WO2012002583A1 - Method for treating schizophrenia and related diseases with a combination therapy - Google Patents
Method for treating schizophrenia and related diseases with a combination therapy Download PDFInfo
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- WO2012002583A1 WO2012002583A1 PCT/JP2011/065646 JP2011065646W WO2012002583A1 WO 2012002583 A1 WO2012002583 A1 WO 2012002583A1 JP 2011065646 W JP2011065646 W JP 2011065646W WO 2012002583 A1 WO2012002583 A1 WO 2012002583A1
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- lurasidone
- serotonin receptor
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- receptor ligand
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Definitions
- the invention relates to a method for treating schizophrenia and/or related diseases comprising administering two or more ingredients, and a pharmaceutical product thereof.
- the instant invention is directed to a method for treating schizophrenia and/or bipolar disorder which comprises administering lurasidone and a serotonin receptor ligand to a mammal in need thereof, and other invention categories thereof.
- Lurasidone [chemical name: (3aR, AS, 1R, laS) -2- ⁇ (If?, 2R) - 2- [4- (1, 2-benzisothiazol-3-yl) piperazin-l-ylmethyl] cyclo- hexylmethyl ⁇ hexahydro-4 , 7-methano-2ff-isoindole-l , 3-dione] of the following formula is a novel psychotropic agent, which is characteristic of a high affinity for dopamine D 2 , serotonin 5-HTi A , 5-HT 2 A, 5-HT 7 , and noradrenaline 2 c receptors and of minimal to no affinity for histamine Hi and muscarinic Mi receptors.
- Lurasidone possesses antipsychotic effects, antidepressant- or anxiolytic-like effects, and pro-cognitive effects with potentially reduced liability for extrapyramidal and CNS depressant side effects, which is expected to be used for the treatment of schizophrenia and bipolar disorder (Japan Patent Application JP-5 (1993) -17440 A; JM Meyer et al. Exp Opin Invest Drugs 18(11): 1715-1726 (2009)).
- Serotonin mediates its diverse physiological effects through at least 14 different receptor subtypes, 13 receptors of which belong to the G-protein-coupled receptor families.
- 5-HTi A and 5-HT 7 receptors are negatively or positively coupled with adenylate cyclase and cyclic adenosine monophosphate (cAMP) production, respectively.
- 5-HT 6 receptor is another receptor which positively regulates adenylate cyclase and cAMP production.
- 5-HT 2 A and 5-HT 2 c receptors are preferentially coupled with G q/ n to increase inositol phosphates and cytosolic [Ca 2+ ] .
- the present inventors have extensively studied to find out more potent psychotropic agents and then have found that the novel combination of the present invention exhibit the desired pharmacological actions. Based upon the new findings, the present invention has been completed.
- the instant invention is directed to a method for treating schizophrenia and/or bipolar disorder which comprises administering a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a therapeutically effective amount of a serotonin receptor ligand to a mammal in need thereof.
- the instant invention is directed to a method for (i) preventing the onset and progression of schizophrenia and/or (ii) improving symptoms in schizophrenia, which comprises administering a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a therapeutically effective amount of a serotonin receptor ligand to a mammal in need thereof.
- the symptoms in schizophrenia include positive symptoms in schizophrenia, negative symptoms in schizophrenia, and cognitive impairment associated with schizophrenia.
- one embodiment of the invention is directed to a method for improving (i) positive symptoms in schizophrenia, (ii) negative symptoms in schizophrenia, and/or (iii) cognitive impairment associated with schizophrenia, which comprises administering a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a therapeutically effective amount of a serotonin receptor ligand to a mammal in need thereof.
- One embodiment of the invention is directed to a pharmaceutical product for treating schizophrenia and/or bipolar disorder which comprises a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a therapeutically effective amount of a serotonin receptor ligand.
- One embodiment of the invention is directed to lurasidone or a pharmaceutically acceptable acid addition salt thereof for use in a method for treating schizophrenia and/or bipolar disorder in combination with a serotonin receptor ligand.
- one embodiment of the invention is directed to a serotonin receptor ligand for use in a method for treating schizophrenia and/or bipolar disorder in combination with lurasidone or a pharmaceutically acceptable acid addition salt thereof.
- One embodiment of the invention is directed to lurasidone or a pharmaceutically acceptable acid addition salt thereof for use in a method for potentiating the efficacy of a serotonin receptor ligand for treating schizophrenia and/or bipolar disorder.
- one embodiment of the invention is directed to a serotonin receptor ligand for use in a method for potentiating the efficacy of lurasidone or a pharmaceutically acceptable acid addition salt thereof for treating schizophrenia and/or bipolar disorder.
- One embodiment of the invention is directed to a kit for treating schizophrenia and/or bipolar disorder which comprises a first composition including lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a second composition including a serotonin receptor ligand.
- One embodiment of the invention is directed to use of a combination comprising lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a serotonin receptor ligand in the manufacture of a pharmaceutical composition for treating schizophrenia and/or bipolar disorder .
- One embodiment of the invention is directed to use of lurasidone or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a medicament for treating schizophrenia and/or bipolar disorder in combination with a serotonin receptor ligand.
- One embodiment of the invention is directed to use of lurasidone or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a pharmaceutical composition for potentiating the efficacy of a serotonin receptor ligand for treating schizophrenia and/or bipolar disorder .
- one embodiment of the invention is directed to use of a serotonin receptor ligand in the manufacture of a pharmaceutical composition for potentiating the efficacy of lurasidone or a pharmaceutically acceptable acid addition salt thereof for treating schizophrenia and/or bipolar disorder.
- One embodiment of the invention is directed to a medicament for treating schizophrenia and/or bipolar disorder which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a serotonin receptor ligand.
- One embodiment of the invention is directed to a medicament for treating schizophrenia and/or bipolar disorder which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof for the administration in combination with a serotonin receptor ligand.
- One embodiment of the invention is directed to a medicament for potentiating the efficacy of a serotonin receptor ligand for treating schizophrenia and/or bipolar disorder which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof.
- one embodiment of the invention is directed to a medicament for potentiating the efficacy of lurasidone or a pharmaceutically acceptable acid addition salt thereof for treating schizophrenia and/or bipolar disorder which comprises a serotonin receptor ligand.
- the serotonin receptor ligand used herein is a 5-HTi A agonist (more preferably, a selective 5-HTi A agonist) , a 5-HT 7 antagonist (more preferably, a selective 5-HT 7 antagonist) , a 5-HT 6 antagonist (more preferably, a selective 5-HT 6 antagonist) or a 5-HT2 C agonist (more preferably, a selective 5-HT 2c agonist) , and more preferably a 5-HT 1A agonist, or a 5-HT 7 antagonist.
- a 5-HTi A agonist more preferably, a selective 5-HTi A agonist
- a 5-HT 7 antagonist more preferably, a selective 5-HT 7 antagonist
- a 5-HT 6 antagonist more preferably, a selective 5-HT 6 antagonist
- a 5-HT2 C agonist more preferably, a selective 5-HT 2c agonist
- the serotonin receptor ligand used herein is a 5-HT 2A antagonist or a 5-HT 2A inverse agonist.
- the serotonin receptor ligand used herein is selected from the compounds listed in the following table and pharmaceutically acceptable salts thereof.
- the serotonin receptor ligand used herein is selected from the group consisting of tandospirone, buspirone, gepirone, flibanserin, osemozotan, befiradol, piclozotan, F-15599, naluzotan, flesionoxan, isapirone, eptapirone, repinotan, Org-13011, alnespirone, lesopitron, adatanserin, zalospirone, ebalzotan, U-93385, EMD-56551, binospirone, CGS-19480A, Ru-24969, R-137696, amisulpride, SB-269970-A, SB-656104-A, DR-4446, DR-4365, DR-4485, SB
- the more preferable serotonin receptor ligand is selected from the group consisting of tandospirone, amisulpride, SB-269970-A, SB-656104-A, eplivanserin, pimavanserin, M100907, lorcaserin hydrochloride, PRX-00933, mCPP, vabicaserin hydrochloride, CP-809101, SB-258585, SAM-531, GSK-742457, Lu-AE-58054, and pharmaceutically acceptable salts, different salts or free forms thereof; and even more preferable serotonin receptor ligand is tandospirone, amisulpride, SB-269970-A, SB- 656104-A, pimavanserin and a pharmaceutically acceptable salt thereof. (List of 5-HT IA agonist)
- Amisulpride 4-Amino-N- (l-ethyl-2- US 4294828 [71675-85-9] pyrrolidinylmethyl) -5- (ethyl- sulfonyl) -2-methoxybenzamide
- serotonin receptor ligand used herein also includes the serotonin receptor ligands disclosed in the following references.
- the combination of the present invention is useful for treating schizophrenia and/or bipolar disorder, especially for improving cognitive impairment associated with schizophrenia .
- the combination of the present invention may include a combination of lurasidone or a pharmaceutically acceptable acid addition salt thereof, and two or more kinds of serotonin receptor ligands.
- the 5-HTi A agonist used herein also includes a 5-HTi A partial agonist.
- the 5-HT 7 antagonist used herein also includes a 5-HT 7 inverse agonist.
- the 5-HT 6 antagonist used herein also includes a 5-HT6 inverse agonist and the 5-HT 2 c agonist used herein also includes a 5-HT 2 c partial agonist.
- the method of the instant invention comprising the combined administration can bring in some unexpected effects in the treatment of schizophrenia and/or bipolar disorder.
- the merits of the instant invention comprising the combined administration include potentiating the efficacy produced by the single-treatment with each medicament, and/or reducing side effects caused by the single-treatment with each medicament.
- the efficacy includes, for example, but is not limited to, improving "positive symptoms” (hallucinations, delusions, and conceptual disorganization) , "negative symptoms” (apathy, social withdrawal, affect, and poverty of speech), and/or "cognitive impairment” (confused thinking and speech or disorganized behavior and perception) of schizophrenia.
- the side effects include, for example, but are not limited to, extrapyramidal or CNS depressant side effects.
- the instant invention is directed to a method for preventing schizophrenia and/or bipolar disorder, especially for preventing cognitive impairment associated with schizophrenia, which comprises administering a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof.
- Another embodiment of the invention is directed to use of lurasidone or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a pharmaceutical composition for preventing schizophrenia and/or bipolar disorder, especially for preventing cognitive impairment associated with schizophrenia.
- Another embodiment of the invention is directed to lurasidone or a pharmaceutically acceptable acid addition salt thereof for use in a method for preventing schizophrenia and/or bipolar disorder, especially for preventing cognitive impairment associated with schizophrenia .
- Another embodiment of the invention is directed to a medicament for preventing schizophrenia and/or bipolar disorder, especially for preventing cognitive impairment associated with schizophrenia, which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof.
- the embodiments in this paragraph include the case that the serotonin receptor ligand mentioned above is used in combination with lurasidone or a pharmaceutically acceptable acid addition salt thereof.
- the instant invention is directed to a method for "curing" schizophrenia and/or bipolar disorder, especially for "curing" cognitive impairment associated with schizophrenia, which comprises administering a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof.
