective disorders, wherein the affective disorder is bipolar disorder.

It is an object of the present invention to provide a composition useful in the treatment of affective disorders, wherein the affective disorder is mania.

It is another object of the present invention to provide a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizing activity and at least one mood stabilizer, in admixture with a pharmaceutically acceptable carrier.

It is another object of the present invention to provide a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizing activity and at least one mood stabilizer, wherein the quinolone derivative is aripiprazole or a metabolite thereof, mixed in a pharmaceutically acceptable carrier.

It is another object of the present invention to provide a composition comprising a carbostyril derivative having a stabilizer activity of dopamine-5-hydroxytryptamine system and at least one mood stabilizer, wherein said carbostyril derivative having a stabilizer activity of dopamine-5-hydroxytryptamine system is a metabolite of aripiprazole and is OPC-14857, DM-1458, DM-1451, DM-1452, DM-1454 or DCPP.

It is another object of the present invention to provide a composition comprising a carbostyril derivative having a stabilizer activity of dopamine-5-hydroxytryptamine system and at least one mood stabilizer, wherein said carbostyril derivative is dehydroaripiprazole.

It is an object of the present invention to provide a method for the treatment of affective disorders.

It is an object of the present invention to provide a method for the treatment of an affective disorder, wherein the affective disorder is bipolar disorder.

It is an object of the present invention to provide a method of treatment of affective disorders, wherein the affective disorder is mania.

It is another object of the present invention to provide a method for treating affective disorders which comprises administering to a patient suffering from affective disorders a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity and at least one mood stabilizer in admixture with a pharmaceutically acceptable carrier.

It is another object of the present invention to provide a method for treating affective disorders which comprises administering to a patient suffering from affective disorders a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity in a pharmaceutically acceptable carrier and a composition comprising at least one mood stabilizer in a pharmaceutically acceptable carrier.

It is another object of the present invention to provide a method for treating affective disorders which comprises administering to a patient suffering from affective disorders a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity and at least one mood stabilizer in admixture with a pharmaceutically acceptable carrier, wherein the quinolone derivative is aripiprazole or a metabolite thereof.

It is another object of the present invention to provide a method for treating affective disorders which comprises administering to a patient suffering from affective disorders a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity in admixture with a pharmaceutically acceptable carrier, wherein the quinolone derivative is aripiprazole or a metabolite thereof, and a composition comprising at least one mood stabilizer in admixture with a pharmaceutically acceptable carrier.

It is a further object of the present invention to provide a method for treating affective disorders which comprises administering to a patient suffering from affective disorders a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity and at least one mood stabilizer, in admixture in a pharmaceutically acceptable carrier, wherein said quinolone derivative is a metabolite of aripiprazole, namely dehydroaripiprazole (OPC-14857), DM-1458, DM-1451, DM-1452, DM-1454 or DCPP.

It is a further object of the present invention to provide a method for treating affective disorders which comprises administering to a patient suffering from affective disorders a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity in admixture with a pharmaceutically acceptable carrier, wherein the quinolone derivative is aripiprazole or a metabolite thereof, i.e. dehydroaripiprazole (OPC-14857), DM-1458, DM-1451, DM-1452, DM-1454 or DCPP, and a composition comprising at least one mood stabilizer in admixture with a pharmaceutically acceptable carrier.

It is another object of the present invention to provide a method for treating a mood disorder comprising administering to a patient suffering from a mood disorder a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity and at least one mood stabilizer in admixture with a pharmaceutically acceptable carrier, wherein the mood disorder is bipolar disorder.

It is another object of the present invention to provide a method for treating a mood disorder comprising administering to a patient suffering from a mood disorder a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity in a pharmaceutically acceptable carrier and a composition comprising at least one mood stabilizer in a pharmaceutically acceptable carrier, wherein the mood disorder is bipolar disorder.

It is a further object of the present invention to provide a method of treatment of affective disorders which comprises administering to a patient suffering from affective disorders a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity and at least one mood stabilizer in admixture with a pharmaceutically acceptable carrier, wherein the affective disorders are mania.

It is a further object of the present invention to provide a method of treatment of affective disorders which comprises administering to a patient suffering from affective disorder which is mania, a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity in admixture with a pharmaceutically acceptable carrier and a composition comprising at least one mood stabilizer in admixture with a pharmaceutically acceptable carrier.

It is another object of the present invention to provide a method for treating affective disorders which comprises administering to a patient suffering from affective disorders a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity and at least one mood stabilizer in admixture with a pharmaceutically acceptable carrier.

It is another object of the present invention to provide a method for treating affective disorders which comprises separately administering to a patient suffering from affective disorders a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity in a pharmaceutically acceptable carrier and a composition comprising at least one mood stabilizer in a pharmaceutically acceptable carrier.

It is another object of the present invention to provide a method for treating affective disorders which comprises administering to a patient suffering from affective disorders a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity and at least one mood stabilizer in admixture with a pharmaceutically acceptable carrier, wherein the quinolone derivative is aripiprazole or a metabolite thereof.

It is a further object of the present invention to provide a method for treating affective disorders which comprises administering to a patient suffering from affective disorders a composition comprising a quinolone derivative having dopamine-5-hydroxytryptamine system stabilizer activity and at least one mood stabilizer, in admixture with a pharmaceutically acceptable carrier, wherein the quinolone derivative is aripiprazole or a metabolite thereof, i.e. OPC-14857, DM-1458, DM-1451, DM-1452, DM-1454 or DCPP.

These and other objects, advantages, and uses of the present invention will become apparent to those skilled in the art upon a reading of the following detailed description of the preferred embodiments and appended claims.

Brief Description of Drawings

FIG. 1 is a thermogravimetric/differential thermogram of aripiprazole hydrate A obtained in reference example 4.

FIG. 2 is a drawing showing the preparation of aripiprazole hydrate A obtained in reference example 4¹H-NMR Spectroscopy (DMSO-d)₆，TMS)。

FIG. 3 is a powder X-ray diffraction pattern of aripiprazole hydrate A obtained in reference example 4.

FIG. 4 shows an embodimentPreparation of Anhydrous aripiprazole Crystal B obtained in example 1¹H-NMR Spectroscopy (DMSO-d)₆，TMS)。

FIG. 5 is a powder X-ray diffraction pattern of anhydrous aripiprazole crystal B obtained in example 1.

Fig. 6 is a thermogravimetric/differential thermogram of aripiprazole hydrate obtained in reference example 3.

FIG. 7 is a powder X-ray diffraction pattern of aripiprazole hydrate obtained in reference example 3.

Figure 8 is a schematic diagram of the chemical structures of aripiprazole and its metabolites. Certain metabolites may be formed by other possible pathways; for example, DM-1431 may be formed by N-dealkylation of DM-1451 and DM-1459.

Detailed Description

The pharmaceutical composition of the present invention comprises a first component comprising a quinolone derivative as a stabilizer of the dopamine-5-hydroxytryptamine system and a second component comprising a mood stabilizer, mixed in a pharmaceutically acceptable carrier. The pharmaceutical compositions of the invention are useful in the treatment of affective disorders, including bipolar disorder and mania.

The pharmaceutical composition comprises: first component

The first component comprises a quinolone derivative as a stabilizer for the dopamine-5-hydroxytryptamine system. Such quinolone derivatives have agonist or partial agonist activity at certain 5-hydroxytryptamine receptors and certain dopamine receptors, preferably as 5-hydroxytryptamine 5HT_1AAgonists or partial agonists of receptors and dopamine D₂Agonists or partial agonists of the receptor. Quinolone derivatives are described in U.S. Pat. No. 5,006,528 and U.S. published patent application 2002/0173513A 1. In one embodiment of the present invention, a carbostyril derivative represented by the following formula (1):

wherein the carbon-carbon bond between the 3-and 4-positions of the quinolone skeleton is a single or double bond.

