JP2017095411A - Crystal of salt of pyrazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide: a crystal of a novel salt of a pyrazole derivative which has excellent cyclic nucleotide phosphodiesterase (PDE) 10A inhibitory action, is useful as a therapeutic agent and/or a preventive, etc. for schizophrenia, etc., and has excellent properties in solubility and absorptivity; a method for producing the crystal; and a pharmaceutical composition containing the crystal of salt.SOLUTION: Provided is a crystal of a specific acid addition salt of 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, or a solvation product thereof, especially a crystal of a mono hydrate of a mono hydrochloric acid salt of, an anhydride of the mono hydrochloric acid salt of, and an anhydride of mono hydrobromic acid salt of the carboxamide, which have excellent PDE 10A inhibitory action and are useful as a therapeutic agent and/or preventive, etc. for schizophrenia, etc. Also provided is a preventive and/or a therapeutic agent for schizophrenia, etc. containing as an active ingredient the crystal which has excellent properties with respect to solubility and bioavailability.SELECTED DRAWING: None

Description

The present invention relates to a novel salt crystal of a pyrazole derivative having an excellent phosphodiesterase 10A inhibitory action and useful as a therapeutic and / or prophylactic agent for schizophrenia, a method for producing the crystal, and a crystal of the salt The present invention relates to a pharmaceutical composition containing

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

The role of PDE in the cellular signal cascade is the cyclic nucleotide adenosine 3 ′, 5′-cyclic monophospho.
ate: cAMP) and / or cyclic guanosine monophosphate (guanosine 3 ′)
, 5′-cyclic monophosphate (cGMP), ie, selectively catalyzing the hydrolysis of the 3′-ester bond to form an inactive 5′-monophosphate. It is metabolically inactive.

Eleven PDE families are based on substrate specificity and are based on cAMP-specific PDEs (PDE4
, 7, 8), cGMP-specific PDE (PDE5, 6, 9), and dual substrate PDE (PDE)
1, 2, 3, 10, 11). (Non-Patent Documents 3 and 4)

cAMP and cGMP are G protein-coupled receptors (GPCR, G Protein)
Because it is an important second messenger in intracellular signal transduction via Coupled Receptors), PDE is involved in a wide range of physiological mechanisms and plays an important role in organism homeostasis. Specifically involved in the control of various physiological processes such as production and action of pro-inflammatory mediators, ion channel function, muscle relaxation, learning and memory formation, differentiation, apoptosis, lipogenesis, glycogenolysis and gluconeogenesis Yes. In particular, nerve cells play an important role in the control of neurotransmission along with the differentiation and survival of neurons (Non-Patent Document 5).

Control of these processes by cAMP and cGMP is protein kinase A (P
With the activation of KA) and protein kinase G (PKG), various substrates controlling various physiological processes including transcription factors, ion channels and receptors are phosphorylated.
The intracellular concentrations of cAMP and cGMP fluctuate in response to signals from outside the cell, and cA
It is regulated by the balance of enzymes involved in the synthesis of MP and cGMP (adenyl cyclase (AC) and guanyl cyclase (GC)) and PDE involved in hydrolysis of these enzymes. (Non-patent document 6)

The existence of PDE10A was reported in 1999 in humans, mice and rats. (Non-Patent Documents 7 and 8) PDE10A is mainly expressed in the brain, testis, thyroid gland and the like in humans. In particular, medium spiny neurons (MSN, medium-sized sp) in the striatum in the brain
iny neuron) and highly expressed in the thalamus, hippocampus, frontal cortex and olfactory nodule. (Non-Patent Documents 9 and 10) PDE10A is also highly expressed in the brain and testis in mice and rats. (Non-patent document 11) Since the brain region where these PDE10A is expressed shows an important role in the pathological mechanism of mental illness, PDE10A
Has been implicated in pathological mechanisms such as mental disorders and neurodegenerative disorders. (Non-patent document 12)

MSN mainly expresses D1 dopamine receptor and forms nigrostriatal tract (direct path), and mainly expresses D2 dopamine receptor and striatal pallidum (indirect path). M to form)
There are two MSNs for SN. The direct path is involved in the performance of exercise and reward learning, and the indirect path is related to the suppression of movement. For example, in Parkinson's disease, the movement becomes worse due to the indirect road working excessively, and in the disorder such as Huntington's disease, the movement becomes excessive due to the direct road working excessively. The activity of the output nucleus of the basal ganglia is regulated by a balance of antagonistic inputs from these two pathways. Since PDE10A is expressed in MSN of both pathways, inhibition of PDE10A is thought to activate both pathways. (Non-patent document 13)
Existing antipsychotics are primarily D2 receptor blockers and are primarily through indirect activation. On the other hand, PDE10A is expressed in both direct and indirect MSNs,
PDE10A inhibitors are expected to have antipsychotic effects similar to existing drugs. Since the direct path is involved in motor performance, it is thought to work against extrapyramidal disturbances due to excessive activation of the indirect path, and this path enhances the output from the striatum-thalamic circuit. Also, it can be expected to promote cognitive functions such as reward learning and problem solving.

An increase in intracellular cAMP levels due to D1 receptor activation seems to regulate a series of neurites involved in working memory in the prefrontal cortex (Non-Patent Document 14),
It has been reported that D1 receptor activation can improve working memory deficits in schizophrenic patients. (Nonpatent literature 15) Therefore, the improvement of the cognitive symptom of schizophrenia can be anticipated by activating D1 receptor.

The potential antipsychotic effect of PDE10A inhibitors is further supported by the study of Kostowski et al. (Non-patent Document 16). US Patent Application Publication No. 2003/0032579
Papaverine (an isoquinoline alkaloid contained in poppy plants, papaverine), a moderately selective PDE10A inhibitor, reduces apomorphine-induced stereotypia in rats, an animal model of psychosis However, it has been shown to increase the haloperidol-induced catalepsy in the rat while simultaneously reducing the dopamine concentration in the rat brain and having the action of a conventional antipsychotic. Further, it is supported by application to patients, and papaverine has been established as a PDE10A inhibitor for the treatment of psychosis. (Patent Document 1)

About the compound (PDE10A inhibitor) which has PDE10A inhibitory effect, there exist the following reports. For example, International Publication No. 2005/082883 (Patent Document 2)
) And European Patent Application Publication No. EP 1250923 (Patent Document 3), PD
Papaverine and various aromatic heterocyclic compounds (such as quinazoline and isoquinazoline compounds) are disclosed as E10A inhibitors. In addition, PDE10A inhibitor is a mental disorder (
For example, schizophrenia, schizophrenia-like disorder, paranoid disorder, substance-induced psychosis, paranoid personality disorder, schizophrenic personality disorder, etc., anxiety disorder (eg panic disorder, agoraphobia, single fear, interpersonal Fear, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, etc.),
Movement disorders (eg, Huntington's disease, dyskinesia associated with dopamine agonist treatment, Parkinson's disease, restless leg syndrome, etc.), drug addiction (eg, alcohol, amphetamine, cocaine or opiate addiction), diseases with symptoms of cognitive impairment (For example, dementia (Alzheimer's disease, multiple cerebral infarction dementia, etc.), delirium, amnestic disorder, post-traumatic stress disorder, mental retardation, learning disorder, attention deficit hyperactivity disorder (ADHD) and age-related cognitive function Depression, etc.), and mood disorders (eg, major depressive disorder, mood modulation disorder, minor depressive disorder, and bipolar disorder (bipolar I disorder, bipolar II disorder), mood circulatory disorder, etc.), Or mood symptoms (eg,
It is disclosed that it is useful for the treatment or prevention of diseases or symptoms such as major depression episodes, manic or mixed episodes, hypomania episodes, etc.). In addition, PDE10A
It has also been disclosed that inhibitors are useful for the treatment or prevention of neurodegenerative diseases such as Parkinson's disease and Huntington's disease.

Menniti et al. Reports that a PDE10A inhibitor has potential as an antipsychotic and has the potential to improve cognitive impairment in schizophrenia. (Non-patent document 17)

WO2003 / 000693 discloses an imidazotriazine compound as a PDE10A inhibitor, and discloses that the PDE10A inhibitor is useful for the treatment or prevention of neurodegenerative diseases (particularly Parkinson's disease). Has been. (Patent Document 4)

From the above, the PDE10A inhibitor is a psychiatric disorder involving PDE10A (for example, (1)
Delusion, dismantling, tension, indistinguishable, or residual schizophrenia, (2) schizophrenia-like disorder, (3) delusional or depressive schizophrenia, (4) delusional Disorders, (5) substance-induced mental disorders such as alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine-induced psychosis, (6) delusional personality disorder, and (7 ) Schizophrenic personality disorder etc.) and neurodegenerative disorders (eg (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) neurodegeneration associated with brain trauma, (5) neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarction, (6) hypoglycemia-induced neurodegeneration, (7) neurodegeneration associated with epileptic seizures, (8) neurodegeneration associated with neurotoxin poisoning. And (9) multisystem atrophy, (10) neurodegeneration of striatal medium spiny neurons, etc.) and the like, and is expected to be a therapeutic agent with reduced side effects .

International Publication No. 2006/0072828 pamphlet (Patent Document 5) includes PDE10.
As an A inhibitor, a compound having a 1-methyl-4-heteroarylpyrazole structure as a partial structure is disclosed, but the molecular structure is completely different from the pyrazole derivative of the present invention.

International Publication No. 2011/036127 Pamphlet (Patent Document 6), International Publication No. 201
In the pamphlet of 1/1117264 (Patent Document 7) and the pamphlet of International Publication No. 2012/076430 (Patent Document 8), compounds having a pyrazole-5-carboxylic acid amide structure are disclosed as PDE10A inhibitors. The compounds of Document 6 and Patent Document 8 have a dicarboxylic amide structure, and the compound of Patent Document 7 is 7-aminoimidazo [1,2
-A] Pyrimidine carboxylic acid amides are all different in molecular structure from the pyrazole derivatives of the present invention.

US Patent Application Publication No. 2003/0032579 Pamphlet International Publication No. 2005/082883 Pamphlet European Patent Application Publication No. 1250923 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

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 FS , Nat Rev Drug Discov, 5 (8), p660-670, 2006. Houselay MD , Cir Res, 100 (7), p950-966, 2007. Omori K. , J Biol Chem, 274 (26), p18438-18445, 1999. Loughney K.M. Gene, 234 (1), p109-117, 1999. Omori K. , Eur J Biochem, 266 (3), p1118-1127, 1999. Menniti FS 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. Mutschler. Arzneimitetelwirkungen. 8th ed. Stuttgart: Wissenschaffliche Verlagsgesellschaft mbH, 2001. Sawaguchi. Parkinsonism Relat Disord. , 7 (1), p 9-19, 2000. Castner SA. , Science. 287 (5460), p2020-2022, 2000. Kostowski W. Pharmacol Biochem Behav. , 5 (1), p15-17, 1976. Menniti FS Curr Opin Investig Drugs. , 8 (1), p54-59, 2007.

In general, a drug having low solubility in water is said to have low bioavailability due to low solubility in the gastrointestinal tract and slow dissolution rate. Therefore, it has an excellent PDE10A inhibitory action and is useful as a therapeutic and / or prophylactic agent for schizophrenia, etc.
One of the pyrazole derivatives, 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 (hereinafter also referred to as Compound A) has solubility, oral absorption (blood concentration, bioavailability), etc., compared to its free form It is useful to find better compounds in In addition, finding an acid addition salt of Compound A capable of obtaining a crystal from the point of supply of a pharmaceutical compound having a certain quality on an industrial scale is useful in drug development.

As a result of intensive studies on the acid addition salt of Compound A in order to solve the above-mentioned problems, the crystal of a specific acid addition salt of Compound A has an excellent PDE10A inhibitory action and is soluble. And the present invention has been completed by finding that it has excellent properties in terms of bioavailability.
The crystal of a specific acid addition salt of the compound A of the present invention is also useful from the viewpoint of supply on an industrial scale. It is expected as a medicament for therapeutic agents and / or preventive agents.