- Another embodiment of the invention is directed to use of lurasidone or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a pharmaceutical composition for "curing" schizophrenia and/or bipolar disorder, especially for "curing" cognitive impairment associated with schizophrenia.
- Another embodiment of the invention is directed to lurasidone or a pharmaceutically acceptable acid addition salt thereof for use in a method for "curing" schizophrenia and/or bipolar disorder, especially for "curing" cognitive impairment associated with schizophrenia.
- Another embodiment of the invention is directed to a medicament for "curing" schizophrenia and/or bipolar disorder, especially for "curing" cognitive impairment associated with schizophrenia, which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof.
- Fig. 1 shows the dose dependent effect of lurasidone HC1 (Lur) against the PCP-induced deficits, i.e. the effect of acute administration of lurasidone HC1 (0.03 and 0.1 mg/kg) , after subchronic PCP treatment.
- Fig. 2 shows the effect of acute administration of tandospirone citrate (0.2 mg/kg), tandospirone citrate (0.2 mg/kg) plus lurasidone HC1 (0.03 mg/kg, a sub-effective dose), and tandospirone citrate (0.2 mg/kg) plus pimavanserin (3 mg/kg) after subchronic PCP treatment.
- Tandospirone citrate alone 0.2 mg/kg, Tand (0.2) did not reverse the PCP-induced deficits.
- Fig. 3 shows the effect of acute administration of SB-
- Fig. 4 shows the effect of acute administration of amisulpride (1 mg/kg) after subchronic PCP treatment. Amisulpride (1 mg/kg, Ami (1)) did not reverse the PCP- induced deficits.
- Fig. 5 shows the effect of acute administration of amisulpride plus lurasidone HC1 (0.03 mg/kg) after subchronic PCP treatment.
- Fig. 6 shows the effect of acute administration of pimavanserin (3 mg/kg) and pimavanserin (3 mg/kg) plus lurasidone HC1 (0.03 mg/kg) after subchronic PCP treatment.
- Fig. 7 shows the effect of acute administration of MK- 212 (0.03 mg/kg) and MK-212 (0.03 mg/kg) plus lurasidone HC1 (0.03 mg/kg) after subchronic PCP treatment.
- Fig. 8 shows the effect of co-administration of a low dose (0.1 mg/kg) and a high dose (1 mg/kg) of lurasidone HC1 with PCP for 7 days (day 1-7) on the onset and the progression of NOR deficits at day 15 and day 22.
- Coadministration of a high dose (1 mg/kg, Lur (1)) but not a low dose (0.1 mg/kg, Lur (0.1)) of lurasidone HC1 with PCP for 7 days (day 1-7) significantly prevented the onset and the progression of the NOR deficits at day 15 and day 22.
- Fig. 9 shows the effect of administration of lurasidone HC1 (1 mg/kg) for 7 days (day 15-21) after subchronic PCP treatment.
- Administration of lurasidone HC1 (1 mg/kg, Lur (1)) for 7 days (day 15-21) "cured" the NOR deficits by day22, which was supposed to be induced by PCP treatment for 7 days (day 1-7) .
- Lurasidone may be used in form of the free base, optionally in form of its pharmaceutically acceptable acid addition salt and/or optionally in form of the hydrate and/or solvate thereof.
- Suitable acid addition salts include, for example, those of the acids selected from succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid and citric acid. Mixtures of the above-mentioned acid addition salts may also be used. From the aforementioned acid addition salts the hydrochloride and the hydrobromide, particularly the hydrochloride, are preferred.
- the serotonin receptor ligands used herein may also be capable of forming its acid addition salt with a pharmaceutically acceptable acid.
- Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, hydrobromide, camsylate, carbonate, hydrochloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, hydroiodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate
- a suitable pharmaceutically acceptable salt thereof may include alkali metal salt, e.g., sodium or potassium salt; alkaline earth metal salt, e.g., calcium or magnesium salt; and salt formed with suitable organic ligand, e.g., quaternary ammonium salt.
- the serotonin receptor ligands used herein may have chiral centers and occur as racemate, racemic mixture and as individual diastereomer, or enantiomer with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention. Further included are all mixtures of the two enantiomers. Also included within the scope of the invention are polymorphs and hydrates of the serotonin receptor ligand of the instant invention.
- the present invention includes within its scope prodrugs of lurasidone and the serotonin receptor ligand.
- prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
- the exemplified prodrugs of the invention include the following types:
- Ester prodrug for carboxyl, hydroxyl or thiol group of the parent drug Phosphate ester prodrug for hydroxyl or amine group of the parent drug.
- Carbonate or carbamate prodrug for carboxyl, hydroxyl or amine group of the parent drug is Carbonate or carbamate prodrug for carboxyl, hydroxyl or amine group of the parent drug.
- Amide prodrug for carboxylic acid or amine group of the parent drug is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-a
- Amino acid-attached prodrug for carboxylic acid or amine group of the parent drug is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe
- Oxime prodrug for ketone, amidine or guanidine group of the parent drug Oxime prodrug for ketone, amidine or guanidine group of the parent drug.
- the prodrugs of the invention can be prepared, for example, by means disclosed in Nature Reviews Drug Discovery 7; 255 - 270 (2008); or Journal of Medicinal Chemistry 2005, 48 (16), 5305-5320.
- terapéuticaally effective amount shall mean the amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
- treating and “treatment” used herein include any treatment of the disease (e.g. improvement of the symptoms, relief of the symptoms, arrest of the development of the symptoms, etc.) as well as any prevention of the disease (e.g. prevention of the onset and/or progression of the disease).
- curing and "cure” used herein mean producing an enduring improvement in animal models and possibly patients with schizophrenia or other psychiatric disorders. We do not conclude from these studies that brain abnormalities can be entirely eliminated without trace. Rather we claim to have produced an enduring effect in the rat that may also be signal enduring improvement in humans with mental illness that persists after drug treatment is stopped for a finite period of time. As contrasted with our results in the present invention (for example, EXAMPLE 10), some drug treatments reverse the effect of sub-chronic PCP only transiently, or not at all. Such treatments do not "cure” the rat or would not be expected to produce enduring improvement in humans .
- the term "pharmaceutical product” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts .
- schizophrenia includes, but is not limited to, the disorganized type, the catatonic type, the paranoid type, the undifferentiated type, the residual type of schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance- induced psychotic disorder, and psychotic disorder not otherwise specified.
- the symptoms of schizophrenia include positive symptoms in schizophrenia, negative symptoms in schizophrenia, and cognitive impairment associated with schizophrenia.
- bipolar disorder includes, but is not limited to, bipolar I, bipolar II, cyclothymia and other types based on the nature and severity of mood episodes experienced.
- lurasidone and the serotonin receptor ligand may be administered separately or together in one pharmaceutical composition.
- the administration of one element of the combination of the present invention may be prior to, concurrent with, or subsequent to the administration of the other element of the combination.
- the elements of the combination of two active ingredients of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant) , buccal, nasal, vaginal, rectal, sublingual, or topical (e.g., ocular eyedrop) routes of administration and may be formulated alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
- the pharmaceutical product for the administration of the two active ingredients of the invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredients into association with a carrier which is constituted of one or more accessory ingredients. In general, the pharmaceutical product is prepared by uniformly and intimately bringing the active ingredients into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired dosage form. In the pharmaceutical compositions the active compounds are included in an amount sufficient to produce the desired pharmacologic effect.
- the pharmaceutical product containing the two active ingredients, separately or together, that are suitable for oral administration may be in the form of discrete units such as hard or soft capsules, tablets, troches or lozenges, each containing a predetermined amount of the active ingredients, in the form of a dispersible powder or granules, and so on.
- Dosage forms intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical formulations and such compositions.
- the excipients used orally may be, for example, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents.
- the dosage of the active ingredients in the compositions of this invention may be varied. However, it is necessary that the amount of the two active ingredients can be such that a suitable dosage form is obtained.
- the selected dosage and the dosage form depend upon the desired therapeutic effect, on the route of administration and on the duration of the treatment. Dosage ranges in the combination are approximately 0.3 to 1.0 time, preferably 0.5 to 1.0 time the clinically effective ranges required to induce the desired therapeutic effect, respectively when the compounds are used singly.
- a daily dosage of each medicament for adults includes the following dosages, for example.
- 400 mg t.i.d means that 400 mg which is a daily dosage is administered in 3 portions.
- Lurasidone HCl 1-400 mg q.d., preferably 10-200 mg q.d., more preferably 20-160 mg q.d.
- Lurasidone (free form) or a pharmaceutically acceptable acid addition salt of Lurasidone: the equivalent dose of the above Lurasidone HCl (i.e., the lurasidone molarity of which corresponds to that of the above Lurasidone HCl) .
- Lurasidone HCl for prevention or "cure” 1-400 mg q.d., preferably 40-320 mg q.d., more preferably 80-240 mg q.d.
- Tandospirone citrate 1-400 mg q.d., b.i.d, or t.i.d., preferably 5-200 mg q.d., b.i.d., or t.i.d., more preferably 5-100 mg q.d., b.i.d., or t.i.d.
- Amisulpride 1-4000 mg q.d., b.i.d., or t.i.d., preferably 10-4000 mg q.d., b.i.d., or t.i.d., more preferably 20-2000 mg q.d., b.i.d., or t.i.d. (recommended single treatment doses in rodent models: 1-10 mg/kg, i.p).
- SB-269970-A 1-4000 mg q.d., b.i.d., or t.i.d., preferably 10-4000 mg q.d., b.i.d., or t.i.d., more preferably 20-2000 mg q.d., b.i.d., or t.i.d. (recommended single treatment doses in rodent models: 1-10 mg/kg, i.p).
- SB-656104-A 1-4000 mg q.d., b.i.d., or t.i.d., preferably 10-4000 mg q.d., b.i.d., or t.i.d., more preferably 20-2000 mg q.d., b.i.d., or t.i.d. (recommended single treatment doses in rodent models: 1-10 mg/kg, i.p).
- the two active ingredients are prepared in a single dosage form, they are incorporated in a ratio of 0.1 to 100 parts by weight, preferably 0.2 to 50 parts by weight of serotonin receptor ligand per 1 part by weight of lurasidone, lurasidone HC1 or a pharmaceutically acceptable acid addition salt thereof.
- the drug combination may include the sum of the ingredients in 0.1 - 70 % (w/w) per the preparation, but not limited thereto.
- PCP Phencyclidine
- Pimavanserin and tandospirone citrate were dissolved in distilled water.
- Lurasidone HC1 was dissolved in 0.5% methylcellulose with 0.2% Tween 80.
- Amisulpride was dissolved in 0.1 M phosphoric acid.
- SB-269970-A and MK-212 was dissolved in saline.
- the object recognition test was performed in an open field comprising a square box made of Plexiglas (52/52/31 cm) placed 37 cm above the floor on an immoveable stand.
- the floor of the box was white with black gridlines forming nine identical squares on it. All other walls were black.
- a video camera connected to a video recorder and monitor was positioned above the box.
- the objects used for the test consisting of four heavy pyramidal structures made of metal or Perspex that could not be displaced by the animals Care was taken to ensure that these objects were not of any natural significance to the rats.