In a preferred embodiment, the quinolone derivative has an activity of 5HT_1AAgonists or partial agonists of receptors and dopamine D₂Agonists or partial agonists of receptor subtypes. In another preferred embodiment, the carbostyril derivative useful as the first component in the present invention is aripiprazole, or a metabolic derivative thereof. Metabolic derivatives of aripiprazole include, but are not limited to, dehydroaripiprazole, also known as OPC-14857. Other metabolic derivatives of aripiprazole include, but are not limited to, the chemical structures OPC-14857, DM-1458, DM-1451, DM-1452, DM-1454 and DCPP as shown in FIG. 8.

The structures and names of the metabolites of aripiprazole shown in figure 8 are shown below.

DCPP: 1- (2, 3-dichlorophenyl) piperazine and N-2, 3-dichlorophenyl piperazine

DM-14857, OPC-14857: 7- {4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy } -2- (1H) -quinolinone (quinolinone), also known as dehydroaripiprazole

DM-1451: 7- {4- [4- (2, 3-dichloro-4-hydroxyphenyl) -1-piperazinyl ] butoxy } -3, 4-dihydro-2- (1H) -quinolinone, and hydroxyazaprazole

DM-1458: 2, 3-dichloro-4- {4- [4- (2-oxo-1, 2, 3, 4-tetrahydroquinolin-7-yloxy) -butyl ] -piperazin-1-yl } -phenyl sulfate, and sulfated hydroxy aripiprazole

DM-1452: 7- {4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy } -3, 4-dihydro-4-hydroxy-2- (1H) -quinolinone, and benzylhydroxyazaprazole

DM-1454: DM-1454 is the glucuronide of DM-1451. The structure also has the following designation: 1 β - (2, 3-dichloro-4- {4- [4- (2-oxo-1, 2, 3, 4-tetrahydroquinolin-7-yloxy) -butyl ] -piperazin-1-yl } -phenoxy) -D-glucopyranosuronic acid (glucopyranosonic acid),

1 β - (2, 3-dichloro-4- {4- [4- (2-oxo-1, 2, 3, 4-tetrahydroquinolin-7-yloxy) -butyl ] -piperazin-1-yl } -phenyl- β) -D-glucopyranosiduronic acid (glucopyranosiduronic acid),

1 β - (2, 3-dichloro-4- {4- [4- (2-oxo-1, 2, 3, 4-tetrahydroquinolin-7-yloxy) -butyl ] -piperazin-1-yl } -phenyl) - β) -D-glucuronide,

1 β - (2, 3-dichloro-4- {4- [4- (2-oxo-1, 2, 3, 4-tetrahydroquinolin-7-yloxy) -butyl ] -piperazin-1-yl } -phenyl- β) -D-glucuronic acid, and the glucuronide aripiprazole.

All of the above-mentioned carbostyril derivatives can be used as the first component in the present invention.

Aripiprazole, also known as 7- {4- [4- (2, 3-dichlorophenyl) -1-piperazinyl]Butoxy } -3, 4-dihydro-2 (1H) -quinolinone, ｃA quinolone compound used as an effective ingredient for treating schizophreniｃA (JP-A-2-191256, U.S. Pat. No. 5,006,528). Aripiprazole is also known as 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl]Butoxy radical]3, 4-dihydroquinolone, Abilify, OPC-14597, OPC-31 and BMS-337039. Aripiprazole has 5-HT_1AReceptor agonistic activity, such that the compounds are useful in the treatment of depressive and refractory types of depression, such as endogenous depression, major depression, melancholia, and the like (WO 02/060423A 2; Jordan et al, U.S. patent application 2002/0173513A 1). Aripiprazole has agonist effect on 5-hydroxytryptamine receptor and dopamine receptor, and can be used as 5-hydroxytryptamine 5HT_1AAgonists or partial agonists of receptors and dopamine D₂Agonists or partial agonists of the receptor.

Aripiprazole is an antipsychotic drug with a new mechanism of action that is different from other atypical antipsychotics. Common typical and atypical antipsychotics may be used as dopamine-D₂An antagonist of the receptor. In contrast, aripiprazole acts as dopamine D₂Partial agonists of the receptor (Ishigooka Jyunya and Inada Ken: RINSHO SEISHIN YAKURI, Vol.4, pp 1653-3894, (2001); Burris, K.D. et al: J.Pharmacol. exp. Ther., 302, pp381-389, (2002)). Except for dopamine-D₂In addition to partial agonism of the receptor, aripiprazole also antagonizes 5-hydroxytryptamine 5-HT_1AThe receptor has partial agonist activity and is 5-hydroxytryptamine 5-HT_2AThe receptor has an antagonistic effect. Aripiprazole is therefore of a new class defined as dopamine-5-hydroxytryptamine system stabilizers (dopamine-5-hydroxytryptamine nervous system stabilizers) (Burris, k.d. et al, j.pharmacol. exp. ther., 302, pp381-389, 2002; Jordan, s. et al, eur.j. pharmacol.441, pp137-140, 2002).

Process for preparing aripiprazole

The aripiprazole and aripiprazole metabolites used in the present invention may be in any form, such as a free base, various polymorphic forms of crystal forms, hydrates, salts (acid addition salts, etc.), and the like. Among the above forms, the anhydrous aripiprazole crystal B is preferable.

As for the method for preparing the anhydrous aripiprazole crystal B, for example, it can be prepared by heating aripiprazole hydrate A according to the following method.

Aripiprazole hydrate A

The aripiprazole hydrate A has the following physicochemical characteristics (1) to (5):

(1) it has an endotherm substantially the same as the thermogravimetric/differential thermal analysis (heating rate 5 ℃/min) endotherm shown in figure 1. In particular, it is characterized by the appearance of a small peak at about 71 ℃ and an increasing endothermic peak at about 60 ℃ to 120 ℃.

(2) It has the same structure as that shown in FIG. 2¹H-NMR Spectroscopy (DMSO-d)₆TMS) are substantially identical¹H-NMR spectrum. Specifically, characteristic peaks are located at 1.55 to 1.63ppm (m, 2H), 1.68 to 1.78ppm (m, 2H), 2.35 to 2.46ppm (m, 4H), 2.48 to 2.56ppm (m, 4H + DMSO), 2.78ppm (t, J ═ 7.4Hz, 2H), 2.97ppm (brt, J ═ 4.6Hz, 4H), 3.92ppm (t, J ═ 6.3Hz, 2H), 6.43ppm (d, J ═ 2.4Hz, 1H), 6.49ppm (dd, J ═ 8.4Hz, J ═ 2.4Hz, 1H), 7.04ppm (d, J ═ 8.1Hz, 1H), 7.11 to 7.17ppm (m, 1H), 7.28 to 7.32ppm (m, 2H) and 10.00ppm (s, 1H).

(3) It has a powder X-ray derivative spectrum substantially the same as that shown in fig. 3. Specifically, the characteristic peaks are located at 12.6 °, 15.4 °, 17.3 °, 18.0 °, 18.6 °, 22.5 °, and 24.8 ° 2 θ.

(4) It is characterised by its spectrum at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and784cm^-1has a distinct infrared absorption band.

(5) It has an average particle diameter of 50 μm or less.

Process for preparing aripiprazole hydrate A

Aripiprazole hydrate A was prepared by milling conventional aripiprazole hydrate. The conventional aripiprazole hydrate may be ground using a conventional grinding method. For example, conventional aripiprazole hydrate may be ground in a mill. Widely used mills are, for example, atomizers, pin mills, jet mills or ball mills. Among them, a nebulizer is preferably used.

As for the specific milling conditions when the atomizer is used, the rotation speed of the spindle may be 5000-.

The aripiprazole hydrate A obtained by milling has an average particle size of generally 50 μm or less, preferably 30 μm or less. The average particle diameter can be measured by the particle diameter measurement method described below.

Anhydrous aripiprazole crystal B

The anhydrous aripiprazole crystals B of the present invention have the physicochemical characteristics shown in the following (6) to (10).