4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2- 2) of the present invention
The crystal of a specific acid addition salt of phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide, or a solvate thereof is It has an excellent PDE10A inhibitory action, has excellent properties in terms of solubility and bioavailability, is also useful from the viewpoint of supply on an industrial scale, and can be administered orally.
It is useful as a pharmaceutical agent for a prophylactic and / or therapeutic agent for a disease involving DE10A, particularly a therapeutic and / or prophylactic agent for schizophrenia and the like.

FIG. 1 is a powder X-ray diffraction pattern of monohydrate monohydrate crystals of (Example 1). FIG. 2 is a thermogravimetric analysis (TGA) curve of the monohydrate monohydrate crystal of (Example 1). FIG. 3 is a powder X-ray diffraction pattern of anhydrous monohydrochloride crystals of (Example 2). FIG. 4 is a thermogravimetric analysis (TGA) curve of the monohydrochloride anhydride crystal of Example 2. FIG. 5 is a powder X-ray diffraction pattern of anhydrous monobromide crystals of (Example 3). FIG. 6 is a thermogravimetric analysis (TGA) curve of anhydrous monobromide crystals of (Example 3).

The present invention has the following formula:
Represented by the formula 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-
A specific acid addition salt of phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide (hereinafter also referred to as Compound A); Or an anhydride or solvate crystal thereof. The present invention also relates to a medicine containing the crystal, a pharmaceutical composition, and a method for producing the crystal.

The present invention includes the following embodiments [1] to [36].
Here, in this specification, the crystal according to any one of the embodiments [1] to [21] is referred to as “
It may be referred to as “a crystal of the salt of the compound A of the present invention” or “a crystal of the salt of the present invention”.

[1] A first embodiment of the present invention is a crystal of hydrochloride or hydrobromide of the above compound A.

[2] A second aspect of the present invention is the crystal of the hydrochloride salt of Compound A or the anhydrous hydrobromide salt in the above aspect [1].

[3] A third aspect of the present invention is a crystal of the hydrochloride salt of the compound A or the solvate of hydrobromide salt in the above aspect [1].

[4] A fourth embodiment of the present invention is a crystal of the hydrochloride or the hydrobromide hydrate of the compound A in the above embodiment [3].

[5] A fifth aspect of the present invention is a crystal of the hydrochloride or the hydrobromide monohydrate of the compound A in the aspect [4].

[6] A sixth aspect of the present invention is the crystal of the monohydrochloride or monohydrobromide salt of compound A in any one of the above aspects [1] to [5].

[7] A seventh aspect of the present invention is a crystal of monohydrate monohydrate of the compound A.

[8] An eighth aspect of the present invention is an anhydrous crystal of the monohydrochloride salt of Compound A.

[9] A ninth aspect of the present invention is an anhydrous monobromide crystal of Compound A.

[10] The tenth aspect of the present invention is that the diffraction angle (2θ) by powder X-ray diffraction is 11.3,
12.4, 15.2, 20.0, 21.7, 23.1, 24.0, 25.9, and 27
. It is a crystal of monohydrate monohydrate of the compound A having a characteristic peak at 8 (°).

[11] An eleventh aspect of the present invention is the monohydrate monohydrate crystal of Compound A, characterized by the powder X-ray diffraction pattern shown in FIG.

[12] A twelfth aspect of the present invention is the monohydrate monohydrate crystal of Compound A having the diffraction angle (2θ) and intensity shown in Table 2 in powder X-ray diffraction.

[13] According to a thirteenth aspect of the present invention, in the thermogravimetric analysis (TGA measurement), the TGA curve shown in FIG. 2 is shown, wherein the aspect [7] and the aspects [10] to [1]
2].

[14] In a fourteenth aspect of the present invention, the diffraction angle (2θ) by powder X-ray diffraction is 13.2,
14.4, 16.3, 17.3, 18.9, 20.4, 21.1, 23.4, 26.6,
Crystals of the monohydrochloride anhydride of Compound A with characteristic peaks at 26.9, 27.5, and 29.0 (°).

[15] A fifteenth aspect of the present invention is the monohydrochloride anhydride crystal of the compound A characterized by the powder X-ray diffraction pattern shown in FIG.

[16] A sixteenth aspect of the present invention is an anhydrous monohydrochloride crystal of Compound A having the diffraction angle (2θ) and intensity shown in Table 3 in powder X-ray diffraction.

[17] According to a seventeenth aspect of the present invention, in the thermogravimetric analysis (TGA measurement), the TGA curve shown in FIG.
6]. The crystal according to any one of 6).

[18] In an eighteenth aspect of the present invention, the diffraction angle (2θ) by powder X-ray diffraction is 12.4,
14.6, 16.5, 17.1, 17.5, 18.1, 19.0, 20.3, 20.7,
21.1, 22.4, 23.5, 23.8, 24.3, 25.1, 25.3, 26.6,
And a monohydrobromide crystal of Compound A having a characteristic peak at 28.8 (°).

[19] A nineteenth aspect of the present invention is a monohydrobromide anhydride crystal of Compound A, characterized by the powder X-ray diffraction pattern shown in FIG.

[20] A twentieth aspect of the present invention is an anhydrous monobromide salt crystal of Compound A having the diffraction angle (2θ) and intensity shown in Table 4 in powder X-ray diffraction.

[21] According to a twenty-first aspect of the present invention, in the thermogravimetric analysis (TGA measurement), the TGA curve shown in FIG. 6 is shown, and the aspects [9] and [18] to [2]
0].

[22] A twenty-second aspect of the present invention is the method for producing a crystal according to any one of the aspects [1] to [21], including the following steps 1 to 3.
(Step 1) Compound A is dissolved or suspended in an inert solvent or a water-containing inert solvent to obtain a solution or suspension, and an acid (for example, hydrochloric acid or hydrobromic acid is contained in the solution or suspension). )
Or a step of adding an aqueous solution of an acid (for example, hydrochloric acid or hydrobromic acid) or an inert solvent solution (step 2) a step of stirring under a constant temperature condition for a predetermined time; and (step 3) collecting the produced solid by filtration Process.
[22-1] A 2nd-2 1st aspect of the present invention comprises the crystal according to any one of Aspects [7] and [10] to [13], comprising the following steps 1 to 3. It is a manufacturing method.
(Step 1) Compound A is dissolved or suspended in an inert solvent or a water-containing inert solvent to obtain a solution or suspension, and hydrochloric acid, an aqueous solution of hydrochloric acid or an inert solvent solution in the solution or suspension (Step 2) A step of stirring under a constant temperature condition for a predetermined time, and (Step 3) A step of collecting the produced solid by filtration.
[22-2] A 22-2th aspect of the present invention includes the following steps 1 to 3 of the crystal according to any one of the above aspect [8] and the aspect [14] to the aspect [17]. It is a manufacturing method.
(Step 1) Compound A is dissolved or suspended in an inert solvent or a water-containing inert solvent to obtain a solution or suspension, and hydrochloric acid, an aqueous solution of hydrochloric acid or an inert solvent solution in the solution or suspension (Step 2) A step of stirring under a constant temperature condition for a predetermined time, and (Step 3) A step of collecting the produced solid by filtration.
[22-3] A twenty-second aspect of the present invention includes the crystal according to any one of the aspect [9] and the aspect [18] to the aspect [21], including the following steps 1 to 3. It is a manufacturing method.
(Step 1) Compound A is dissolved or suspended in an inert solvent or a hydrous inert solvent to obtain a solution or suspension, and hydrobromic acid or hydrobromic acid is added to the solution or suspension. A step of adding an aqueous solution or an inert solvent solution (step 2) a step of stirring for a predetermined time under a constant temperature condition;

In the present invention, the acid addition salt of Compound A is suitable for use as a pharmaceutical preparation, and the pharmaceutically acceptable salt is obtained from a pharmaceutically acceptable inorganic acid or organic acid. Or inorganic acid salts or organic acid salts.
Preferable examples of the salt with inorganic acid include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,
Examples thereof include salts with sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid 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, salt with aliphatic monocarboxylic acid such as mandelic acid, oxalic acid , Salts with aliphatic dicarboxylic acids such as malonic acid, succinic acid, fumaric acid, maleic acid, malic acid and tartaric acid, salts with aliphatic tricarboxylic acids such as citric acid, and aromatic monocarboxylic acids such as benzoic acid and salicylic acid Salt, aromatic dicarboxylic acid salt such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, salt with organic carboxylic acid such as N-acetylcysteine, methanesulfonic acid, benzenesulfonic acid, Examples include salts with organic sulfonic acids such as p-toluenesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamic acid. .
Of these, hydrochloride or hydrobromide is preferable as the pharmaceutically acceptable acid addition salt.
In the present invention, the acid addition salt of Compound A includes an anhydrous form or a solvate (for example, hydrate) form.
In the present invention, the acid addition salt of Compound A includes, for example, monohydrochloride, dihydrochloride and trihydrochloride, or monobromide, dihydrobromide and trihydrobromide. Can do. Preferably,
Monohydrochloride or hydrobromide.

Solvates of the salt of Compound A of the present invention include hydrates or solvates of organic solvents. The hydrates or solvates of the acid addition salts in the present invention are, for example, 1-, 2-, 3-, 4-
, Penta-, hexa-hydrate or solvate, respectively. Preferable is monohydrate or monosolvate.
Solvents used for crystallization, such as alcohols, especially methanol, ethanol, aldehydes, ketones, especially acetone, esters, such as ethyl acetate, can be embedded in the crystal lattice.
Preference is given to pharmaceutically acceptable solvents. The extent to which the selected solvent or water is led to a solvate or hydrate in crystallization and subsequent manufacturing steps or directly to the free acid is generally unpredictable, a combination of manufacturing conditions and compound A and It depends on the various interactions between the selected solvent, especially water.
As the salt of Compound A of the present invention, monohydrochloride monohydrate, monohydrochloride anhydride, and monohydrobromide anhydride are preferable.

In the present invention, the acid addition salt of Compound A can be produced by the following method:
(Step 1) Compound A is dissolved or suspended in an inert solvent or a water-containing inert solvent to obtain a solution or suspension, and an acid or an aqueous solution of an acid or an inert solvent solution in the solution or suspension Add;
(Step 2) stirring for a certain time under a constant temperature condition (preferably room temperature condition); and
(Step 3) The produced solid is collected by filtration.

If necessary, one or more steps selected from the group consisting of the following steps may be performed before or after step 2:
(Step a) Dry.
(Step b) adding seed crystals;
(Step c) distilling off the solvent;
(Step d) heating;
(Step e) cooling;
(Step f) adding a poor solvent (an inert solvent that does not dissolve the acid addition salt); and
(Step g) Precipitation of crystals is initiated or accelerated by applying mechanical stimulation such as ultrasonic stimulation or rubbing of the surface of the reaction vessel.

In Step 1, an acid or an aqueous solution of an acid or an inert solvent solution can be appropriately added to an inert solvent solution or suspension of Compound A or a hydrous inert solvent solution or suspension.

Compound A used in the method for producing the salt will be described later.
As the compound A, any of isolated and purified compounds, solid reaction crude products, or solutions of reaction crude products can be used.
The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, pentane, petroleum ether, cyclohexane; benzene, toluene Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, dibutyl ether, butyl methyl ether, sec- Ethers such as butyl methyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; like acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone Ketones; esters such as ethyl acetate, propyl acetate and butyl acetate; nitriles such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile; methanol, ethanol, 1-propanol, 2-propanol, 1- Alcohols such as butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol; such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide Amides; water; or mixtures thereof.