- Tl In Trial 1 (Tl) or the acquisition trial, the animals were allowed to explore two identical objects (Al and A2) for 3 min.
- T2 In the second trial (T2) or the retention trial, the animals explored a familiar object (A) from Tl and a novel object (B) for 3 min.
- the familiar object presented during T2 was a duplicate of the object presented in Tl to avoid any olfactory trails.
- Each rat was tested three or four times in the NOR paradigm. To reduce carryover effects, a 7-day washout period was given between each of the test sessions. The criterion for continuing to test the rats was based on mean total exploration time in the acquisition or retention phase 5 seconds. If a rat did not explore at least that amount, they were excluded from the analysis. This happened rarely and not enough to affect the ability to use the remaining animals for analysis.
- Behavior in all trials was recorded on video for subsequent blind scoring for the following parameters: total exploration time of both objects in the acquisition trial (s) , total exploration time of objects in the retention trial (s).
- Object exploration is defined by animals licking, sniffing, or touching the object with the forepaws while sniffing, but not leaning against, turning around, standing, or sitting on the object.
- the exploration time(s) of each object in each trial was recorded by use of two stopwatches.
- 5-HTi A agonism, 5-HT 7 antagonism, 5-HT 2 A inverse agonism or 5-HT 2 c agonism is relevant to the ability of atypical APDs (antipsychotic drugs) to ameliorate the PCP-induced NOR deficits, which is used as an animal model of cognitive impairment associated with schizophrenia.
- atypical APDs antipsychotic drugs
- the combined administration of serotonin receptor ligands with at least some atypical APDs may be a way to minimize side effects from the atypical APDs and possibly enhance efficacy for cognition and other domains of psychopathology.
- the combined effect of lurasidone and tandospirone or of lurasidone and SB-269970- A can be evaluated in the improvement of positive symptoms in schizophrenia.
- Lurasidone HC1 0.3-10 mg/kg, p.o., 10 mL/kg in 0.5% methylcellulose
- tandospirone citrate 0.1-1 mg/kg, i.p., 10 mL/kg in saline
- SB-269970-A 0.1-10 mg/kg, i.p 10 mL in saline
- PCP 4.5 mg/kg, s.c, 10 mL/kg in saline
- spontaneous locomotor activity of each mouse is automatically measured with SCANET (MV-20 plus, Melquest Co., Ltd.) for 55 min. Total activities for 55 min are statistically compared among groups .
- Lurasidone HC1 (0.3-10 mg/kg, p.o., 10 mL/kg in 0.5% methylcellulose) is administered 30 min prior to administration of tandospirone citrate (0.1-1 mg/kg, i.p., 10 mL/kg in saline) or of SB-269970-A (0.1-10 mg/kg, i.p., 10 mL/kg in saline) in combination with methamphetamine (4 mg/kg, i.p., 10 mL/kg in saline) and chlordiazepoxide (10 mg/kg, i.p., 10 mL/kg in saline).
- Lurasidone HCl 0.1 mg/kg and 1 mg/kg
- PCP 2 mg/kg, twice a day, i.p.
- the rats are given a 7-days or 14-days drug-free period prior to NOR testing (day 8-14 or day 8-21, respectively) .
- day 15 or day 22 the NOR test is performed. Data are shown in the following table as mean ⁇ SEM of exploration time.
- EXAMPLE 8 The same experiment as EXAMPLE 8 is carried out using any one of the medicaments listed in Paragraph [0018] (especially, amisulpride, SB-656104-A, eplivanserin, pimavanserin, M100907, lorcaserin hydrochloride, PRX-00933, mCPP, Vabicaserin hydrochloride, CP-809101, SB-258585, SAM- 531, GSK-742457, or Lu-AE-58054) or a pharmaceutically acceptable salt, different salt or free form thereof, instead of tandospirone citrate or SB-269970-A.
- the combined effect of lurasidone and each medicament can be evaluated in the treatment to prevent the onset and progression of schizophrenia.
- EXAMPLE 10 the combined effect of lurasidone and each medicament can be evaluated in the treatment to prevent the onset and progression of schizophrenia.
- PCP 10 mg/kg, s.c.
- mice are placed in an acrylic square arena (30 x 45 x 40 cm) for 3 hrs under light, each mouse is separated and habituated to the arena under dark condition for 15 min. Then every mouse is randomly assigned to an unfamiliar partner in each drug-treated group.
- Tandospirone citrate 0.2 mg/kg
- SB-269970-A 0.1 mg/kg
- lurasidone HC1 lurasidone HC1
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Abstract
The invention relates to a method for treating schizophrenia and/or related diseases comprising administering lurasidone and a serotonin receptor ligand to a mammal in need thereof.
Description
DESCRIPTION
METHOD FOR TREATING SCHIZOPHRENIA AND RELATED DISEASES WITH
A COMBINATION THERAPY
TECHNICAL FIELD
[0001]
The invention relates to a method for treating schizophrenia and/or related diseases comprising administering two or more ingredients, and a pharmaceutical product thereof. In more detail, the instant invention is directed to a method for treating schizophrenia and/or bipolar disorder which comprises administering lurasidone and a serotonin receptor ligand to a mammal in need thereof, and other invention categories thereof.
BACKGROUND ART
[0002]
Lurasidone [chemical name: (3aR, AS, 1R, laS) -2-{ (If?, 2R) - 2- [4- (1, 2-benzisothiazol-3-yl) piperazin-l-ylmethyl] cyclo- hexylmethyl }hexahydro-4 , 7-methano-2ff-isoindole-l , 3-dione] of the following formula is a novel psychotropic agent, which is characteristic of a high affinity for dopamine D2, serotonin 5-HTiA, 5-HT2A, 5-HT7 , and noradrenaline 2c receptors and of minimal to no affinity for histamine Hi
and muscarinic Mi receptors. Lurasidone possesses antipsychotic effects, antidepressant- or anxiolytic-like effects, and pro-cognitive effects with potentially reduced liability for extrapyramidal and CNS depressant side effects, which is expected to be used for the treatment of schizophrenia and bipolar disorder (Japan Patent Application JP-5 (1993) -17440 A; JM Meyer et al. Exp Opin Invest Drugs 18(11): 1715-1726 (2009)).
[0003]
Serotonin mediates its diverse physiological effects through at least 14 different receptor subtypes, 13 receptors of which belong to the G-protein-coupled receptor families. 5-HTiA and 5-HT7 receptors are negatively or positively coupled with adenylate cyclase and cyclic adenosine monophosphate (cAMP) production, respectively. 5-HT6 receptor is another receptor which positively regulates adenylate cyclase and cAMP production. On the other hand, 5-HT2A and 5-HT2c receptors are preferentially coupled with Gq/n to increase inositol phosphates and cytosolic [Ca2+] . These receptor subtypes are widely distributed throughout the central nervous system, especially including the cortex, hippocampus, and basal
ganglia, and are involved in mood regulation and learning and memory function (Behavioural Brain Research (2008) 195, 198-213) . DISCLOSURE OF INVENTION
[0004]
The present inventors have extensively studied to find out more potent psychotropic agents and then have found that the novel combination of the present invention exhibit the desired pharmacological actions. Based upon the new findings, the present invention has been completed.
[0005]
In one embodiment, the instant invention is directed to a method for treating schizophrenia and/or bipolar disorder which comprises administering a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a therapeutically effective amount of a serotonin receptor ligand to a mammal in need thereof.
[0006]
In one embodiment, the instant invention is directed to a method for (i) preventing the onset and progression of schizophrenia and/or (ii) improving symptoms in schizophrenia, which comprises administering a therapeutically effective amount of lurasidone or a
pharmaceutically acceptable acid addition salt thereof, and a therapeutically effective amount of a serotonin receptor ligand to a mammal in need thereof. The symptoms in schizophrenia include positive symptoms in schizophrenia, negative symptoms in schizophrenia, and cognitive impairment associated with schizophrenia.
Accordingly, one embodiment of the invention is directed to a method for improving (i) positive symptoms in schizophrenia, (ii) negative symptoms in schizophrenia, and/or (iii) cognitive impairment associated with schizophrenia, which comprises administering a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a therapeutically effective amount of a serotonin receptor ligand to a mammal in need thereof.
[0007]
One embodiment of the invention is directed to a pharmaceutical product for treating schizophrenia and/or bipolar disorder which comprises a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a therapeutically effective amount of a serotonin receptor ligand.
[0008]
One embodiment of the invention is directed to
lurasidone or a pharmaceutically acceptable acid addition salt thereof for use in a method for treating schizophrenia and/or bipolar disorder in combination with a serotonin receptor ligand.
In addition, one embodiment of the invention is directed to a serotonin receptor ligand for use in a method for treating schizophrenia and/or bipolar disorder in combination with lurasidone or a pharmaceutically acceptable acid addition salt thereof.
[0009]
One embodiment of the invention is directed to lurasidone or a pharmaceutically acceptable acid addition salt thereof for use in a method for potentiating the efficacy of a serotonin receptor ligand for treating schizophrenia and/or bipolar disorder.
In addition, one embodiment of the invention is directed to a serotonin receptor ligand for use in a method for potentiating the efficacy of lurasidone or a pharmaceutically acceptable acid addition salt thereof for treating schizophrenia and/or bipolar disorder.
[0010]
One embodiment of the invention is directed to a kit for treating schizophrenia and/or bipolar disorder which comprises a first composition including lurasidone or a pharmaceutically acceptable acid addition salt thereof, and
a second composition including a serotonin receptor ligand.
[0011]
One embodiment of the invention is directed to use of a combination comprising lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a serotonin receptor ligand in the manufacture of a pharmaceutical composition for treating schizophrenia and/or bipolar disorder .
[0012]
One embodiment of the invention is directed to use of lurasidone or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a medicament for treating schizophrenia and/or bipolar disorder in combination with a serotonin receptor ligand.
[0013]
One embodiment of the invention is directed to use of lurasidone or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a pharmaceutical composition for potentiating the efficacy of a serotonin receptor ligand for treating schizophrenia and/or bipolar disorder .
In addition, one embodiment of the invention is directed to use of a serotonin receptor ligand in the manufacture of a pharmaceutical composition for potentiating the efficacy of lurasidone or a
pharmaceutically acceptable acid addition salt thereof for treating schizophrenia and/or bipolar disorder.
[0014]
One embodiment of the invention is directed to a medicament for treating schizophrenia and/or bipolar disorder which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a serotonin receptor ligand.
[0015]
One embodiment of the invention is directed to a medicament for treating schizophrenia and/or bipolar disorder which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof for the administration in combination with a serotonin receptor ligand.
[0016]
One embodiment of the invention is directed to a medicament for potentiating the efficacy of a serotonin receptor ligand for treating schizophrenia and/or bipolar disorder which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof.
In addition, one embodiment of the invention is directed to a medicament for potentiating the efficacy of lurasidone or a pharmaceutically acceptable acid addition salt thereof for treating schizophrenia and/or bipolar
disorder which comprises a serotonin receptor ligand.