(6) They have the same structure as described in FIG. 4¹H-NMR Spectroscopy (DMSO-d)₆TMS) are substantially identical¹H-NMR spectrum. Specifically, characteristic peaks are located at 1.55 to 1.63ppm (m, 2H), 1.68 to 1.78ppm (m, 2H), 2.35 to 2.46ppm (m, 4H), 2.48 to 2.56ppm (m, 4H + DMSO), 2.78ppm (t, J ═ 7.4Hz, 2H), 2.97ppm (br t, J ═ 4.6Hz, 4H), 3.92ppm (t, J ═ 6.3Hz, 2H), 6.43ppm (d, J ═ 2.4Hz, 1H), 6.49ppm (dd, J ═ 8.4Hz, J ═ 2.4Hz, 1H), 7.04ppm (d, J ═ 8.1Hz, 1H), 7.11 to 7.17ppm (m, 1H), 7.28 to 7.32ppm (m, 2H) and 10.00ppm (s, 1H).

(7) They have a powder X-ray diffraction spectrum substantially the same as the powder X-ray derivation spectrum shown in FIG. 5. Specifically, they have characteristic peaks at 11.0 °, 16.6 °, 19.3 °, 20.3 °, and 22.1 ° 2 θ.

(8) They are 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779cm in the IR (KBr) spectrum^-1Has a distinct infrared absorption band.

(9) They show an endothermic peak near about 141.5 ℃ in thermogravimetric/differential thermal analysis (heating rate 5 ℃/min).

(10) They show an endothermic peak in differential scanning calorimetry (heating rate 5 ℃/min) close to about 140.7 ℃.

When small particles are required for solid formulations such as tablets and other solid dosage forms including, for example, fast-melt formulations, the average particle size is preferably 50 μm or less.

Method for preparing anhydrous aripiprazole crystal B

The anhydrous aripiprazole crystals B of the present invention are prepared by, for example, heating the aforementioned aripiprazole hydrate A at 90-125 ℃. The heating time is usually about 3 to 50 hours, but this is not unconditional because the heating time differs depending on the heating temperature. The heating time and the heating temperature are inversely related, so that the heating temperature is lower if the heating time is longer, and the heating time is shorter if the heating temperature is higher. Specifically, if the heating temperature of aripiprazole hydrate a is 100 ℃, the heating time may be 18 hours or more, or preferably about 24 hours. On the other hand, if the heating temperature of aripiprazole hydrate A is 120 deg.C, the heating time may be about 3 hours. The anhydrous aripiprazole crystals B of the present invention can be prepared by heating aripiprazole hydrate A at 100 ℃ for 18 hours and then at 120 ℃ for about 3 hours, as a matter of course. The anhydrous aripiprazole crystals B of the present invention can be obtained if the heating time is further extended, but this method may not be economical.

If the formulation does not require a small particle size, for example, when the drug is prepared for injectable or oral solution formulation, the anhydrous aripiprazole crystals B can also be obtained according to the following method.

The anhydrous aripiprazole crystals B of the present invention are prepared by, for example, heating conventional anhydrous aripiprazole crystals at 90-125 ℃. The heating time is usually about 3 to 50 hours, but this is not unconditional because the heating time differs depending on the heating temperature. The heating time and the heating temperature are inversely related, so that the heating temperature is lower if the heating time is longer, and the heating time is shorter if the heating temperature is higher. Specifically, if the heating temperature of the anhydrous aripiprazole crystals is 100 deg.C, the heating time may be about 4 hours, and if the heating temperature is 120 deg.C, the heating time may be about 3 hours.

Further, the anhydrous aripiprazole crystals B of the present invention are prepared by, for example, heating the conventional aripiprazole hydrate at 90-125 ℃. The heating time is usually about 3 to 50 hours, but this is not unconditional because the heating time differs depending on the heating temperature. The heating time and the heating temperature are inversely related, so that the heating temperature is lower if the heating time is longer, and the heating time is shorter if the heating temperature is higher. Specifically, if the heating temperature of the aripiprazole hydrate is 100 deg.C, the heating time may be about 24 hours, and if the heating temperature is 120 deg.C, the heating time may be about 3 hours.

The anhydrous aripiprazole crystals, which are the starting materials for preparing the anhydrous aripiprazole crystals B of the present invention, are prepared, for example, by the following method a or B.

The method A comprises the following steps: process for preparing crude aripiprazole crystals

Conventional anhydrous aripiprazole crystals are prepared by a known method, for example, the method described in example 1 of Japanese unexamined patent publication No. 191256/1990. 7- (4-bromobutoxy) -3, 4-dihydroquinolone was reacted with 1- (2, 3-dichlorophenyl) piperazine to obtain crude aripiprazole crystals, which were recrystallized from ethanol.

The method B comprises the following steps: process for preparing conventional anhydrous aripiprazole

Method B is described in the fourth Japanese-Korean symposium on isolation technology (1996, 10.6-8 days) paper set. Aripiprazole hydrate which gives the starting material for preparing the anhydrous aripiprazole crystal B of the present invention is prepared by, for example, the following method C.

The method C comprises the following steps: process for preparing conventional aripiprazole hydrate

Aripiprazole hydrate can be conveniently obtained by dissolving the anhydrous aripiprazole crystals obtained by method A in an aqueous solvent, heating and cooling the resulting solution. Using this method, aripiprazole hydrate is precipitated in crystalline form in an aqueous solvent.

An aqueous organic solvent is generally used as the aqueous solvent. Such organic solvents are preferably miscible with water, for example alcohols such as methanol, ethanol, propanol or isopropanol, ketones such as acetone, ethers such as tetrahydrofuran, dimethylformamide or mixtures thereof, particularly preferably ethanol. The water content of the aqueous solvent may be from 10 to 25 volume percent, or preferably close to 20 volume percent of the solvent.

Aripiprazole may conveniently form acid addition salts with pharmaceutically acceptable acids. As such an acid, inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, hydrobromic acid, and the like; organic acids such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like. Similar to aripiprazole in free form, these acid addition salts may also be used as the active ingredient in the present invention.

The target compound obtained by the various preparation steps is separated from the reaction system by means of a common separation method, and then may be further purified. As the separation and purification method, for example, distillation method, solvent extraction method, dilution method, recrystallization method, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography and the like can be exemplified.

The pharmaceutical composition comprises: second component

In the composition of the present invention, a mood stabilizer is used as the second ingredient. Compounds having mood stabilizer function are known to those of ordinary skill in the art and all of them can be used as mood stabilizers.

Non-limiting examples of mood stabilizers useful in the present invention include lithium, valproic acid, divalproex sodium, carbamazapine, oxcarbamazapine, zonisamide, lamotrigine, topiramate, gabapentin, levetiracetam and clonazepam.

The mood stabilising agent can be either in the form of a free base or in the form of a salt (acid addition salt or the like). In addition, the mood stabilizer can be either a racemic mixture or the R and S enantiomers. Mood stabilizer one mood stabilizer may be used alone, and two or more mood stabilizers may be used in combination if necessary. Preferably, a mood stabilizer is used.

The mood stabilising agent may conveniently form an acid addition salt with a pharmaceutically acceptable acid. As such an acid, for example, inorganic acids such as sulfuric acid, hydrochloric acid, phosphoric acid, hydrobromic acid and the like; organic acids such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like. Like the reuptake inhibitors in free form, these acid addition salts may also be used as active ingredients in the compositions of the present invention.

Among the above mood stabilizers, a compound having an acidic group can conveniently form a salt by reacting with a pharmaceutically acceptable basic compound. As such a basic compound, there can be exemplified metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like; alkaline earth metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like; metal alcoholates such as sodium methylate, potassium ethylate and the like.

The salt form of the obtained mood stabilizer is separated from the reaction system by a common separation method and then can be further purified. As the separation and purification method, for example, distillation method, solvent extraction method, dilution method, recrystallization method, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography and the like can be exemplified.

Combination of a first component and a second component

Non-limiting examples of aripiprazole and dehydroaripiprazole are described herein with respect to compositions containing a quinolone derivative having dopamine-5-hydroxytryptamine stabilizer activity in combination with a mood stabilizer. It is to be understood that the present invention also includes combinations of quinolone derivatives having dopamine-5-hydroxytryptamine stabilizer activity, and mood stabilizers, wherein the quinolone derivatives are other metabolites of aripiprazole as described herein.