The inert solvent used is preferably ethers, ketones, esters, alcohols, water, or mixtures thereof, more preferably ethanol, 1,4-dioxane, acetone, or A mixture of these solvents, or a mixture of these solvents and water, more preferably a mixture of ethanol and water, a mixture of 1,4-dioxane and water, or acetone. It is also preferable that an appropriate amount of water is present in the reaction solution.

When the acid used is a monovalent acid, the amount of acid used is, for example, 1 mol (mol) of compound A
0.4 to 10 moles, and preferably 0.8 to 6 moles.

When the acid used is a divalent acid, the amount of the acid used can be, for example, 0.2 to 10 mol, preferably 0.3 to 6 mol, relative to 1 mol of compound A.

When the acid used is a trivalent acid, the amount of the acid used can be, for example, 0.1 to 10 mol, preferably 0.2 to 6 mol, relative to 1 mol of compound A.

The concentration of the aqueous acid solution or inert solvent solution used can be, for example, from 0.1 mol / liter (mol / l) to a saturated solution. The amount is preferably 1 to 20 mol / liter.

The reaction temperature is usually −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., more preferably 10 ° C. to 60 ° C.

While the reaction time varies depending on the acid, solvent, reaction temperature, etc. used, it is generally 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

The resulting solid can be isolated, for example, by filtration, centrifugation, or gradient methods. The isolated solid can be washed with an inert solvent (preferably the inert solvent used in the reaction), if necessary.

The isolated solid is usually dried at 20 to 80 ° C., preferably 30 to 60 ° C. under reduced pressure. The drying time is usually the time until the weight does not substantially change, but is preferably 30 minutes to 12 hours, and more preferably 1 to 6 hours. If necessary, the solid can be dried in the presence of a desiccant such as silica gel and / or calcium chloride.

In the present invention, the crystal of the salt of compound A means a solid whose internal structure consists of a regular repeating structure of three-dimensional constituent atoms (or a group thereof), and has such a regular internal structure. Distinguishable from non-amorphous solids.
Whether or not the solid is a crystal can be examined by a crystallographically well-known method (for example, powder X-ray crystal analysis, differential scanning calorimetry, etc.). For example, an X-ray powder X-ray crystallographic analysis by X-rays obtained by irradiation of copper Kα ray is performed on a certain solid, and the X
If a clear peak is observed in the line diffraction diagram, the solid can be determined to be crystalline, and if no clear peak is observed, the solid can be determined to be amorphous. . If the peak can be read but the peak is not clear (for example, broad), the solid is determined to be a crystal with low crystallinity, and such a crystal with low crystallinity is also included in the present invention. In the crystal of the salt of Compound A.

Crystallization is usually performed using a suitable crystallization solvent such as water; alcohol-based solvents such as methanol, ethanol, 2-propanol and butanol; diethyl ether, tetrahydrofuran,
Ether solvents such as 1,2-dimethoxyethane, 1,4-dioxane and tert-butyl methyl ether; hydrocarbon solvents such as n-hexane, cyclohexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene Solvent; N, N-dimethylformamide, N
Polar solvents such as N, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide; halogenated hydrocarbon solvents such as chloroform, dichloromethane, 1,2-dichloroethane; nitrile solvents such as acetonitrile; A ketone solvent such as acetone or diphenyl ketone; an ester solvent such as methyl acetate, ethyl acetate, or isopropyl acetate; a solvent such as an organic acid such as acetic acid, trifluoroacetic acid, or methanesulfonic acid is used. These solvents can be used alone, or two or more kinds of solvents can be used in an appropriate ratio, for example, 1
: You may mix and use in the ratio of 1-1: 10.

In the present invention, examples of the solvent that forms the monohydrate monohydrate crystal of Compound A include water, ethanol, 1,4-dioxane, acetone, and the like. Preferably, it is a mixed solvent of water and ethanol.

In the present invention, the solvent for forming a crystal of anhydrous monohydrochloride of Compound A is water,
Examples of the solvent include ethanol, 1,4-dioxane, and acetone. Preferably with water and 1
, 4-dioxane and the like.

In the present invention, examples of the solvent for forming a monohydrobromide crystal of compound A include water, ethanol, 1,4-dioxane, acetone and the like. Preferably,
Acetone.

In the present invention, crystallization is carried out at a temperature at which the solvent that forms crystals starts at about 0 ° C., preferably at ambient temperature.

As a method for analyzing the obtained crystal, a crystal analysis method by X-ray diffraction is generally used. Furthermore, methods for determining crystal orientation include mechanical or optical methods (e.g.,
FT-Raman spectrum, solid NMR spectrum) and the like. In addition, thermal analysis of crystals (differential scanning calorimetry, differential scanning calorimetry
etry (DSC)), thermogravimetric analysis (, Thermogravimetry Analysis)
Sis (TGA)) infrared absorption spectrum (IR) analysis (KBr method, solution method) and the like can also be measured according to ordinary methods.

A spectrum peak obtained by the above analysis method inevitably has a certain measurement error due to its nature. Those having a spectrum peak value within the error range are also included in the salt crystals of the present invention. For example, in the diffraction angle (2θ) by powder X-ray diffraction, “± 0.2” or “± 0
. It means that an error of “1” is allowed.

In the thermogravimetric analysis (TGA) test, the salt crystals of the present invention are 2
A thermogravimetric analysis (TGA) curve including weight loss is shown when measuring in the range of 5 ° C to 400 ° C.

The monohydrate monohydrate crystal of Compound A of the present invention is a crystal having a thermogravimetric analysis (TGA) curve shown in FIG. 2 in thermogravimetric analysis (TGA measurement).
The monohydrochloride anhydride crystal of Compound A of the present invention is a crystal having a thermogravimetric analysis (TGA) curve shown in FIG. 4 in thermogravimetric analysis (TGA measurement).
The monohydrate crystal of the monohydrobromide salt of Compound A of the present invention is a crystal having a thermogravimetric analysis (TGA) curve shown in FIG. 6 in thermogravimetric analysis (TGA measurement).

[23] A twenty-third aspect of the present invention is a medicament containing the crystal according to any one of the above-described aspects [1] to [21] as an active ingredient.

[24] A twenty-fourth aspect of the present invention is a pharmaceutical composition comprising the crystal according to any one of the above-mentioned aspects [1] to [21] as an active ingredient.

[25] A twenty-fifth aspect of the invention relates to certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychosis, anxiety disorders such as panic disorder and obsessive-compulsive disorder, Parkinson's disease and Huntington A medicament for treating at least one disease or condition selected from the group consisting of movement disorders including diseases, mood disorders, neurodegenerative disorders, disorders including attention and / or cognitive deficits, obesity, and drug addiction A pharmaceutical composition comprising, as an active ingredient, the crystal according to any one of the above embodiments [1] to [21] in an amount effective to treat the disease or condition.

“Psychiatric disorders and conditions” that can be treated by the pharmaceutical composition of the present invention include:
For example, (1) delusion type, dismantling type, tension type, indistinguishable type, or residual type schizophrenia, (2
) Schizophrenia-like disorder, (3) delusional or depressive schizophrenic disorder, (4) delusional disorder, (5) substance-induced mental disorder, such as alcohol, amphetamine, cannabis, cocaine, hallucinogen, inhalation Psychosis induced by drugs, opioids, or phencyclidine, (
6) delusional personality disorder, and (7) schizophrenic personality disorder. However, it is not limited to these.

In the present specification, unless otherwise specified, as symptoms of “schizophrenia, schizophrenia-like disorder”, for example, (1) positive symptoms, negative symptoms, and related delusions and / or hallucination symptoms, ( 2) Disorganized conversations (frequent derailments and disorganized conversations), (3) flattened emotions (
(4) Allergy (decrease in conversation content and volume), (5)
Anhedonia (disappearance / decline of pleasure sensation), (6) inappropriate emotion, (7) unpleasant feeling (eg, depression, anxiety, or anger), (8) reduced motivation, (9) non-social (social interaction) Lack of ability to get joy from) and (10) some of cognitive dysfunction. However, it is not limited to these.

Examples of “movement disorders” that can be treated by the pharmaceutical composition of the present invention include, for example, (
1) Huntington's disease, and aberrant motility associated with Dopamine agonist therapy, (
2) Parkinson's disease, (3) Restless Legs Syndr
ome: RLS), and (4) essential tremor. However, it is not limited to these.

“Other disorders” that can be treated by the pharmaceutical composition of the present invention include, for example, (
Examples include 1) obsessive-compulsive disorder, (2) Tourette syndrome, and (3) tic disorder.
However, it is not limited to these.

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

In this specification, unless otherwise specified, “drug addiction” means an abnormal desire for a drug,
It is generally characterized by motivational disorders such as impulsive compulsory attempts to take the desired drug, and episodes of intense drug craving. Examples include alcohol, amphetamine, cocaine, or opium addiction.

In this specification, unless otherwise noted, “deficit of attention and / or cognition” in “disorders including lack of attention and / or cognition” refers to a particular individual compared to other individuals of the same age. Mean that one or more cognitive functions, such as memory, intelligence, or learning and logic ability, are subnormal. In addition, “lack of attention and / or cognition” means, for example,
By a decrease in function in any particular individual of one or more cognitive aspects, such as occurs with age-related cognitive decline.

Examples of “disorders including attention and / or lack of cognition” that can be treated by the pharmaceutical composition of the present invention include (1) dementia such as Alzheimer's disease, multiple cerebral infarction, alcoholic dementia or other Drug-related dementia, dementia related to intracranial tumors or brain trauma, dementia related to Huntington's disease or Parkinson's disease, or AIDS-related dementia, (2) delirium, (3) amnestic disorder, (4) mental Posttraumatic stress disorder (Posttra
umatic stress disorder (PTSD), (5) mental retardation, (6)
Learning disabilities, such as reading disabilities, arithmetic disabilities, or written expression disabilities, (7) attention deficit / hyperactivity disorder (Attention Defective / Hyperactivity Disorder)
er: 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 by the pharmaceutical composition of the present invention include (1) major depression episode (mild, moderate, or severe type), manic episode, mixed episode , Hypomania episode, (2) atypical depression, (3) melancholic depression, (4) catatonic depression, (5) postpartum mood episode, (6) post-stroke depression, (7) large Depressive disorder, (8) Dysthymia disorder / Dysthymia, (9) Minor depressive disorder, (10) Premenstrual dysphoric disorder, (12) Depressive disorder after schizophrenia, (13)
Major depressive disorder associated with mental disorders such as delusional disorder or schizophrenia, (14) bipolar disorder such as bipolar I disorder, bipolar II disorder, and (15) mood circulatory disorder . However, it is not limited to these.

As used herein, unless otherwise specified, “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 includes preventing dysfunction and / or death of neurons in a critical state and / or resulting from dysfunction or death of neurons in a critical state In order to compensate for the loss of function, administration of a drug capable of enhancing the function of damaged or normally functioning neurons can be mentioned.

Examples of “neurodegenerative disorders and conditions” that can be treated by the pharmaceutical composition of the present invention include (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) neurodegeneration associated with brain trauma, (5) neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarction, (6) hypoglycemia-induced neurodegeneration, (7) neurodegeneration associated with epileptic seizures, (8
) Neurodegeneration associated with neurotoxin poisoning, (9) multisystem atrophy, (10) neurodegeneration of striatal medium spiny neurons, and the like. However, it is not limited to these.

In this specification, unless otherwise specified, “neurotoxic poisoning” refers to poisoning caused by a neurotoxin. A neurotoxin is any chemical or substance that can cause neuronal death, ie neurological damage.
An example of a neurotoxin is alcohol. If alcohol is abused by a pregnant woman,
Newborns can develop alcoholism and neurological damage, a fetal alcohol syndrome.
Examples of other neurotoxins include kainic acid, domoic acid, and achromeric acid, certain pesticides (eg, dichlorodiphenyltrichloroethane)
l trichloroethane (DDT)), certain insecticides (eg, organic phosphoric acids, etc.), volatile organic solvents (eg, toluene, etc.), metals (eg, lead, mercury, arsenic,
Phosphorus, aluminum, and the like), certain chemicals used as weapons (for example, agent orange or nerve gas as a dead leaf agent), and neurotoxic antitumor agents. However, it is not limited to these.

