JP6851318B2 - Pyrazole derivative crystals - Google Patents

Description

The present invention is a novel crystal form (type I crystal and type II crystal) of a pyrazole derivative which has an excellent phosphodiesterase 10A inhibitory action and is useful as a therapeutic agent and / or a preventive agent for schizophrenia and the like, and those crystals. The present invention relates to a method for producing the above crystal and a pharmaceutical composition containing the crystal.

Phosphodiesterases (PDEs, cyclic nucleotide phosphodiesterases) are a superfamily of enzymes encoded by 21 different genes. To date, 11 species have been identified in mammals based on structural / functional properties such as amino acid sequence homology, biochemical properties, and inhibitor characterization. (Non-Patent Documents 1 and 2)

The role of PDE in the cellular signal cascade is the cyclic nucleotides cyclic adenosine monophosphate (adenosine 3', 5'-cyclic monophosphate: cAMP) and / or cyclic guanosine monophosphate (guanosine 3', 5'-cyclic monophodies: cAMP): Cyclic inactivation by hydrolyzing the phosphodiester bond of cGMP), i.e., by selectively catalyzing the hydrolysis of the 3'-ester bond to form the inactive 5'-monophosphate. It is to be.

The 11 PDE families are based on substrate specificity: cAMP-specific PDE (PDE4, 7, 8), cGMP-specific PDE (PDE5, 6, 9), and dual substrate PDE (PDE1, 2, 3, 10, It is classified into three categories of 11). (Non-Patent Documents 3 and 4)

Since cAMP and cGMP are important second messengers in intracellular signal transduction via G protein-coupled receptors (GPCRs), PDE is involved in a wide range of physiological mechanisms and is constant in the organism. Plays an important role in sex. Specifically, it is involved in the production and action of pro-inflammatory mediators, ion channel function, muscle relaxation, learning and memory formation, differentiation, apoptosis, lipogenesis, glycogenolysis and regulation of various physiological processes such as gluconeogenesis. There is. In particular, in nerve cells, it plays an important role in controlling neurotransmission as well as differentiation and survival of nerve cells (Non-Patent Document 5).

Regulation of these processes by cAMP and cGMP involves activation of protein kinase A (PKA) and protein kinase G (PKG), controlling a variety of physiological processes including transcription factors, ion channels and receptors. Various substrates are phosphorylated. Intracellular concentrations of cAMP and cGMP fluctuate in response to extracellular signals and are involved in the synthesis of cAMP and cGMP (adenylcyclase (AC) and guanylcyclase (GC)) and their hydrolysis. It is regulated by the balance with PDE involved in. (Non-Patent Document 6)

PDE10A was reported to be present in humans, mice and rats in 1999. (Non-Patent Documents 7 and 8) PDE10A is mainly expressed in the brain, testis, thyroid gland and the like in humans. In particular, it is highly expressed in medium spiny neurons (MSN, medium-sized spiny neurons) of the striatum in the brain, and is moderately expressed in the thalamus, hippocampus, frontal cortex and olfactory tubercle. (Non-Patent Documents 9 and 10) PDE10A is also highly expressed in the brain and testis of mice and rats. (Non-Patent Document 11) Since these brain regions expressing PDE10A play an important role in the pathological mechanism of psychiatric disorders, PDE10A is a pathological mechanism such as psychiatric disorders and neurodegenerative disorders. It has been suggested to be involved in the introduction. (Non-Patent Document 12)

The MSN, mainly express D ₁ dopamine receptors, expressed and MSN forming nigrostriatal path (direct path), the main D ₂ dopamine receptor, striatopallidal path ( There are two MSNs that form an indirect path). The direct route is involved in the functions of exercise performance and reward learning, and the indirect route is involved in the suppression of exercise. For example, in Parkinson's disease, poor movement is due to excessive work of the indirect route, and in disorders such as Huntington's disease, excessive movement is due to excessive work of the direct route. The activity of the output nucleus of the basal ganglia is regulated by the balance of antagonistic inputs from these two pathways. Since PDE10A is expressed on MSNs of both pathways, it is considered that inhibition of PDE10A activates both pathways. (Non-Patent Document 13)
Existing antipsychotics are primarily D ₂ receptor blocking agent, it is mainly through the activation of the indirect path. On the other hand, PDE10A is expressed in both direct and indirect MSNs, and PDE10A inhibitors are expected to have the same antipsychotic effects as existing drugs. Since the direct pathway is involved in exercise performance, it is thought that it works against extrapyramidal disorders due to excessive activation of the indirect pathway, and this pathway further enhances the output from the striatum-thalamic circuit. , It can also be expected to promote cognitive functions such as reward learning and problem solving.

Elevated intracellular cAMP levels due to D ₁ receptor activation appear to regulate a series of neural processes involved in working memory in the prefrontal cortex (Non-Patent Document 14), and D ₁ receptors. It has been reported that activation can improve working memory deficits in patients with schizophrenia. [15] Therefore, by D ₁ receptor is activated, it can be expected improvement of cognitive symptoms of schizophrenia.

The potential antipsychotic effects of PDE10A inhibitors are further supported by the study of Kostoski et al. (Non-Patent Document 16). In US Patent Application Publication No. 2003/0032579, the moderately selective PDE10A inhibitor papaverine (an isoquinoline alkaloid in catalepsy plants, papaverine) is found in rats, which are animal models of psychosis. It has been shown to reduce apomorphin-induced stereotypes and increase haloperidol-induced catalepsy in rats, while simultaneously reducing dopamine levels in rat brains, with the action of conventional antipsychotics. Further supported by its application to patients, papaverine has been established as a PDE10A inhibitor for the treatment of psychosis. (Patent Document 1)

The following reports have been made regarding compounds having a PDE10A inhibitory action (PDE10A inhibitor). For example, in International Publication No. 2005/082883 (Patent Document 2) and European Patent Application Publication No. EP1250923 (Patent Document 3), papaverin as a PDE10A inhibitor and various aromatic heterocyclic compounds (quinazoline and isoquinazoline) Compounds, etc.) are disclosed. In addition, PDE10A inhibitors include psychiatric disorders (eg, schizophrenia, schizophrenia-like disorders, delusional disorders, substance-induced mental illness, delusional personality disorder, schizophrenia-type personality disorder, etc.), anxiety disorders (eg, panic). Disorders, open space fear, single fear, interpersonal fear, compulsive disorder, post-traumatic stress disorder, acute stress disorder, general anxiety disorder, etc., motor disorders (eg, Huntington's disease, dyskinesia associated with dopamine agonist treatment, Parkinson's disease) , Lower limb immobility syndrome, etc.), drug addiction (eg, alcohol, amphetamine, cocaine or achen drug addiction, etc.), diseases with symptoms of cognitive impairment (eg, delusion (Alzheimer's disease, multiple cerebral infarction dementia, etc.)) , Delusional disorder, forgetfulness disorder, post-traumatic stress disorder, mental retardation, learning disorder, attention deficit hyperactivity disorder (ADHD) and age-related cognitive decline, etc.), and mood disorder (eg, major depressive disorder, mood) Modulatory disorders, minor delusional disorders, and bipolar disorders (bipolar I disorder, bipolar II disorder), mood and circulatory disorders, etc.) or mood symptoms (eg, major delusional episodes, manic or mixed episodes) , Mild manic disorder episodes, etc.), etc.) are disclosed to be useful for the treatment or prevention of diseases or symptoms. Furthermore, it is also disclosed that PDE10A inhibitors are useful for the treatment or prevention of neurodegenerative diseases (eg, Parkinson's disease, Huntington's disease, etc.).

The literature of Menniti et al. Reported that PDE10A inhibitors have potential as antipsychotics and have the potential to improve cognitive impairment in schizophrenia. (Non-Patent Document 17)

International Publication No. 2003/000693 discloses an imidazolazine compound as a PDE10A inhibitor, which discloses that the PDE10A inhibitor is useful for the treatment or prevention of neurodegenerative diseases (particularly Parkinson's disease). Has been done. (Patent Document 4)

Based on the above, PDE10A inhibitors are psychiatric disorders associated with PDE10A (eg, (1) delusional, disassembled, tensioned, indistinguishable, or residual psychiatric disorders, (2) schizophrenia-like disorders. , (3) Delusional or depressive schizophrenia, (4) Delusional disorders, (5) Substance-induced psychiatric disorders, such as alcohol, amphetamine, cannabis, cocaine, psychiatric agents, inhalants, opioids, or Psychiatric disorders induced by fencyclidine, (6) delusional personality disorders, and (7) schizophrenia-type personality disorders, etc.) and neurodegenerative disorders (eg, (1) Parkinson's disease, (2) Huntington's disease, etc. (3) Dementia, such as Alzheimer's disease, multiple cerebral infarction dementia, AIDS-related dementia, and frontotemporal dementia, (4) neurodegeneration associated with brain trauma, (5) neurodegeneration associated with stroke , Neurodegeneration associated with cerebral infarction, (6) Hypoglycemic-induced neurodegeneration, (7) Neurodegeneration associated with epilepsy, (8) Neurodegeneration associated with neurotoxicity poisoning, and (9) Multisystem atrophy , (10) Neurodegeneration of medium-sized spinous neurons in the striatum, etc.), etc.), and is expected to be useful as a therapeutic agent with reduced side effects.

International Publication No. 2006/0072828 (Patent Document 5) discloses a compound having a 1-methyl-4-heteroarylpyrazole structure as a partial structure as a PDE10A inhibitor, but the crystal structure of the present invention is disclosed. Is different from.

International Publication No. 2011/036127 (Patent Document 6), International Publication No. 2011/117264 (Patent Document 7), and International Publication No. 2012/076430 (Patent Document 8) include pyrazole as a PDE10A inhibitor. Although compounds having a 5-carboxylic acid amide structure are disclosed, the compounds of Patent Documents 6 and 8 have a dicarboxylic acid amide structure, and the compounds of Patent Document 7 are 7-aminoimidazo [1,2-a]. ] The structure of the crystal of the present invention is different from that of the carboxylic acid amide of pyrimidine.

International Publication No. 2014/133046 (Patent Document 9), International Publication No. 2016/017711 (Patent Document 10), and International Publication No. 2016/017719 (Patent Document 11) include 4-as a PDE10A inhibitor. Heteroaryl-N- (2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1H-pyrazole-5-carboxylic acid amide derivative is disclosed.

US Patent Application Publication No. 2003/0032579 Pamphlet International Publication No. 2005/082883 Pamphlet European Patent Application Publication No. 1250923 Pamphlet International Publication No. 2003/000693 Pamphlet International Publication No. 2006/072828 Pamphlet International Publication No. 2011/036127 Pamphlet International Publication No. 2011/117264 Pamphlet International Publication No. 2012/076430 Pamphlet International Publication No. 2014/133046 Pamphlet International Publication No. 2016/017711 Pamphlet International Publication No. 2016/017719 Pamphlet

Essayan DM. , J Allergy Clin Immunol, 108, p671-680, 2001. Francis SH. , Prog Nucleic Acid Res Mol Biol. , 65, p1-52, 2001. Soderling SH. , Proc Natl Acad USA, 96 (12), p7071-7076, 1999. Chappie TA. , Journal of Medicinal Chemistry, 55, p7299-7331, 2012. Menniti F.S. , Nat Rev Drag Discov, 5 (8), p660-670, 2006. Houseray MD. , Cir Res, 100 (7), p950-966, 2007. Omori K. , J Biol Chem, 274 (26), p18438-18445, 1999. Loughney K. , Gene, 234 (1), p109-117, 1999. Omori K. , Eur J Biochem, 266 (3), p1118-1127, 1999. Menniti F.S. , Brain Res, 985 (2), p113-126, 2003. Xie Z. , Neuroscience. , 139 (2), p597-607, 2006. Lapiz et al. , Neurosci Behav Physiol, 33 (1), p13-29, 2003. Mustcher. , Arzneimitterwirkungen. 8th ed. Stuttgart: Wissenschaftriche Verlagsgesellschaft mbH, 2001. Sawaguchi. , Parkinsonism Relat Disord. , 7 (1), p 9-19, 2000. Castner SA. , Science. , 287 (5460), p2020-2022, 2000. Kostoski W. , Pharmacol Biochem Behave. , 5 (1), p15-17, 1976. Menniti F.S. , Curr Opin Investig Drugs. , 8 (1), p54-59, 2007.

4- (2,5-dimethylpyrimidine-4-yl)-which has an excellent PDE10A inhibitory effect and is one of the pyrazole derivatives useful as a therapeutic agent and / or a preventive agent for schizophrenia and the like. Excellent stability of N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide It is desired to develop a crystal having such properties.

"Polymorph" means that a substance has two or more crystalline forms (crystal structures). Also, the different crystalline forms of a particular substance are called "polymorphs". "Polymorphs" generally have different atomic arrangements in the crystal lattice of various polymorphs by changing their conformation or by being affected by intermolecular or intramolecular interactions (especially hydrogen bonds). It is reflected. On the other hand, the overall outer shape of a substance is called "morphology", which represents the outer shape and plane of existence of the crystal, regardless of its internal structure. Crystals may exhibit different morphologies depending on different conditions (eg, growth rate, stirring method (rate, temperature), presence of impurities, etc.).