When aripiprazole is combined with at least one mood stabilising agent, the following are non-limiting examples of such combinations: aripiprazole/lithium, aripiprazole/valproic acid, aripiprazole/divalproex sodium, aripiprazole/carbamazepine, aripiprazole/oxcarbamazapine, aripiprazole/zonisamide, aripiprazole/lamotrigine, aripiprazole/topiramate, aripiprazole/gabapentin, aripiprazole/levetiracetam, and aripiprazole/clonazepam. Of these combinations, the following combinations are particularly preferred: aripiprazole/carbamazepine, aripiprazole/oxcarbamazapine, aripiprazole/zonisamide, aripiprazole/lamotrigine, aripiprazole/topiramate, aripiprazole/gabapentin, aripiprazole/levetiracetam, and aripiprazole/clonazepam. Pharmaceutical compositions containing the preferred combinations described above have excellent efficacy. Such compositions therefore have fewer side effects and excellent safety profiles.

In another embodiment of the invention, aripiprazole, or a metabolite thereof, may be combined with more than one mood stabilizer. Metabolites of aripiprazole that may be used in the present invention include, but are not limited to, OPC-14857, DM-1458, DM-1451, DM-1452, DM-1454 and DCPP as shown in FIG. 8. Any of the above metabolites may be used in the present invention. Combinations containing dehydroaripiprazole with specific mood stabilising agents are described in the following paragraphs, however it will be appreciated that any of DM-1458, DM-1451, DM-1452, DM-1454 or DCPP as shown in figure 8 may be substituted for the dehydroaripiprazole in the disclosed combinations. Dehydroaripiprazole (also referred to as OPC-14857 in FIG. 8) is a preferred metabolite of aripiprazole. As regards the combination of dehydroaripiprazole and one or more mood stabilising agents, the following non-limiting examples of such combinations are exemplified: dehydroaripiprazole/lithium, dehydroaripiprazole/valproic acid, dehydroaripiprazole/divalproex sodium, dehydroaripiprazole/carbamazepine, dehydroaripiprazole/oxcarbamazapine, dehydroaripiprazole/zonisamide, dehydroaripiprazole/lamotrigine, dehydroaripiprazole/topiramate, dehydroaripiprazole/gabapentin, dehydroaripiprazole/levetiracetam, and dehydroaripiprazole/clonazepam. Among these combinations, the following combinations are particularly preferred: dehydroaripiprazole/carbamazepine, dehydroaripiprazole/oxcarbamazapine, dehydroaripiprazole/zonisamide, dehydroaripiprazole/lamotrigine, dehydroaripiprazole/topiramate, dehydroaripiprazole/gabapentin, dehydroaripiprazole/levetiracetam and dehydroaripiprazole/clonazepam. Pharmaceutical compositions containing the preferred combinations described above have excellent efficacy. Such compositions therefore have fewer side effects and excellent safety profiles.

Method for treating affective disorders, in particular bipolar disorder or mania

Patients suffering from affective disorders can be treated with the compositions of the invention. Such affective disorders include, but are not limited to, bipolar disorder I, bipolar disorder I I, bipolar disorder with or without psychotic features, mania, acute mania, bipolar depression or mixed episodes. Preferred conditions for treatment using the methods and compositions of the present invention are bipolar disorder and mania. Treatment regimens include administering to a patient suffering from a mood disorder, such as bipolar disorder or mania with or without psychotic features, a composition of the invention in an amount and in a dosing regimen effective to treat the mood disorder. The present invention includes a method of treating affective disorders in which a carbostyril derivative having the aforementioned activity and a mood stabilizer are combined in a composition with a pharmaceutically acceptable carrier. The invention further includes a method of treating affective disorders in which a quinolone derivative having the aforementioned activity is combined with a pharmaceutically acceptable carrier in a first composition, a mood stabilizer is combined with a pharmaceutically acceptable carrier in a second composition, and the two compositions are administered simultaneously or non-simultaneously for the purpose of treating a desired condition.

Dosage form

The dosage of the drug used in the present invention depends on the properties of the respective constituent drugs to be combined, the properties of the drug after combination, and the symptoms of the patient. As described above, the carbostyril derivative and the mood stabilizer may be used separately without being combined in the same composition. The following guidelines provide general guidelines for dosing.

Aripiprazole, or a metabolite thereof, such as dehydroaripiprazole, DM-1458, DM-1451, DM-1452, DM-1454 or DCPP: generally from about 0.1 to about 100 mg/day (or from about 0.05 to about 50 mg/day twice), preferably from about 1 to about 30 mg/day (or from about 0.5 to about 15 mg/day twice).

Aripiprazole, or a metabolite thereof, may be administered in combination with at least one of the following mood stabilising agents, or separately, in the dosage ranges indicated:

lithium: typically about 300 to about 2400 mg/day, 300mg to 1200mg twice a day, preferably to a plasma lithium concentration of about 0.8-1.2 mmol/L.

Valproic acid: typically about 750mg to 2000 mg/day, or 10-20 mg/kg/day.

Divalproex sodium: typically about 500 and 2500 mg/day.

Carbamazepine: typically about 100-1000 mg/day, preferably up to a plasma concentration of about 6.0-9.0 mg/L.

Oxcarbazazepine: typically about 600 and 2100 mg/day.

Zonisamide: typically about 100-500 mg/day.

Lamotrigine: usually about 50-500 mg/day, preferably 100-400 mg/day.

Topiramate: typically from about 25 to about 500 mg/day.

Gabapentin: typically about 600-2400 mg/once a day.

Levetiracetam: typically from about 250 to about 3000 mg/day.

Clonazepam: usually about 0.1-60 mg/day.

Typically, the weight ratio of the first component to the second component is determined according to the above guidelines. Regarding the ratio of the first component and the second component, if the first component is about 1 part by weight, the second component may be used in an amount of about 0.01 to about 500 parts by weight, preferably about 0.1 to about 100 parts by weight.

Pharmaceutically acceptable carriers

Pharmaceutically acceptable carriers include diluents and excipients commonly used in pharmaceutical formulations, such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, and lubricants.

The pharmaceutical composition of the present invention may be formulated into general pharmaceutical preparations such as tablets, fast-melt tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories or injections (liquids, suspensions, etc.), troches, nasal sprays, transdermal patches, and the like.

If formulated into tablets, various carriers known in the art may be used. Examples thereof include lactose, sucrose, sodium chloride, glucose, urea, starch, xylitol, mannitol, erythritol, sorbitol, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and other excipients; water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dried starch, sodium alginate, agar powder, laminarin powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, and other disintegrating agents; white sugar, stearin, cocoa butter, hydrogenated oil, and other disintegration inhibitors; quaternary ammonium salts, sodium lauryl sulfate, and other absorption enhancers; glycerin, starch, and other humectants; starch, lactose, kaolin, bentonite, colloidal silicic acid, and other absorbents; and refined talc, stearate, boric acid powder, polyethylene glycol, and other lubricants, etc. If desired, the tablets can also be formulated into tablets having conventional coatings, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets and film-coated tablets, as well as double-layered tablets and multi-layered tablets.

If formulated as a pill, various carriers known in the art may be used. Examples thereof include glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc and other excipients; acacia powder, tragacanth powder, gelatin, ethanol, and other binders; and laminarin, agar, and other disintegrating agents.

If formulated as suppositories, a variety of carriers known in the art can be used. Examples thereof include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin semisynthetic glycerides and the like.

Capsules can be prepared according to a conventional method by mixing anhydrous aripiprazole crystals as the first and second components, and various above-mentioned carriers, and then encapsulating in hard gelatin capsules, soft capsules, hydroxypropylmethylcellulose capsules (HPMC capsules), or the like.

In addition, the pharmaceutical composition may contain coloring agents, preservatives, aromatics, flavors, sweeteners, and the like, and other drugs.

The content of the first component and the second component in the pharmaceutical composition of the present invention may be suitably selected from a wide range depending on the disease to be treated. In general, about 1 to 70 parts by weight, preferably about 1 to 30 parts by weight of the first component and the second component may be mixed, calculated on the total amount of the pharmaceutical composition.