In this specification, unless stated otherwise, “treating” as in “treating a disease or condition” refers to the progression of “disease or condition” or one or more “disease or condition”.
Means to recover, alleviate or suppress In the present specification, “treat” refers to the onset of “disease or condition” or “disease or condition” depending on the patient's condition.
Also included is the prevention of a “disease or condition” that includes preventing the onset of any symptom associated with and reducing the severity of the “disease or condition” or any symptom thereof before onset. As used herein, “treating” is intended to include preventing and ameliorating the recurrence of a “disease or condition”.

[26] A twenty-sixth aspect of the present invention relates to certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychosis, anxiety disorders such as panic disorder and obsessive-compulsive disorder, Parkinson's disease and Huntington 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 attention and / or cognitive deficits, obesity, and drug addiction A pharmaceutical composition comprising, as an active ingredient, a crystal according to any one of the above embodiments [1] to [21] in an amount effective to inhibit PDE10A.

[27] A twenty-seventh aspect of the present invention is a mental disorder, a delusional disorder, and a drug-induced psychosis comprising the crystal according to any one of the aspects [1] to [21] as an active ingredient. Disorders including certain mental disorders and conditions such as anxiety disorders such as panic disorder and obsessive compulsive disorder, movement disorders including Parkinson's disease and Huntington's disease, mood disorders, neurodegenerative disorders, lack of attention and / or cognition And / or a prophylactic and / or therapeutic agent for at least one disease or condition selected from the group consisting of obesity and drug addiction.

[27-1] In the above aspect [27], preferably, the above aspect [1] to [21]
] The preventive agent and / or therapeutic agent of the disease or condition of schizophrenia which contains the crystal | crystallization as described in either aspect as an active ingredient.

[28] A twenty-eighth aspect of the present invention is a mental disorder, a delusional disorder, and a drug-induced psychosis comprising the crystal according to any one of the aspects [1] to [21] as an active ingredient. Disorders including certain mental disorders and conditions such as anxiety disorders such as panic disorder and obsessive compulsive disorder, 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 obesity, and drug addiction.

[28-1] In the above embodiment [28], preferably, the above embodiments [1] to [21].
] The therapeutic agent of the disease or condition of schizophrenia which contains the crystal | crystallization as described in any one aspect | mode as an active ingredient.

[29] In a twenty-ninth aspect of the present invention, a disease involving the PDE10A receptor, comprising the crystal according to any one of the above aspects [1] to [21] as an active ingredient Preventive agent and / or therapeutic agent.

[30] In a thirtieth aspect of the present invention, a disease involving the PDE10A receptor, comprising the crystal according to any one of the above aspects [1] to [21] as an active ingredient It is a therapeutic agent.

[31] A thirty-first aspect of the present invention is the use of the crystal according to any one of the above-described aspects [1] to [21] as a medicine.

[32] A thirty-second aspect of the present invention is the use of the crystal according to any one of the aspects [1] to [21] in the manufacture of a pharmaceutical product.

[33] A thirty-third aspect of the present invention is the use of the crystal according to any one of the aspects [1] to [21] in the production of a PDE10A inhibitor.
[33-1] A thirty-third aspect of the present invention is a PDE10A inhibitor comprising the crystal according to any one of the above-described aspects [1] to [21] as an active ingredient. is there.

[34] A thirty-fourth aspect of the present invention relates to certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychosis, anxiety disorders such as panic disorder and obsessive-compulsive disorder, Parkinson's disease and Huntington A method of treating at least one disease or condition selected from the group consisting of movement disorders including disease, mood disorders, neurodegenerative disorders, disorders including attention and / or cognitive deficits, obesity, and drug addiction Administering a crystal of any of the embodiments [1] to [21] in an amount effective to treat the disease or condition to a subject in need of treatment of the disease or condition. It is a method including.

[35] A thirty-fifth aspect of the invention relates to certain psychiatric disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychosis, anxiety disorders such as panic disorder and obsessive-compulsive disorder, Parkinson's disease and Huntington A method of treating at least one disease or condition selected from the group consisting of movement disorders including disease, mood disorders, neurodegenerative disorders, disorders including attention and / or cognitive deficits, obesity, and drug addiction A method comprising administering to a subject in need of treatment of the disease or condition, an amount effective to inhibit PDE10A, according to any of the embodiments [1] to [21]. It is.

[36] In a thirty-sixth aspect of the present invention, the disease or condition is (1) delusional, dismantled, tension, indistinguishable, or residual schizophrenia, (2) schizophrenia-like Disability, (3) delusional or depressive schizophrenic emotional disorder, (4) delusional disorder, (5) substance-induced mental disorder, (6
) Psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine, (7) delusional personality disorder, (8) schizophrenic personality disorder, (9) Huntington's disease , (10) aberrant motility associated with Dopamine agonist therapy, (11) Parkinson's disease, (12) restless leg syndrome, (13) essential tremor, (14) obsessive compulsive disorder, (15) Tourette syndrome, ( 16) tic disorder, (17) panic disorder, (18) agoraphobia, (19) specific phobia, (20) social phobia, (21) post-traumatic stress disorder, (22) acute stress disorder, (23) Generalized anxiety disorder, (24)
Dementia; Alzheimer's disease, multiple cerebral infarction, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumor or brain injury, dementia associated with Huntington's disease or Parkinson's disease, AIDS-related dementia, Or frontotemporal dementia (25) delirium, (
26) amnestic disorder, (27) mental retardation, (28) learning disorder; reading disorder, arithmetic disorder, or writing expression disorder, (29) attention deficit / hyperactivity disorder, (30) age-related cognitive decline, (31) major depression episodes (mild, moderate or severe), manic episodes, mixed episodes, hypomania episodes, (32) atypical depression, (33) melancholic depression, (34) catatonic illness Sexual depression, (35) postpartum-onset mood episodes, (36) post-stroke depression, (37) major depressive disorder, (38) dysthymic disorder / dysthymia, (39) minor depressive disorder, (40)
Premenstrual dysphoric disorder, (41) post-schizophrenic depressive disorder, (42) major depressive disorder associated with mental disorders such as delusional disorder or schizophrenia, (43) bipolar disorder; bipolar I Type disorder,
Bipolar type II disorder, (44) mood circulatory disorder, (45) neurodegeneration associated with brain trauma, (46
) Neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarction, (47) hypoglycemia-induced neurodegeneration, (48) neurodegeneration associated with epileptic seizures, (49) neurodegeneration associated with neurotoxin poisoning, ( Any of the above aspects [1] to [21], wherein the system is at least one disease or condition selected from the group consisting of 50) multisystem atrophy, and (51) neurodegeneration of striatal medium spiny neurons Pharmaceutical composition or embodiment comprising the crystal according to the embodiment as an active ingredient [
[34] to [35].

Crystalline PDE10A according to any one of aspects [1] to [21] of the present invention
The inhibitory action can be measured by an appropriately selected method, for example, Pharmacological Experimental Example 1 (human-derived PDE10A inhibitory action) described later.

The crystal according to any one of aspects [1] to [21] of the present invention has excellent PDE10A inhibitory activity in Pharmacological Experimental Example 1 (human PDE10A inhibitory action). In addition, the crystal according to any one of aspects [1] to [21] of the present invention is obtained by using PDE10.
It is very selective for A and is a selective PDE10A inhibitor.

Unless otherwise specified in this specification, “selective PDE10A inhibitor” means PDE1.
Means a compound having a significant PDE10A inhibitory activity compared to ˜9 or PDE11 inhibitory activity.

In one embodiment, a “selective PDE10A inhibitor” is preferably any other P
DE enzymes (eg, PDE1A, 2A, 3A, 4A, 4B, 5A, 6, 7A, 7B, 8A
, 9A, and 11A) for inhibition, about 1/1000 of the IC ₅₀ value that the compound has.
The following compounds have PDE10A inhibitory activity. (In other words, the compound
Approximately 1/1000 of the dose of IC ₅₀ value required when inhibiting any other PDE enzyme
The following inhibits PDE10A activity to the same extent. )

Crystals of the salts of the present invention include isotopes (eg, hydrogen isotopes, ² H and ³ H, carbon isotopes, ¹¹ C, ¹³ C, and ¹⁴ C, chlorine isotopes, ³⁶ Cl, etc. , Fluorine isotopes, iodine isotopes, such as ¹⁸ F, nitrogen isotopes, such as ¹²³ I and ¹²⁵ I, ^1
3 N and ¹⁵ N, such as oxygen isotopes, ¹⁵ O, ¹⁷ O, and ¹⁸ O, such as phosphorus isotopes, ³² P, and sulfur isotopes, such as ³⁵ S) Are also included.

Crystals of the salts of the invention labeled or substituted with certain isotopes (eg, positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be obtained, for example, by positron tomography (Pos).
It can be used as a tracer (PET tracer) used in the Ion Emission Tomography (PET), and is useful in fields such as medical diagnosis.

Crystals of the salts of the present invention labeled or substituted with certain isotopic labels are useful in drug and / or substrate tissue distribution studies. For example, ³ H and ¹⁴ C are useful for this research purpose because they are easy to label or displace and easy to detect.

Isotopically labeled crystals of the salts of the invention can be obtained by conventional techniques known to those skilled in the art or by methods analogous to the synthetic methods described in the examples below. In addition, the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.

[4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1 -Methyl-1H-
Method for producing pyrazole-5-carboxamide (hereinafter also referred to as compound A)]
Below, the manufacturing method of the compound A used for crystallization of a salt in this invention is demonstrated.
Compound A can be easily produced by combining a known general chemical production method 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. And can be manufactured according to a typical manufacturing method shown in Scheme 1 below. Further, the present invention provides a manufacturing method described below,
It is not limited at all.

In the production method of Compound A, each raw material compound used for the production of Compound A may form a salt, and such a salt is particularly limited as long as it is a pharmaceutically acceptable salt. However, examples include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic salts, and salts with acidic amino acids.
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, monosodium salt, disodium salt,
Including dipotassium salts).
Preferable examples of the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine. Ethanolamine, piperidine, morpholine, pyridine,
Picoline, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-lutidine,
Examples include salts with ethanolamine, diethanolamine, triethanolamine, N, N′-dibenzylethylenediamine and the like.
Preferable examples of the salt with inorganic acid include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,
Examples thereof include salts with sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid 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, salt with aliphatic monocarboxylic acid such as mandelic acid, oxalic acid , Salts with aliphatic dicarboxylic acids such as malonic acid, succinic acid, fumaric acid, maleic acid, malic acid and tartaric acid, salts with aliphatic tricarboxylic acids such as citric acid, and aromatic monocarboxylic acids such as benzoic acid and salicylic acid Salt, aromatic dicarboxylic acid salt such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, salt with organic carboxylic acid such as N-acetylcysteine, methanesulfonic acid, benzenesulfonic acid, Examples include salts with organic sulfonic acids such as p-toluenesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamic acid. .
Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned.
Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (
Inorganic salts such as calcium salts, magnesium salts, barium salts, etc.), ammonium salts, etc., and when the compound has a basic functional group, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphorus Salt with inorganic acid such as acid, or acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid,
And salts with organic acids such as maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
In addition, each raw material compound used in the production of Compound A can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from a reaction mixture according to a conventional method, and is known per se. It can be easily purified by means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.

Unless otherwise indicated, the reaction conditions in the production method of Compound A are as follows. The reaction temperature ranges from −78 ° C. to the temperature at which the solvent is refluxed. When no temperature is described, the reaction temperature is room temperature (0 to 35 ° C.), and the reaction time is the time for which the reaction proceeds sufficiently. .