[0017]
In one preferable embodiment, the serotonin receptor ligand used herein is a 5-HTiA agonist (more preferably, a selective 5-HTiA agonist) , a 5-HT7 antagonist (more preferably, a selective 5-HT7 antagonist) , a 5-HT6 antagonist (more preferably, a selective 5-HT6 antagonist) or a 5-HT2C agonist (more preferably, a selective 5-HT2c agonist) , and more preferably a 5-HT1A agonist, or a 5-HT7 antagonist.
In addition, in one preferable embodiment, the serotonin receptor ligand used herein is a 5-HT2A antagonist or a 5-HT2A inverse agonist.
[0018]
In one preferable embodiment, the serotonin receptor ligand used herein, but is not limited to, is selected from the compounds listed in the following table and pharmaceutically acceptable salts thereof. In more preferable embodiment, the serotonin receptor ligand used herein is selected from the group consisting of tandospirone, buspirone, gepirone, flibanserin, osemozotan, befiradol, piclozotan, F-15599, naluzotan, flesionoxan, isapirone, eptapirone, repinotan, Org-13011, alnespirone, lesopitron, adatanserin, zalospirone, ebalzotan, U-93385, EMD-56551, binospirone, CGS-19480A, Ru-24969, R-137696,
amisulpride, SB-269970-A, SB-656104-A, DR-4446, DR-4365, DR-4485, SB-258741, DR-4004, SB-258719, LY-215840, eplivanserin, pimavanserin, ritanserin, pruvanserin, irindalone tartate, ICI-170809, seganserin, M100907, lorcaserin hydrochloride, PRX-00933, ATHX-105, mCPP, vabicaserin hydrochloride, CP-809101, MK-212, latrepirdine hydrochloride, SB-258585, AVN-211, SA -531, GSK-742457, Lu- AE-58054, SYN-120, AVN-322, SYN-114, SUVN-502, AVN-458, and pharmaceutically acceptable salts, different salts or free forms thereof. The more preferable serotonin receptor ligand is selected from the group consisting of tandospirone, amisulpride, SB-269970-A, SB-656104-A, eplivanserin, pimavanserin, M100907, lorcaserin hydrochloride, PRX-00933, mCPP, vabicaserin hydrochloride, CP-809101, SB-258585, SAM-531, GSK-742457, Lu-AE-58054, and pharmaceutically acceptable salts, different salts or free forms thereof; and even more preferable serotonin receptor ligand is tandospirone, amisulpride, SB-269970-A, SB- 656104-A, pimavanserin and a pharmaceutically acceptable salt thereof.
(List of 5-HT IA agonist)
Drug Name Compound Name (Structure) Reference
[CAS Reg. No.]
Tandospirone (lR*,2S*,3R*,4S*)-N-[4-[4-(2- US 5011841 citrate Pyrimidinyl) piperazin-1-
[112457-95-1] yl] butyl ] -2 , 3-norbornane- dicarboximide citrate
Buspirone 8- [4- [4- (2-Pyrimidinyl) - US 4640921 [36505-84-7] piperazin-l-yl] butyl] -8- azaspiro [4.5] decane-7, 9-dione
0
Gepirone 4, 4-Dimethyl-l- [4- [4- (2- US 4782060 hydrochloride pyrimidinyl) piperazin-l-
[83928-66-9] yl] butyl] piperidine-2, 6-dione
hydrochloride
Flibanserin 1- [2- [4- [3- (Trifluoromethyl) - WO 1993/003016 [167933-07-5] phenyl] piperazin-l-yl] ethyl] - 2 , 3-dihydro-lH-benzimidazol-
2-one
Osemozotan 2 (S) - [3- (1, 3-Benzodioxol-5- EP 0446921 hydrochloride yloxy) propylaminomethyl] -1, 4-
[137275-80-0] benzodioxane hydrochloride
ϊ°> -HCI
Drug Name Compound Name (Structure) Reference
[CAS Reg. No.]
Befiradol 1- (3-Chloro-4-fluorophenyl) - WO 1998/022459 fumarate 1- [4-fluoro-4- (5-methyl- [208110-64-9] pyridin-2-ylmethylamino- (free base) methyl) piperidin-1- yl] methanone fumarate
0
Piclozotan 3-Chloro-4- [4- [4- (2-pyridyl) - WO 1996/024594 hydrochloride 1,2,3, 6-tetrahydropyridin-l- hydrate yl] butyl] -1, 4-benzoxazepin- [182415-09-4] 5(4H)-one dihydrochloride
(anhydrous , dihydrate
free base)
[182415-13-0]
(anhydrous;
monoHCl) fi Ύ o HCI
F-15599 1- (3-Chloro-4-fluorophenyl) - WO 2003/106449 [635323-95-4] 1- [4-fluoro-4- (5-methyl- pyrimidin-2-ylmethylamino- methyl) iperidin-l-yl] - methanone
0
Naluzotan N- [3- [4- [4- (Cyclohexylmethyl- WO 2004/069794 hydrochloride sulfonamido) butyl] piperazin- PRX-00023 1-yl] phenyl] acetamide
[740873-82-9] dihydrochloride
(List of 5-HT7 antagonist)
Drug Name Compound Name (Structure) Reference
[CAS Reg. No.]
Amisulpride 4-Amino-N- (l-ethyl-2- US 4294828 [71675-85-9] pyrrolidinylmethyl) -5- (ethyl- sulfonyl) -2-methoxybenzamide
0
SB-269970-A 3- [2 (R) - [2- (4-Methyl- WO 1997/048681 [201038-74-6] piperidin-l-yl) ethyl] - pyrrolidin-l-ylsulfonyl] - phenol
0XX8
Drug Name Compound Name (Structure) Reference
[CAS Reg. No.]
SB-656104-A 6- [2 (R)-[2-[4-(4-Chloro- WO 2002/062788 [446020-51-5 phenoxy) piperidin-l-yl] - (free base) ] ethyl] pyrrolidin-l-yl- sulfonyl] -lH-indole
hydrochloride
3- [4- [4- (4-Chlorophenyl) - WO 2005/109987 piperazin-l-yl] butyl] -3- ethyl-6-fluoro-2 , 3-dihydro- lH-indol-2-one
5, 7-Dichloro-3- [4- [4- (4- WO 2005/109987 chlorophenyl ) piperazin-l-yl ] - butyl] -3-ethyl-2, 3-dihydro- lH-indol-2-one
[372182-67-7] N2- [2- (4-Fluorophenoxy) - WO 2001/085701 ethyl] -N4- [1 (S) - (4-fluoro- phenyl) ethyl] -1,3, 5-triazine- 2,4, 6-triamine
Drug Name Compound Name (Structure) Reference
[CAS Reg. No.]
6- (6, 7-Dimethoxy-l, 2, 3, 4- WO 2004/087124 tetrahydroisoquinolin-2-yl- methylideneamino) indan-l-ol
DR-4446 l-Methyl-2a- [4- (4, 5, 6,7- tetrahydrothieno [3, 2-c] - pyridin-5-yl) butyl] - 1,2, 2a, 3, 4, 5-hexahydrobenzo [cd] indol-2-one
DR-4365 N,N-Dimethyl-2- [4- [2-oxo- WO 1999/033804 [230300-64-8] 1, 2, 2a, 3,4, 5-hexahydrobenzo [cd] indol-2-yl] butyl] - 2, 3, 4, 9-tetrahydro-lH-beta- carboline-9-carboxamide
DR-4485 6-Chloro-2a- [4- [4- (4-chloro- WO 2002/018367 [402942-54-5] phenyl ) -1 , 2 , 3 , 6-tetrahydro- pyridin-l-yl] butyl] -1, 2, 2a, 3,
4 , 5-hexahydrobenzo [cd] indol- 2-one
Drug Name Compound Name (Structure) Reference
[CAS Reg. No.]
SB-258741 4-Methyl-l-[2-[l- (3-methyl- WO 1997/048681 [201038-58-6] phenylsulfonyl) pyrrolidin- 2 (R) -yl] ethyl] piperidine
DR-4004 2a- [4- (4-Phenyl-l,2, 3, 6- WO 1998/000400 [201608-41-5] tetrahydropyridin-l-yl) - butyl]-l,2,2a,3,4,5- hexahydrobenz [cd] indol-2-one
SB-258719 N, 3-Dimethyl-N- [ 1 (R) -methyl- WO 1997/029097 [195199-95-2] 3- (4-methyl-l-piperidinyl) - propyl] benzenesulfonamide
LY-215840 N- [2 (R) -Hydroxycyclopent- US 5043341 [137328-52-0] 1 (S) -yl] -4-isopropyl-7- EP 0452074 methyl-4, 6, 6a (R) , 7, 8, 9, 10,
10a (R) -octahydroindolo [4, 3- fg] quinoline-9 (R) -carboxamide
q
(List of 5-HT6 antagon
Lu-AE-58054 Neuropsychopharm acology 2005, 30 (Suppl. 1) : S54
SYN-120 Synosia
Therapeutics Press Release 2009, May 13
AVN-322 9th Int Conf
Alzheimer
Parkinson Dis (AD/PD) (March 11-15, Prague) 2009, Abst
SYN-114 Synosis
Therapeutics Web Site 2007, January 04
SUVN-502 WO 2004/048330
AVN-458 Avineuro Web
Site 2010, February 23
(List of 5-HT2c agonist)
[6640-24-0]
ATHX-105 DailyDrugNews . co m (Daily Essentials) July 30, 2007
Vabicaserin (-) - (9aR*, 12aS*) -4,5, 6, 7, 9, WO 2003/091250 hydrochloride 9a, 10, 11, 12, 12a-Decahydro-
[620948-34-7] cyclopenta [c] [1, 4] diazepino- [6,7, 1-ij ] quinoline
hydrochloride
CP-809101 2- (3-Chlorobenzyloxy) -6- (1- WO 2003/000666 [479683-64-2] piperazinyl) pyrazine
MK-212 2-Chloro-6- (1-piperazinyl) - WO 2004/096196 [61655-58-1 pyrazine
(hydrochloride
) ]
(List of 5-HT2A antagonist)
Drug Name Compound Name (Structure) Reference
[CAS Reg. No.]
Eplivanserin 1- (2-Fluorophenyl) -3- (4- FR 2639942 [130579-75-8] hydroxyphenyl ) -2(E) -propenone EP 373998
(Z) -0- [2- (dimethylamino) - ethyl] oxime
Pimavanserin N- (4-Fluorobenzyl) -N' - (4- WO 2005/112927 tartrate isobutoxybenzyl) -N- (1-methyl-
[706782-28-7] piperidin-4-yl) urea L- tartrate (2:1)
Ritanserin 6- [2- [4- [Bis (4-fluorophenyl) - EP 0110435 [87051-43-2] methylene] piperidino] ethyl] -
7-methyl-5H-thiazolo [3, 2-a] - pyrimidin-5-one
F
Drug Name Compound Name (Structure) Reference
[CAS Reg. No.]