The method of administering the pharmaceutical composition of the present invention is not particularly limited. The administration of the composition depends on the types of the various preparation forms, and the age, sex, and other conditions (severity and condition of disease, etc.) of the patient. For example, tablets, pills, liquid preparations, suspensions, emulsions, granules, and capsules can be administered orally. For injections, they can be administered intravenously, either alone or in admixture with conventional auxiliary solutions, such as solutions of glucose or amino acids. In addition, the injection can be administered alone intradermally, subcutaneously or intraperitoneally, if necessary. For suppositories, administration may be intrarectal.

The pharmaceutical composition of the present invention may be administered in any form that provides both aripiprazole and mood stabilizer in effective concentrations in the body. In one embodiment, the aripiprazole and mood stabilizer are contained in the same pharmaceutical composition, and such composition may be administered. On the other hand, if the pharmaceutical preparations contain aripiprazole and one of the mood stabilizer separately, each of the above preparations may be taken simultaneously or not.

For the treatment and improvement of affective disorders, the dosage of the pharmaceutical composition of the present invention can be used in relatively small amounts because of its excellent efficacy. Thus, the composition has less side effects and an excellent safety profile.

The pharmaceutical compositions of the present invention may exhibit a wide variety of neurotransmission modulating behaviors. As a result, the compositions of the present invention can establish pseudo-homeostasis (a result of partial agonism) of dopamine and 5-hydroxytryptamine neurotransmission, since neurophysiologic activity has ceased to function normally. Affective Disorders treatable by the pharmaceutical compositions of the present invention include affective Disorders classified in the "Diagnostic and Statistical Manual of Mental Disorders" fourth edition (DSM-IV) published by the American Psychiatric Association. Such affective disorders include, for example, bipolar disorders such as bipolar disorder I or II, bipolar disorder with or without psychotic features, mania, acute mania, bipolar depression or mixed episodes.

In addition, the pharmaceutical composition of the present invention is also effective for schizophrenia and other psychoses. These diseases include, for example, depressive disorders such as major depression, intrinsic depression, melancholia, depression with psychotic episodes, refractory depression, Alzheimer's disease with depressive symptoms, Parkinson's disease with depressive symptoms, senile dementia, and affective disorders associated with cerebral blood vessels. Affective disorder after head injury, etc.; anxiety disorders such as panic disorder, obsessive compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, social phobia, specific phobias, and the like; eating disorders; sleep disorders; adaptation disorders; personality disorder; the intelligence is delayed to develop; cognitive disorders; generalized mental development disorder; attention deficit and disruptive behavior disorders; tic disorders; delirium; dementia; amnesia; other cognitive disorders; alcohol-related disorders; disorders associated with amphetamines; cocaine-related disorders; nicotine-related disorders; a tranquil, hypnotic or anxiety-related disorder; sexual disease and sexing disorders. These Disorders are classified in the fourth edition (DSM-IV) of "Diagnostic and Statistical Manual of Mental Disorders" published by the American Psychiatric Association.

The present invention will be described in more detail by way of examples of various reference examples, examples and preparation sample examples. First, the analysis method will be explained.

Analytical method

(1)¹H-NMR Spectroscopy in DMSO-d₆Measured using TMS as a standard.

(2) Powder X-ray diffraction

Powder X-ray diffraction patterns were measured at room temperature using a RAD-2B diffractometer manufactured by Rigaku Denki using a Cu Ka filled tube (35kV 20mA) as an X-ray source with a wide angle goniometer, 1 ℃ scattering slit, 0.15mm light interception slit, graphite secondary monochromator and scintillation counter. In the 2 theta continuous scan mode, data acquisition is accomplished in scan steps of 0.02 deg. over a range of 3 deg. -40 deg. at a scan speed of 5 deg./minute.

(3) IR spectra were measured by the KBr method.

(4) Thermogravimetric/differential thermal analysis

Thermogravimetric/differential thermal analysis was performed by using the SSC 5200 control unit and TG/DTA 220 synchronous differential thermal/thermogravimetric unit manufactured by Seiko Corp. Samples (5-10mg) were placed in open aluminum pans and heated at a heating rate of 5 ℃/min at 20 ℃ -200 ℃ under a dry nitrogen atmosphere. Alpha-alumina was used as standard.

(5) Differential scanning calorimetry

Thermogravimetric/differential thermal analysis was performed by using SSC 5200 control unit manufactured by Seiko Corp and DSC 220C differential scanning calorimeter. Samples (5-10mg) were placed in a crimped aluminum pan and heated at a heating rate of 5 ℃/min at 20 ℃ -200 ℃ under a dry nitrogen atmosphere. Alpha-alumina was used as standard.

(6) Measurement of particle diameter

The particles to be measured (0.1g) were suspended in a solution of 0.5g of soybean lecithin in 20ml of n-hexane, and the particle size was measured using a particle size distribution meter (Microtrack HRA, manufactured by Microtrack co.).

Reference example 1

7- (4-Neobutoxy) -3, 4-dihydroquinolone (19.4g) and 16.2g of 1- (2, 3-dichlorophenyl) piperidine 1 hydrochloride are added to a solution of 8.39g of potassium carbonate dissolved in 140ml of water, and stirred under reflux for 3 hours. After completion of the reaction, the mixture was cooled, and the precipitated crystals were collected by filtration. These crystals were dissolved in 350ml of ethyl acetate and approximately 210ml of the water/ethyl acetate azeotrope was removed under reflux. After the residual solution was cooled, the precipitated crystals were collected by filtration. The resulting crystals were dried at 60 ℃ for 14 hours to give 20.4g (74.2%) of crude aripiprazole product.

The crude aripiprazole (30g) obtained above was recrystallized again from 450ml of ethanol according to the method described in Japanese unexamined patent publication No. 191256/1990. The resulting crystals were dried at 80 ℃ for 40 hours to give anhydrous aripiprazole crystals. The yield was 29.4g (98.0%).

These anhydrous aripiprazole crystals had a melting point (mp) of 140 ℃ which was consistent with that of the anhydrous aripiprazole crystals described in Japanese unexamined patent publication No. 191256/1990.

Reference example 2

The crude aripiprazole (6930g) obtained in reference example 1 was dissolved by heating in 138 liters of aqueous ethanol (water content 20 vol%) according to the method provided by the fourth japan-korean institute for separation technology, the solution was gradually (2-3 hours) cooled to room temperature, and then frozen to approximately 0 ℃. The precipitated crystals were collected by filtration to obtain about 7200g of aripiprazole hydrate (wet state).

The previously obtained wet aripiprazole hydrate crystals were dried at 80 ℃ for 30 hours to obtain 6480g (93.5%) of aripiprazole hydrate crystals. The melting point (mp) of these crystals was 139.5 ℃.

The water content in the above crystals was confirmed by the Karl Fischer method, and the humidity value was 0.03%, thus confirming that these crystals were anhydrous products.

Reference example 3

The wet aripiprazole hydrate (820g) obtained in reference example 2 was dried at 50 ℃ for 2 hours to give 780g of aripiprazole hydrate crystals. These crystals had a moisture value of 3.82% as measured by the Karl Fischer method. As shown in fig. 6, thermogravimetric/differential thermal analysis showed endothermic peaks at 75.0, 123.5 and 140.5 ℃. No clear melting point (mp) was observed as dehydration began near 70 ℃.

As shown in fig. 7, the aripiprazole hydrate obtained by this method had a powder X-ray diffraction pattern having characteristic peaks at 2 θ ═ 12.6 °, 15.1 °, 17.4 °, 18.2 °, 18.7 °, 24.8 ° and 27.5 °.

The powder X-ray diffraction pattern of this aripiprazole hydrate was the same as that provided by the fourth japan-korean institute for separation technology.

Reference example 4

The aripiprazole hydrate crystal (500.3g) obtained in reference example 3 was ground by a sample grinder (fine-diameter atomizer). The spindle rotation rate was set at 12,000rpm, the feed rotation rate was set at 17rpm, and a 1.0mm chevron screen was used. The trituration was completed in 3 minutes to give 474.6g (94.9%) aripiprazole hydrate A.

The aripiprazole hydrate A (powder) obtained according to the above method had an average particle size of 20-25 μm. The melting point (mp) was not measured since onset of dehydration was observed near 70 ℃.