Further, each step in the production method can be carried out without solvent or by dissolving or suspending the raw material compound in a solvent not involved in an appropriate 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, 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-dimethoxy Ether solvents such as tan; ester solvents such as methyl acetate, ethyl acetate and butyl acetate; ketone solvents such as acetone and methyl ethyl ketone; halogenated hydrocarbon systems such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane Solvent; triethylamine, N, N-
Basic solvents such as diisopropylethylamine, pyridine and lutidine; acid anhydrides such as acetic anhydride; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid and methanesulfonic acid; inorganic acids such as hydrochloric acid and sulfuric acid; One kind of solvent may be used alone, or two or more kinds of solvents may be mixed and used in an appropriate ratio by appropriately selecting depending on the reaction conditions.

As the base (or deoxidizer) used in the production method of the compound A, specifically,
Inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate; triethylamine, N, N-diisopropylethylamine, tributylamine , Cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3. 0] -5-nonene, 1
, 4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7
Organic bases such as undecene and imidazole; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; alkali metal hydrides such as sodium hydride and potassium hydride; sodium amide and lithium Metal amides such as diisopropylamide and lithium hexamethyldisilazide;
And organic lithium reagents such as methyllithium, n-butyllithium, sec-butyllithium, and tert-butyllithium. In addition, as an acid or an acid catalyst used in the production method of compound A, specifically, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid; acetic acid, trifluoroacetic acid, oxalic acid, phthalate Organic acids such as acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid; boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride Lewis acids such as anhydrous zinc chloride and anhydrous iron chloride. However, it is not necessarily limited to those described above.

[Combination agent with salt crystals of the present invention]
The salt crystal of the present invention or a medicine using the crystal can be used in combination with another drug or drug by a general method performed in the medical field. Examples of the drug that can be used in combination with the salt crystal of the present invention include (A) mental illness, particularly schizophrenia, or bipolar disorder, obsessive compulsive disorder, major depression, Parkinson's disease, Huntington's disease, Alzheimer's disease, cognition Therapeutic drugs for functional disorders and memory disorders, and (B) therapeutic drugs for diseases that are likely to occur simultaneously with schizophrenia.

Examples of the drug (A) include: (1) atypical antipsychotic drugs [specifically, olanzapine, quetiapine, clozapine, ziprasidone, risperidone, paliperidone, perospirone, blonanserin, lurasidone, aripiprazole, sertindol, amisulpride , Iloperidone, bifeprunox, asenapine, melperone, brexpiprazole, zotepine, etc.], (2) typical antipsychotics [specifically, chlorpromazine, pchlorperazine, perphenazine, levomepromazine, fluphenazine, thioridazine, propericazine, Spiperone, moperone, haloperidol, timiperone, bromperidol,
Pimozide, fluropipamide, sulpiride, thioprid, sulpride, nemonapride, oxypertin, etc.], (3) selective serotonin reuptake inhibitor (SSRI) [specifically, escitalopram, citalopram, paroxetine, sertraline, fluvoxamine, fluoxetine, etc.], 4) Selective serotonin / noradrenaline reuptake inhibitor (SN)
RI) [specifically, milnacipran, duloxetine, venlafaxine, nefazodone, etc.], (5) selective noradrenaline dopamine reuptake inhibitor (NDRI) [specifically, bubropine, etc.], (6) Noradrenergic / specific serotonergic antidepressants (NaSSA) [specifically, mirtazapine and the like], (7) triazolopyridine antidepressants (SARI) [specifically, trazodone and the like], (8 ) Tetracyclic antidepressants [specifically, cettipline, mianserin, maprotiline, etc.], (9) tricyclic antidepressants [specifically, amitriptyline, trimipramine, imipramine, nortriptyline, clomipramine, lofepramine, amoxapine, Dosrepin etc.], (10) Other antidepressants [specifically, NS-2359, Lu AA21004, DOV21947, etc.], (11) α7 nicotinic receptor agonist, (12) α7 nicotinic receptor activity modulator, (13) α7 nicotinic receptor partial modulator [specifically, SSR-180711, PNU-120596] Etc.], (1
4) Other PDE inhibitors [PDE1 inhibitor, PDE2 inhibitor, PDE4 inhibitor, PDE
5 inhibitor, PDE7 inhibitor, PDE9 inhibitor, etc.], (15) NK2 antagonist, (16) NK
3 antagonists, (17) muscarinic M1 acetylcholine receptor activity modulator, (18) muscarinic M2 acetylcholine receptor activity regulator, (19) adenosine receptor modulator, (20
) Muscarinic M4 acetylcholine receptor activity modulator, (21) Muscarinic M5 acetylcholine receptor activity modulator, (22) Adenosine receptor modulator, (23) Glycine transporter 1 (GlyT1) inhibitor [specifically , ALX5407, SSR504734
Etc.], (24) glutamate enhancer [specifically, ampakine], (25) NMDA receptor inhibitor [specifically, memantine hydrochloride, etc.], (26) metabolic glutamate receptor modulator (mGlu) [Specifically, CDPPB, MPEP, etc.], (27) Anti-anxiety drugs ((i) benzodiazepine anxiolytic drugs [specifically, chlordiazepoxide, diazepam, oxazolam, medazepam, cloxazolam, lorazepam, dipotassium chlorazepate, Prazepam, bromazepam, fludiazepam, mexazolam, alprazolam, furtoprazepam,
Flutazolam, ethyl loflazepate, etc.], (ii) thienodiazepine anxiolytics [specifically, etizolam, clothiazepam, etc.], (iii) serotonin 5-HT1A agonists [specifically, tandospirone, etc.)], (28 ) Sleep inducer ((i) benzodiazepine sleep inducer [specifically, nitrazepam, estazolam, flurazepam hydrochloride, nimetazepam,
Flurazepam, haloxazolam, flunitrazepam, rilmazapine hydrochloride, lormetazepam, triazolam, etc.], (ii) thienodiazepine sleep inducer [specifically, brotizolam, etc.], (iii) non-benzodiazepine sleep inducer [specifically, zolpidem, etc. ], (I
v) melatonin receptor agonist [specifically, ramelteon, etc.]), (v) cyclopyrrolone sleep inducer [specifically, zopiclone, etc.], (29) β-amyloid vaccine, (30) β
Amyloid degrading enzymes, etc. (31) brain function activators [specifically, aniracetam, nicergoline, etc.], (32) cannabinoid modulators, (33) cholinesterase inhibitors [specifically, donepezil hydrochloride, rivastigmine, bromide] Galantamine hydride etc.], (34) MAO-
B inhibitors [specifically, lasalidine, etc.] (35) Parkinson's disease therapeutic agents ((i) dopamine receptor agonists [specifically, levodopa, amantadine hydrochloride, bromocriptine mesylate, pergolide mesylate, cabergoline, hydrochloric acid] Talipexol, pramipexole hydrochloride hydrate, selegiline hydrochloride, ropinirole hydrochloride, etc.], (ii) monoamine oxidase inhibitors [specifically, deprenyl, sergiline (selegiline), remasemide, riluzole, etc.], (ii)
i) an anticholinergic agent [specifically, trihexyphenidyl, prophenamine, biperidene, pyroheptin hydrochloride, methixene hydrochloride, mazaticol hydrochloride, etc.], (iv) a COMT inhibitor [specifically, entacapone, etc.], (v ) Amyotrophic lateral sclerosis therapeutic agent [specifically, riluzole, etc., neurotrophic factor, etc.] (vi) Apoptosis inhibitor [specifically, CPI-1189
IDN-6556, CEP-1347, etc.], (vii) nerve differentiation / regeneration promoter [specifically, leteprinim, xaliprode]
n; SR-57746-A], SB-216763 etc.]) and the like.

Examples of the drug (B) include (36) antidiabetic ((i) PPARγ
Agonist (agonist, inhibitor) [specifically, pioglitazone, rosiglitazone, troglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, etc.], (ii)
Insulin secretion promoter [(a) sulfonylurea (specifically, tolbutamide, acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, glipentide, glyquidone, glisolamide, tolazamide, etc.), (b) non-sulfonyl Urea agents, etc.], (iii) fast-acting insulin secretagogues (specifically, nateglinide, mitiglinide, repaglinide, etc.), (iv) α-glucosidase inhibitors [specifically, acarbose, voglibose, miglitol, camiglibose, adiposine , Emigrate, pradimicin-Q, sarvostatin, etc.], (v) an insulin sensitizer [specifically, (
a) PPARγ agonist, (b) PTP-1B inhibitor, (c) DPP-4 inhibitor [specifically, sitagliptin, vildagliptin, alogliptin, saxagliptin, NVP-
DPP-728 etc.], (d) GLP-1 and GLP-1 agonists [specifically, exenatide, liraglutide etc.], (e) 11β-HSD inhibitors etc., (f) GPR40 agonists, (g
) GPR119 agonist, (h) GPR120 agonist], (vi) hepatic gluconeogenesis inhibitor [specifically, glucagon antagonist, etc.], (vii) biguanide [specifically, metformin,
Buformin, phenformin, etc.], (viii) Insulin or insulin derivatives [specifically, insulin zinc suspension, insulin lispro, insulin aspart, regular insulin, NPH insulin, insulin glargine, insulin detemir, mixed insulin, etc.] , (Ix) α2 antagonist [specifically, midaglyzol, isagridol, deliglidol, idazoxan, efaloxane, etc.]), (37) anti-obesity drug ((i) adrenergic β3 receptor agonist [specifically, KRP- 204, TRK-380 / TAC-
301, etc.], (ii) CB-1 receptor antagonist [specifically, rimonabant, SR-1477
78, BAY-65-2520 etc.], (iii) Neuropeptide Y (NPY) receptor antagonist [specifically, S-2367 etc.], (iv) antifeedant [monoamine reuptake inhibitor [specific] Specifically, sibutramine, mazindol, etc.]], (v) lipase inhibitors [specifically, orlistat, cetiristat, etc.], (vi) peptide YY (PYY) receptor antagonists, etc.) (I) ω3 fatty acids [specifically, ethyl icosapentate (EPA-E preparation, for example, product name: Epadale (registered trademark), etc.), docosahexaenoic acid (DHA), icosapent, etc. Mixed preparations of ethyl acetate and ethyl docosahexaenoate (for example, product names: Lovaza ^™ , Omacol (registered trademark) etc.)
(Ii) HMG-CoA reductase inhibitor [specifically, atorvastatin, simvastatin, pitavastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, etc.] (iii) HMG-CoA synthetase inhibitor, (iv)
) Cholesterol absorption inhibitors [specifically ezetimibe], (v) acyl-CoA-cholesterol acyltransferase (ACAT) inhibitors, (vi) CETP inhibitors, (vii) squalene synthase inhibitors, (viii) Antioxidants [specifically, probucol, etc.], (i
x) PPARα agonist [specifically, clofibrate, etofibrate, fenofibrate, bezafibrate, ciprofibrate, gemfibrozil, KRP-101
Etc.], (x) PPARδ agonist, (xi) LXR agonist, (xii) FXR agonist [specifically, INT-747, etc.], (xiii) MTTP inhibitor, (xiv) squalene eposidase inhibitor Etc.), (39) antihypertensive agents ((i) diuretics [specifically, trichloromethiazide, hydrochlorothiazide, mefluside, indapamide, meticran, chlorthalidone,
Trypamide, furosemide, torasemide, bumetanide, ethacrynic acid, spironolactone,
Triamterene, eplerenone, etc.], (ii) calcium receptor antagonists [specifically, amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nitrendipine, nilvadipine, alanidipine, azelnidipine, manidipine, varnidipine, efonidipine, cilnidipine, benidipine, etc. ], (Iii) Angiotensin converting enzyme inhibitor (ACEI) [specifically, captopril, lisinopril, enalapril, delapril, perindopril, benazepril, trandolapril, quinapril, alacepril, imidapril, temocapril, cilazapril, etc.], (iv) Angiotensin receptor antagonist (ARB) [specifically, losartan, olmesartan, telmisartan, valsartan, candesartan sile Cetyl, irbesartan etc.], (v) direct renin inhibitors [specifically, aliskiren, etc.], (vi) alpha receptor blocker [Specifically, tolazoline,
Phentolamine, doxazosin, prazosin, bunazosin, terazosin, urapidil, etc.]
, (Vii) β receptor blockers [specifically, bopindolol, pindolol, timolol, dichloroisoprenalin, alprenolol, carteolol, indenolol, bunitrolol, penbutolol, propranolol, nadolol, nipradilol, chirisolol, acebutolol, ceriprolol , Metoprolol, atenolol, bisoprolol, betaxolol, practolol, bevantolol, butoxamine, carvedilol, amosulalol, arotinolol, labetalol, etc.], (viii) α ₁ β blocker [
Specifically, carvedilol, labetalol, arotinolol, bevantolol, etc.], (
ix) α ₂ receptor stimulant [specifically, clonidine, methyldopa, guanfacine, etc.])
(40) Nonsteroidal anti-inflammatory drugs [specifically, meloxicam, teoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.], (41) disease modifying antirheumatic drugs (DMARDs), (42) Anti-cytokine 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 and the like], (45) parathyroid hormone (PTH) and the like.