Since various "polymorphs" of a substance can have different crystal lattice energies, polymorphs have different physical properties (eg, shape, density, melting point, color, stability, solubility, dissolution rate, etc.) in the solid state. ) May be shown. The above physical properties are the stability, solubility, and bioavailability (internal absorption, drug action, etc.) of certain polymorphs used in pharmaceuticals or pharmaceutical compositions, as well as the shelf life of the drug. , Formulation properties, processing properties, etc. may be affected. Polymorphs may induce higher or lower biological activity than their inherent activity in that they have different rates of absorption in the body. If an unknown polymorph is generated during the manufacturing process, it will have various great effects.

Controlling the "polymorphism" of pharmaceuticals is important in the research and development of new drugs. Predicting the polymorphisms that a pharmaceutical compound can form may reduce the likelihood of polymorphic dislocations due to other polymorphic forms during the manufacturing or storage process. If the possibility of polymorphic translocation is overlooked and unintended polymorphic crystallization occurs during the manufacturing process after the drug has been distributed, it may take weeks to months to suspend production. .. During this period, researchers will investigate the cause of the new crystal morphology and take measures to prevent recurrence, or redesign the formulation in the new crystal morphology and then conduct clinical trials to obtain approval for the application. You will be forced to choose to perform a retest that shows equivalence. Therefore, it is important to clarify whether it is a single polymorph or whether there are multiple polymorphs. Furthermore, if one polymorph is more thermodynamically stable than another, it may be more suitable than the other polymorph at the time of formulation preparation, so it is important to confirm the thermodynamic stability. ..

In addition, researchers, etc. can clarify what kind of "polymorphism" can occur by placing the drug under what manufacturing conditions and storage conditions, so that the characteristics required for the compound of the drug (for example, dissolution) can be obtained. It is possible to maximize properties, formulation properties, processing properties, shelf life, etc.). By discovering various factors related to these "polymorphs" at an early stage of research and development of new drugs, it becomes possible to provide drugs with high activity, high stability, and low manufacturing cost.

As a result of diligent research to solve the above problems, the present inventor has conducted solid 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2, 4] Triazolo [1,5-a] Pyridine-7-yl) -1-Methyl-1H-Pyrazole-5-Carboxamide has been successfully crystallized, and two crystal forms, each of which has distinctly different physical properties. (These two crystal forms described in the present specification are hereinafter referred to as a type I crystal and a type II crystal in the present specification, and a type I crystal may be referred to as a Form I and a type II crystal may be referred to as a Form II. I found that there can be). We also succeeded in obtaining a crystal form with high thermodynamic, chemical and physical stability.
In addition, by examining the crystallization process, the selective formation of one of the above two forms (type I crystal or type II crystal) is achieved by controlling the process parameters during crystallization. I was able to do it.
Furthermore, it was found for the first time that the obtained crystals having high chemical purity have an excellent PDE10A inhibitory action and can be satisfied as a pharmaceutical for a therapeutic agent and / or a preventive agent for schizophrenia and the like. Based on these findings, the present invention was completed.

4- (2,5-Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl) of the present invention) Crystals of -1-methyl-1H-pyrazol-5-carboxamide are compounds having a PDE10A inhibitory effect, and by inhibiting PDE10A, they inhibit the hydrolysis of the phosphodiester bond of cAMP in the striatal GABA nerve. By increasing nerve firing and promoting activation of the striatum, it has an ameliorating effect on various diseases (for example, mental disorders, neurodegenerative disorders, etc.) associated with PDE10A.
4- (2,5-Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl) of the present invention) Pharmaceuticals containing crystals of -1-methyl-1H-pyrazole-5-carboxamide as an active ingredient are preferably orally administrable and are expected as prophylactic and / or therapeutic agents for diseases associated with PDE10A.

4- (2,5-Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl) of the present invention) Crystals of -1-methyl-1H-pyrazole-5-carboxamide show excellent PDE10A inhibitory action, have low toxicity, and are excellent in stability, and are therefore useful as pharmaceuticals.

FIG. 1 is a powder X-ray diffraction pattern of the type I crystal of (Example 1). FIG. 2 is a photomicrograph of the type I crystal of (Example 1). FIG. 3 is a powder X-ray diffraction pattern of the type II crystal of (Example 2). FIG. 4 is DSC thermal analysis data of the type II crystal of (Example 2). FIG. 5 is FT-IR spectrum data of the type II crystal of (Example 2). FIG. 6 is a photomicrograph of the type II crystal of (Example 2).

The present invention relates to 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl). ) -Type I crystals and type II crystals of -1-methyl-1H-pyrazole-5-carboxamide. It also relates to a medicine containing the crystal, a pharmaceutical composition, and a method for producing the crystal.

The present invention includes the following aspects [1] to [25].
Here, in the present specification, the crystal according to any one of aspects [1] to [8-1] is referred to as "4- (2,5-dimethylpyrimidine-4-yl) -N- (of the present invention). Crystals of 6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide "or" crystals of the present invention May be said. The crystal according to any one of aspects [1] to [5-1] may be referred to as "type I crystal of the present invention". The crystal according to any one of aspects [6] to [8-1] may be referred to as "type II crystal of the present invention".
[1] In the first aspect of the present invention, the diffraction angles (2θ) by powder X-ray diffraction are 7.8, 8.8, 10.9, 14.7, 15.7, 16.3, 18.7. 4- (2,5-dimethylpyrimidine-4) with characteristic peaks at 2,0.0, 21.4, 23.6, 24.9, 25.2, 25.7, and 26.5 (°). -Il) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide II It is a type crystal.

[2] A second aspect of the present invention is characterized by the powder X-ray diffraction pattern shown in FIG. 3, 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-). It is a type II crystal of phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl) -1-methyl-1H-pyrazole-5-carboxamide.

[3] A third aspect of the present invention is 4- (2,5-dimethylpyrimidine-4-yl) -N- (2,5-dimethylpyrimidine-4-yl) having the diffraction angle (2θ) and intensity shown in Table 3 in powder X-ray diffraction. It is a type II crystal of 6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide.

[4] A fourth aspect of the present invention is 4- (2,5-dimethylpyrimidine-4-yl), characterized in that the differential scanning calorimetry (DSC measurement) extrapolation melting point start temperature is 225 ° C. -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide type II crystal is there.

[5] A fifth aspect of the present invention is characterized by the FT-IR spectrum diagram shown in FIG. 5 and the data value (cm ^-1 ) shown in Table 4, 4- (2,5-dimethylpyrimidine-4). -Il) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide II It is a type crystal.
[5-1] The 5-1 aspect of the present invention is the type II crystal according to any one of the above aspects [1] to [5] in the form of a columnar crystal.

[6] A sixth aspect of the present invention is that the diffraction angle (2θ) by powder X-ray diffraction is 4.4, 8.5, 9.2, 12.3, 15.6, 16.0, 16.4. , 18.5, 19.4, 21.2, 23.1, 23.7, 24.5, 27.0, and 4- (2,5-) with characteristic peaks at 29.8 (°). Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5 -A type I crystal of carboxamide.

[7] A seventh aspect of the present invention is characterized by the powder X-ray diffraction pattern shown in FIG. 1, 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-). It is a type I crystal of phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl) -1-methyl-1H-pyrazole-5-carboxamide.

[8] An eighth aspect of the present invention is 4- (2,5-dimethylpyrimidine-4-yl) -N-(having a diffraction angle (2θ) and intensity shown in Table 2 in powder X-ray diffraction. It is a type I crystal of 6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide.
[8-1] The eighth aspect of the present invention is the type I crystal according to any one of the above aspects [6] to [8], which is in the form of needle-shaped crystals.

[9] A ninth aspect of the present invention is the method for producing a type II crystal according to any one of the above aspects [1] to [5-1], which is 4- (2,5-dimethyl). Pyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazol-5- This method includes a step of suspending a solid carboxamide in a solvent, then adding concentrated hydrochloric acid to dissolve it, and then adding aqueous ammonia to make a suspension and allowing it to cool to obtain crystals.

Another aspect of the ninth aspect of the present invention is 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,2]. 5-a] Pyridine-7-yl) -1-methyl-1H-pyrazole-5-carboxamide was suspended in a solvent, and then concentrated hydrochloric acid was added to the suspension under heating to dissolve it to prepare a solution. 4. According to any one of the above aspects [1] to [5-1], which comprises a step of adding aqueous ammonia to the solution to prepare a suspension, allowing the suspension to cool, and stirring at room temperature. -(2,5-Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl -1H-Pyrazole-5-Carboxamide is a method for producing a type II crystal.

[9-1] The solvent in the above aspect [9] is preferably hydrous ethanol, and more preferably 10% hydrous ethanol.

[10] A tenth aspect of the present invention is the method for producing a type I crystal according to any one of the above aspects [6] to [8-1], which is 4- (2,5-dimethyl). Pyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5- This method includes a step of dissolving a solid carboxamide in a solvent and then quenching the obtained solution to obtain crystals.

[10-1] The solvent in the above aspect [10] is preferably acetone.

4- (2,5-Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl) in the present invention. The crystalline form of -1-methyl-1H-pyrazole-5-carboxamide is not hydrate, i.e. anhydrous.

4- (2,5-Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl) in the present invention -1-Methyl-1H-pyrazole-5-carboxamide may be a deuterium converter.

The crystals of the present invention contain 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5] containing a plurality of crystal forms. -A] It can be produced by crystallizing pyridine-7-yl) -1-methyl-1H-pyrazole-5-carboxamide.

Crystal transition is a phenomenon in which the crystal structure changes when a certain temperature or pressure is exceeded.
Examples of the "crystal transition method" include methods known per se, such as crystallization from a solution (for example, concentration method, slow cooling method, reaction method (diffusion method, electrolysis method), hydrothermal growth method, melting agent method, etc.). ), Crystallization from steam (for example, vaporization method (sealing method, air flow method), vapor phase reaction method, chemical transport method), crystallization from melt (for example, normal freezing method (pulling method, temperature gradient method)). , Bridgeman method), band melting method (zone leveling method, float zone method), special growth method (VLS method, liquid phase epitaxy method)), evaporation method (dissolve crystals in solvent, evaporate solvent under atmospheric conditions after filtration) Method), slurry method (a method in which crystals are added to a solvent so that excess solid remains to form a suspension, and the solid is collected by filtration at atmospheric temperature or heating or cooling), dried under reduced pressure, and ground. Examples include crushing and pressurization.
In order to obtain the type I crystal of the present invention or the type II crystal of the present invention, the slow cooling method or the slurry method is preferable among the above methods.

As a method for analyzing the obtained crystal, a method for crystal analysis by X-ray diffraction is generally used. Further, as a method for determining the crystal orientation, a mechanical method or an optical method (for example, FT-Raman spectrum, solid-state NMR spectrum) and the like can be mentioned. Further, thermal analysis of crystals (differential scanning calorimetry, differential scanning calorimetry (DSC)), infrared absorption spectrum (IR) analysis (KBr method, solution method) and the like can also be measured according to a usual method.

The peak of the spectrum obtained by the above analysis method inevitably has a certain measurement error due to its nature. Crystals of the present invention also include those in which the numerical values of the peaks of the spectrum are within the error range. For example, in the diffraction angle (2θ) of powder X-ray diffraction, an error of “± 0.2” or “± 0.1” is found, and in the FT-IR spectrum n infrared absorption (cm ^-1 ), “±”. An error of "0.2" or "± 0.1" means that an error of "± 1" is acceptable at the DSC measurement temperature (° C.).

The type II crystal of the present invention is characterized in that the differential scanning calorimetry (DSC measurement) extrapolation melting point start temperature is 225 ° C. under the condition of a temperature rise rate of 10 ° C./min.

Crystallization is usually performed with a suitable crystallization solvent such as water; an alcohol solvent such as methanol, ethanol, 2-propanol, butanol; diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, tert. -Ether-based solvents such as butyl methyl ether; hydrocarbon solvents such as n-hexane, cyclohexane and heptane, aromatic hydrocarbon solvents such as benzene, toluene and xylene; N, N-dimethylformamide, N, N-dimethyl Polar solvents such as acetoamide, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide; halogenated hydrocarbon solvents such as chloroform, dichloromethane, 1,2-dichloroethane; nitrile solvents such as acetonitrile; acetone, diphenylketone Etc. Ketone-based solvent; Ester-based solvent such as methyl acetate, ethyl acetate, isopropyl acetate; Organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, etc. are used. These solvents may be used alone, or two or more kinds of solvents may be mixed and used in an appropriate ratio, for example, in a ratio of 1: 1 to 1:10.

In the present invention, examples of the solvent for forming the type I crystal include solvents such as acetone, isopropyl acetate, and acetonitrile. Acetone is preferred.

In the present invention, examples of the solvent for forming the type II crystal include solvents such as ethyl acetate, ethanol, 2-propanol, and hydrous ethanol. Preferably, it is 10% hydrous ethanol.

In the present invention, crystallization is carried out at a temperature of about −30 ° C. to 80 ° C., preferably type I crystals at a temperature of −20 ° C. and type II crystals at room temperature (1 ° C. to 30 ° C.). ..

In the present invention, the type I crystal is obtained in the form of needles (acicular crystals) as shown in FIG. 2 by crystallizing under certain conditions.

In the present invention, the type II crystal is obtained as a columnar form (columnar crystal) as shown in FIG. 6 by crystallizing under certain conditions.