The aripiprazole hydrate A (powder) obtained previously had the same structure as shown in FIG. 2¹The H-NMR spectra being substantially identical¹H-NMR(DMSO-d₆TMS) spectrum. Specifically, the peaks are characterized by 1.55-1.63ppm (m, 2H), 1.68-1.78ppm (m, 2H), 2.35-2.46ppm (m, 4H), 2.48-2.56ppm (m, 4H + DMSO), 2.78ppm (t, J ═ 7.4Hz, 2H), 2.97ppm (br)t, J ═ 4.6Hz, 4H), 3.92ppm (t, J ═ 6.3Hz, 2H), 6.43ppm (d, J ═ 2.4Hz, 1H), 6.49ppm (dd, J ═ 8.4Hz, J ═ 2.4Hz, 1H), 7.04ppm (d, J ═ 8.1Hz, 1H), 7.11-7.17ppm (m, 1H), 7.28-7.32ppm (m, 2H) and 10.00ppm (s, 1H).

The aripiprazole hydrate A (powder) obtained previously had a powder X-ray diffraction pattern substantially the same as that shown in FIG. 3. Specifically, the characteristic peaks are located at 12.6 °, 15.4 °, 17.3 °, 18.0 °, 18.6 °, 22.5 °, and 24.8 ° 2 θ. This pattern is different from the powder X-ray spectrum of the unmilled aripiprazole hydrate as shown in figure 7.

The aripiprazole hydrate A (powder) obtained previously had infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784cm-1 on the IR (KBr) spectrum.

As shown in fig. 1, the aripiprazole hydrate a (powder) obtained previously had a weak peak at 71.3 ℃ in thermogravimetric/differential thermal analysis and a broad endothermic peak between 60-120 ℃ (the observed weight loss corresponds to 1 mole of water), which is clearly different from the endothermic curve of the unground aripiprazole hydrate (see fig. 6).

It is understood that other embodiments and applications will be apparent to those skilled in the art, and thus the invention is not limited by these specific exemplary embodiments.

Example 1

Aripiprazole hydrate A (powder) (44.29kg) obtained in the reference example was dried at 100 ℃ for 24 hours using a hot air dryer, and further heated at 120 ℃ for 3 hours to give 42.46kg (yield; 99.3%) of anhydrous aripiprazole crystals B. These anhydrous aripiprazole crystals B had a melting point (mp) of 139.7 ℃.

The resulting anhydrous aripiprazole crystals B had the same structure as that shown in FIG. 4¹The H-NMR spectra being substantially identical¹H-NMR(DMSO-d₆TMS) spectrum. In particular, it is characterized byPeaks are located at 1.55-1.63ppm (m, 2H), 1.68-1.78ppm (m, 2H), 2.35-2.46ppm (m, 4H), 2.48-2.56ppm (m, 4H + DMSO), 2.78ppm (t, J ═ 7.4Hz, 2H), 2.97ppm (brt, J ═ 4.6Hz, 4H), 3.92ppm (t, J ═ 6.3Hz, 2H), 6.43ppm (d, J ═ 2.4Hz, 1H), 6.49ppm (dd, J ═ 8.4Hz, J ═ 2.4Hz, 1H), 7.04ppm (d, J ═ 8.1Hz, 1H), 7.11-7.17ppm (m, 1H), 7.28-7.32ppm (m, 2H) and 10.00ppm (s, 1H).

The previously obtained anhydrous aripiprazole crystal B had a powder X-ray diffraction pattern substantially the same as that shown in FIG. 5. Specifically, the characteristic peaks are located at 11.0 °, 16.6 °, 19.3 °, 20.3 °, and 22.1 ° 2 θ.

The anhydrous aripiprazole crystals B obtained previously had spectra at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779cm in the IR (KBr) spectrum^-1A distinct infrared absorption peak of (a). The previously obtained anhydrous aripiprazole crystal B had an endothermic peak at about 141.5 ℃ in the thermogravimetric/differential thermal analysis. The previously obtained anhydrous aripiprazole crystal B has an endothermic peak at about 140.7 ℃ in differential scanning calorimetry.

Example 2

For 5HT_1AReceptor binding capacity of receptor

1. Materials and methods

1.1 test Compounds

7- {4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] -butoxy-3, 4-dihydroquinolone (aripiprazole) was used as a test compound.

1.2 reference Compounds

5-hydroxytryptamine (5-HT) and WAY-100635(N- [2- [4- (2-methoxyphenyl) -1-piperazinyl) are used]Ethyl radical]-N- (2-pyridyl) -cyclohexanecarboxamide (a 5-HT manufactured by RBI (Natick, Mass.))_1AReceptor antagonists) as reference compounds.

1.3 solvent

Dimethyl sulfoxide (DMSO) manufactured by Sigma Chemical Co, (st.louis, Mo.) was used as a solvent.

1.4 preparation of test and reference Compounds

Test compounds were dissolved in 100% Dimethylsulfoxide (DMSO) to give 100. mu.M stock solutions (DMSO final concentration 1%, v/v in all test tubes containing test compounds). All other reference compounds were prepared according to the same method using double distilled water instead of DMSO.

1.5[³⁵S]Experimental procedure for measuring GTP gamma S binding force

Test and reference compound pairs were investigated at 10 different concentrations (0.01, 0.1, 1, 5, 10, 50, 100, 1000, 10000 and 50000nM) in triplicate samples for h5-HT_1ABasic value of CHO cell membrane³⁵S]The effect of GTP γ S binding. The reaction was carried out in a medium containing 792. mu.l of buffer (25mM Tris HCl, 50mM NaCl, 5mM MgCl)₂0.1mM EGTA, pH 7.4) in a 5ml glass tube containing 8. mu.l of the test/reference drug in a buffer solution containing GDP (1. mu.M)³⁵S]GTPS (0.1nM) and h5-HT_1ACHO cell membranes (10. mu.g protein/reaction; NEN Life science Products, Boston, Mass.; catalog # CRM035, batch # 501-. The reaction was carried out at room temperature for 60 minutes, stopped by rapid filtration through Whatman GF/B filter paper, washed with a Brandel trap and ice-cold buffer of 4x3 ml. The S radioactivity bound to the filter paper was measured using liquid scintillation counting (1272 Clinigma, LKB/Wallach).

1.6 for the determination of the test compound aripiprazole p-h 5-HT_1AExperimental procedure for binding affinity of receptors

Test compound substitutions were investigated in triplicate samples at 10 different concentrations (0.01, 0.1, 1, 10, 50, 100, 500, 1000, 5000 and 10000nM)³H]8-OH-DPAT (1 nM; NEN Life Sciences; catalog # NET 929, lot #3406035, specific activity 124.9 Ci/mmol) on CHO cell membranes (15-20. mu.g protein;h5-HT of NEN Life Science Products, catalog # CRM035, batch #501-_1AThe binding capacity of the receptor. The cell membrane (396. mu.l) was incubated in a 5ml glass tube containing [, ], [ alpha ], [³H]8-OH-DPAT (396. mu.l), test compound or vehicle (8. mu.l) and buffer A (50mM Tris. HCl, 10mM MgSO. RTM.)₄0.5mM EDTA, 0.1% (w/v) ascorbic acid, pH 7.4). All assays were performed at room temperature for 60 min, stopped by rapid filtration through Whatman GF/B filter paper (pre-soaked in buffer B; 50mM tris. hcl, pH 7.4), washed with Brandel trap and 4 × 1ml ice cold buffer B. Nonspecific binding was measured in the presence of 10. mu.M (+) 8-OH-DPAT.