Pruvanserin 7- [4- [2- (4-Fluorophenyl) - WO 2001/007435 hydrochloride ethyl] piperazin-l-yl-
[320714-97-4] carbonyl] -lH-indole-3- carbonitrile hydrochloride
Irindalone (+)-(lR,3S)-l-[2-[4-(p- WO 2001/041766 tartrate Fluorophenyl) -1-indanyl] -1-
[104113-57-7] piperazinyl] ethyl] -2- imidazolidinone L-(+)- tartrate
ICI-170809 2- (2-Dimethylamino-2-methyl- EP 0066993 [85275-48-5] propylthio) -3-phenylquinoline
hydrochloride
Seganserin 3- [2- [4- [Bis (4-fluorophenyl) - EP 0110435 methylene] piperidino] ethyl] - 2-methyl-4H-pyrido[l,2-a] - pyrimidin-4-one
Expert Opinion on Therapeutic Patents (2010) 20(6), 739-754.
Expert Opinion on Therapeutic Patents (2004) 14(7), 1009-1027.
[0019]
The combination of the present invention is useful for treating schizophrenia and/or bipolar disorder, especially for improving cognitive impairment associated with schizophrenia .
[0020]
The combination of the present invention may include a combination of lurasidone or a pharmaceutically acceptable acid addition salt thereof, and two or more kinds of serotonin receptor ligands.
[0021]
The 5-HTiA agonist used herein also includes a 5-HTiA partial agonist. The 5-HT7 antagonist used herein also includes a 5-HT7 inverse agonist. Additionally, the 5-HT6 antagonist used herein also includes a 5-HT6 inverse agonist and the 5-HT2c agonist used herein also includes a 5-HT2c partial agonist.
[0022]
The method of the instant invention comprising the combined administration can bring in some unexpected effects in the treatment of schizophrenia and/or bipolar disorder. The merits of the instant invention comprising the combined administration include potentiating the efficacy produced by the single-treatment with each medicament, and/or reducing side effects caused by the single-treatment with each medicament. The efficacy includes, for example, but is not limited to, improving "positive symptoms" (hallucinations, delusions, and conceptual disorganization) , "negative symptoms" (apathy, social withdrawal, affect, and poverty of speech), and/or "cognitive impairment" (confused thinking and speech or disorganized behavior and perception) of schizophrenia. The side effects include, for example, but are not limited to, extrapyramidal or CNS depressant side effects.
[0023]
In one embodiment, the instant invention is directed to a method for preventing schizophrenia and/or bipolar disorder, especially for preventing cognitive impairment associated with schizophrenia, which comprises administering a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof.
Another embodiment of the invention is directed to use
of lurasidone or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a pharmaceutical composition for preventing schizophrenia and/or bipolar disorder, especially for preventing cognitive impairment associated with schizophrenia.
Another embodiment of the invention is directed to lurasidone or a pharmaceutically acceptable acid addition salt thereof for use in a method for preventing schizophrenia and/or bipolar disorder, especially for preventing cognitive impairment associated with schizophrenia .
Another embodiment of the invention is directed to a medicament for preventing schizophrenia and/or bipolar disorder, especially for preventing cognitive impairment associated with schizophrenia, which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof.
The embodiments in this paragraph include the case that the serotonin receptor ligand mentioned above is used in combination with lurasidone or a pharmaceutically acceptable acid addition salt thereof.
[0024]
In one embodiment, the instant invention is directed to a method for "curing" schizophrenia and/or bipolar disorder, especially for "curing" cognitive impairment associated with schizophrenia, which comprises
administering a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof.
Another embodiment of the invention is directed to use of lurasidone or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a pharmaceutical composition for "curing" schizophrenia and/or bipolar disorder, especially for "curing" cognitive impairment associated with schizophrenia.
Another embodiment of the invention is directed to lurasidone or a pharmaceutically acceptable acid addition salt thereof for use in a method for "curing" schizophrenia and/or bipolar disorder, especially for "curing" cognitive impairment associated with schizophrenia.
Another embodiment of the invention is directed to a medicament for "curing" schizophrenia and/or bipolar disorder, especially for "curing" cognitive impairment associated with schizophrenia, which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof.
The embodiments in this paragraph include the case that the serotonin receptor ligand mentioned above is used in combination with lurasidone or a pharmaceutically acceptable acid addition salt thereof.
BRIEF DESCRIPTION OF DRAWINGS
[0025]
Fig. 1 shows the dose dependent effect of lurasidone HC1 (Lur) against the PCP-induced deficits, i.e. the effect of acute administration of lurasidone HC1 (0.03 and 0.1 mg/kg) , after subchronic PCP treatment. A high dose (0.1 mg/kg, Lur (0.1)) but not a low dose (0.03 mg/kg, Lur (0.03)) of lurasidone HC1 significantly reversed the PCP- induced deficits.
Fig. 2 shows the effect of acute administration of tandospirone citrate (0.2 mg/kg), tandospirone citrate (0.2 mg/kg) plus lurasidone HC1 (0.03 mg/kg, a sub-effective dose), and tandospirone citrate (0.2 mg/kg) plus pimavanserin (3 mg/kg) after subchronic PCP treatment. Tandospirone citrate alone (0.2 mg/kg, Tand (0.2)) did not reverse the PCP-induced deficits. Co-administration of tandospirone citrate with lurasidone HC1 (0.03 mg/kg, Lur (0.03)) but not with pimavanserin (3 mg/kg, Pirn (3)) significantly reversed the PCP-induced deficits.
Fig. 3 shows the effect of acute administration of SB-
269970-A (0.1 mg/kg) and SB-269970-A (0.1 mg/kg) plus lurasidone HC1 (0.03 mg/kg) after subchronic PCP treatment. SB-269970-A alone (0.1 mg/kg, SB (0.1)) did not reverse the PCP-induced deficits. Co-administration of SB-269970-A with lurasidone HC1 (0.03 mg/kg, Lur (0.03)) significantly
reversed the PCP-induced deficits.
Fig. 4 shows the effect of acute administration of amisulpride (1 mg/kg) after subchronic PCP treatment. Amisulpride (1 mg/kg, Ami (1)) did not reverse the PCP- induced deficits.
Fig. 5 shows the effect of acute administration of amisulpride plus lurasidone HC1 (0.03 mg/kg) after subchronic PCP treatment. Co-administration of amisulpride (1 mg/kg, Ami (1)) with lurasidone HC1 (0.03 mg/kg, Lur (0.03)) significantly reversed the PCP-induced deficits.
Fig. 6 shows the effect of acute administration of pimavanserin (3 mg/kg) and pimavanserin (3 mg/kg) plus lurasidone HC1 (0.03 mg/kg) after subchronic PCP treatment. Co-administration of pimavanserin (3 mg/kg, Pirn (3) ) with lurasidone HC1 (0.03 mg/kg, Lur (0.03)) but not pimavanserin alone significantly reversed the PCP-induced deficits .
Fig. 7 shows the effect of acute administration of MK- 212 (0.03 mg/kg) and MK-212 (0.03 mg/kg) plus lurasidone HC1 (0.03 mg/kg) after subchronic PCP treatment. Coadministration of MK-212 (0.03 mg/kg, MK (0.03)) with lurasidone HC1 (0.03 mg/kg, Lur (0.03)) but not MK-212 alone significantly reversed the PCP-induced deficits.
Fig. 8 shows the effect of co-administration of a low dose (0.1 mg/kg) and a high dose (1 mg/kg) of lurasidone
HC1 with PCP for 7 days (day 1-7) on the onset and the progression of NOR deficits at day 15 and day 22. Coadministration of a high dose (1 mg/kg, Lur (1)) but not a low dose (0.1 mg/kg, Lur (0.1)) of lurasidone HC1 with PCP for 7 days (day 1-7) significantly prevented the onset and the progression of the NOR deficits at day 15 and day 22.
Fig. 9 shows the effect of administration of lurasidone HC1 (1 mg/kg) for 7 days (day 15-21) after subchronic PCP treatment. Administration of lurasidone HC1 (1 mg/kg, Lur (1)) for 7 days (day 15-21) "cured" the NOR deficits by day22, which was supposed to be induced by PCP treatment for 7 days (day 1-7) .
BEST MODE FOR CARRYING OUT THE INVENTION
[0026]
Lurasidone may be used in form of the free base, optionally in form of its pharmaceutically acceptable acid addition salt and/or optionally in form of the hydrate and/or solvate thereof. Suitable acid addition salts include, for example, those of the acids selected from succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid and citric acid. Mixtures of the above-mentioned acid addition salts may also be used. From the aforementioned acid
addition salts the hydrochloride and the hydrobromide, particularly the hydrochloride, are preferred.
[0027]
The serotonin receptor ligands used herein may also be capable of forming its acid addition salt with a pharmaceutically acceptable acid. Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, hydrobromide, camsylate, carbonate, hydrochloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, hydroiodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate) , palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
[0028]
Furthermore, where the serotonin receptor ligands used herein carries an acidic moiety, a suitable pharmaceutically acceptable salt thereof may include alkali
metal salt, e.g., sodium or potassium salt; alkaline earth metal salt, e.g., calcium or magnesium salt; and salt formed with suitable organic ligand, e.g., quaternary ammonium salt.
[0029]
The serotonin receptor ligands used herein may have chiral centers and occur as racemate, racemic mixture and as individual diastereomer, or enantiomer with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention. Further included are all mixtures of the two enantiomers. Also included within the scope of the invention are polymorphs and hydrates of the serotonin receptor ligand of the instant invention.
[0030]
The present invention includes within its scope prodrugs of lurasidone and the serotonin receptor ligand. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
The exemplified prodrugs of the invention, but are not limited to, include the following types:
Ester prodrug for carboxyl, hydroxyl or thiol group of the parent drug.
Phosphate ester prodrug for hydroxyl or amine group of the parent drug.
Carbonate or carbamate prodrug for carboxyl, hydroxyl or amine group of the parent drug.
Amide prodrug for carboxylic acid or amine group of the parent drug.
Amino acid-attached prodrug for carboxylic acid or amine group of the parent drug.
Oxime prodrug for ketone, amidine or guanidine group of the parent drug.
The prodrugs of the invention can be prepared, for example, by means disclosed in Nature Reviews Drug Discovery 7; 255 - 270 (2008); or Journal of Medicinal Chemistry 2005, 48 (16), 5305-5320.
[0031]
The term "therapeutically effective amount" shall mean the amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
The terms "treating" and "treatment" used herein include any treatment of the disease (e.g. improvement of the symptoms, relief of the symptoms, arrest of the development of the symptoms, etc.) as well as any
prevention of the disease (e.g. prevention of the onset and/or progression of the disease).
The terms "curing" and "cure" used herein mean producing an enduring improvement in animal models and possibly patients with schizophrenia or other psychiatric disorders. We do not conclude from these studies that brain abnormalities can be entirely eliminated without trace. Rather we claim to have produced an enduring effect in the rat that may also be signal enduring improvement in humans with mental illness that persists after drug treatment is stopped for a finite period of time. As contrasted with our results in the present invention (for example, EXAMPLE 10), some drug treatments reverse the effect of sub-chronic PCP only transiently, or not at all. Such treatments do not "cure" the rat or would not be expected to produce enduring improvement in humans .