However, it is also understood that the morphology can form another crystal habit under certain circumstances, and therefore all such other crystal habits are considered to be within the scope of the present invention.

In the present specification, unless otherwise specified, "needle-shaped" means a needle-shaped prism. This shape is also called "needle thread-like".

In the present specification, unless otherwise specified, "columnar" means an elongated prismatic crystal grown in parallel in one direction.

The chemical purity of the type I crystal or the type II crystal in the present invention is about 95% to 100%, preferably about 97% to 100%, and more preferably about 99% to 100%.

In the present invention, the type II crystal is particularly useful as a pharmaceutical because it has good long-term storage stability and photostability and does not have a problem of hygroscopicity.

In the present invention, in particular, type II crystals can be used as therapeutic agents and / or preventive agents for schizophrenia and the like, which have extremely high chemical and physical stability and have a PDE10A inhibitory effect.

In the present invention, in particular, the type II crystal is a crystal having excellent thermodynamic stability, so that it is easy to handle, and a solid pharmaceutical composition (pharmaceutical preparation) can be produced with good reproducibility, which is useful. Crystal can be.

The type I crystal of the present invention or the type II crystal of the present invention obtained as described above, particularly the type II crystal of the present invention, has an excellent PDE10A inhibitory effect and has low toxicity, and is therefore useful as a pharmaceutical product.

The type I crystal of the present invention or the type II crystal of the present invention obtained as described above, particularly the type II crystal of the present invention, has a more preferable characteristic profile such as more preferable solubility and more preferable absorbability in the production of a pharmaceutical preparation. Have.

[11] The eleventh aspect of the present invention is a pharmaceutical composition containing the crystal according to any one of the above aspects [1] to [8-1] as an active ingredient.

[12] A twelfth aspect of the present invention includes certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychiatric disorders, anxiety disorders such as dysphoric and obsessive disorders, Parkinson's disease and Huntington. A drug for treating at least one disease or condition selected from the group consisting of movement disorders including diseases, mood disorders, neurodegenerative disorders, disorders including lack of attention and / or cognition, obesity, and drug addiction. It is a pharmaceutical composition containing, as an active ingredient, a certain amount of the crystal according to any one of the above aspects [1] to [8-1], which is effective for treating the disease or condition. ..

"Mental disorders and conditions" that can be treated according to the present invention include, for example, (1) delusional type, disassembled type, tension type, indistinguishable type, or residual type schizophrenia, and (2) schizophrenia. Similar disorders, (3) delusional or depressive schizophrenia, (4) delusional disorders, (5) substance-induced psychotic disorders such as alcohol, amphetamine, cannabis, cocaine, psychiatric agents, inhalants, opioids, Alternatively, there are psychosis induced by fencyclidine, (6) paranoid personality disorder, and (7) schizophrenia-type personality disorder. However, it is not limited to these.

Unless otherwise specified, the symptoms of "schizophrenia, schizophrenia-like disorder" in the present specification include, for example, (1) positive symptoms, negative symptoms, and related delusional and / or hallucinatory symptoms. 2) Disassembled conversations (frequently delusional or incoherent conversations), (3) Flattening of emotions (significant decrease in width and strength of emotional expression), (4) Alogia (decrease in content and volume of conversations) , (5) Anhedonia (loss / decline of pleasure ability), (6) Disproportionate emotions, (7) Discomfort (eg, depression, anxiety, or anger, etc.), (8) Decreased motivation, (9) Nonsocial (Lack of ability to obtain joy from social interaction) and (10) Part of cognitive dysfunction. However, it is not limited to these.

"Movement disorders" that can be treated according to the present invention include, for example, (1) Huntington's disease and abnormal motility associated with Dopamine agonist therapy, (2) Parkinson's disease, and (3) Restless Legs Syndrome. : RLS), and (4) essential tremor and the like. However, it is not limited to these.

Examples of "other disorders" that can be treated according to the present invention include (1) obsessive-compulsive disorder, (2) Tourette's syndrome, and (3) tic disorder. However, it is not limited to these.

Examples of "anxiety disorders" that can be treated according to the present invention include (1) panic disorder, (2) agoraphobia, (3) specific phobia, (4) social phobia, and (5) obsessive-compulsive disorder. Disorders include (6) post-traumatic stress disorder, (7) acute stress disorder, and (8) generalized anxiety disorder. However, it is not limited to these.

Unless otherwise noted herein, "drug addiction" means an abnormal desire for a drug, generally an episode of motivational disorders such as urge to take the desired drug, and intense drug cravings. It is characterized by. For example, alcohol, amphetamine, cocaine, opium addiction and the like can be mentioned.

Unless otherwise noted herein, "lack of attention and / or cognition" in "disorders including lack of attention and / or cognition" refers to "lack of attention and / or cognition" in a particular individual as compared to other individuals of the same age. , Memory, intelligence, or one or more cognitive functions such as learning and logical abilities are subnormal. Also, "lack of attention and / or cognition" means diminished function in any particular individual of one or more cognitive aspects, such as that that occurs with age-related cognitive decline.

"Disabilities including attention and / or cognitive deficiency" that can be treated according to the present invention include, for example, (1) dementia, such as Alzheimer's disease, multiple cerebral infarction, alcoholic dementia or other drug-related dementia. , Dementia associated with intracranial tumor or brain trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia, (2) dementia, (3) forgetfulness disorder, (4) post-traumatic stress disorder (Postramic stress disorder: PTSD), (5) Mental retardation, (6) Learning disabilities, such as reading disabilities, arithmetic disabilities, or writing disabilities, (7) Attention deficit / hyperactivity disorder : ADHA), and (8) age-related cognitive decline and the like. However, it is not limited to these.

Examples of "mood disorders" and "mood episodes" that can be treated according to the present invention include (1) major depression episodes (mild, moderate, or severe), manic episodes, mixed episodes, and mild manic episodes. , (2) Atypical depression, (3) Melancholic depression, (4) Tension depression, (5) Postpartum mood episodes, (6) Post-stroke depression, (7) Major depressive disorder , (8) dysthymia / dysthymia, (9) minor depressive disorder, (10) premenopausal discomfort dysfunction, (12) post-schizophrenia depressive disorder, (13) depressive disorder or Major depressive disorder associated with mental disorders such as schizophrenia, (14) bipolar disorder, for example, bipolar I disorder, bipolar II disorder, and (15) mood and circulation disorder. However, it is not limited to these.

Unless otherwise stated herein, "neurodegenerative disorder or condition" means a neurological dysfunction or condition resulting from neuronal dysfunction and / or neuronal death in the central nervous system. Treatment of the disorder and condition results in the dysfunction or death of the neuron in crisis and / or the dysfunction or death of the neuron in crisis in the disorder or condition. In order to compensate for the loss of function, a drug that can enhance the function of damaged or normally working neurons may be administered.

"Neurodegenerative disorders and conditions" that can be treated according to the present invention include, for example, (1) Parkinson's disease, (2) Huntington's disease, (3) dementia, such as Alzheimer's disease, multiple cerebral infarction dementia, AIDS. Related dementia and frontotemporal dementia, (4) brain trauma-related neurodegeneration, (5) stroke-related neurodegeneration, cerebral infarction-related neurodegeneration, (6) hypoglycemic-induced neurodegeneration , (7) Neurodegeneration associated with epilepsy, (8) Neurodegeneration associated with neurotoxic poisoning, and (9) Multilineage atrophy, (10) Neurodegeneration of medium-sized striatum spinous neurons, etc. .. However, it is not limited to these.

In the present specification, unless otherwise specified, "neurotoxin poisoning" refers to poisoning due to neurotoxin. A neurotoxin is any chemical or substance that can cause nerve death, or neurological damage. Alcohol is an example of a neurotoxin. When alcohol is abused by pregnant women, newborns can develop fetal alcohol syndrome, alcoholism and neurological damage. Examples of other neurotoxins include kainic acid, domoic acid, and achromeric acid, certain pesticides (eg, Dichloro diphenyl trichloroethane: DDT), certain pesticides (eg, organic phosphates). Etc.), volatile organic solvents (eg toluene), metals (eg lead, mercury, arsenic, phosphorus, and aluminum, etc.), certain chemicals used as weapons (eg, the dead leaf agent Agent Orange or Nerve gas, etc.), and neurotoxic antitumor agents and the like. However, it is not limited to these.

Unless otherwise noted herein, "treating" as in "treating a disease or condition" refers to the progression of a "disease or condition" or to one or more "diseases or conditions". It means to recover, alleviate, or suppress. Also, as used herein, "treating" includes preventing the onset of a "disease or condition" or any symptom associated with that "disease or condition", depending on the condition of the patient. It also includes prevention of the "disease or condition" as well as reducing the severity of the "disease or condition" or any of its symptoms prior to onset. As used herein, "treating" also includes preventing and ameliorating the recurrence of a "disease or condition".

[13] A thirteenth aspect of the present invention includes certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychiatric disorders, anxiety disorders such as dysphoric and obsessive-compulsive disorders, Parkinson's disease and Huntington's disease. A pharmaceutical composition for treating at least one disease or condition selected from the group consisting of movement disorders including diseases, mood disorders, neurodegenerative disorders, disorders including lack of attention and / or cognition, obesity, and drug addiction. A pharmaceutical composition containing, as an active ingredient, a certain amount of the crystal according to any one of the above aspects [1] to [8-1], which is effective for inhibiting PDE10A.

[14] A fourteenth aspect of the present invention comprises a psychiatric disorder, a delusional disorder, and a drug-induced disorder containing the crystal according to any one of the above aspects [1] to [8-1] as an active ingredient. Certain psychiatric disorders and conditions such as sexual psychiatric disorders, anxiety disorders such as panic and obsessive-compulsive disorders, movement disorders including Parkinson's disease and Huntington's disease, mood disorders, neurodegenerative disorders, lack of attention and / or cognition A prophylactic and / or therapeutic agent for at least one disease or condition selected from the group consisting of disorders, obesity, and drug addiction, including.

[14-1] In the above aspect [14], preferably, a disease or condition of schizophrenia containing the crystal according to any one of the above aspects [1] to [8-1] as an active ingredient. A prophylactic and / or therapeutic agent for.

[15] A fifteenth aspect of the present invention comprises a psychiatric disorder, a delusional disorder, and a drug-induced disorder containing the crystal according to any one of the above aspects [1] to [8-1] as an active ingredient. Certain psychiatric disorders and conditions such as sexual psychiatric disorders, anxiety disorders such as panic and obsessive-compulsive disorders, movement disorders including Parkinson's disease and Huntington's disease, mood disorders, neurodegenerative disorders, lack of attention and / or cognition A therapeutic agent for at least one disease or condition selected from the group consisting of disorders including, obsessive-compulsive disorder, and drug addiction.

[15-1] In the above aspect [15], preferably, a disease or condition of schizophrenia containing the crystal according to any one of the above aspects [1] to [8-1] as an active ingredient. It is a therapeutic agent for.

[16] A sixteenth aspect of the present invention involves a PDE10A receptor, which comprises the crystal according to any one of the above aspects [1] to [8-1] as an active ingredient. It is a prophylactic and / or therapeutic agent for the disease.

[17] A 17th aspect of the present invention involves a PDE10A receptor, which comprises the crystal according to any one of the above aspects [1] to [8-1] as an active ingredient. It is a therapeutic agent for diseases that occur.

[18] An eighteenth aspect of the present invention is a pharmaceutical composition containing the crystal according to any one of the above aspects [1] to [8-1] as an active ingredient, which is a PDE10A inhibitor. ..

[19] A nineteenth aspect of the present invention is the use of the crystal according to any one of the above aspects [1] to [8-1] as a pharmaceutical composition.

[20] A twentieth aspect of the present invention is the use in the production of a pharmaceutical composition of crystals according to any one of the above aspects [1] to [8-1].

[21] A 21st aspect of the present invention is the use of the crystal according to any one of the above aspects [1] to [8-1] as a PDE10A inhibitor.

[22] A 22nd aspect of the present invention is the use in the production of a PDE10A inhibitor of a crystal according to any one of the above aspects [1] to [8-1].

[23] A 23rd aspect of the present invention includes certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychiatric disorders, anxiety disorders such as dysphoric and obsessive disorders, Parkinson's disease and Huntington. A method of treating at least one disease or condition selected from the group consisting of movement disorders including diseases, mood disorders, neurodegenerative disorders, disorders including lack of attention and / or cognition, obesity, and drug addiction. , An amount of the crystal according to any one of aspects [1] to [8-1], effective for treating the disease or condition, to a subject in need of treatment for the disease or condition. A method that involves administration.

[24] A twenty-fourth aspect of the invention is certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychiatric disorders, anxiety disorders such as dysphoric and obsessive disorders, Parkinson's disease and Huntington. A method of treating at least one disease or condition selected from the group consisting of movement disorders including diseases, mood disorders, neurodegenerative disorders, disorders including lack of attention and / or cognition, obesity, and drug addiction. , A certain amount of the crystal according to any one of aspects [1] to [8-1], which is effective in inhibiting PDE10A, is administered to a subject in need of treatment for the disease or condition. It is a method including.