By using in combination with existing drugs for the above diseases, the dosage of existing drugs can be reduced, and the side effects of existing drugs can be reduced. Of course, the combination method using the said drug is not limited to the said disease, and the drug used together is not limited to the compound illustrated above.

The administration form of the salt crystal of the present invention and the concomitant drug is not particularly limited, as long as the salt crystal of the present invention and the concomitant drug are combined at the time of administration. Such dosage forms include, for example,
(1) administration of a single preparation obtained by simultaneously formulating the salt crystal of the present invention and a concomitant drug,
(2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating the salt crystals of the present invention and the concomitant drug,
(3) Administration of two types of preparations obtained by separately formulating the salt crystal of the present invention and the concomitant drug separately with a time difference in the same administration route,
(4) Simultaneous administration of two types of preparations obtained by separately formulating the salt crystal of the present invention and the concomitant drug by different administration routes,
(5) Administration of two types of preparations obtained by separately formulating the salt crystals of the present invention and the concomitant drug at different administration routes (for example, the salt crystals of the present invention-the concomitant drug Administration in the order or administration in the reverse order).
Hereinafter, these administration forms are collectively abbreviated as a combination of salt crystals of the present invention.

In administering the concomitant drug of the salt crystal of the present invention, the concomitant drug and the crystal of the salt of the present invention may be administered at the same time, but after administration of the concomitant drug, the crystal of the salt of the present invention is administered. May be administered,
A concomitant drug may be administered after administration of the salt crystals of the present invention. When administering at 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 administering the concomitant drug first, within 1 minute to 3 days, preferably within 10 minutes to 1 day after administering the concomitant drug,
More preferred is a method of administering the salt crystal of the present invention within 15 minutes to 1 hour. When administering the salt crystal of the present invention first, within 1 minute to 1 day after administering the salt crystal of the present invention,
A method of administering a concomitant drug within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour is preferable.

Any amount of the concomitant drug can be set as long as side effects are not a problem. The daily dose as a concomitant drug varies depending on the administration subject, administration route, target disease, symptom, etc. For example, when administered orally to a patient with schizophrenia (adult, body weight of about 60 kg), it is usually a single dose. 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 once to several times a day.
It is desirable to administer (eg 3 times).

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

The salt crystal concomitant drug of the present invention has low toxicity. For example,
Tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc. It can be safely administered parenterally.

As the pharmacologically acceptable carrier that may be used in the preparation of the salt crystal concomitant drug of the present invention, the same ones as those used for the above-mentioned salt crystal medicament of the present invention are used. be able to.

The compounding ratio of the salt crystal of the present invention and the concomitant drug in the salt crystal concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like. Two or more of the above concomitant drugs may be used in combination 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 salt crystal of the present invention and the concomitant drug is the subject of administration, administration route, target disease,
It can be appropriately selected depending on symptoms, combinations and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the salt crystal of the present invention. For example, the content of the salt crystals of the present invention in the combination of salt 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 based on the whole preparation. Yes,
Preferably it is in the range of about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight.
The range of the degree.

The content of the concomitant drug in the salt crystal concomitant 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, based on the whole preparation. .
It is in the range of 1 to 50% by weight, more preferably in the range of about 0.5 to 20% by weight.

The content of an additive such as a carrier in the salt crystal concomitant 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 with respect to the whole preparation, preferably about It is in the range of 10 to 90% by weight.

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

As described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, and it may be necessary to administer beyond the range.

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

[Formulation of the preventive / therapeutic agent of the present invention]
The salt crystal medicament of the present invention is administered in the form of a pharmaceutical composition.
The pharmaceutical composition of the crystalline salt of the present invention comprises 4- (2,5-dimethylpyrimidine-4-
Yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a]
It contains crystals of the salt of pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide and is made in combination with pharmaceutically acceptable additives. More particularly, excipients (eg;
Lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch), binders (eg celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC)), crystalline cellulose, saccharides (lactose, Man knit,
Sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PV
P), macrogol, polyvinyl alcohol (PVA)), lubricant (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrant (eg;
Starches (corn starch, potato starch), sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) ), Aminoalkyl methacrylate copolymer E, methacrylic acid copolymer LD), plasticizer (eg triethyl citrate, macrogol)
, Hiding agents (eg, titanium oxide), colorants, flavoring agents, preservatives (eg, benzalkonium chloride, paraoxybenzoate), tonicity agents (eg, glycerin, sodium chloride, calcium chloride, mannitol, glucose) ), PH adjuster (eg; buffer solution such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphate buffer), stabilizer (eg, sugar, sugar alcohol, xanthan gum), dispersant, Antioxidants (eg; ascorbic acid, butylhydroxyanisole (BHA), propyl gallate, dl-α-tocopherol), buffers, preservatives (eg; paraben, benzyl alcohol, benzalkonium chloride), fragrances (eg Vanillin, l-menthol, rose oil), solubilizer (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, phosphorus) Quality cholesterol, triethanolamine), absorption promoters (e.g., sodium glycolate, sodium edetate, sodium caprate,
Acylcarnitines, limonene), gelling agents, suspending agents, or emulsifiers, commonly used suitable additives or solvents are combined with the salt crystals of the present invention to form various dosage forms. I can do it.

Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, lozenges, liquids, spirits, suspensions, Examples include extract and elixir. Oral, subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration, intraventricular administration, intrarectal administration It can be administered to patients by inhalation and the like.

The salt crystals of the present invention can be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Injectable formulations may be presented as unit dosage forms, for example, in ampoules or multi-dose containers, with the addition of preservatives. These formulations can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and contain formulation agents such as suspending, stabilizing, and / or dispersing agents. be able to. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

If a product solution is required, the product solution is isolated and included 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 into rapidly dispersed dosage forms (fddf) that are 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 rapid dispersion dosage forms utilize gelatin as a carrier or structure-forming agent.
Gelatin is typically used to give a dosage form sufficient strength to prevent breakage when removed from the package, but once in the mouth, gelatin allows the dosage form to break down immediately. . Alternatively, various starches are used to achieve the same effect.

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

For intranasal administration or administration by inhalation, the crystals of the salts of the invention may be 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, such as Aerosol spray from a pressurized container or nebulizer using dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas
as a presentation). In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a metered amount. A pressurized container or nebulizer can contain a solution or suspension of the active compound.
Capsules and cartridges (eg, made from gelatin) for use in an inhaler or insufflator are formulated with a mixed powder of a salt crystal of the present invention and a suitable powder base such as lactose or starch. can do.

Aerosol formulations for treating the above conditions in the average adult preferably have about 20 mg to about 10 mg of aerosol doses or “one puff” of salt crystals of the invention.
Set to contain 00 mg. The total daily dose with an aerosol will be within 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 salt crystal of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, the dose of the salt crystal of the present invention, etc., and is, for example, about 0.01 to 100 relative to the total amount of the composition. % By weight, preferably 0.1 to 95% by weight.

In order to treat the above-mentioned conditions, the dosage of the crystalline salt of the present invention is determined according to the administration subject, administration route (
Oral, parenteral, rectal, or oral cavity), depending on the target disease, symptoms, etc.
When administered orally to a patient with schizophrenia (adult, body weight about 60 kg), it is usually about 0.1 as a single dose.
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 once to several times a day (for example, 3 times) It is desirable to administer.

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

Pharmacological Experiment Example 1: In vitro compound evaluation (Evaluation of enzyme inhibitory activity: human PDE10A inhibitory action)
IMAP TR-FRET Phosphodiester Evalu
It measured using ion Assay Kit (Molecular device). 10 μL of test compound at each concentration diluted in 384 well plate (Corning) and 1 × IMAP
Reaction Buffer containing 0.1% BSA (prepared from 5x attached to kit, 10 mM Tris-HCl, pH = 7.2, 10 mM MgCl ₂ ,
PDE10A diluted to 2 ng / mL with 0.05% NaN ₃ and 0.1% BSA)
5 μL of enzyme (BPA bioscience) was added and preincubated for 5 minutes at room temperature. 1 x IMAP Reaction Buffer containing 0.1%
5 μL of the cAMP substrate attached to the kit diluted to 400 nM with BSA was added and reacted at room temperature for 60 minutes. Furthermore, IMAP TR-FRET Binding so included in the kit
After adding 60 μL of the solution and leaving it to stand for 3 hours or more, ARVO SX (Perk
inElmer) at the excitation wavelength of 340 nm, the fluorescence intensity of Terbium (Emissio)
n = 490 nm) and TR-FRET (Emission = 520 nm) were measured to calculate the amount of 5′-AMP produced. The count of wells to which a solvent was added instead of the test compound was 0%, and the count of wells to which no PDE10A enzyme was added was 100
The inhibitory activity of each test compound was calculated as%.

Test compound 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7- Il) -1
The PDE10A inhibitory activity of -methyl-1H-pyrazole-5-carboxamide (Compound A) is shown in Table 1 as IC ₅₀ value.

Pharmacological experiment example 2 shown below (experiment regarding suppression of locomotor activity by orally administering a test compound to rats 30 minutes before administration of MK-801) demonstrates its effectiveness as a therapeutic agent for mental disorders and neurodegenerative disorders. .

Pharmacological experiment example 2: MK-801-induced locomotor activity evaluation (animal)
After purchasing male Sprague-Dawley rats and arriving at the breeding facility, the animals are used for experiments with an acclimatization period of at least one week. Animals are housed in a laboratory with controlled temperature and humidity under a 12 hour light / dark cycle, with free access to food and water.

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

(Antagonism against MK-801-induced spontaneous momentum enhancement)
Evaluation of spontaneous locomotor activity by rodents with psychostimulants (eg, amphetamine, cocaine, methamphetamine, MK-801 and phencyclidine) is widely used as an animal model of schizophrenia (Schizophrenia Bulleti).
n 2010, vol. 36: 1066-1072; Psychopharmaco
logic 1999, vol. 145: 237-250). The test compound is tested for antagonism against MK-801-induced increased locomotor activity of the test compound in rats. Until the test, male Sprague-Dawley rats (approximately 300 g) are acclimated to the room in which the measurements are performed in the housing cage for at least 60 minutes. After acclimation, the animal is given a solvent or compound (0.3 or 1
mg / kg body weight) is orally administered and immediately returned to the cage. Sixty minutes after the administration of the test compound, the animal is again taken out of the cage and solvent (saline) or MK-8.
01 (0.2 mg / kg body weight) is subcutaneously administered, and the animal is immediately placed in a spontaneous momentum measurement chamber (Muromachi Kikai Co., Ltd.) equipped with an infrared sensor to start measurement. Spontaneous exercise is counted every 10 minutes. A cumulative count of 120 minutes after MK-801 administration is calculated for each treatment group. All data are expressed as mean and standard error of the mean.
Statistical analysis was conducted for Student for comparison between the control group and the MK-801 single administration group.
's t-test (p <0.05 has a significant difference), and for comparison between the MK-801 single administration group and the test compound administration group, Dunnett's test (p <0.05 has a significant difference) To analyze.