[0032]
As used herein, the term "pharmaceutical product" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts .
[0033]
As used herein, the term "schizophrenia" includes, but
is not limited to, the disorganized type, the catatonic type, the paranoid type, the undifferentiated type, the residual type of schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance- induced psychotic disorder, and psychotic disorder not otherwise specified. In addition, the symptoms of schizophrenia include positive symptoms in schizophrenia, negative symptoms in schizophrenia, and cognitive impairment associated with schizophrenia.
[0034]
As used herein, the term "bipolar disorder" includes, but is not limited to, bipolar I, bipolar II, cyclothymia and other types based on the nature and severity of mood episodes experienced.
[0035]
In the combination of the present invention, lurasidone and the serotonin receptor ligand may be administered separately or together in one pharmaceutical composition. In addition, the administration of one element of the combination of the present invention may be prior to, concurrent with, or subsequent to the administration of the other element of the combination.
The elements of the combination of two active ingredients of the invention (lurasidone and the serotonin receptor ligand) may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant) , buccal, nasal, vaginal, rectal, sublingual, or topical (e.g., ocular eyedrop) routes of administration and may be formulated alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
[0037]
The pharmaceutical product for the administration of the two active ingredients of the invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredients into association with a carrier which is constituted of one or more accessory ingredients. In general, the pharmaceutical product is prepared by uniformly and intimately bringing the active ingredients into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired dosage form. In the pharmaceutical compositions the active compounds are
included in an amount sufficient to produce the desired pharmacologic effect.
[0038]
The pharmaceutical product containing the two active ingredients, separately or together, that are suitable for oral administration may be in the form of discrete units such as hard or soft capsules, tablets, troches or lozenges, each containing a predetermined amount of the active ingredients, in the form of a dispersible powder or granules, and so on.
[0039]
Dosage forms intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical formulations and such compositions. The excipients used orally may be, for example, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents.
[0040]
The dosage of the active ingredients in the compositions of this invention may be varied. However, it is necessary that the amount of the two active ingredients can be such that a suitable dosage form is obtained. The selected dosage and the dosage form depend upon the desired therapeutic effect, on the route of administration and on the duration of the treatment. Dosage ranges in the
combination are approximately 0.3 to 1.0 time, preferably 0.5 to 1.0 time the clinically effective ranges required to induce the desired therapeutic effect, respectively when the compounds are used singly.
[0041]
A daily dosage of each medicament for adults includes the following dosages, for example. In the following list, for example, "400 mg t.i.d." means that 400 mg which is a daily dosage is administered in 3 portions.
Lurasidone HCl: 1-400 mg q.d., preferably 10-200 mg q.d., more preferably 20-160 mg q.d.
Lurasidone (free form) or a pharmaceutically acceptable acid addition salt of Lurasidone: the equivalent dose of the above Lurasidone HCl (i.e., the lurasidone molarity of which corresponds to that of the above Lurasidone HCl) .
Lurasidone HCl for prevention or "cure": 1-400 mg q.d., preferably 40-320 mg q.d., more preferably 80-240 mg q.d.
Tandospirone citrate: 1-400 mg q.d., b.i.d, or t.i.d., preferably 5-200 mg q.d., b.i.d., or t.i.d., more preferably 5-100 mg q.d., b.i.d., or t.i.d.
Amisulpride: 1-4000 mg q.d., b.i.d., or t.i.d., preferably 10-4000 mg q.d., b.i.d., or t.i.d., more preferably 20-2000 mg q.d., b.i.d., or t.i.d. (recommended single treatment doses in rodent models: 1-10 mg/kg, i.p).
SB-269970-A: 1-4000 mg q.d., b.i.d., or t.i.d., preferably 10-4000 mg q.d., b.i.d., or t.i.d., more preferably 20-2000 mg q.d., b.i.d., or t.i.d. (recommended single treatment doses in rodent models: 1-10 mg/kg, i.p).
SB-656104-A: 1-4000 mg q.d., b.i.d., or t.i.d., preferably 10-4000 mg q.d., b.i.d., or t.i.d., more preferably 20-2000 mg q.d., b.i.d., or t.i.d. (recommended single treatment doses in rodent models: 1-10 mg/kg, i.p).
Other serotonin receptor ligands listed in Paragraph [0018]: 1-4000 mg q.d., b.i.d, t.i.d.
[0042]
When the two active ingredients are prepared in a single dosage form, they are incorporated in a ratio of 0.1 to 100 parts by weight, preferably 0.2 to 50 parts by weight of serotonin receptor ligand per 1 part by weight of lurasidone, lurasidone HC1 or a pharmaceutically acceptable acid addition salt thereof. And, the drug combination may include the sum of the ingredients in 0.1 - 70 % (w/w) per the preparation, but not limited thereto.
EXAMPLE 1
[0043]
Experimental procedure
Female Long-Evans rats received vehicle or PCP (2 mg/kg, i.p.) twice daily for 7 days, followed by a 7-day
washout period (n = 6-9/group) . Phencyclidine (PCP) which is known to induce schizophrenia-like symptoms in human normal subjects and to exacerbate symptoms in patients with schizophrenia was dissolved in distilled water and administered in a volume of 1 ml/kg.
On the test day (any day between day 15 and day 43 is available), lurasidone HC1 (0.03 and 0.1 mg/kg; produced by Dainippon Sumitomo Pharma Co., Ltd.), tandospirone citrate (0.2 mg/kg; produced by Dainippon Sumitomo Pharma Co., Ltd.), amisulpride (1 mg/kg; Tocris Bioscience), SB-269970- A (0.1 mg/kg; Tocris Bioscience), pimavanserine (3 mg/kg; Tocris Bioscience), MK-212 (0.03 mg/kg; Tocris Bioscience) alone, or tandospirone citrate (0.2 mg/kg), amisulpride (1 mg/kg), SB-269970-A (0.1 mg/kg), pimavanserine (3 mg/kg), or MK-212 (0.03 mg/kg) in combination with lurasidone HC1 (0.03 mg/kg), or pimavanserine (3 mg/kg) in combination with tandospirone citrate (0.2 mg/kg) were administered intraperitoneally in a volume of 1 mL/kg, 30 min before the novel object recognition (NOR) test.
Pimavanserin and tandospirone citrate were dissolved in distilled water. Lurasidone HC1 was dissolved in 0.5% methylcellulose with 0.2% Tween 80. Amisulpride was dissolved in 0.1 M phosphoric acid. SB-269970-A and MK-212 was dissolved in saline.
[0044]
Novel object recognition (NOR) test
Apparatus .
The object recognition test was performed in an open field comprising a square box made of Plexiglas (52/52/31 cm) placed 37 cm above the floor on an immoveable stand. The floor of the box was white with black gridlines forming nine identical squares on it. All other walls were black. A video camera connected to a video recorder and monitor was positioned above the box. The objects used for the test consisting of four heavy pyramidal structures made of metal or Perspex that could not be displaced by the animals Care was taken to ensure that these objects were not of any natural significance to the rats.
[0045]
Object Recognition Testing.
Testing was carried out according to a previously validated method (Grayson et al., Behav. Brain Res. 2007 184, 31-38; Snigdha et al., J. Pharmacol. Exp. Ther., 2010 332 (2) , 622-31) . The rats were familiarized to the test environment and NOR arena before the test day. Habituation consisting of placing the subjects in the empty NOR arena for 1 h, on the day before the test day (day 1) . Before behavioral testing on day 2, rats were given a further 3- min habituation. For each experimental trial after the 3- min habituation period, the rats were given two 3-min
trials (Tl and T2), separated by a 1-min intertrial interval in the home cage during which the objects were changed and the arena was cleaned. In Trial 1 (Tl) or the acquisition trial, the animals were allowed to explore two identical objects (Al and A2) for 3 min. In the second trial (T2) or the retention trial, the animals explored a familiar object (A) from Tl and a novel object (B) for 3 min. The familiar object presented during T2 was a duplicate of the object presented in Tl to avoid any olfactory trails. Each rat was tested three or four times in the NOR paradigm. To reduce carryover effects, a 7-day washout period was given between each of the test sessions. The criterion for continuing to test the rats was based on mean total exploration time in the acquisition or retention phase 5 seconds. If a rat did not explore at least that amount, they were excluded from the analysis. This happened rarely and not enough to affect the ability to use the remaining animals for analysis.
[0046]
Data Collection.
Behavior in all trials was recorded on video for subsequent blind scoring for the following parameters: total exploration time of both objects in the acquisition trial (s) , total exploration time of objects in the retention trial (s). Object exploration is defined by
animals licking, sniffing, or touching the object with the forepaws while sniffing, but not leaning against, turning around, standing, or sitting on the object. The exploration time(s) of each object in each trial was recorded by use of two stopwatches.
[0047]
Result 1
The effect of acute administration of lurasidone HC1 (0.03 mg/kg and 0.1 mg/kg), after subchronic PCP treatment. Data are shown in the following table as mean + SEM of exploration time. n = 7 to 8 rats per group.
The summarized result is shown in Figure 1. Sub- chronic PCP treatment had no significant effect on object exploration in the acquisition trial. In the retention trial, vehicle-treated rats had a clear preference for novel compared to familiar objects. This effect was abolished in sub-chronic PCP treated rats which explored both objects for an equal amount of time. Acute treatment with lurasidone HC1 reversed the PCP-induced NOR deficits and the effective dose was 0.1 mg/kg.
Acquisition (sec) Retention (sec)
Left Right Familiar Novel
Vehicle 8.9 9.0 3.9 10.3
± 1.0 ± 1.4 ± 0.6 ± 2.1
PCP + Vehicle 11.5 9.5 5.9 6.8
± 2.7 + 1.2 ± 0.9 ± 0.8
PCP 11.4 8.3 7.6 8.9
+ Lurasidone HC1 (0.03 mg/kg) ± 3.1 ± 1.8 ± 2.3 ± 1.7
PCP 10.9 10.9 4.6 11.4
+ Lurasidone HC1 (0.1 mg/kg) ± 1.3 ± 0.8 ± 1.0 + 2.2
[0048]
Result 2
The effect of acute administration of tandospirone citrate (0.2 mg/kg) , tandospirone citrate (0.2 mg/kg) plus lurasidone HC1 (0.03 mg/kg, sub-effective dose), and tandospirone citrate (0.2 mg/kg) plus pimavanserin (3 mg/kg) after subchronic PCP treatment. Data are shown in the following table as mean ± SEM of exploration time, n = 7 to 9 rats per group.
The summarized result is shown in Figure 2. Tandospirone citrate alone did not attenuate the PCP- induced NOR deficits. However, co-administration of tandospirone citrate with sub-effective dose of lurasidone HC1 significantly reversed the PCP-induced deficits, but the co-administration with pimavanserin did not significantly reverse the PCP-induced deficits.