[25] In the 25th aspect of the present invention, the disease or condition is (1) dementia-type, disassembled-type, tension-type, indistinguishable-type, or residual-type schizophrenia, (2) schizophrenia-like. Disorders, (3) dementia or depressive schizophrenia, (4) dementia, (5) substance-induced psychiatric disorders, (6) alcohol, amphetamine, cannabis, cocaine, psychedelics, inhalants, opioids , Or phencyclidine-induced dementia, (7) dementia-type personality disorder, (8) schizophrenia-type personality disorder, (9) Huntington's disease, (10) abnormal motility associated with Dopamine agonist therapy, (11) ) Parkinson's disease, (12) restless lower limb syndrome, (13) essential tremor, (14) compulsive disorder, (15) Tourette syndrome, (16) tic disorder, (17) depressive disorder, (18) open space Fear, (19) Specific phobia, (20) Social phobia, (21) Post-traumatic stress disorder, (22) Acute stress disorder, (23) General anxiety disorder, (24) Dementia; Alzheimer's disease , Multiple cerebral infarction, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumor or brain trauma, dementia associated with Huntington or Parkinson's disease, AIDS-related dementia, or frontotemporal type Dementia (25) dementia, (26) forgetfulness disorder, (27) mental retardation, (28) learning disorder; reading disorder, arithmetic disorder, or writing disorder, (29) attention defect / hyperactivity disorder, ( 30) Age-related cognitive decline, (31) Major depression episodes (mild, moderate, or severe), manic episodes, mixed episodes, mild dementia episodes, (32) atypical depression, (33) melancholic type Dementia, (34) tension dementia, (35) postpartum mood episodes, (36) post-stroke depression, (37) major dementia, (38) dysthymia / dysthymia, (38) 39) Minor depressive disorder, (40) Premenstrual discomfort disorder, (41) Post-dementia depressive disorder, (42) Dementia or major depressive disorder associated with mental disorders such as dementia Disorders, (43) Bipolar Disorders; Bipolar Type I Disorders, Bipolar Type II Disorders, (44) Mood Circulation Disorders, (45) Brain Trauma-Related Neurodementia, (46) Stroke-Related Neurodementia, Cerebral Infarction Dementia associated with, (47) hypoglycemic-induced dementia, (48) dementia associated with epilepsy, (49) dementia associated with neurotoxicity, (50) multilineage atrophy, and (51) ) From neurodementia of medium-sized spinous neurons in the striatum The pharmaceutical composition according to aspect [12] or aspect [13], the therapeutic agent according to aspect [14] or aspect [15], or embodiment, which is at least one disease or condition selected from the group. [23] or the method according to aspect [24].

The PDE10A inhibitory effect of the crystal according to any one of aspects [1] to [8-1] of the present invention is measured by an appropriately selected method, for example, Pharmacological Experimental Example 1 (human-derived PDE10A inhibitory effect) described later. Can be done.

The crystal according to any one of aspects [1] to [8-1] of the present invention has excellent PDE10A inhibitory activity in Pharmacological Experimental Example 1 (human PDE10A inhibitory action). In addition, the crystals according to any one of aspects [1] to [8-1] of the present invention are highly selective for PDE10A and are selective PDE10A inhibitors.

Unless otherwise specified herein, "selective PDE10A inhibitor" means a compound having significantly PDE10A inhibitory activity as compared to PDE1-9 or PDE11 inhibitory activity.

In one embodiment, the "selective PDE10A inhibitor" is preferably any other PDE enzyme (eg, PDE1A, 2A, 3A, 4A, 4B, 5A, 6, 7A, 7B, 8A, 9A, and 11A) for inhibition, which is a compound having a PDE10A inhibitory activity is about 1/1000 or less of _{an IC 50} value with its compound. (In other words, the compounds, comparable inhibit PDE10A activity at about 1/1000 or less of _{an IC 50} value, which would be required if that inhibit any other PDE enzyme.)

The crystals of the invention, an isotope (e.g., isotopes of ^hydrogen, such as ² H and ³ H, ^carbon, 11 ^{C, 13} C, and the like ¹⁴ C, ^chlorine, such as 36 Cl, fluorine Isotopes of, iodine isotopes such as ¹⁸ F, nitrogen isotopes such as ¹²³ I and ¹²⁵ I, oxygen isotopes such as ¹³ N and ¹⁵ N, and phosphorus ^{isotopes such as 15} O, ¹⁷ O, and ^{18 O.} Also included are isotopes, ³² P, etc., as well as crystals labeled or substituted with ^{isotopes of sulfur, 35 S, etc.).}

Crystals of the invention labeled or substituted with certain isotopes (eg, ^{positron emitting isotopes such as 11} C, ¹⁸ F, ¹⁵ O, and ¹³ N) are described, for example, by positron emission tomography (PET). ) Can be used as a tracer (PET tracer), and is useful in fields such as medical diagnosis.

Crystals of the invention labeled or substituted with certain isotope labels are useful in studying the tissue distribution of drugs and / or substrates. For example, ^{3 H} and ^{14 C} are easy to their label or substituted, and from the viewpoint detection means is easy, useful in the research purposes.

Isotope-labeled crystals of the invention can be obtained by conventional techniques known to those of skill in the art or by methods similar to the synthetic methods described in Examples below. Moreover, the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.

[4- (2,5-Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1 -Methyl-1H-Pyrazole-5-Carboxamide Production Method]
Below, 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-] used for crystallization in the present invention a] A method for producing pyridine-7-yl) -1-methyl-1H-pyrazole-5-carboxamide will be described. 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Methyl-1H-pyrazole-5-carboxamide is a combination of known general chemical production methods using a commercially available compound or a compound that can be easily obtained from a commercially available compound by a production method known in the literature as a starting material or a synthetic intermediate. Therefore, it can be easily produced, and can be produced according to the typical production method shown in the following Cheme1. Further, the present invention is not limited to the manufacturing method described below.

4- (2,5-Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl)- In the method for producing 1-methyl-1H-pyrazol-5-carboxamide, 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] Each raw material compound used in the production of pyridine-7-yl) -1-methyl-1H-pyrazole-5-carboxamide may form a salt, and such a salt may be used. The salt is not particularly limited as long as it is pharmaceutically acceptable, but for example, with a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic or acidic amino acid. Salt and the like.
Preferable examples of the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt. (For example, in addition to monosalt, disodium salt and dipotassium salt are also included).
Preferable examples of salts with organic bases include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, tri. Ethanolamine, piperidine, morpholine, pyridine, picolin, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, N , N'-dibenzylethylenediamine and the like.
Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, etc. Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid. Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvate, oxylic acid, salicylic acid, N-acetylcysteine, etc. Examples thereof include salts with organic carboxylic acids, salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamate.
Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Can be mentioned.
Of these, pharmaceutically acceptable salts are preferable. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.), Ammonium salts, etc., and when the compound has a basic functional group, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitrate, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, etc. Examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
In addition, 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl)- Each of the starting compounds used in the production of 1-methyl-1H-pyrazole-5-carboxamide can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method. It can be readily purified by means known per se, such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and other separation means.

4- (2,5-Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl)- Unless otherwise specified, the reaction conditions in the method for producing 1-methyl-1H-pyrazole-5-carboxamide are as follows. The reaction temperature is in the range of −78 ° C. to the temperature at which the solvent refluxes, and unless the temperature is specified, it is room temperature (1 to 30 ° C.; specified by the Japanese Pharmacopoeia), and the reaction time is sufficient for the reaction. It's time to go.

In addition, each step in the production method can be carried out without a solvent or by dissolving or suspending the raw material compound in a suitable solvent not involved in the reaction before the reaction. Specific examples of the solvent not involved in the reaction include water; saturated hydrocarbon solvents such as cyclohexane and hexane; aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene and xylene; methanol, ethanol, 1-propanol and 2 -Alcohol solvents such as propanol, tert-butyl alcohol, 2-methoxyethanol; N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone Polar amide solvents such as: Sulfoxide solvents such as dimethyl sulfoxide; nitrile solvents such as acetonitrile and propionitrile; diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like. Ether solvent; ester solvent such as methyl acetate, ethyl acetate, butyl acetate; ketone solvent such as acetone, methyl ethyl ketone; halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane; triethylamine , N, N-diisopropylethylamine, pyridine, rutidin and other basic solvents; acid anhydrides such as anhydrous acetic acid; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid and methanesulfonic acid; inorganic acids such as hydrochloric acid and sulfuric acid. Although it is an acid, one kind of solvent may be used alone, or two or more kinds of solvents may be appropriately selected depending on the reaction conditions and used in an appropriate ratio.

4- (2,5-Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl) -1 Specific examples of the base (or deoxidizing agent) used in the method for producing -methyl-1H-pyrazol-5-carboxamide include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and lithium carbonate. Inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogencarbonate; triethylamine, N, N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N , N-dimethylaniline, N-methylpiperidin, N-methylpyrrolidin, N-methylmorpholin, 1,5-diazabicyclo [4.3.0] -5-nonen, 1,4-diazabicyclo [2.2.2] Organic bases such as octane, 1,8-diazabicyclo [5.4.0] -7-undecene, imidazole; metal reagents such as sodium methoxyd, sodium ethoxydo, potassium tert-butoxide, sodium tert-butoxide; hydrogenation Alkali metal hydrides such as sodium and potassium hydride; metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide; organic such as methyl lithium, n-butyl lithium, sec-butyl lithium and tert-butyl lithium. Lithium reagent; Further, as the acid or acid catalyst used in the method for producing the compound of the present invention, specifically, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and phosphoric acid; acetic acid, trifluoroacetic acid, oxalic acid, etc. Organic acids such as phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-campersulfonic acid; boron trifluoride ether complex, zinc iodide, anhydrous chloride Lewis acids such as aluminum, anhydrous zinc chloride, and anhydrous iron chloride; However, it is not necessarily limited to those described above.

[Concomitant agent with crystals of the present invention]
The crystal of the present invention, or a drug using the crystal, can be used in combination with another drug or drug by a general method used in the medical field. Drugs that can be used in combination with the crystals of the present invention include, for example, (A) psychiatric disorders, especially schizophrenia, or bipolar disorder, obsessive disorder, major depression, Parkinson's disease, Huntington's disease, Alzheimer's disease, cognitive dysfunction. And drugs for treating memory disorders, (B) drugs for diseases that are likely to occur with schizophrenia, and the like.

Examples of the drug (A) include (1) atypical antidepressants [specifically, olanzapine, quetiapine, clozapine, ziplacidone, risperidone, pariperidone, perospyrone, bronanserin, lulacidone, alipiprazole, serotonin, and amisulfride. , Iroperidone, Bifepurnox, Acenapine, Melperon, Brexpiprazole, Zotepine, etc.], (2) Typical antidepressants [Specifically, chlorpromazine, puchlorperazine, perphenazine, levomepromazine, flufenazine, thioridazine, propericiadin, Spiperon, moperon, haloperidol, timiperon, bromperidol, pimodide, fluoropipamide, sulpylide, thiaprid, thrutprid, nemonapride, oxypertin, etc.], (3) Selective serotonin reuptake inhibitor (SSRI) [Specifically, escitaloplum, citaroplum , Paroxetin, Celtraline, Fluboxamine, Fluoxetine, etc.], (4) Selective serotonin / noradrenaline reuptake inhibitor (SNRI) [Specifically, mirunashiplan, duroxetin, benrafaxin, nephazodon, etc.], (5) Selection Noradrenergic and dopamine reuptake inhibitors (NDRI) [specifically, bubropine, etc.], (6) Noradrenergic and specific serotonin-operated antidepressants (NaSSA) [specifically, mirtazapine, etc.], ( 7) Triazolopyridine antidepressants (SARI) [specifically, trazodon, etc.], (8) tetracyclic antidepressants [specifically, serotonin, myanserin, maprotin, etc.], (9) tricyclic Antidepressants [Specifically, amitriptilin, trimipramine, imiplamine, nortryptrin, chromipramine, lofeplamine, amoxapine, dosrepin, etc.], (10) Other antidepressants [specifically, NS-2359, Lu AA21004, DOV21947, etc. ], (11) α7 nicotine receptor agonist, (12) α7 nicotine receptor activity regulator, (13) α7 nicotine receptor partial regulator [specifically, SSR-180711, PNU-120596, etc.], ( 14) Other PDE inhibitors [PDE1 inhibitor, PDE2 inhibitor, PDE4 inhibitor, PDE5 inhibitor, PDE7 inhibitor, PDE9 inhibitor, etc.], (15) NK2 antagonist, (16) NK3 antagonist, (17) ) Muscarin-type M1 acetylcholine receptor activity regulator, (18) Musca Phosphorus M2 acetylcholine receptor activity regulator, (19) Adenosine receptor regulator, (20) Muscarin type M4 acetylcholine receptor activity regulator, (21) Muscarin type M5 acetylcholine receptor activity regulator, (22) Adenosine receptor Body regulators, (23) Glycin transporter 1 (GlyT1) inhibitors [specifically, ALX5407, SSR504734, etc.], (24) Glutamic acid enhancers [specifically, ampakine], (25) NMDA receptor inhibition Drugs [specifically, memantin hydrochloride, etc.], (26) metabolic glutamate receptor regulators (mGlu) [specifically, CDPPB, MPEP, etc.], (27) anxiolytics ((i) benzodiazepines) Anxiolytics [Specifically, chlordiazepoxide, diazepam, oxazolam, medazepam, cloxazolam, lorazepam, dipotassium chlorazepate, placepam, bromazepam, fludiazepine, mexazolam, alprazolam, flutoprazepam, flutazolam, lofrazepine iethyl, etc.] Anxiolytics [specifically, etizolam, crothiazepam, etc.], (iii) serotonin 5-HT1A agonists [specifically, tandospirone, etc.]), (28) sleep-inducing agents ((i) benzodiazepine-based sleep induction Agents [specifically, nitrazepam, estazolam, flulazepam hydrochloride, nimetazepam, flulazepam, haloxazolam, flunitrazepam, lylmazapon hydrochloride, lormetazepam, triazolam, etc.], (ii) thienodiazepine-based sleep-inducing agents [specifically, brothizolems, etc.], ( iii) Non-benzodiazepine sleep-inducing agents [specifically, solpidem, etc.], (iv) melatonin receptor agonists [specifically, lamerteon, etc.]), (v) cyclopyrrolone-based sleep-inducing agents [specifically Zopiclone, etc.], (29) β-amyloid vaccine, (30) β-amyloid degrading enzyme, etc., (31) Brain function activators [specifically, anilasetam, nicergoline, etc.], (32) cannabinoid regulators, (33) ) Cholinesterase inhibitors [specifically, benzodiazepine hydrochloride, rivastigmine, galantamine hydrobromide, etc.], (34) MAO-B inhibitors [specifically, lasalidine, etc.] (35) Parkinson's disease therapeutic agents ((i) ) Dopamine receptor agonists [Specifically, levodopa, amantazine hydrochloride, bromocryptine mesylate, pergolide mesylate, cabergolin, talipexol hydrochloride, pramipexol hydrochloride hydrate Selegiline hydrochloride, ropinilol hydrochloride, etc.], (ii) Monoamine oxidase inhibitor [specifically, deprenyl, selegiline (selegiline), remasemide, lysole, etc.], (iii) anticholinergic agent [specifically, trihe Xyphenidyl, profenamine, biperiden, pyroheptin hydrochloride, metixene hydrochloride, mazaticol hydrochloride, etc.], (iv) COMT inhibitor [specifically, entacapone, etc.], (v) therapeutic agent for myotrophic lateral sclerosis [specifically Specifically, selegiline, etc., neurotrophic factors, etc.], (vi) apoptosis inhibitor [specifically, CPI-1189, IDN-6556, CEP-1347, etc.], (vii) nerve differentiation / regeneration promoter [specifically. Examples thereof include Leteprinim, Xaliproden (SR-57746-A), SB-216763, etc.].