Pharmacological Experiment Example 3: Metabolic Stability Test A 10 mM DMSO solution of the salt crystals of the present invention was adjusted to a final concentration of 1 μM in a liver microsome solution (human, mouse; XenoTech), NADPH generating solution (β-NADP,
Glucose-6-phosphate, G-6-PDH (Y), water containing MgCl ₂ ). The solution is incubated at 37 ° C. for 20 minutes and then quenched with acetonitrile. The reaction solution is subjected to centrifugal filtration using a filter plate (MultiScreen HTS-HV plate (Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry. Similarly, a sample with a reaction time of 0 minutes was measured as a control, and the degradation rate (%
) Is calculated.

Pharmacological Experiment Example 4: hERG Inhibition Test by Patch Clamp Method The action on the hERG (human ether-a-go-related gene) channel is fully automated patch clamp system (Patchliner (Nani
on)). HERG of cells (hERG-HEK (Upstate))
In order to confirm the I _Kr current, a depolarizing pulse is periodically applied while maintaining the membrane potential at −80 mV. After the generated current has stabilized, 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 depolarizing pulse followed by a -40 mV, 0.5 second repolarizing 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.

By calculating this inhibition rate, drug QT prolongation and subsequent fatal side effects (
The possibility of inducing ventricular tachycardia or sudden death).

Pharmacological Experiment Example 5: Protein Binding Test A 10 mM DMSO solution of the salt crystals of the present invention is added to normal plasma (human, rat) to a final concentration of 10 μM. Simple equilibrium dialysis machine (RED Device (Linde
n Bioscience)) for 4 hours at 37 ° C., then the inner (plasma side) solution and the outer (PBS side) solution of the dialysis membrane are subjected to high-performance liquid chromatogram / mass spectrometry using the test compound in the sample. Measure. The unbound fraction (%) is calculated from the ratio between the PBS side and the plasma side, and the protein binding rate (%) is calculated from 100-unbound fraction (%).

Pharmacological experiment example 6: Safety test The salt crystals of the present invention were orally administered to mice or rats once, and no deaths were observed and no marked behavioral abnormalities were observed. Safety is shown.

From the above results, it was shown that the crystal of the salt of Compound A of the present invention has an excellent PDE10A inhibitory action. In addition, no abnormality is observed in the safety test, indicating the low toxicity of the present invention.

Furthermore, the crystals of the salt of the compound A of the present invention can be obtained by conducting the above test to obtain metabolic stability, h
It is confirmed that it is favorable in one point such as avoidance of ERG channel inhibitory action.

Thus, the salt crystals of Compound A of the present invention are selective PDE10A inhibitors, such as certain mental disorders and conditions such as psychiatric disorders, delusional disorders, and drug-induced psychosis, panic disorders and obsessive compulsive disorders. For the prevention and / or treatment of diseases such as anxiety disorders, motor disorders including Parkinson's disease and Huntington's disease, mood disorders, neurodegenerative disorders, disorders including attention and / or cognitive deficits, obesity, and drug addiction It is expected to be used.

The crystals of the salt of the compound A of the present invention are expected to show promising preventive or therapeutic effects for various diseases shown below. Specifically, (1) delusion, dismantling, tension, indistinguishable or residual schizophrenia, (2) schizophrenia-like disorder, (3) delusion or depression schizophrenia Emotional disorders, (4) paranoid disorders, (5) substance-induced mental disorders, (6) alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine-induced psychosis (7 ) Delusional personality disorder, (8) schizophrenic personality disorder, (9) Huntington's disease, (10) abnormal motility associated with Dopamine agonist therapy, (11) Parkinson's disease, (12) restless leg syndrome, (13) ) Essential tremor, (14)
Obsessive-compulsive disorder, (15) Tourette syndrome, (16) tic disorder, (17) panic disorder,
(18) agoraphobia, (19) specific phobia, (20) social phobia, (21) post-traumatic stress disorder, (22) acute stress disorder, (23) generalized anxiety disorder, (24) cognition Alzheimer's disease, multiple cerebral infarction, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumor or brain injury, dementia associated with Huntington's disease or Parkinson's disease, AIDS-related dementia, or Frontotemporal dementia (25) delirium, (26) amnestic disorder, (27) mental retardation, (28) learning disorder; reading disorder, arithmetic disorder, or written expression disorder, (29) attention deficit / hyperactivity Sexual disorders, (30) Age-related cognitive decline, (31) Major depression episodes (mild, moderate, or severe), manic episodes, mixed episodes, hypomania episodes, (32) atypical depression (33) melancholic depression, (34) catatonic depression, (35) postpartum mood episodes, (36) poststroke depression, (37) major depressive disorder, (38) mood modulation disorder / Concomitant with dysthymia, (39) minor depressive disorder, (40) premenstrual dysphoric disorder, (41) post-schizophrenic depressive disorder, (42) delusional disorder or psychiatric disorder such as schizophrenia Major depressive disorder, (43) bipolar disorder; bipolar type I disorder, bipolar type II disorder, (44) mood circulatory disorder, (45) neurodegeneration associated with brain trauma, (46) associated with stroke Neurodegeneration, neurodegeneration associated with cerebral infarction, (47) hypoglycemia-induced neurodegeneration, (48
) Neurodegeneration associated with epileptic seizures, (49) neurodegeneration associated with neurotoxin poisoning, (50)
Promising therapeutic effects can be expected for multiple system atrophy, (51) neurodegeneration of striatal medium spiny neurons, and the like.

Next, in order to explain the present invention in more detail, examples and test examples will be given. However, these examples are merely implementations, and do not limit the present invention, and do not depart from the scope of the present invention. It may be changed with.

For the measurement of nuclear magnetic resonance spectrum (NMR), Geol JNM-ECX400P (J
EOL JNM-ECX400P) FT-NMR (manufactured by JEOL Ltd.), Geol JN
M-ECX300 (JEOL JNM-ECX300) FT-NMR (manufactured by JEOL Ltd.) was used. LC-Mass was measured by one of the following methods. Waters Fr
The actionLynx MS system (manufactured by Waters) was used, and the column was manufactured by Shiseido, C
An APCELL Pak column (2.0 mm × 50 mm, 3 μm) was used, and the mobile phase was methanol: 0.05% trifluoroacetic acid aqueous solution = 10: 90 (0 minutes) to 100: 0 (2 minutes).
Gradient conditions of ˜100: 0 (3 minutes) were used.

In (physical property data) of (Example), LC-MS means LC-Mass (liquid chromatography-mass spectrometry spectrum), M is molecular weight, RT is retention time (retention time), [ M + H] ⁺ , [M + 3H] ³⁺ , and [M + Na] ⁺ shall mean molecular ion peaks. ¹ H-NMR (proton nuclear magnetic resonance) data, NMR signal pattern, s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad, J is coupling constant, Hz
Means Hertz, CDCl ₃ means deuterated chloroform, DMSO-d ₆ means deuterated dimethyl sulfoxide. ^{In 1} 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. The “room temperature” in the examples is usually about 10 ° C. to about 35 ° C.
It shall indicate a temperature of ° C.

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

X-ray powder diffraction analysis was performed using R-AXIS IV diffractometer Ultra.
Using X18 (manufactured by Rigaku Corporation), the debye-scherrer method (X-ray sou
rce: 50 kV, 100 mA, Wavelength: 1.5418 mm (CuKa
lpha), Camera length: 200 mm, temperature: room temperature, Phi Posi
tion: 0 degree, Exposure time: 10 minutes, Delta Phi: 120
Degree). Alternatively, Bragg-Brentano method (X-ray source: 4) using D8 Discover with GADDS CS (Bruker).
0 kV, 40 mA, Wavelength: 1.5418 mm (CuKalpha), C
amera length: 250 mm, temperature: room temperature, Phi Position: 0
Degree, Exposure time: 2 minutes, Theta 1: 7 degrees, Theta 2: 7 degrees).
For elemental analysis, C, H, and N are CHN automatic analysis methods and vario EL III (El
measured by an elementary Analytical Co.). In addition, Cl and Br were measured by DX-AQ-1120 (manufactured by Dionex) by flask combustion-ion chromatography.
Thermogravimetric analysis (TGA) measured the range of 25 degreeC to 400 degreeC at 10 degree-C / min using Q50 (made by TA Instruments).
Purity measurement is performed using the apparatus: Waters ACQUITY UPLC H-Class (Wat
ers column): watersACQUITYBEHShieldRP18 (particle diameter 1.7 μm, size 2.1 × 50 mm) was used. The moving bed was 10 mmol / L ammonium bicarbonate buffer pH 9.0 and acetonitol, and the sample was 50 μg / mL 1
4-Dioxane: acetonitrile: 10 mmol / L ammonium hydrogen carbonate buffer = 20: 20: 60 solution was prepared and carried out.
The solubility test was performed as follows. The salt crystal of the present invention is added to artificial gastric juice (SGF) so as to be 1 mg / mL. The solution is incubated for 2 hours at 37 ° C. with stirring at 1000 rpm and then filtered through a filter plate. The filtrate is analyzed by HPLC, the 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 a test compound (0.01, 0.03, 0.1, 0.3, 1 μg / mL) was added as a standard curve standard solution. The solubility (μg / mL) of the compound was calculated from the peak area of the calibration curve.
The artificial gastric fluid (SGF, stirred for 2 hours) is water, phosphate buffer (pH 6.8, 24 hours)
, Buffer solution (pH 3.0, 24 hours), or artificial intestinal fluid (FaSSIF, pH 6.5, 6 hours / FeSSIF, pH 5.0, 6 hours), etc. .

Reference Example 1 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2
Synthesis of -phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide (Compound A)

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

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) dipalladium (0) (0.16)
g) and triethylamine (3.7 mL) in 1,4-dioxane (19 mL)
, 4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 mL) was added, and the mixture was stirred at 100 ° C. for 30 minutes in a nitrogen atmosphere. 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 mL) was added to the reaction solution, and the mixture was stirred at the same temperature for 30 minutes, and then an aqueous solution of potassium carbonate (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) were sequentially added, and 1 at the same temperature. Stir for hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel: eluent; heptane: ethyl acetate = 3: 1 to 1: 1 to 0: 1) to give the title compound ( 1.9 g) was obtained as an orange liquid.
(Physical property data) LC-MS: M = 246, RT = 0.37 (min), [M + H] ⁺ = 24
7. 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 (3
H, s).