Acquisition (sec) Retention (sec)
Left Right Familiar Novel
Vehicle 13.6 17.1 4.7 15.2
± 2.2 ± 2.9 ± 0.5 ± 2.5
PCP
16.0 16.4 12.6 12.3
+ tandospirone citrate (0.2
± 2.4 ± 3.6 ± 1.9 ± 1.5 mg/kg)
PCP
+ tandospirone citrate (0.2 14.0 12.9 2.9 10.5 mg/kg) ± 1.7 + 3.0 + 0.7 ± 1.3
+ lurasidone HC1 (0.03 mg/kg)
PCP
+ tandospirone citrate (0.2 16.5 14.5 10.7 12.7 mg/kg) ± 3.7 ± 2.9 ± 2.1 + 2.9
+ Pimavanserin (3 mg/kg)
[0049]
Result 3
The effect of acute administration of SB-269970-A (0.1 mg/kg) and SB-269970-A (0.1 mg/kg) plus lurasidone HC1 (0.03 mg/kg) after subchronic PCP treatment. Data are shown in the following table as mean ± SEM of exploration time, n = 7 or 8 rats per group.
The summarized result is shown in Figure 3. SB- 269970-A did not reverse the PCP-induced NOR deficits. Co- administration of SB-269970-A with lurasidone HC1 significantly reversed the NOR deficits induced by PCP.
[0050]
Result 4
The effect of acute administration of amisulpride (1 mg/kg) after subchronic PCP treatment. Data are shown in the following table as mean ± SEM of exploration time, n = 8 rats per group.
The summarized result is shown in Figure 4. Amisulpride did not reverse the PCP-induced deficits.
Acquisition (sec) Retention (sec)
Left Right Familiar Novel
Vehicle 19.6 17.9 8.3 23.0
± 3.2 ± 3.0 ± 1.7 ± 3.8
PCP 20.5 21.5 9.6 13.5
+ amisulpride (1 mg/kg) ± 2.5 ± 4.8 ± 1.6 ± 3.1
[0051]
Result 5
The effect of acute administration of amisulpride (1 mg/kg) plus lurasidone HC1 (0.03 mg/kg) after subchronic PCP treatment. Data are shown in the following table as mean + SEM of exploration time, n = 8 or 9 rats per group.
The summarized result is shown in Figure 5. Coadministration of amisulpride with lurasidone HC1 significantly reversed the PCP-induced NOR deficits.
[0052]
Result 6
The effect of acute administration of pimavanserin (3 mg/kg) and pimavanserin (3 mg/kg) plus lurasidone HC1 (0.03 mg/kg) after subchronic PCP treatment. Data are shown in the following table as mean ± SEM of exploration time. n = 7 to 8 rats per group.
The summarized result is shown in Figure 6. Sub- chronic PCP treatment had no significant effect on object exploration in the acquisition trial. In the retention trial, vehicle-treated rats had a clear preference for novel compared to familiar objects. This effect was abolished in sub-chronic PCP treated rats which explored both objects for an equal amount of time. Acute treatment with pimavanserin alone did not reverse the PCP-induced NOR deficits. On the other hand, co-administration of pimavanserin with lurasidone HCl significantly reversed the PCP-induced NOR deficits.
[0053]
Result 7
The effect of acute administration of K-212 (0.03 mg/kg) and MK-212 (0.03 mg/kg) plus lurasidone HCl (0.03 mg/kg) after subchronic PCP treatment. Data are shown in the following table as mean ± SEM of exploration time. n = 6 to 9 rats per group.
The summarized result is shown in Figure 7. Sub- chronic PCP treatment had no significant effect on object exploration in the acquisition trial. In the retention trial, vehicle-treated rats had a clear preference for novel compared to familiar objects. This effect was abolished in sub-chronic PCP treated rats which explored both objects for an equal amount of time. Acute treatment with MK-212 alone did not reverse the PCP-induced NOR deficits. On the other hand, co-administration of MK-212 with lurasidone HC1 significantly reversed the PCP-induced NOR deficits.
[0054]
These results indicate that 5-HTiA agonism, 5-HT7 antagonism, 5-HT2A inverse agonism or 5-HT2c agonism is relevant to the ability of atypical APDs (antipsychotic drugs) to ameliorate the PCP-induced NOR deficits, which is used as an animal model of cognitive impairment associated with schizophrenia. This suggests that the combined
administration of serotonin receptor ligands with at least some atypical APDs may be a way to minimize side effects from the atypical APDs and possibly enhance efficacy for cognition and other domains of psychopathology.
EXAMPLE 2
[0055]
The same experiment as mentioned above is carried out using any one of the medicaments listed in Paragraph [0018] (especially, SB-656104-A, eplivanserin, M100907, lorcaserin hydrochloride, PRX-00933, mCPP, Vabicaserin hydrochloride, CP-809101, SB-258585, SAM-531, GSK-742457, or Lu-AE-58054) or a pharmaceutically acceptable salt, different salt or free form thereof, instead of tandospirone citrate, amisulpride, SB-269970-A, pimavanserin, or MK-212. According to the experiment, the combined effect of lurasidone and each medicament can be evaluated in the improvement of cognitive impairment associated with schizophrenia .
EXAMPLE 3
[0056]
Using the following method, the combined effect of lurasidone and tandospirone or of lurasidone and SB-269970- A can be evaluated in the improvement of positive symptoms
in schizophrenia.
Effect of lurasidone adjunctive with 5-ΗΊΊΑ agonist tandospirone or 5-HT7 antagonist SB-269970-A is examined in an animal model with phencyclidine (PCP) for predicting antipsychotic activity. Male C57BL/6J mice at age of 8 weeks (n = 8 per group) are used for experiment. Lurasidone HC1 (0.3-10 mg/kg, p.o., 10 mL/kg in 0.5% methylcellulose) and tandospirone citrate (0.1-1 mg/kg, i.p., 10 mL/kg in saline) or SB-269970-A (0.1-10 mg/kg, i.p 10 mL in saline) are administered 60 min and 30 min prior to administration of PCP (4.5 mg/kg, s.c, 10 mL/kg in saline) , respectively. Subsequently, spontaneous locomotor activity of each mouse is automatically measured with SCANET (MV-20 plus, Melquest Co., Ltd.) for 55 min. Total activities for 55 min are statistically compared among groups .
EXAMPLE 4
[0057]
The same experiment as EXAMPLE 3 is carried out using any one of the medicaments listed in Paragraph [0018] (especially, amisulpride, SB-656104-A, eplivanserin, pimavanserin, M100907, lorcaserin hydrochloride, PRX-00933, mCPP, Vabicaserin hydrochloride, CP-809101, SB-258585, SAM- 531, GSK-742457, or Lu-AE-58054) or a pharmaceutically
acceptable salt, different salt or free form thereof, instead of tandospirone citrate or SB-269970-A. According to the experiment, the combined effect of lurasidone and each medicament can be evaluated in the improvement of positive symptoms in schizophrenia.
EXAMPLE 5
[0058]
Using the following method, the combined effect of lurasidone and tandospirone or of lurasidone and SB-269970- A can be evaluated in the treatment of bipolar disorder (K. Okada et al. , Pharmacol Biochem Behav. 35(4): 897-901 (1990) ) .
Effect of lurasidone adjunctive with 5-HTiA agonist tandospirone or 5-HT7 antagonist SB-269970-A is examined in an animal model with methamphetamine and chlordiazepoxide mixture for predicting antimanic activity. Male C57BL/6J mice (n = 8 per group, 20-26 g body weight) are used for experiment. Lurasidone HC1 (0.3-10 mg/kg, p.o., 10 mL/kg in 0.5% methylcellulose) is administered 30 min prior to administration of tandospirone citrate (0.1-1 mg/kg, i.p., 10 mL/kg in saline) or of SB-269970-A (0.1-10 mg/kg, i.p., 10 mL/kg in saline) in combination with methamphetamine (4 mg/kg, i.p., 10 mL/kg in saline) and chlordiazepoxide (10 mg/kg, i.p., 10 mL/kg in saline). Subsequently, digital
image for freely moving mouse in acrylic cage (W 360 mm x D 230 mm x H 310 mm) is recorded for 90 min and travel distance for 60 min after initial 30 min habituation period is automatically measured with Noldus Ethovision software ver 3.1. Travel distances are statistically compared among groups .
EXAMPLE 6
[0059]
The same experiment as EXAMPLE 5 is carried out using any one of the medicaments listed in Paragraph [0018] (especially, amisulpride, SB-656104-A, eplivanserin, pimavanserin, M100907, lorcaserin hydrochloride, PRX-00933, mCPP, Vabicaserin hydrochloride, CP-809101, SB-258585, SAM- 531, GSK-742457, or Lu-AE-58054) or a pharmaceutically acceptable salt, different salt or free form thereof, instead of tandospirone citrate or SB-269970-A. According to the experiment, the combined effect of lurasidone and each medicament can be evaluated in the treatment of bipolar disorder.
EXAMPLE 7
[0060]
Using the following method with NOR test as shown in EXAMPLE 1, the effect of lurasidone was evaluated in the
treatment to prevent the onset and progression of schizophrenia. Lurasidone HCl (0.1 mg/kg and 1 mg/kg) was administered intraperitoneally in a volume of 1 mL/kg to female Long-Evans rats (n = 6-9/group) 30 min before every treatment with PCP (2 mg/kg, twice a day, i.p.) for 7 days (day 1-7). Subsequently, the rats are given a 7-days or 14-days drug-free period prior to NOR testing (day 8-14 or day 8-21, respectively) . On day 15 or day 22, the NOR test is performed. Data are shown in the following table as mean ± SEM of exploration time.
The summarized result is shown in Figure 8. Sub- chronic PCP treatment had no significant effect on object exploration in the acquisition trial. In the retention trial, vehicle-treated rats had a clear preference for novel compared to familiar objects. This effect was abolished in sub-chronic PCP treated rats which explored both objects for an equal amount of time. Coadministration of a high dose (1 mg/kg) but not a low dose (0.1 mg/kg) of lurasidone HCl with PCP for 7 days (day 1-7) prevented the onset and the progression of the NOR deficits at day 15 and day 22.
Acquisition (sec) Retention (sec)
Left Right Familiar Novel
Vehicle 18.2 16.3 5.4 14.9
± 2.2 ± 2.3 ± 1.5 ± 3.1
PCP + Vehicle 20.4 22.1 12.6 16.9
(day 15) ± 3.6 ± 3.1 ± 3.4 ± 4.4
PCP 17.5 18.2 8.3 15.2
+ Lurasidone HC1 (0.1 mg/kg) ± 3.4 ± 3.2 ± 2.1 ± 3.5
(day 15)
PCP 22.0 23.0 6.6 21.1
+ Lurasidone HC1 (1 mg/kg) ± 2.8 ± 1.3 ± 0.9 + 3.5
(day 15)
PCP 20.3 19.1 8.0 19.3
+ Lurasidone HC1 (1 mg/kg) ± 2.4 ± 3.2 ± 1.6 ± 2.4
(day 22)
EXAMPLE 8
[0061]
Using the following method with NOR test as shown in EXAMPLE 7, the combined effect of lurasidone and tandospirone or of lurasidone and SB-269970-A can be evaluated in the treatment to prevent the onset and progression of schizophrenia. Tandospirone citrate (0.2 or 2 mg/kg) or SB-269970-A (0.1 or 1 mg/kg) and lurasidone HC1 (0.03 or 3 mg/kg) are co-administered intraperxtoneally in a volume of 1 mL/kg to female Long-Evans rats (n = 6- 9/group) 30 min before every treatment with PCP (2 mg/kg, twice a day, i.p.) for 7 days (dayl-7). Subsequently, rats are given a 7-days drug-free period prior to NOR testing (day 8-14). On day 15, the NOR test is performed.