In addition, examples of the drug (B) include (36) a therapeutic drug for diabetes ((i) PPARγ agonist (acting agent, inhibitor)] [specifically, pioglycazone, rosiglitazone, troglycazone, siglitazone, dalglycazone. , Englitazone, netoglytazone, etc.], (ii) Insulin secretagogue [(a) sulfonylurea (specifically, tolbutamide, acetohexamide, chlorpropamide, glibenclamid, glycladide, gripidide, glymepyride, glypentide, glycidone) , Glysolamide, trazamide, etc.), (b) Non-sulfonylurea, etc.], (iii) Fast-acting insulin secretagogue (specifically, nateglycinide, mitiglinide, repaglinide, etc.), (iv) α-glucosidase inhibitor [specifically , Acarbose, Boglibose, Migitol, Camiglibose, Adiposine, Emigritate, Prazimicin-Q, Salvostatin, etc.], (v) Insulin resistance improving agents [Specifically, (a) PPARγ agonists, (b) PTP- 1B inhibitor, (c) DPP-4 inhibitor [specifically, sitagliptin, bildaglycin, allogliptin, saxagliptin, NVP-DPP-728, etc.], (d) GLP-1 and GLP-1 agonists [specifically Exenatide, liraglutide, etc.], (e) 11β-HSD inhibitor, etc., (f) GPR40 agonist, (g) GPR119 agonist, (h) GPR120 agonist], (vi) hepatic glycosylation inhibitor [specifically Glucagon antagonists, etc.], (vii) biguanide agents [specifically, metformin, buformin, fenformin, etc.], (viii) insulin or insulin derivatives [specifically, insulin zinc suspension, insulin, etc.] Lispro, insulin aspart, regular insulin, NPH insulin, insulin glargine, insulin detemil, mixed insulin, etc.], (ix) α2 antagonist [specifically, midaglyzol, isagridol, deligidol, idazoxane, efaloxane, etc.]), ( 37) Anti-obestinants ((i) adrenaline β3 receptor agonists [specifically, KRP-204, TRK-380 / TAC-301, etc.], (ii) CB-1 receptor antagonists [specifically. , Limonavan, SR-147778, BAY-65-2520, etc.], (iii) Neuropeptide Y (NPY) receptor antagonist [specifically, S-2367, etc.], (iv) Insulin inhibitor [monoamine re- Insulin uptake [Specifically, cibutramine, mazindole, etc.]], (v) Lipase inhibitors [specifically, orlistat, setilistat, etc.], (vi) Peptide YY (PYY) receptor antagonists, etc.), (38) Cholesterol Drugs for treating hyperlipidemia such as inhibitors ((i) ω3 fatty acids [specifically, ethyl icosapanthate (EPA-E preparation, for example, product name: Epadel (registered trademark), etc.)), docosahexaenoic acid (DHA) , Mixed preparations of ethyl icosapentate and ethyl docosahexaenoate (for example, product names: Robaza ^TM , Omacol®, etc.), etc.], (ii) HMG-CoA reductase inhibitors [Specifically, atorvastatin, simvastatin, etc. Pitabastatin, Itabastatin, Fulvastatin, Robastatin, Pravastatin, Rivastatin, Losvastatin, etc.] (iii) HMG-CoA synthase inhibitor, (iv) Cholesterol absorption inhibitor [Specifically, ezetimib], (v) Acyl-CoA Cholesterol acyl transferase (ACAT) inhibitor, (vi) CETP inhibitor, (vii) squalene synthase inhibitor, (viii) antioxidant [specifically, Probucol, etc.], (ix) PPARα agonist [ Specifically, clofibrate, etofibrate, phenofibrate, bezafibrate, cyprofibrate, gemfibrodil, KRP-101, etc.], (x) PPARδ inhibitor, (xi) LXR inhibitor, (xii) FXR inhibitor [specifically , INT-747, etc.], (xiii) MTTP inhibitor, (xiv) squalene eposidase inhibitor, etc.), (39) antihypertensive agent ((i) diuretic agent [specifically, trichloromethiazide, hydrochlorothiazide, etc. Mefluside, indapamide, methiclan, chlortalidone, trypamide, frosemide, trasemido, bumethanide, etaclinic acid, spironolactone, triamterene, eprelenone, etc.] , Nitolendipine, Nirvazipine, Alanidipine, Azernidipine, Manidipine, Barnidipine, Ehonidipine, Sylnidipine, Benidipine, Zyrthiazem, etc.], (iii) Angiotensin converting enzyme inhibitor (ACEI) [Specifically, captopril, ricinopril, enalapril, enalapril, enalapril Benazepril, Trandrapril, Kinapril, Aracep Lil, imidapril, temocapril, sirazapril, etc.], (iv) Angiotensin receptor antagonist (ARB) [Specifically, rosartan, olmesartan, thermisartan, balsartan, candesartan cilexetil, ilbesartan, etc.], (v) Direct renin Inhibitors [specifically, aliskiren, etc.], (vi) α-receptor blockers [specifically, trazoline, fentramin, doxazosin, prazosin, bunazocin, terrazosin, urapidil, etc.], (vii) β-receptor blockers [Specifically, bopindolol, pindrol, timorol, dichloroisoprenalin, alprenorol, carvedilol, indenolol, bunitrolol, penbutrol, propranolol, nadrol, nipradilol, chilisolol, acebutrol, seriprolol, metprolol, atenolol, bisoprolol, betasolol. Practolol, bevantolol, butoxamine, carvedilol, amoslarol, arotinolol, labetalol, etc.], (viii) α ₁ β-blocker [specifically, carvedilol, labetalol, arotinolol, bevantolol, etc.], (ix) α ₂ receptor stimulant [Specifically, chronidine, methyldopa, guanfacin, etc.]), (40) Non-steroidal anti-inflammatory agents [Specifically, meroxycam, teoxycam, indomethacin, ibuprofen, selecoxib, lofecoxib, aspirin, indomethacin, etc.], (41 ) Disease-modifying anti-rheumatic drugs (DMARDs), (42) anti-cytocytotic drugs [specifically, TNF inhibitors, MAP kinase inhibitors], (43) steroid drugs [specifically, dexamethasone, hexestrol, Cortisone acetate, etc.], (44) Sex hormones or derivatives thereof [specifically, progesterone, estradiol, estradiol benzoate, etc.], (45) parathyroid hormone (PTH) and the like.

By using in combination with an existing drug for the above-mentioned disease, it is possible to reduce the dosage of the existing drug and reduce the side effects of the existing drug. Of course, the concomitant method using the drug is not limited to the disease, and the concomitant drug is not limited to the compounds exemplified above.

The administration form of the crystal of the present invention and the concomitant drug is not particularly limited, and it is sufficient that the crystal of the present invention and the concomitant drug are combined at the time of administration. Such an administration form includes, for example,
(1) Administration of a single preparation obtained by simultaneously formulating the crystal of the present invention and a concomitant drug,
(2) Simultaneous administration of two preparations obtained by separately formulating the crystal of the present invention and the concomitant drug by the same route of administration.
(3) Administration of two preparations obtained by separately formulating the crystal of the present invention and the concomitant drug in the same route of administration with a time lag.
(4) Simultaneous administration of two preparations obtained by separately formulating the crystal of the present invention and the concomitant drug by different administration routes.
(5) Administration of two preparations obtained by separately formulating the crystal of the present invention and the concomitant drug at different administration routes (for example, administration of the crystal of the present invention and the concomitant drug in this order). , Or administration in the reverse order).
Hereinafter, these administration forms are collectively abbreviated as a concomitant drug for crystals of the present invention.

When administering the concomitant agent of the crystals of the present invention, the concomitant drug and the crystals of the present invention may be administered at the same time, but the crystals of the present invention may be administered after the administration of the concomitant drug. , The concomitant drug may be administered after the administration of the crystals of the present invention. When administered with a time lag, the time difference varies depending on the active ingredient to be administered, the dosage form, and the administration method. For example, when the concomitant drug is administered first, it is preferably within 1 minute to 3 days after the concomitant drug is administered. Is a method of administering the crystal of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the crystals of the present invention are administered first, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the crystals of the present invention are administered. There is a way to do it.

The concomitant drug can be set in any amount as long as side effects are not a problem. The daily dose as a concomitant drug varies depending on the administration target, administration route, target disease, symptom, etc., but for example, when orally administered to a patient with schizophrenia (adult, body weight about 60 kg), it is usually a single dose. It is about 0.1 to about 20 mg / kg body weight, preferably about 0.2 to 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight, and this amount is applied once to several times a day. It is desirable to administer (for example, 3 times).

When the crystals of the present invention are used in combination with concomitant drugs, the amount of each agent can be reduced within a safe range in consideration of the opposite effects of those agents.

The concomitant drug of the crystals of the present invention has low toxicity, for example, the crystals of the present invention or (and) the concomitant drug described above are mixed with a pharmacologically acceptable carrier according to a known method to obtain a drug, for example, a tablet. It can be dragees (including sugar-coated tablets, film-coated tablets), powders, granules, capsules, (including soft capsules), solutions, injections, suppositories, sustained-release agents, etc., which may be oral or non-oral. It can be safely administered orally.

As the pharmacologically acceptable carrier that may be used in the production of the concomitant agent for the crystals of the present invention, the same carriers as those used in the above-mentioned pharmaceuticals for the crystals of the present invention can be used.

The compounding ratio of the crystal of the present invention and the concomitant drug in the concomitant drug of the crystal of the present invention can be appropriately selected depending on the administration target, administration route, disease and the like. The above-mentioned concomitant drug may be used in combination of two or more kinds at an appropriate ratio.

The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the crystal of the present invention and the concomitant drug can be appropriately selected depending on the administration target, administration route, target disease, symptom, combination and the like. For example, when the administration target is a human, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the crystal of the present invention. For example, the content of the crystals of the present invention in the concomitant drug of the crystals of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by weight, preferably about 0.01 to 99.9% by weight, based on the whole preparation. It is in the range of about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight.

The content of the concomitant drug in the concomitant drug of the crystal of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by weight, preferably about 0.1. It is in the range of ~ 50% by weight, more preferably in the range of about 0.5-20% by weight.

The content of additives such as carriers in the crystal concomitant agent of the present invention varies depending on the form of the preparation, but is usually in the range of about 1 to 99.99% by weight, preferably about 10 to 10% by weight, based on the whole preparation. It is in the range of 90% by weight.

The same content may be used when the crystals of the present invention and the concomitant drug are separately formulated.

As described above, the dose varies depending on various conditions, so a dose smaller than the above dose may be sufficient, or it may be necessary to administer beyond the range.