1.7 measurement of parameters

5-hydroxytryptamine (5-HT) is a 5-HT_1AFull agonists of receptors which stimulate h5-HT in recombinant CHO cell membranes_1ABase of receptor [ alpha ]³⁵S]Increase of GTP γ S binding force. The test compound was studied at 10 different concentrations to determine the binding force to base relative to the binding force generated by 10. mu.M 5-HT³⁵S]The effect of GTP γ S binding. The relative potency (EC) of each compound was calculated by computer nonlinear regression analysis of the complete concentration-effect data₅₀95% confidence interval) and intrinsic agonist activity (for 10. mu.M 5-HT E_maxPercent of). Test Compound Pair h5-HT_1ABy which the binding affinity of the receptor is prevented³H]The ability of 8-OH-DPAT to bind to CHO cell membranes expressing this receptor. Inhibition Constants (IC) were calculated by non-linear regression analysis of competitive binding data₅₀95% confidence interval), i.e., occupied by³H]H5-HT of specific binding of 8-OH-DPAT_1AConcentration of test compound at half of the site. Test Compound Pair h5-HT_1AThe receptor affinity (Ki, 95% confidence interval) is given by the equation Ki ═ (IC)₅₀)/(1+([[³H]8-OH-DPAT]a/Kd calculation, wherein³H]Kd of 8-OH-DPAT is located at h5-HT_1A0.69nm (nen Life sciences). All for drug pair h5-HT_1AEvaluation of binding affinity, potency and intrinsic potency of receptorsCalculated using GraphPad Prism version 3.00(GraphPad Software, San Diego, Calif.) from Windows.

2. Results

The test compound and the resulting 5-HT concentration-dependently increased base³⁵S]GTP γ S binding. 1% DMSO alone for basal or drug induced³⁵S]GTP γ S binding has no effect.

Test Compounds (EC)₅₀＝2.12nM)、5-HT(EC₅₀2.67 nM) significantly stimulates [ alpha ], [ beta ] -a³⁵S]GTP γ S binding. By using the correlation coefficient (r) in each case²) Nonlinear regression analysis was performed to obtain estimates of potency and intrinsic agonistic potency > 0.98 (table 1). The test compounds showed partial agonist activity in the range of 65-70%. WAY-100635 at base [2 ] at all different concentrations tested³⁵S]There was no significant change in GTP γ S binding (unpaired Student' S-test) (table 1). However, WAY-100635 does completely inhibit the pair of 5-HT and the test compound³⁵S]GTP gamma S and h5-HT in CHO cell membrane_1ABinding capacity of the receptor (table 2). Tables 1 and 2 are shown below.

The test compounds showed h5-HT in CHO cell membranes_1AThe receptor has high affinity binding capacity (IC)₅₀4.03nM with a 95% confidence interval of 2.67-6.08 nM; ki 1.65nM, 95% confidence interval 1.09-2.48).

TABLE 1

TABLE 2

Example 3

Formulation examples

Several non-limiting formulation examples of aripiprazole or dehydroaripiprazole with mood stabilising agents are listed below.

Formulation samples example 1

Tablets containing the above formulations are prepared according to methods of manufacture well known to those of ordinary skill in the art.

Formulation samples example 2

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 3

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 4

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 5

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 6

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 7

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 8

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 9

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 10

Tablets containing the above formulation were prepared according to conventional methods.

Several non-limiting formulation examples of dehydroaripiprazole and mood stabilising agents are listed below. It is understood that any of DM-1458, DM-1451, DM-1452, DM-1454, or DCPP as shown in FIG. 8 may be used in place of the disclosed formulation of dehydroaripiprazole.

Formulation samples example 11

Tablets containing the above formulations are prepared according to methods of manufacture well known to those of ordinary skill in the art.

Formulation samples example 12

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 13

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 14

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 15

Tablets containing the above formulation were prepared according to conventional methods.

Formulation sample example 16

Tablets containing the above formulation were prepared according to conventional methods.

Formulation sample example 17

Tablets containing the above formulation were prepared according to conventional methods.

Formulation sample example 18

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 19

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 20

Tablets containing the above formulation were prepared according to conventional methods.

Formulation samples example 21

Tablets containing the above formulation were prepared according to conventional methods.

Formulation sample example 22

Tablets containing the above formulation were prepared according to conventional methods.

Example 4

Method of treating patients with newly diagnosed bipolar disorder (I or II) episodes with or without recurrent or refractory psychotic features, mania or mixed episodes as defined by DSM-IV-R criteria

The efficacy of a combination comprising aripiprazole, or an aripiprazole metabolite, and at least one mood stabilising agent, for the treatment of patients with newly diagnosed, recurrent or refractory bipolar disorder episodes (I or II), acute mania, or bipolar depression is assessed. Patients aged 18-65 years who were diagnosed with bipolar disorder (I or II), acute Mania, or bipolar depression were evaluated to ensure a baseline Young person's Mania Rating Scale (YMRS) score of over 24. Only patients who meet this YMRS score receive treatment. These patients are examined for a complete medical and psychiatric history. Aripiprazole, or an aripiprazole metabolite, was first administered at a dose of 10 mg/day and then increased to 30 mg/day as necessary according to the opinion of the supervising psychologist. Aripiprazole, or an aripiprazole metabolite, is administered to these patients at a dose of 10 mg/day to 30 mg/day for at least four weeks, and for up to 8 weeks for patients with a good response to treatment during the first four weeks. Administering aripiprazole, or an aripiprazole metabolite, with at least one mood stabilising agent, wherein the mood stabilising agent is lithium, valproic acid, divalproex sodium, carbamazapine, oxcarbamazapine, zonisamide, lamotrigine, topiramate, gabapentin, levetiracetam or clonazepam.

The aripiprazole, or aripiprazole metabolite, may be administered in the same dosage form, e.g., tablet, and the mood stabilizer may be administered in a separate dosage form, e.g., tablet. Administration may be at the same time or at different times of the day. The dosage of aripiprazole, aripiprazole metabolite, and mood stabilizer may be within the dosage ranges provided above.

Alternatively, a dosage form comprising aripiprazole, or a metabolite of aripiprazole is administered in combination with at least one mood stabilising agent and a pharmaceutically acceptable carrier. Such combinations include, but are not limited to, the following combinations: aripiprazole/lithium, aripiprazole/valproic acid, aripiprazole/divalproex sodium, aripiprazole/carbamazepine, aripiprazole/oxcarbamazapine, aripiprazole/zonisamide, aripiprazole/lamotrigine, aripiprazole/topiramate, aripiprazole/gabapentin, aripiprazole/levetiracetam, and aripiprazole/clonazepam. As indicated by the results of the tests performed during or after the administration of aripiprazole, or an aripiprazole metabolite, and a mood stabilizer, an improvement in the symptomatic relief of bipolar disorder (I or II), acute mania, or bipolar depression was observed in these patients after the administration of aripiprazole, or an aripiprazole metabolite, and one or more mood stabilizers. These patients are given YMRS and other conditions such as CGI, AIMS, SAS, Simpson & Angus and Barnes, as are well known to those of ordinary skill in the art. The results indicated that the mood was normal.

Example 5

Therapeutic effect of aripiprazole in combination with valproate or lithium in the treatment of mania in patients partially non-responsive to valproate or lithium monotherapy

To determine the efficacy of aripiprazole in combination with either valproate or lithium relative to either valproate or lithium alone in the treatment of acute mania or mixed bipolar patients, a 6 week double blind, randomized, placebo controlled trial was performed. The methods used are generally described in Tohen et al, (Arch. Gen. Psychiatry, 2002 Jan; 59 (1): 62-9). When aripiprazole (1-30 mg/day) is added to placebo treatment over ongoing mood stabilizer treatment, the objective is to evaluate the efficacy of aripiprazole (1-30 mg/day) on placebo, the results of which can be judged by a reduction in the mania rating scale (YMRS) score in young people. Patients with bipolar disorder, mania or mixed episodes do not respond adequately to lithium (600 mg/day) or valproate (500 mg/day) treatment for more than two weeks, and are randomized to combination therapy (aripiprazole + mood stabilising agent) or monotherapy (placebo + mood stabilising agent). The results indicate that aripiprazole combination treatment increased the patient's overall YMRS score relative to monotherapy. The clinical response rate (YMRS > or 50% improvement) was higher for the combination therapy. The aripiprazole combination treatment improved the overall score of 21 Hamilton Depression Rating scales (HAMD-21) more than the monotherapy treatment. In patients with mixed episodes with moderate to severe depressive symptoms (DSM-IV mixed episode with baseline HAMD-21 score > or ═ 20), aripiprazole combination treatment increased HAMD-21 score relative to monotherapy. Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathia Scale, Absnormal invasion modification Scale) did not change significantly from baseline to endpoint throughout the treatment groups. The addition of aripiprazole shows excellent efficacy in the treatment of manic and mixed bipolar disorder episodes relative to valproate or lithium alone.