EXAMPLE 9
[0062]
The same experiment as EXAMPLE 8 is carried out using any one of the medicaments listed in Paragraph [0018] (especially, amisulpride, SB-656104-A, eplivanserin, pimavanserin, M100907, lorcaserin hydrochloride, PRX-00933, mCPP, Vabicaserin hydrochloride, CP-809101, SB-258585, SAM- 531, GSK-742457, or Lu-AE-58054) or a pharmaceutically acceptable salt, different salt or free form thereof, instead of tandospirone citrate or SB-269970-A. According to the experiment, the combined effect of lurasidone and each medicament can be evaluated in the treatment to prevent the onset and progression of schizophrenia. EXAMPLE 10
[0063]
Using the following method with NOR test as shown in EXAMPLE 1, the effect of lurasidone was evaluated in the treatment to "cure" schizophrenia. PCP (2 mg/kg) was administered intraperitoneally to female Long-Evans rats (n = 5-9/group) twice a day for 7 days (day 1-7) . After a 7- day washout period (day 8-14), they also received lurasidone HC1 (1 mg/kg) for 7-days (day 15-21) . NOR was tested in the vehicle- or PCP-treated rats one day after the end of lurasidone administration (day 22) . Data are
shown in the following table as mean ± SEM of exploration time .
The summarized result is shown in Figure 9. Sub- chronic PCP treatment had no significant effect on object exploration in the acquisition trial. In the retention trial, vehicle-treated rats had a clear preference for novel compared to familiar objects. This effect was abolished in sub-chronic PCP treated rats which explored both objects for an equal amount of time. Administration of lurasidone HC1 (1 mg/kg) for 7 days (day 15-21) "cured" the NOR deficits at day 22, which was supposed to be induced by sub-chronic PCP treatment (day 1-7) .
EXAMPLE 11
[0064]
Using the following method with NOR test as shown in EX7AMPLE 10, the combined effect of lurasidone and tandospirone or of lurasidone and SB-269970-A can be evaluated in the treatment to "cure" schizophrenia. PCP (2 mg/kg) is administered intraperitoneally to female Long- Evans rats (n = 5-9/group) twice a day for 7 days (day 1-7) .
After a 7-day washout period (day 8-14), they also receive tandospirone citrate (0.2 or 2 mg/kg) or SB-269970-A (0.1 or 1 mg/kg) and lurasidone HC1 (0.03 or 3 mg/kg). NOR is tested in the vehicle- or PCP-treated rats one day after the end of the co-administration (day 22).
EXAMPLE 12
[0065]
The same experiment as EXAMPLE 11 is carried out using any one of the medicaments listed in Paragraph [0018] (especially, amisulpride, SB-656104-A, eplivanserin, pimavanserin, M100907, lorcaserin hydrochloride, PRX-00933, mCPP, Vabicaserin hydrochloride, CP-809101, SB-258585, SAM- 531, GSK-742457, or Lu-AE-58054) or a pharmaceutically acceptable salt, different salt or free form thereof, instead of tandospirone citrate or SB-269970-A. According to the experiment, the combined effect of lurasidone and each medicament can be evaluated in the treatment to "cure" schizophrenia .
EXAMPLE 13
[0066]
Using the following method, the combined effect of lurasidone and tandospirone or SB-269970-A can be evaluated in the improvement of negative symptoms in schizophrenia.
PCP (10 mg/kg, s.c.) is administered to male ICR mice (6 weeks of age, n = 8/group) twice a day for 5 days. Two to five days later, the social interaction test is carried out according to a previously validated method (D. Wang, et al . , Neuropharmacology 2007, 52, 1179-1187) . After mice are placed in an acrylic square arena (30 x 45 x 40 cm) for 3 hrs under light, each mouse is separated and habituated to the arena under dark condition for 15 min. Then every mouse is randomly assigned to an unfamiliar partner in each drug-treated group. Immediately after partnering in the arena, the behavior is recorded by a video camera for 10 min, and the time that a pair spent in social interaction (sniffing and grooming the partner, following, mounting, and crawling under or over the partner) is recorded by an observer who is blind to the drug treatment. Tandospirone citrate (0.2 mg/kg) or SB-269970-A (0.1 mg/kg) and lurasidone HC1 (0.03 mg/kg) are co-administered intraperitoneally in a volume of 1 mL/kg to mice 30 min before partnering.
EXAMPLE 14
[0067]
The same experiment as EXAMPLE 13 is carried out using any one of the medicaments listed in Paragraph [0018] (especially, amisulpride, SB-656104-A, eplivanserin,
pimavanserin, M100907, lorcaserin hydrochloride, PRX-00933, mCPP, Vabicaserin hydrochloride, CP-809101, SB-258585, SAM- 531, GSK-742457, or Lu-AE-58054) or a pharmaceutically acceptable salt, different salt or free form thereof, instead of tandospirone citrate or SB-269970-A. According to the experiment, the combined effect of lurasidone and each medicament can be evaluated in the improvement of negative symptoms in schizophrenia.
Claims
1. A medicament for treating schizophrenia and/or bipolar disorder which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a serotonin receptor ligand selected from the group consisting of 5- HTIA agonists, 5-HT7 antagonists, 5-ΗΤδ antagonists and 5- HT2c agonists.
2. The medicament of claim 1 wherein the serotonin receptor ligand is a 5-HTiA agonist.
3. The medicament of claim 1 wherein the serotonin receptor ligand is a 5-HT7 antagonist. 4. The medicament of claim 1 wherein the serotonin receptor ligand is a 5-HT6 antagonist.
The medicament of claim
ceptor ligand is a 5-HT2c agoni
6. The medicament of claim 1 wherein the serotonin receptor ligand is one or more selected from the group consisting of tandospirone, buspirone, gepirone, flibanserin, osemozotan, befiradol, piclozotan, F-15599, naluzotan, flesionoxan, isapirone, eptapirone, repinotan, Org-13011, alnespirone, lesopitron, adatanserin, zalospirone, ebalzotan, U-93385, EMD-56551, binospirone, CGS-19480A, Ru-24969, R-137696, amisulpride, SB-269970-A, SB-656104-A, DR-4446, DR-4365, DR-4485, SB-258741, DR-4004, SB-258719, LY-215840, lorcaserin hydrochloride, PRX-00933, ATHX-105, mCPP, vabicaserin hydrochloride, CP-809101, MK- 212, latrepirdine hydrochloride, SB-258585, AVN-211, SAM- 531, GSK-742457, Lu-AE-58054, SYN-120, AVN-322, SYN-114, SUVN-502, AVN-458, and pharmaceutically acceptable salts, different salts or free forms thereof.
7. The medicament of claim 1 wherein the serotonin receptor ligand is one or more selected from the group consisting of tandospirone, amisulpride, SB-269970-A, SB- 656104-A, lorcaserin hydrochloride, PRX-00933, mCPP, vabicaserin hydrochloride, CP-809101, SB-258585, SAM-531, GSK-742457, Lu-AE-58054, and pharmaceutically acceptable salts, different salts or free forms thereof.
8. A pharmaceutical product for treating schizophrenia and/or bipolar disorder which comprises a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a therapeutically effective amount of a serotonin receptor ligand selected from the group consisting of 5-ΗΤχΑ agonists, 5-HT7 antagonists, 5-HTe antagonists and 5-HT2c agonists .
9. A medicament for improving cognitive impairment associated with schizophrenia which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a serotonin receptor ligand selected from the group consisting of 5-HTi¾ agonists, 5-HT7 antagonists, 5-HT6 antagonists and 5-HT2c agonists.
10. A medicament for treating schizophrenia and/or bipolar disorder which comprises lurasidone or a pharmaceutically acceptable acid addition salt thereof for the administration in combination with a serotonin receptor ligand selected from the group consisting of 5-HTiA agonists, 5-HT7 antagonists, 5-HT6 antagonists and 5-HT2c agonists .
11. Lurasidone or a pharmaceutically acceptable acid addition salt thereof for use in a method for treating schizophrenia and/or bipolar disorder in combination with a serotonin receptor ligand selected from the group consisting of 5-HTiA agonists, 5-HT7 antagonists, 5-HT6 antagonists and 5-HT2c agonists.
12. A use of lurasidone or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a medicament for treating schizophrenia and/or bipolar disorder in combination with a serotonin receptor ligand selected from the group consisting of 5-HTiA agonists, 5-HT7 antagonists, 5-HT6 antagonists and 5-HT2c agonists.
13. A method for treating schizophrenia and/or bipolar disorder which comprises administering a therapeutically effective amount of lurasidone or a pharmaceutically acceptable acid addition salt thereof, and a therapeutically effective amount of a serotonin receptor ligand selected from the group consisting of 5-HTiA agonists, 5-HT7 antagonists, 5-HT6 antagonists and 5-HT2c agonists to a mammal in need thereof.
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| US36107710P | 2010-07-02 | 2010-07-02 | |
| US61/361,077 | 2010-07-02 |
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| US10369134B2 (en) | 2017-12-05 | 2019-08-06 | Sunovion Pharmaceuticals Inc. | Nonracemic mixtures and uses thereof |
| US10377708B2 (en) | 2017-12-05 | 2019-08-13 | Sunovion Pharmaceuticals Inc. | Crystal forms and production methods thereof |
| US11160758B2 (en) | 2019-06-04 | 2021-11-02 | Sunovion Pharmaceuticals Inc. | Modified release formulations and uses thereof |
| WO2022094230A1 (en) * | 2020-11-02 | 2022-05-05 | Acadia Pharmaceuticals Inc. | Compounds for treating psychosis or depression |
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| US11370753B2 (en) | 2017-12-05 | 2022-06-28 | Sunovion Pharmaceuticals Inc. | Crystal forms and production methods thereof |
| US12161623B2 (en) | 2017-12-05 | 2024-12-10 | Sunovion Pharmaceuticals Inc. | Nonracemic mixtures and uses thereof |
| US11517558B2 (en) | 2017-12-05 | 2022-12-06 | Sunovion Pharmaceuticals Inc. | Nonracemic mixtures and uses thereof |
| US10377708B2 (en) | 2017-12-05 | 2019-08-13 | Sunovion Pharmaceuticals Inc. | Crystal forms and production methods thereof |
| US11654113B2 (en) | 2019-06-04 | 2023-05-23 | Sunovion Pharmaceuticals Inc. | Modified release formulations and uses thereof |
| US11160758B2 (en) | 2019-06-04 | 2021-11-02 | Sunovion Pharmaceuticals Inc. | Modified release formulations and uses thereof |
| US12161758B2 (en) | 2019-06-04 | 2024-12-10 | Sunovion Pharmaceuticals Inc. | Modified release formulations and uses thereof |
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