The crystals of the invention can be administered either alone or in multiple doses, either alone or in combination with a pharmaceutically acceptable carrier. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions, and various organic solvents. The pharmaceutical composition thus formed can then be readily administered in various dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injections and the like. These pharmaceutical compositions may optionally contain additional ingredients such as flavoring agents, binders, excipients and the like. Thus, the crystals of the invention are for oral, oral, nasal, parenteral (eg, intravenous, intramuscular, or subcutaneous), transdermal (eg, patch), or rectal administration, or inhalation or injection. It can be formulated in a form suitable for administration by.

[Formulation of preventive / therapeutic agent of the present invention]
The crystalline drug of the present invention is administered in the form of a pharmaceutical composition.
The pharmaceutical composition of the crystal of the present invention is 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,2] of the present invention. 5-a] Pyridine-7-yl) -1-methyl-1H-pyrazole-5-carboxamide crystals are included and made in combination with pharmaceutically acceptable additives. More specifically, excipients (eg lactose, sucrose, mannit, crystalline cellulose, silicic acid, corn starch, potato starch), binders (eg celluloses (hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (eg)). HPMC))), crystalline cellulose, sugars (lactose, mannit, sucrose, sorbitol, erythritol, xylitol,), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl Alcohol (PVA)), lubricants (eg magnesium stearate, calcium stearate, talc, carboxymethyl cellulose), disintegrants (eg starches (corn starch, potato starch), sodium carboxymethyl starch, carmellose, carmellose calcium , Croscarmellose sodium, crospopidone), coating agents (eg, celluloses (hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer LD), plastics (eg, starch) Triethyl acid acid, macrogol), masking agent (eg titanium oxide), colorant, flavoring agent, preservative (eg benzalconium chloride, paraoxybenzoic acid ester), isotonic agent (eg glycerin, sodium chloride, Calcium chloride, mannitol, starch), pH adjusters (eg buffers such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, starch phosphate), stabilizers (eg sugar, sugar alcohol, etc.) Xanthan gum), dispersants, antioxidants (eg ascorbic acid, butylhydroxyanisole (BHA), propyl starchate, dl-α-tocopherol), buffers, preservatives (eg parabens, benzyl alcohol, benzalconium chloride) ), Fragrances (eg vanillin, l-menthol, rose oil), solubilizers (eg polyoxyethylene hydrogenated starch oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol, triethanolamine), absorption enhancers (eg Sodium glycolate, sodium edetate, sodium caprate, acylcarnitines, limonene), gelling agents, suspending agents, or emulsifiers, commonly used suitable additives or solvents of the invention. It can be combined with crystals as appropriate to form various dosage forms. come.

Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, lozenges, liquids, alcohols, suspensions, Examples include extract agents and elixir agents. Oral, subcutaneous, intramuscular, intranasal, transdermal, intravenous, intraarterial, perineural, epidural, subdural, intraventricular, rectal. , Can be administered to patients by inhalation or the like.

The crystals of the invention can be formulated for parenteral administration by injection, including using conventional catheter techniques or injections. The injectable formulation can be provided as a unit dosage form, for example in ampoules or multi-dose containers, with the addition of preservatives. These formulations can take the form of suspensions, liquids, or emulsions in oily or aqueous vehicles and contain formulation agents such as suspending agents, stabilizers, and / or dispersants. be able to. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg sterile pyrogen-removed water, prior to use.

If a product solution is required, the product solution is isolated and encapsulated in water (or other aqueous medium) in an amount sufficient to produce a solution of the strength required for oral or parenteral administration to the patient. It can be produced by dissolving the complex. These compounds can be formulated in a rapid dispersion dosage form (fddf) designed to release the active ingredient in the oral cavity. These formulations are often formulated using a matrix based on fast-dissolving gelatin. These dosage forms are well known and can be used to deliver a wide range of drugs. Most rapidly dispersed dosage forms utilize gelatin as a carrier or structure-forming agent. Gelatin is typically used to impart sufficient strength to the dosage form to prevent breakage when removed from the packaging, but once in the mouth, gelatin allows the dosage form to decompose immediately. .. Alternatively, various starches are used to achieve the same effect.

The crystals of the invention can also be formulated into rectal compositions such as suppositories or retention enemas containing, for example, conventional suppository bases such as cocoa butter or other glycerides.

For intranasal or inhalation administration, the crystals of the invention are in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or a suitable propellant, eg, dichloro. It is conveniently delivered as an aerosol spray from a pressurized vessel or nebulizer using difluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. For pressurized aerosols, the unit of administration can be determined by providing a valve that delivers a metered amount. The pressurized container or nebulizer can contain a solution or suspension of the active compound. Capsules and cartridges used in inhalers or injectors (eg, made from gelatin) shall be formulated with a mixed powder of the crystals of the invention and a suitable powder base such as lactose or starch. Can be done.

Aerosol formulations for treating the above-mentioned conditions in the average adult are preferably set so that each metered dose of aerosol or "puff" contains from about 20 mg to about 1000 mg of crystals of the invention. The total daily dose of aerosol is in the range of about 100 mg to about 10 mg. Administration can be several times daily, for example 2, 3, 4, or 8 times, for example 1, 2, or 3 doses each time.

The content of the crystals of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, the dose of the crystals of the present invention, etc., but is preferably about 0.01 to 100% by weight, preferably about 0.01 to 100% by weight, based on the total amount of the composition. Is 0.1 to 95% by weight.

In order to treat the above-mentioned conditions, the dose of the crystal of the present invention varies depending on the administration target, administration route (oral, parenteral, rectal, oral, etc.), target disease, symptomatology, etc., but for example, schizophrenia. When orally administered to a patient with a disease (adult, body weight of about 60 kg), the usual single dose is about 0.1 to about 20 mg / kg body weight, preferably about 0.2 to 10 mg / kg body weight, and more preferably about 0. The body weight is 5 to about 10 mg / kg, and it is desirable to administer this amount once to several times (for example, three times) a day.

[Pharmacological experiment example]
The present invention will be specifically described below with reference to experimental examples, but the present invention is not limited thereto.
The following Pharmacological Example 1 provides a method for testing the effectiveness of the crystals of the present invention.

Pharmacological Experiment Example 1: Evaluation of in vitro compounds (evaluation of enzyme inhibitory activity: human PDE10A inhibitory action)
Measurements were made using an IMAP TR-FRET Phosphorsterase Evaluation Assay Kit (molecular device). 10 μL of each concentration of test compound diluted in 384-well plates (Corning) and 1 × IMAP Reaction Buffer coating 0.1% BSA (prepared from 5 × attached to kit, 10 mM Tris-HCl, pH = 7.2, 10 mM MgCl) 5 μL of PDE10A enzyme (BPA bioscience) diluted to 2 ng / mL with ₂ , 0.05% NaN _{3 and 0.1% BSA) was added and preincubated for 5 minutes at room temperature.} 1 × IMAP Reaction Buffer cotton 5 μL of the cAMP substrate attached to the kit diluted to 400 nM with 0.1% BSA was added and reacted at room temperature for 60 minutes. Further, 60 μL of IMAP TR-FRET Binding solution attached to the kit was added and left for 3 hours or more, and then Terbium fluorescence intensity (Emission = 490 nm) and TR-FRET (Emission = 520 nm) at an excitation wavelength of 340 nm by ARVO SX (PerkinElmer). ) Was measured to calculate the amount of 5'-AMP produced. The inhibitory activity of each test compound was calculated by setting the count of the wells to which the solvent was added instead of the test compound to 0% and the count of the wells to which the PDE10A enzyme was not added to 100%.

The test compound 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7- yl)-1-PDE10A inhibition activity methyl -1H- pyrazole-5-carboxamide are shown in Table 1 as _{IC 50} values.

The following pharmacological experiment example 2 (experiment on suppression of locomotor activity by oral administration of the test compound to rats 30 minutes before administration of MK-801) shows its effectiveness as a therapeutic agent for psychiatric disorders and neurodegenerative disorders. ..

Pharmacological Experiment Example 2: Evaluation of MK-801-induced locomotor activity (animal)
Male Sprague-Dawley rats are purchased and used in the experiment after arriving at the breeding facility with a habituation period of at least one week. Animals are bred in a temperature and humidity controlled laboratory under a 12-hour light-dark cycle and fed freely with food and water.

(Drug administration)
The test compound is suspended in a 0.5 w / v% methylcellulose 400 solution (Wako Pure Chemical Industries, Ltd., Japan) and orally administered (po.). (+)-MK-801 saline ((5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-hydrogen maleate, Sigma Aldrich, St. Louis, Missouri) is dissolved in saline and administered subcutaneously (s.c.). The test compound is administered to rats at a volume of 5 mL / kg body weight, and MK-801 is administered at a volume of 1 mL / kg body weight.

(Antagonist to MK-801-induced hypermotility)
Assessment of locomotor activity by psychostimulants (eg, amphetamine, cocaine, methamphetamine, MK-801 and phencyclidine) in rodents has been widely used as an animal model for schizophrenia (Schizophrenia Bulletin 2010, vol.36: 1066-1072; Psychopharmacology 1999, vol.145: 237-250). The antagonistic effect of the test compound on MK-801-induced locomotor activity in rats will be tested. Until the test, male Sprague-Dawley rats (about 300 g) are acclimatized in a rearing cage to the room where the measurements are taken for at least 60 minutes. After acclimation, animals are orally administered either solvent or compound (0.3 or 1 mg / kg body weight) and immediately returned to the rearing cage. 60 minutes after administration of the test compound, the animal was removed from the rearing cage again, the solvent (saline) or MK-801 (0.2 mg / kg body weight) was subcutaneously administered, and the animal was immediately spontaneously equipped with an infrared sensor. Put it in the momentum measurement chamber (Muromachi Kikai Co., Ltd., Japan) and start the measurement. The amount of spontaneous exercise is counted every 10 minutes. A cumulative count of 120 minutes after administration of MK-801 is calculated for each treatment group. All data are expressed as the standard error between the mean and the mean. For statistical analysis, Student's t-test was used for comparison between the control group and the MK-801 single administration group (there was a significant difference at p <0.05), and the comparison between the MK-801 single administration group and the test compound administration group was performed. Is analyzed using Dunnett's test (with a significant difference at p <0.05).

Pharmacological Experimental Example 3: Solubility Test (1) DMSO Precipitation Solubility (Kinetic Solution)
A 10 mM DMSO solution of the crystals of the present invention is added to 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 μM. The solution is incubated at room temperature for 1.5 hours with stirring at 600 rpm, filtered through a filter plate (0.4 μm, MultiScreen HTS-PCF filter plate (Merck Millipore)), and filtered through a plate reader (Powerscan HT (Dainippon Pharmaceutical Co., Ltd.)). )) Is used to measure the absorbance of the filtrate at the maximum absorption wavelength. At the same time, the absorbance of each standard solution is measured using a DMSO solution to which a known concentration of the test compound (1, 3, 10, 30, 100 μM) is added as a calibration curve standard solution, and a calibration curve is prepared. The solubility (μM) of the compound is calculated from the absorbance values of the filtrate and standard solution.

(2) Crystal solubility (Thermodynamic Solution)
The crystals of the present invention are added to water so as to be 1 mg / mL. The solution is incubated at 37 ° C. for 24 hours at 1000 rpm with stirring, and then filtered through a filter plate. The filtrate is analyzed by HPLC, a peak is detected at the maximum absorption wavelength, and the peak area is measured. Similarly, each peak area was measured using a 1,4-dioxane solution to which a known concentration of the test compound (0.01, 0.03, 0.1, 0.3, 1 μg / mL) was added as a calibration curve standard solution. , Calculate the solubility (μg / mL) of the compound from the peak area of the calibration curve.

Pharmaceutical Experiment Example 4: Metabolic Stability Test Liver microsome solution (human, mouse; XenoTech) and NADPH production solution (β-NADP, Glucose-6-Phosphate) so that the final concentration of the 10 mM DMSO solution of the crystal of the present invention is 1 μM. , G-6-PDH (Y), water containing _{MgCl 2).} The solution is incubated at 37 ° C. for 20 minutes and then the reaction is stopped with acetonitrile. The reaction is centrifuged on a filter plate (MultiScreen HTS-HV plate (Millipore)) and the test compound in the filtrate is measured using high performance liquid chromatography / mass spectrometry. Similarly, a sample having a reaction time of 0 minutes is measured as a control, and the decomposition rate (%) is calculated from the ratio of the microsome reaction sample to the control.

Pharmacological Experimental Example 5: HERG inhibition test by patch clamp method The action on the hERG (human ether-a-go-go related gene) channel is measured using a fully automatic patch clamp system (Patchliner (Nanion)). _{To confirm the hERG I Kr} current of cells (herG-HEK (Upstate)), the membrane potential is maintained at −80 mV and depolarizing pulses are periodically applied. After the generated current stabilizes, the test compound is added. The effect of the test compound on the hERG channel is confirmed by a change in tail current induced by a 40 mV, 0.5 second depolarization pulse followed by a -40 mV, 0.5 second repolarization pulse. Stimulation is performed once every 10 seconds. The measurement is performed at room temperature. The hERG channel inhibition rate is calculated as the reduction rate (suppression rate) of the tail current 2 minutes after application with respect to the maximum tail current before application of the test compound.

Calculation of this suppression rate indicates the possibility of inducing QT prolongation by the drug and subsequent fatal side effects (such as ventricular tachycardia and sudden death).