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

Reference Example 1 Methyl 4- (2,5-dimethylpyrimidine-4-) obtained in <Step 1>
Yl) -1-methyl-1H-pyrazole-5-carboxylate (1.9 g) methano-
Sodium hydroxide (0.31 g) was added to a mixed solution of water (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 5-6 with 1N hydrochloric acid, and then water was distilled off under reduced pressure. The resulting residue is washed with methylene chloride,
The filtrate was concentrated under reduced pressure to obtain the title compound (0.94 g) as a yellow solid.
(Physical property data) LC-MS: M = 232, RT = 0.65 (min), [M + H] ⁺ = 23
3. 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-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-
Synthesis of phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide (Compound A)

Reference Example 1 4- (2,5-dimethylpyrimidin-4-yl)-obtained in <Step 2>
1-methyl-1H-pyrazole-5-carboxylic acid (715 mg), 6-
Fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-amine hydrochloride (WO 2012/076430 pamphlet, p80,
Acquired according to the method described in Example 30-h)) (815 mg), 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate -Tometanaminium (2.34 g) and diisopropylethylamine (2.
69 mL) in 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 chromatography (NH silica gel: eluent; heptane: ethyl acetate = 3: 1 to 1: 1).
The obtained fraction was concentrated under reduced pressure. The obtained residue (solid) was triturated with methanol to give the title compound (377 mg) as a colorless solid.
(Physical property data) LC-MS: M = 442, RT = 1.13 (min), [M + H] ⁺ = 44
3.1 ¹ H-NMR (400 MHz, CDCl ₃ , δ ppm): 11.72 (1H, s)
, 8.78 (1H, d, J = 8 Hz), 8.63 (1H, s), 8.59 (1H, d, J
= 8 Hz), 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-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Methyl-1H-
Crystalline monohydrate of pyrazole-5-carboxamide monohydrochloride 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [ 1,5-a] pyridin-7-yl) -1-methyl-1H-
A solid (13.0 g) of pyrazole-5-carboxamide was added to ethanol containing 10% water (
1.04 L) was suspended, concentrated hydrochloric acid (14.7 mL) was added, and the mixture was dissolved with heating under reflux. Activated carbon (0
. 65 g) was added and heated to reflux. Activated carbon was removed by hot filtration using Celite.
The resulting solution was allowed to cool and stirred at room temperature for 16 hours. The resulting suspension was stirred for 30 minutes under ice cooling. The solid was collected by filtration and 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridine-7. -Ill)-
1-methyl-1H-pyrazole-5-carboxamide monohydrochloride monohydrate crystals (12.
6 g) was obtained.

<Elemental analysis> As C23H19FN8O.1HCl.1H2O;
Calculated: C, 55.59; H, 4.46; N, 22.55; Cl, 7.13.
Found: C, 55.58; H, 4.50; N, 22.78; Cl, 6.89.

The measurement results of the powder X-ray diffraction of the monohydrochloride monohydrate crystals obtained in Example 1 are shown in Table 2 below and FIG. The thermogravimetric analysis (TGA) curve of the crystal is shown in FIG.

(Example 2)
4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Methyl-1H-
Crystal of anhydrous monohydrochloride of pyrazole-5-carboxamide 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1 , 5-a] pyridin-7-yl) -1-methyl-1H-
The solid (220 mg) of pyrazole-5-carboxamide was converted to 1,4-dioxane (8 mL).
Was dissolved at about 60 ° C., and 1 M aqueous hydrochloric acid solution (0.5 mL) was immediately added. The mixture was allowed to stand at room temperature for 1 hour, and the precipitated solid was collected by filtration to give 4- (2,5-dimethylpyrimidin-4-yl) -N- (6
Anhydrous crystals of -fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide monohydrochloride (2
08 mg) was obtained.

The measurement results of the powder X-ray diffraction of the monohydrochloride anhydride crystals obtained in Example 2 are shown in Table 3 and FIG. In addition, a thermogravimetric analysis (TGA) curve of the crystal is shown in FIG.

(Example 3)
4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Methyl-1H-
Crystalline anhydrous hydrobromide of pyrazole-5-carboxamide 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] Triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-
A solid of pyrazole-5-carboxamide (440 mg) was added to 1,4-dioxane (14 mL).
) Was dissolved at 50 ° C., and 1N aqueous hydrobromic acid solution (1 mL) was added. Thereafter, the solvent was distilled off, 80 mg of the obtained amorphous was weighed, acetone (0.8 mL) was added, dissolved at an external temperature of 73 ° C., allowed to cool to room temperature, and stirred for 2 hours. The solid was collected by filtration, and 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [
1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide monohydrobromide crystals (66 mg) were obtained.

<Elemental analysis> As C23H19FN8O · 1HBr;
Calculated: C, 52.78; H, 3.85; N, 21.41; Br, 15.27.
Found: C, 52.70; H, 3.82; N, 21.48; Br, 14.86.

The measurement results of the powder X-ray diffraction of the anhydrous monohydrobromide crystals obtained in Example 3 are shown in Table 4 and FIG. 5 below. In addition, a thermogravimetric analysis (TGA) curve of the crystal is shown in FIG.

Test Example 1 Solubility Test According to the above method, the salt crystals of the present invention were tested.
When the solubility test was performed in artificial gastric juice (SGF) with modified solubility in various forms, it was about 11 times and 27 times more soluble in monohydrochloride hydrate and hydrobromide than the free form. An improvement was seen.

(Test Example 2) Pharmacokinetic test (rat, dog)
<Rat>
30 or 100 m of 10 weeks old male RccHanTM: WIST
After oral single administration at g / kg (administration solvent is Corn oil, 5 mL / kg), 1, 2
Blood is collected from the jugular vein after 4, 8, and 24 hours. Using plasma obtained by centrifuging blood (3000 rpm, 15 minutes, 4 ° C.), the test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry. Similarly, known concentrations of the test compound (0.001, 0
. 002, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1,
2 μg / mL) standard solution was measured, and the plasma concentration (μg / m 2) was determined from the prepared calibration curve.
L), the maximum plasma concentration is Cmax (μg / mL), the area under plasma concentration is AUC (
μg · hr / mL). The solvent used, measurement conditions, etc. can be appropriately set by those skilled in the art.

<Dog>
30 mg / kg of the salt crystal of the present invention in about 1 to 2 years old male Beagle dog
(Administration solvent is Corn oil, 2 mL / kg), and 0.25, 0.
Blood is collected from the forelimb cephalic vein after 5, 1, 2, 4, 8, and 24 hours. Centrifuge the blood (30
The test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry using plasma obtained by 00 rpm, 15 minutes, 4 ° C.). Similarly, known concentrations of the test compound (0.001, 0.002, 0.005, 0.01, 0.02, 0.05, 0.1, 0
. 2, 0.5, 1, 2 μg / mL) was measured, the plasma concentration (μg / mL) was calculated from the prepared calibration curve, the maximum plasma concentration was Cmax (μg / mL), The area under the plasma concentration was AUC (μg · hr / mL). The solvent used, measurement conditions, etc. can be appropriately set by those skilled in the art.

From the above results, it was revealed that the salt crystals of the present invention have very high solubility and absorbability.

Since the crystal of the salt of Compound A of the present invention exhibits an excellent PDE10A inhibitory action, it can provide a clinically useful prophylactic and / or therapeutic agent for diseases such as schizophrenia. Further, the salt crystals of the compound A of the present invention are excellent in medicinal properties, safety, pharmacokinetics, stability, etc. (especially solubility and absorbability), and are industrial products of pharmaceutical compounds having a certain quality. Useful in terms of supply on a large scale

Although several specific embodiments of the present invention have been described in detail, those skilled in the art will recognize that various modifications may be made to the specific embodiments shown without departing from the teachings and advantages of the invention. It is possible to make changes. Accordingly, all such modifications and changes are intended to be included within the spirit and scope of the present invention as claimed.

Claims (27)

4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Methyl-1H-
Crystals of pyrazole-5-carboxamide hydrochloride or hydrobromide. The crystal according to claim 1, which is an anhydride of the hydrochloride or hydrobromide. The crystal according to claim 1, which is a solvate of the hydrochloride or hydrobromide. 4. The crystal according to claim 3, which is a hydrate of the hydrochloride or hydrobromide. 5. The crystal according to claim 4, wherein the hydrochloride or hydrobromide hydrate is a monohydrate. The crystal according to any one of claims 1 to 5, wherein the hydrochloride or hydrobromide is monohydrochloride or monohydrobromide. 4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Methyl-1H-
Pyrazole-5-carboxamide monohydrochloride monohydrate crystals. 11.3, 12.4, 15.2, 20.0 as diffraction angles (2θ) by powder X-ray diffraction
Crystal according to claim 7, characterized by having characteristic peaks at 21.7, 23.1, 24.0, 25.9, and 27.8 (°). 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1] characterized by the powder X-ray diffraction pattern shown in FIG. , 5
-A] Pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide monohydrochloride monohydrate crystals. In powder X-ray diffraction, the diffraction angle (2θ) shown in Table 2 and the intensity of 4- (2,5-
Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4]
Triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5
Carboxamide monohydrochloride monohydrate crystals. 11. The crystal according to claim 7, wherein the crystal according to claim 7 shows a TGA curve shown in FIG. 2 in thermogravimetric analysis measurement (TGA measurement). 4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Methyl-1H-
Crystal of anhydrous monohydrochloride of pyrazole-5-carboxamide. As diffraction angle (2θ) by powder X-ray diffraction, 13.2, 14.4, 16.3, 17.3,
18.9, 20.4, 21.1, 23.4, 26.6, 26.9, 27.5, and 29
. The crystal according to claim 12, which has a characteristic peak at 0 (°). 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1] characterized by the powder X-ray diffraction pattern shown in FIG. , 5
-A] Pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide monohydrochloride anhydride crystal. In powder X-ray diffraction, the diffraction angle (2θ) shown in Table 3 and the intensity of 4- (2,5-
Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4]
Triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5
Carboxamide monohydrochloride anhydride crystals. The crystal according to any one of claims 12 to 16, wherein in the thermogravimetric analysis measurement (TGA measurement), the TGA curve shown in Fig. 4 is shown. 4- (2,5-Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1- Methyl-1H-
Pyrazole-5-carboxamide monohydrobromide anhydrous crystals. As diffraction angles (2θ) by powder X-ray diffraction, 12.4, 14.6, 16.5, 17.1,
17.5, 18.1, 19.0, 20.3, 20.7, 21.1, 22.4, 23.5,
The crystal according to claim 17, characterized by having characteristic peaks at 23.8, 24.3, 25.1, 25.3, 26.6, and 28.8 (°). 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4] triazolo [1] characterized by the powder X-ray diffraction pattern shown in FIG. , 5
-A] Pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide monohydrobromide anhydrous crystals. In powder X-ray diffraction, the diffraction angle (2θ) shown in Table 4 and the intensity of 4- (2,5-
Dimethylpyrimidin-4-yl) -N- (6-fluoro-2-phenyl- [1,2,4]
Triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5
Carboxamide monohydrobromide crystals. The crystal according to any one of claims 17 to 20, wherein the TGA curve shown in Fig. 6 is shown in thermogravimetric analysis (TGA measurement). The manufacturing method of the monohydrochloride monohydrate crystal | crystallization of Claim 7 including the following processes 1-3:
(Step 1) 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2
-Phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide is dissolved or suspended in an inert solvent or a water-containing inert solvent. A step of adding hydrochloric acid, an aqueous solution of hydrochloric acid or an inert solvent solution to the solution or suspension (step 2), a step of stirring under a constant temperature condition for a predetermined time; and (Step 3) A step of collecting the produced solid by filtration. The manufacturing method of the crystal | crystallization of the monohydrochloride anhydride of Claim 12 including the following processes 1-3:
(Step 1) 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2
-Phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide is dissolved or suspended in an inert solvent or a water-containing inert solvent. A step of adding hydrochloric acid, an aqueous solution of hydrochloric acid or an inert solvent solution to the solution or suspension (step 2), a step of stirring under a constant temperature condition for a predetermined time; and (Step 3) A step of collecting the produced solid by filtration. The method for producing anhydrous monohydrobromide crystals of claim 17, comprising the following steps 1-3:
(Step 1) 4- (2,5-dimethylpyrimidin-4-yl) -N- (6-fluoro-2
-Phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl) -1-methyl-1H-pyrazole-5-carboxamide is dissolved or suspended in an inert solvent or a water-containing inert solvent. Step of adding hydrobromic acid or an aqueous solution of hydrobromic acid or an inert solvent solution to the solution or suspension (step 2) A step of stirring for a period of time; and (step 3) a step of collecting the produced solid by filtration. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 21 as an active ingredient. A PDE10A inhibitor comprising the crystal according to any one of claims 1 to 21 as an active ingredient. A prophylactic and / or therapeutic agent for a schizophrenia disease or condition, comprising the crystal according to any one of claims 1 to 21 as an active ingredient.