Example 6

Therapeutic effect of dehydroaripiprazole in combination with valproate or lithium in the treatment of mania in patients partially non-responsive to valproate or lithium monotherapy

To determine the efficacy of any of the combination of dehydroaripiprazole and valproate or lithium relative to valproate or lithium alone in treating patients with acute mania or mixed bipolar episodes, a 6-week double-blind, randomized, placebo-controlled trial was performed. The methods used are generally described in Tohen et al, (Arch. Gen. Psychiatry, 2002 Jan; 59 (1): 62-9). When increasing dehydroaripiprazole (1-30 mg/day) with placebo treatment over ongoing mood stabilizer treatment, the aim was to evaluate the efficacy of dehydroaripiprazole (1-30 mg/day) on placebo, the results of which could be judged by a decrease in the mania rating scale (YMRS) score in young people. Patients with bipolar disorder, mania or mixed episodes do not respond adequately to lithium (600 mg/day) or valproate (500 mg/day) treatment for more than two weeks, and are randomized to combination therapy (dehydroaripiprazole + mood stabilising agent) or monotherapy (placebo + mood stabilising agent). The results indicate that combination treatment with dehydroaripiprazole increases the patient's total YMRS score relative to monotherapy. The clinical response rate (YMRS > or 50% improvement) was higher for the combination therapy. The combination treatment with dehydroaripiprazole improved the overall score of 21 Hamilton Depression Rating scales (HAMD-21) more than the monotherapy. In patients with mixed episodes with moderate to severe depressive symptoms (mixed episode DSM-IV; baseline HAMD-21 score > or ═ 20), combination therapy with dehydroaripiprazole increased HAMD-21 score relative to monotherapy. Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathia Scale, Absnormal invasion modification Scale) did not change significantly from baseline to endpoint throughout the treatment groups. The addition of dehydroaripiprazole shows excellent efficacy in the treatment of mania and mixed bipolar disorder episodes relative to valproate or lithium alone.

Example 7

Double-blind, randomized, placebo-controlled study of aripiprazole for the adjuvant treatment of juvenile mania

The randomized, double-blind, placebo-controlled study evaluated the efficacy and tolerability of aripiprazole in combination with divalproex sodium (DVP) for the treatment of acute mania in adolescents with bipolar disorder. The method used is described essentially in Deltello et al, (J.Am.Acad.Child adolesc.Psychiatry, 2002 Oct; 41 (10): 1216-23). It is hypothesized that DVP in combination with aripiprazole is more effective than DVP alone for treating mania associated with bipolar disorder in adolescents. 30 mania or mixed bipolar I adolescents (12-18 years) were initially given a dose of 20mg/kg DVP and then randomized to a 6 week combination of about 10 mg/day aripiprazole, or placebo. There was a change in the mental rating scale (YMRS) score and the main degree of efficacy (measure) in the YMRS response ratio in young people from baseline to endpoint. Safety and tolerability were evaluated weekly. The YMRS score from baseline to endpoint was more reduced in the DVP + aripiprazole group relative to DVP + placebo. In addition, the proportion of YMRS response in the DVP + aripiprazole group was significantly higher than in the DVP + placebo group. Note that the degree of safety (measure) does not vary significantly from baseline to endpoint. Mild or moderate sedation was observed to be more prevalent in the DVP + aripiprazole group than in the DVP + placebo group. The results indicate that aripiprazole in combination with DVP can be more effective in treating juvenile bipolar mania than DCP alone. In addition, the results also indicate that aripiprazole is better tolerated when used in combination with DVP for the treatment of mania.

Example 8

Double-blind, randomized, placebo-controlled study of dehydroaripiprazole for the adjuvant treatment of juvenile mania

The randomized, double-blind, placebo-controlled study evaluated the efficacy and tolerability of dehydroaripiprazole in combination with divalproex sodium (DVP) for the treatment of acute mania in teenagers with bipolar disorder. The method used is described essentially in Deltello et al, (J.Am.Acad.Child adolesc.Psychiatry, 2002 Oct; 41 (10): 1216-23). It is hypothesized that DVP in combination with dehydroaripiprazole is more effective than DVP alone for the treatment of mania associated with bipolar disorder in adolescents. 30 mania or mixed bipolar I adolescents (12-18 years) were initially given a dose of 20mg/kg DVP and then randomized to about 10 mg/day of dehydroaripiprazole, or placebo combination therapy for 6 weeks. There was a change in the mental rating scale (YMRS) score and the main degree of efficacy (measure) in the YMRS response ratio in young people from baseline to endpoint. Safety and tolerability were evaluated weekly. The YMRS score from baseline to endpoint was more reduced for the DVP + dehydroaripiprazole group relative to DVP + placebo. In addition, the proportion of YMRS response in the DVP + dehydroaripiprazole group was significantly higher than that in the DVP + placebo group. Note that the degree of safety (measure) does not vary significantly from baseline to endpoint. Mild or moderate sedation was observed to be more prevalent in the DVP + dehydroaripiprazole group than in the DVP + placebo group. The results indicate that the combination of dehydroaripiprazole and DVP is more effective in treating juvenile bipolar mania than DVP alone. In addition, the results also indicate that aripiprazole is better tolerated when used in combination with DVP for the treatment of mania.

All patents, patent applications, scientific and medical publications mentioned herein are incorporated by reference in their entirety. It should be understood, of course, that the foregoing relates only to preferred embodiments of the present invention and that numerous changes and modifications may be made herein without departing from the spirit and scope of the invention as set forth in the following claims.

Claims (12)

1. A pharmaceutical composition for the treatment of affective disorders, which comprises in combination at least one quinolone derivative selected from aripiprazole, dehydroaripiprazole, DM-1458, DM-1451, DM-1452, DM-1454 or DCPP; the mood stabilizer is selected from lithium, valproic acid, divalproex sodium and salts thereof.

2. The composition of claim 1, wherein the at least one carbostyril derivative is dehydroaripiprazole, DM-1458, DM-1451, DM-1452, DM-1454, or DCPP, and the at least one mood stabilizer is lithium.

3. The composition of claim 1, wherein the at least one carbostyril derivative is dehydroaripiprazole, DM-1458, DM-1451, DM-1452, DM-1454, or DCPP, and the at least one mood stabilizer is valproic acid or divalproex sodium.

4. The composition of any one of claims 1-3, further comprising at least one pharmaceutically acceptable carrier.

5. Use of a composition according to any one of claims 1-3 for the manufacture of a medicament for the treatment of bipolar disorder.

6. Use of a composition according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of mania.

7. Use of a combination of at least one carbostyril derivative selected from aripiprazole, dehydroaripiprazole, DM-1458, DM-1451, DM-1452, DM-1454 or DCPP, and at least one mood stabilizer, for the preparation of a medicament for the treatment of a mood disorder in a patient; said mood stabilising agent is selected from the group consisting of lithium, valproic acid, divalproex sodium, and salts thereof, and said treatment comprises administering an amount of a drug effective to treat a mood disorder in said patient.

8. Use of a carbostyril derivative for the manufacture of a medicament for the treatment of an affective disorder in a patient, said treatment comprising separately administering a medicament comprising a carbostyril derivative and at least one mood stabilising agent; the carbostyril derivative is selected from aripiprazole, dehydroaripiprazole, DM-1458, DM-1451, DM-1452, DM-1454 and DCPP; the mood stabilizer is selected from lithium, valproic acid, divalproex sodium and salts thereof; the administration is effective to treat the affective disorder in the patient.

9. The use of claim 7 or 8, wherein the at least one carbostyril derivative is dehydroaripiprazole, DM-1458, DM-1451, DM-1452, DM-1454 or DCPP and the at least one mood stabilizer is lithium.

10. The use of claim 7 or 8, wherein the at least one carbostyril derivative is dehydroaripiprazole, DM-1458, DM-1451, DM-1452, DM-1454 or DCPP and the at least one mood stabilizer is valproic acid, divalproex sodium or a salt thereof.

11. Use according to claim 7 or 8, wherein the affective disorder is bipolar disorder.

12. The use according to claim 7 or 8, wherein the affective disorder is mania.