Pharmacological experiment example 6: Pharmacokinetic test (mouse cassette PK)
After a single oral administration of the crystals of the present invention to a 7- or 8-week-old male C57BL / 6JJcl at 1 mg / kg (administration solvent is DMSO: Tween80: ultrapure water = 1: 1: 8, 10 mL / kg). , 0.25, 0.5, 1, 2 hours later, blood is collected from the abdominal vena cava. Using plasma obtained by centrifuging blood (3000 rpm, 15 minutes, 4 ° C.), test compounds in plasma are measured by high performance liquid chromatography / mass spectrometry. Similarly, a standard solution to which a known concentration of the test compound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 μg / mL) was added was measured, and from the prepared calibration curve. The plasma concentration (μg / mL) is calculated, and the maximum plasma concentration is defined as Cmax (μg / mL).

Pharmacological Experiment Example 7: Protein binding test A 10 mM DMSO solution of the crystal of the present invention is added to normal plasma (human, rat) so as to have a final concentration of 10 μM. After dialysis at 37 ° C. for 4 hours on a simple equilibrium dialysis machine (RED Device (Linden Bioscience)), the inner (plasma side) and outer (PBS side) solutions of the dialysis membrane are subjected to high performance liquid chromatography / mass spectrometry. Use to measure the test compound in the sample. The non-binding fraction (%) is calculated from the ratio of the PBS side and the plasma side, and the protein binding ratio (%) is calculated from the 100-non-binding fraction (%).

Pharmaceutical Experiment Example 8: Safety Test The safety of the crystals of the present invention was demonstrated by the fact that the crystals of the present invention were orally administered to mice or rats in a single dose, no deaths were observed, and no noticeable behavioral abnormalities were observed. Is done.

From the above results, it was shown that the crystal of the present invention has an excellent PDE10A inhibitory effect. In addition, no abnormality was found in the safety test, indicating the low toxicity of the crystals of the present invention.

Furthermore, the crystals of the present invention are confirmed to be good in one respect such as solubility, metabolic stability, pharmacokinetics, and avoidance of hERG channel inhibitory action by performing the above tests.

Thus, the crystals of the invention, as selective PDE10A inhibitors, include certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychiatric disorders, anxiety disorders such as dysphoric and obsessive-compulsive disorders, and Expected to be used as a prophylactic and / or therapeutic agent for disorders such as movement disorders, mood disorders, neurodegenerative disorders, disorders including lack of attention and / or cognition, obesity, and drug addiction, including Parkinson's disease and Huntington's disease. To.

The crystals of the present invention are expected to exhibit promising preventive or therapeutic effects on the following various diseases. Specifically, (1) dementia-type, dismantling-type, tension-type, indistinguishable-type, or residual-type schizophrenia, (2) schizophrenia-like disorder, (3) dementia-type or depressive-type schizophrenia. Emotional disorders, (4) dementia disorders, (5) substance-induced mental disorders, (6) alcohol, amphetamine, cannabis, cocaine, psychedelics, inhalants, opioids, or phencyclidine-induced mental disorders, (7) ) Dementia-type personality disorder, (8) schizophrenia-type personality disorder, (9) Huntington's disease, (10) abnormal motility associated with Dopamine agonist therapy, (11) Parkinson's disease, (12) restless lower limb syndrome, (13) ) Essential tremor, (14) obsessive disorder, (15) Tourette syndrome, (16) tic disorder, (17) depressive disorder, (18) square dementia, (19) specific dementia, (20) Social phobia, (21) post-traumatic stress disorder, (22) acute stress disorder, (23) general anxiety disorder, (24) dementia; Alzheimer's disease, multiple cerebral infarction, alcoholic dementia or other drugs Related dementia, intracranial tumor or brain trauma-related dementia, Huntington's disease or Parkinson's disease-related dementia, AIDS-related dementia, or frontotemporal dementia (25) dementia, (26) forgetfulness disorder, (27) Mental retardation, (28) Learning disorder; Reading disorder, Arithmetic disorder, or Writing disorder, (29) Attention deficiency / hyperactivity disorder, (30) Age-related cognitive decline, (31) Major depression Disease episodes (mild, moderate, or severe), dementia episodes, mixed episodes, mild dementia episodes, (32) atypical depression, (33) melancholic depression, (34) tension dementia, ( 35) Postpartum mood episodes, (36) Post-stroke depression, (37) Major dementia, (38) Dementia / dementia, (39) Minor dementia, (40) Premenstrual Discomfort mood disorder, (41) Post-dementia depressive disorder, (42) Major depressive disorder associated with mental disorders such as dementia or schizophrenia, (43) Bipolar disorder; Bipolar type I disorder , Bipolar type II disorder, (44) mood and circulation disorder, (45) brain trauma-related dementia, (46) stroke-related dementia, cerebral infarction-related dementia, (47) hypoglycemic-induced For dementia, (48) dementia associated with epilepsy, (49) dementia associated with neurotoxic poisoning, (50) multilineage atrophy, (51) dementia of medium-sized striatum spinous neurons, etc. A promising therapeutic effect can be expected.

All documents and publications described in this specification shall be incorporated herein by reference in their entirety, regardless of their purpose. In addition, this specification discloses the scope of claims, the specification, and the drawings of Japanese Patent Application No. 2015-230163 (filed on November 26, 2015), which is the Japanese patent application on which the priority claim of the present application is based. Including.

Next, Examples and Test Examples will be given to explain the present invention in more detail. However, these examples are merely examples, do not limit the present invention, and do not deviate from the scope of the present invention. May be changed with.

For the measurement of nuclear magnetic resonance spectrum (NMR), Jeol JNM-ECX400P (JEOL JNM-ECX400P) FT-NMR (manufactured by JEOL Ltd.), Jeol JNM-ECX300 (JEOL JNM-ECX300) FT-NMR (JEOL Ltd.) (Manufactured by Co., Ltd.) was used. LC-Mass was measured by the following method. A Waters FractionLynx MS system (manufactured by Waters) was used, the column was a CAPCELL Pak column (2.0 mm × 50 mm, 3 μm) manufactured by Shiseido, and the mobile phase was methanol: 0.05% trifluoroacetic acid aqueous solution = 10:90 (). A gradient condition of 0 minutes) to 100: 0 (2 minutes) to 100: 0 (3 minutes) was used.

In (physical property data) of (reference example), LC-MS means LC-Mass (liquid chromatography-mass spectrometry spectrum), and in LC-MS, M is the molecular weight, RT is the retention time, and [ M + H] ⁺ , [M + 3H] ³⁺ , and [M + Na] ⁺ shall mean molecular ion peaks. ^{1 In} H-NMR (proton nuclear magnetic resonance) data, the pattern of NMR signals is s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, br for broad, and J for coupling constant. Hz means Hertz, CDCl ₃ means deuterated chloroform, and DMSO-d ₆ means deuterated dimethyl sulfoxide. ^{1 In the} H-NMR data, signals that cannot be confirmed due to broadband, such as hydroxyl group (OH group), amino group (NH ₂ ), and carboxyl group (COOH) protons, are not described in the data. In addition, "room temperature" in the examples usually indicates a temperature of 1 ° C. to 30 ° C. (specified by the Japanese Pharmacopoeia).

The solvent used for crystallization was a commercial grade and was used without further purification.

Powder X-ray diffraction analysis is performed using the R-AXIS IV differential shutter UltraX18 (manufactured by Rigaku) by the debye-shutter method (X-ray source: 50 kV, 100 mA, Wavelength: 1.5418 Å (CuKalpha), CaKalpha). Temperature: room temperature, Ph Position: 0 ° C., Exposure time: 10 minutes, Delta Ph: 120 ° C.). Alternatively, using the D8 Discover with GADDS CS (manufactured by Bruker), the Bragg-Brentano method (X-ray source: 40 kV, 40 mA, Wavelength: 1.5418 Å (CuKalpha), Camera length: 250 mm, temperature: 250 mm, temperature: Measurement was performed at 0 ° C., Exposure time: 2 minutes, Theta 1: 7 ° C., Theta 2: 7 ° C.).

For differential scanning calorimetry (DSC), a differential scanning calorimeter DSC Q2000 (manufactured by TA instruments) was used to measure the temperature range from 40 ° C. to 300 ° C. at a heating rate of 10 ° C. per minute. FT-IR was measured by the KBr method using FT-720 (manufactured by HORIBA). Micrographs were measured using a Leica DFC450 (manufactured by Leica).

For the stability test, a small environmental tester (manufactured by ESPEC) SH-641 was used to store about 15 mg of the sample at 25 ° C / 60% RH and 40 ° C / 75% RH for 1 month in an open or sealed state to obtain purity. And the change in crystal form was measured.

For the purity measurement, an apparatus: Waters ACQUITY UPLC H-Class (manufactured by Waters) column: Waters ACQUITYBEHShideRP18 (particle size 1.7 μm, size 2.1 x 50 mm) was used. 10 mmol / L ammonium hydrogencarbonate buffer pH 9.0 and acetonitol were used for the moving layer, and the sample was 50 μg / mL 1,4-dioxane: acetonitrile: 10 mmol / L ammonium hydrogencarbonate buffer = 20:20:60. A solution was prepared and carried out.

(Reference Example 1) 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7- Il) Synthesis of -1-methyl-1H-pyrazole-5-carboxamide

＜工程１＞メチル ４−（２，５−ジメチルピリミジン−４−イル）−１−メチル−１Ｈ−ピラゾール−５−カルボキシレートの合成

<Step 1> Synthesis of methyl 4- (2,5-dimethylpyrimidine-4-yl) -1-methyl-1H-pyrazole-5-carboxylate

メチル ４−ブロモ−１−メチル−１Ｈ−ピラゾール−５−カルボキシレート（１．９ｇ）、２−ジシクロヘキシルフォスフィノ−２’，６’−ジメトキシ−１，１’−ビフェニル（０．１５ｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（０．１６ｇ）及びトリエチルアミン（３．７ｍＬ）の１，４−ジオキサン（１９ｍＬ）溶液に、４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン（１．５ｍＬ）を加え、窒素雰囲気下、１００℃にて３０分撹拌した。反応溶液に、４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン（１．５ｍＬ）を加え、３０分同温にて撹拌した後、炭酸カリウム（３．６ｇ）の水溶液（３．９ｍＬ）及び４−クロロ−２，５−ジメチルピリミジン（ＣＡＳレジストリー番号：７５７１２−７４−２）（１．０ｇ）の１，４−ジオキサン（４ｍＬ）溶液を順次加え、同温度にて１時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し得られた残渣ををシリカゲルカラムクロマトグラフフィ−（シリカゲル：溶出液；ヘプタン：酢酸エチル＝３：１〜１：１〜０：１）にて精製し、標記化合物（１．９ｇ）を橙色液体として得た。
（物性データ）ＬＣ−ＭＳ：Ｍ＝２４６，ＲＴ＝０．３７（分），［Ｍ＋Ｈ］^＋＝２４７. １Ｈ−ＮＭＲ （ＣＤＣｌ_３） δ：８．４９（１Ｈ，ｓ），７．５７（１Ｈ，ｓ），４．２１（３Ｈ，ｓ），３．７０（３Ｈ，ｓ），２．７１（３Ｈ，ｓ），２．１５（３Ｈ，ｓ）．

Methyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate (1.9 g), 2-dicyclohexylphosphino-2', 6'-dimethoxy-1,1'-biphenyl (0.15 g), tris (Dibenzylideneacetone) In a solution of dipalladium (0) (0.16 g) and triethylamine (3.7 mL) in 1,4-dioxane (19 mL), 4,4,5,5-tetramethyl-1,3,2 -Dioxabolorane (1.5 mL) was added, and the mixture was stirred at 100 ° C. for 30 minutes under a nitrogen atmosphere. To the reaction solution, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 mL) was added, and the mixture was stirred at the same temperature for 30 minutes, and then an aqueous solution of potassium carbonate (3.6 g) (3.6 g). 3.9 mL) and 4-chloro-2,5-dimethylpyrimidine (CAS registry number: 75712-74-2) (1.0 g) in 1,4-dioxane (4 mL) solutions were added sequentially and at the same temperature 1 Stirred for hours. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatograph (silica gel: eluate; heptane: ethyl acetate = 3: 1 to 1: 1 to 0: 1), and the title compound ( 1.9 g) was obtained as an orange liquid.
(Physical characteristics data) LC-MS: M = 246, RT = 0.37 (minutes), [M + H] ⁺ = 247.1 H-NMR (CDCl ₃ ) δ: 8.49 (1H, s), 7.57 ( 1H, s), 4.21 (3H, s), 3.70 (3H, s), 2.71 (3H, s), 2.15 (3H, s).

<Step 2> Synthesis of 4- (2,5-dimethylpyrimidine-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid

（参考例１）＜工程１＞で得られたメチル ４−（２，５−ジメチルピリミジン−４−イル）−１−メチル−１Ｈ−ピラゾール−５−カルボキシレート（１．９ｇ）のメタノ−ル（１５ｍＬ）及び水（１５ｍＬ）混合溶液に、水酸化ナトリウム（０．３１ｇ）を加え、５０℃で１時間撹拌した。減圧下、反応溶液中のメタノ−ルを留去し、１規定塩酸にてｐＨを５〜６とした後、減圧下、水を留去した。得られた残渣を塩化メチレンで洗浄し、ろ液を減圧下濃縮することで、標記化合物（０．９４ｇ）を黄色固体として得た。
（物性データ）ＬＣ−ＭＳ：Ｍ＝２３２，ＲＴ＝０．６５（分），［Ｍ＋Ｈ］^＋＝２３３. ^１Ｈ−ＮＭＲ （ＤＭＳＯ−ｄ_６） δ：８．４９（１Ｈ，ｓ），７．６１（１Ｈ，ｓ），４．０７（３Ｈ，ｓ），２．５５（３Ｈ，ｓ），２．１５（３Ｈ，ｓ）．

(Reference Example 1) Metall of methyl 4- (2,5-dimethylpyrimidine-4-yl) -1-methyl-1H-pyrazole-5-carboxylate (1.9 g) obtained in <Step 1> Sodium hydroxide (0.31 g) was added to a mixed solution of (15 mL) and water (15 mL), and the mixture was stirred at 50 ° C. for 1 hour. The methanol in the reaction solution was distilled off under reduced pressure, the pH was adjusted to 5 to 6 with 1N hydrochloric acid, and then water was distilled off under reduced pressure. The obtained residue was washed with methylene chloride, and the filtrate was concentrated under reduced pressure to give the title compound (0.94 g) as a yellow solid.
(Physical data) LC-MS: M = 232 , RT = 0.65 ( ^{min), [M + H] +} = 233 1 H-NMR (DMSO-d 6) δ:. 8.49 (1H, s), 7 .61 (1H, s), 4.07 (3H, s), 2.55 (3H, s), 2.15 (3H, s).

<Step 3> 4- (2,5-Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl ) Synthesis of -1-methyl-1H-pyrazole-5-carboxamide

（参考例１）＜工程２＞で得られた４−（２，５−ジメチルピリミジン−４−イル）−１−メチル−１Ｈ−ピラゾール−５−カルボキシリック アシッド（７１５ｍｇ）、６−フルオロ−２−フェニル−［１，２，４］トリアゾロ［１，５−ａ］ピリジン−７−アミン ハイドロクロライド（国際公開第２０１２／０７６４３０号パンフレット、ｐ８０、実施例３０−ｈ）に記載の方法に準じて取得）（８１５ｍｇ）、２−（１Ｈ−７−アザベンゾトリアゾール１−イル）−１，１，３，３−テトラメチルウロニウムヘキサフルオロフォスフェ−ト メタナミニウム（２．３４ｇ）及びジイソプロピルエチルアミン（２．６９ｍＬ）のＮ−メチルピロリドン（７．７ｍＬ）溶液を、８０℃にて３時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を合わせて無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去した。得られた残渣ををシリカゲルカラムクロマトグラフフィ−（ＮＨシリカゲル：溶出液；ヘプタン：酢酸エチル＝３：１〜１：１）にて精製し、得られたフラクションを減圧下濃縮した。得られた残渣（固体）をメタノ−ルでトリチュレ−トすることで、標記化合物（３７７ｍｇ）を無色固体として得た。
（物性データ）ＬＣ−ＭＳ：Ｍ＝４４２，ＲＴ＝１．１３（分），［Ｍ＋Ｈ］^＋＝４４３. ^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３，δｐｐｍ）: １１．７２（１Ｈ，ｓ），８．７８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．６３（１Ｈ，ｓ），８．５９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．２７−８．２４（２Ｈ，ｍ），７．７０（１Ｈ，ｓ），７．５１−７．４９（３Ｈ，ｍ），４．３１（３Ｈ，ｓ），２．７８（３Ｈ，ｓ），２．４２（３Ｈ，ｓ）．

(Reference Example 1) 4- (2,5-dimethylpyrimidine-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid (715 mg), 6-fluoro-2 obtained in <Step 2> -Phenyl- [1,2,4] Triazolo [1,5-a] Pyridine-7-amine Hydrochloride (International Publication No. 2012/076430, p80, Example 30-h). Obtained) (815 mg), 2- (1H-7-azabenzotriazole1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphofate metanaminium (2.34 g) and diisopropylethylamine (2) A solution of .69 mL) of N-methylpyrrolidone (7.7 mL) was stirred at 80 ° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatograph (NH silica gel: eluate; heptane: ethyl acetate = 3: 1 to 1: 1), and the obtained fraction was concentrated under reduced pressure. The obtained residue (solid) was triturated with a metalol to give the title compound (377 mg) as a colorless solid.
(Physical data) LC-MS: M = 442 , RT = 1.13 ( ^{min), [M + H] +} = 443 1 H-NMR (400MHz, CDCl 3, δppm):. 11.72 (1H, s), 8.78 (1H, d, J = 8Hz), 8.63 (1H, s), 8.59 (1H, d, J = 8Hz), 8.27-8.24 (2H, m), 7. 70 (1H, s), 7.51-7.49 (3H, m), 4.31 (3H, s), 2.78 (3H, s), 2.42 (3H, s).

(Example 1)
4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Methyl-1H-pyrazole-5-carboxamide type I crystal 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,2,4] 5-a] Pyridine-7-yl) -1-methyl-1H-pyrazole-5-carboxamide solid (20 mg) was dissolved in acetone (3 mL) at an external temperature of 90 ° C., and the solution was rapidly cooled to -20 ° C to room temperature. I stayed still for 1 hour. The solid was collected by filtration and 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7. -Il) -1-methyl-1H-pyrazole-5-carboxamide (9.3 mg) was obtained as type I crystals.

The measurement results of powder X-ray diffraction of type I crystals are shown in Table 2 and FIG. 1 below. A micrograph of the crystal is shown in FIG.

(Example 2)
4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Type II Crystals of Methyl-1H-Pyrazole-5-Carboxamide 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,2,4] 5-a] A solid (6.55 g) of pyridine-7-yl) -1-methyl-1H-pyrazole-5-carboxamide was suspended in ethanol (655 mL) containing 10% water and concentrated hydrochloric acid (2.5 mL). ) Was added and dissolved by heating at 60 to 70 ° C. 28% aqueous ammonia (2.7 mL) was added to the obtained solution at about 50 ° C., and the mixture was allowed to cool. The resulting suspension was stirred at room temperature for 2 hours. The solid was collected by filtration and 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7. -Il) -1-methyl-1H-pyrazole-5-carboxamide (5.81 g) was obtained as a type II crystal.

The measurement results of powder X-ray diffraction of type II crystals are shown in Table 3 and FIG. 3 below. Further, the DSC thermal analysis data of the crystal is shown in FIG. The FT-IR spectrum data of the crystal is shown in Table 4 and FIG. A micrograph of the crystal is shown in FIG.

(Test Example 1) Examination of crystallization from various solvents (Reference Example 1) 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2) obtained by the same method. -Phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide solid (125 mg) in dimethyl sulfoxide (7.5 mL) And dispensed into 24 SY-06 vials (0.6 mL vial manufactured by Nichiden Rika Glass Co., Ltd.). After freezing with acetone-dry ice, it was freeze-dried using a freeze-dryer FDU-2100 (Tokyo Rika Kikai Co., Ltd.). Various solvents were added to each vial to a concentration of 100-200 mg / mL. This solution was shaken and stirred at 100 rpm at room temperature for 7 days using a shaker NR-3 (manufactured by Titec). Formed 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl)- Crystals of 1-methyl-1H-pyrazole-5-carboxamide were collected by filtration, and the crystal form of the crystallized product was confirmed (slurry method). For several solvents, a stirrer chip was added to the above solution, and the mixture was heated and stirred at 100 ° C. to dissolve it, then allowed to cool to room temperature, the precipitated solid was removed, and the crystal form of the crystallized product was confirmed (slow cooling method). The results are shown in Table 5.

(Test Example 2) Solvent suspension test of crystalline mixture 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] obtained by crystallization ] Triazolo [1,5-a] Pyridine-7-yl) -1-Methyl-1H-Pyrazole-5-Carboxamide crystallized mixture of the same weight of each crystal form (type I crystal, type II crystal) It was prepared and the total amount was 6 mg. The crystalline mixture is mixed with various solvents (0.05 mL) and suspended, one glass bead (manufactured by AS ONE, BZ-3) is added, and a constant temperature shaker M.BR-022UP (manufactured by Titec) is used. The mixture was stirred at 25 ° C. or 50 ° C. at 2500 rpm for 72 hours. Formed 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7-yl)- Crystals of 1-methyl-1H-pyrazole-5-carboxamide were collected by filtration, and the crystal form was confirmed. The results are shown in Table 6.

As described above, all the mixtures of various crystal forms were transferred to type II crystals after 72 hours in a suspended state under the conditions of 25 ° C. or 50 ° C. From this result, it was clarified that the type II crystal of the present invention is thermodynamically stable in a suspended state under the condition of 25 ° C. or 50 ° C.

(Test Example 3) Storage stability test 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo obtained by crystallization [1,5-a] Type II crystals (about 15 mg) of pyridine-7-yl) -1-methyl-1H-pyrazole-5-carboxamide were placed in a glass bottle and stored under the conditions shown in Table 7. After the storage period was completed, the sample was taken out, and the purity was measured by high performance liquid chromatography and the crystal form was confirmed by powder X-ray. The results are shown in Table 7.

(Test Example 3-2) Apart from the long-term storage stability test (Test Example 3), 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-) obtained by crystallization was obtained. Double LDPE of type II crystals (about 2 g) of 2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide After being placed in (low density polyethylene), it was placed in a fiber drum and stored under the conditions shown in Table 8. After the storage period was completed, the sample was taken out, and the purity was measured by high performance liquid chromatography and the crystal form was confirmed by powder X-ray. The results are shown in Table 8.

(Test Example 4) Photostability test 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo obtained by crystallization [1,5-a] Type II crystals (about 2 g) of pyridine-7-yl) -1-methyl-1H-pyrazol-5-carboxamide were placed in a glass dish-shaped container, and ICH Q1B shown in Table 9 was placed. It was subjected to a photostability test according to (Photostability test guidelines for new drug substance and new formulation) (Photostability test samples are stored under separate lamps that emit visible light and UV-A light, and are approximately stored. At 25 ° C., the total exposure should be at least 1.2 million lux hours and 200 watt hours / m ² , respectively. The 5-day test is referred to as 0.5 ICH and the 10-day test is referred to as 1 ICH). After the test was completed, the sample was taken out, the purity was measured by high performance liquid chromatography, and the crystal form was confirmed by powder X-ray. The results are shown in Table 9.

From the above results, it was clarified that the type II crystal of the present invention has very high chemical and physical stability.

Since the crystals of the present invention exhibit an excellent PDE10A inhibitory effect, it is possible to provide a clinically useful preventive agent and / or therapeutic agent for diseases such as schizophrenia. Further, the crystal of the present invention is useful as a medicine because it is excellent in terms of drug efficacy, safety, pharmacokinetics, stability and the like (particularly, stability).

Although some of the specific embodiments of the present invention have been described in detail above, various modifications to the specific embodiments shown by those skilled in the art will be made without substantially deviating from the teachings and advantages of the present invention. It is possible to make changes. Accordingly, all such modifications and modifications are within the spirit and scope of the invention claimed in the claims.

Claims (11)

Diffraction angles (2θ) by powder X-ray diffraction are 7.8, 8.8, 10.9, 14.7, 15.7, 16.3, 18.7, 20.0, 21.4, 23.6. , 24.9, 25.2, 25.7, and 26.5 (°) with characteristic peaks, 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2). -Phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide type II crystals. 4- (2,5-Dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,] having a diffraction angle (2θ) and relative intensity shown in the table below in powder X-ray diffraction. 2,4] Type II crystals of triazolo [1,5-a] pyridine-7-yl) -1-methyl-1H-pyrazole-5-carboxamide.

4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1], characterized by powder X-ray diffraction pattern shown in the figure below. , 5-a] Pyridine-7-yl) -1-methyl-1H-pyrazole-5-carboxamide type II crystals.

The type II crystal according to any one of claims 1 to 3, wherein the differential scanning calorimetry (DSC measurement) extrapolation melting point start temperature is 225 ° C. The type II crystal according to any one of claims 1 to 4 in the form of a columnar crystal. 4- (2,5-dimethylpyrimidine-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Methyl-1H-pyrazole-5-carboxamide was suspended in ethanol containing 10% water, and then concentrated hydrochloric acid was added to the suspension under heating to dissolve it, and then aqueous ammonia was added to the solution. 4- (2,5-Dimethylpyrimidine-4-yl) -N- (6--) according to any one of claims 1 to 5 , which comprises a step of making a suspension and further allowing the suspension to cool. A method for producing type II crystals of fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide. A pharmaceutical composition containing the crystal according to any one of claims 1 to 5 as an active ingredient. The pharmaceutical composition according to claim 7 , which is a PDE10A inhibitor. The pharmaceutical composition according to claim 7 , which is a prophylactic and / or therapeutic agent for a disease or condition of schizophrenia. Use of the crystal according to any one of claims 1 to 5 in the production of a pharmaceutical composition. In a method of treating at least one disease or condition selected from the group consisting of psychiatric disorders , anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, disorders including lack of attention and / or cognition, obesity, and drug addiction. There is a pharmaceutical composition for use ,
The pharmaceutical composition contains the crystal according to any one of claims 1 to 5.
It said method, a certain amount effective to treat said disease or condition, comprising administering said crystal to a subject in need of treatment of said disease or condition, a pharmaceutical composition.

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