NZ618944B2 - Crystal of fused heterocyclic compound - Google Patents

Abstract

Disclosed herein is a crystal of 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one which is thermodynamically, chemically and physically stable. The crystal shows an X-ray powder diffraction pattern having characteristic peaks at interplaner spacings (d) of 13.59 ± 0.2, 6.76 ± 0.2, 9.22 ± 0.2, 7.88 ± 0.2, 6.21 ± 0.2, 6.13 ± 0.2, 5.73 ± 0.2, 4.64 ± 0.2, 3.79 ± 0.2 and 3.75 ± 0.2 Angstroms in powder X-ray diffraction. The crystal also shows an initial temperature of 222-224 °C of an endothermic behaviour caused by melting in DSC measurement (temperature increase rate 5 °C/min). The crystal is a phosphodiesterase 10A (PDE10A) inhibitor useful in the treatment of schizophrenia. terplaner spacings (d) of 13.59 ± 0.2, 6.76 ± 0.2, 9.22 ± 0.2, 7.88 ± 0.2, 6.21 ± 0.2, 6.13 ± 0.2, 5.73 ± 0.2, 4.64 ± 0.2, 3.79 ± 0.2 and 3.75 ± 0.2 Angstroms in powder X-ray diffraction. The crystal also shows an initial temperature of 222-224 °C of an endothermic behaviour caused by melting in DSC measurement (temperature increase rate 5 °C/min). The crystal is a phosphodiesterase 10A (PDE10A) inhibitor useful in the treatment of schizophrenia.

Description

CRYSTAL OE FUSED HETEROCYCLIC COMPOUND TECHNICAL FIELD OF THE INVENTION The t invention s to a crystal of a fused heterocyclic compound, which has a superior phosphodiesterase 10A inhibitory action, and is useful as an agent for the treatment or prophylaxis of schizophrenia etc., and the like.

(Background of the Invention) Phosphodiesterases (PDEs) are a superfamily of enzymes d by 21 genes and subdivided into ll distinct families ing to structural and functional properties. These enzymes metabolically inactivate the ubiquitous intracellular second messengers, cyclic adenosine osphate (CAMP) and cyclic guanosine monophosphate (cGMP); PDEs selectively catalyze the hydrolysis of the 3’-ester bond, forming the inactive 5’—monophosphate. Oh the basis of substrate specificity, the PDE families can be further classified into three groups: i) the cAMP—PDEs (PDE4, PDE7, PDE8), ii) the cGMP—PDEs (PDES, PDE6 and PDE9), and iii) the dual—substrate PDES (PDEI, PDEZ, PDE3, PDEIO and PDEIl).

The CAMP and cGMP are involved in the regulation of virtually every physiolOgical process such as pro—inflammatory or production and action, ion channel function, muscle relaxation, learning and memory ion, differentiation, apoptosis, lipogenesis, glycogenolysis and gluconeogenesis.

Especially, in neurOns, these second messengers have important role in the regulation of synaptic transmission as well as in neuronal differentiation and survival (non—patent document 1).

Regulation of these processes by cAMP and cGMP are accompanied by activation of protein kinase A (PKA) and protein kinase G (PKG), which in turn phosphorylate a variety of substrates, including transcription factors, ion channels and receptors W0 2012/176934 that regulate a variety of physiological ses.

Intracellular CAMP and CGMP concentrations seem to be temporally, Spatially, and functionally compartmentalized by regulation of adenyl and guanyl es in se to extracellular signaling and their degradation by PDEs (non— patent document 2). PDEs provide the only means of degrading the cyclic nucleotides CAMP and cGMP in cells, thus PDEs play an essential role in cyclic nucleotide signal transduction.

Thereby, PDEs could be promising targets for various therapeutic drugs. nPhosphodiesterase'lOA (EDElOA) was discovered in 1999 (non—patent documents 3—5).I ExpresSion studies have shown that PDElOA has the most restricted distribution within the all known PDE families; the PDElOA mRNA is highly expressed only in brain and testes (non—patent documents 6 and 7). In the brain, mRNA and protein of PDElOA are highly enriched in medium spiny neurons (MSNs) of the striatum (non—patent documents 8 and 9). MSNs are classified into two groups: the MSN that express D1 dopamine ors responsible for a direct tonigral) pathway and the MSN that express D2 dopamine receptors responsible for an indirect (striatopallidal) pathway. The function of direct pathway is to plan and execution, while indirect pathway is to act as a brake on behavioral activation. As PDElOA is expressed in both MSNs, PDElOA inhibitors could activate both of these ys. The antipsychotic efficacy of current tions, D2 or Dz/S—HTfl; antagonists, mainly s from their activation of the indirect pathway in the striatum. As PDElOA inhibitors are able to activate this pathway, this suggests that PDElOA inhibitors are promising as ychotic drugs. The excessive D2 receptor antagonism in the brain by D2 antagonists causes problems of extrapyramidal side-effects and hyperprolactinaemia. However the expression of PDElOA is limited to these striatal pathways in the brain, thus side WO 76934 effects by PDElOA inhibitors were expected to be weaker compared with current D2 nists. ing hyperprolactinaemia, PDElOA inhibitors would e no prolactin elevation due to lack of D2 receptor antagonism in the pituitary, Moreover, the presence of PDElOA in a direct pathway makes it likely that PDElOA inhibitors will have some advantage over current D2 antagonists; the direct pathway is thought to promote desired action, and activation of this pathway by PDElOA inhibitors may counteract extrapyramidal ms induced by excessive D2 receptor antagonism. In addition, activation of this pathway could facilitate striatal—thalamic w, promoting the execution of procedural strategies. Furthermore, enhancement of second messenger levels without blockade of ne and/or other neurotransmitter receptors may also provide therapeutic advantages with fewer adverse side—effects ed with current antipsychotics (e.g., hyperprolactinaemia and weight gain). This unique distribution and function in the brain tes that PDElOA represents an important new target for the treatment of neurological and psychiatric disorders, in particular psychotic disorders like schizophrenia.

Patent document 1 describes, as a phosphodiesterase (PDE) inhibitor, a compound represented by the formula:

[0006] R10 0/ 7E"\M,,& R11/U\ / wherein each symbol is as defined in patent document 1, W0 2012/176934 and the following compounds: Patent document 2 describes, as a odiesterase (PDE) inhibitor, a compound represented by the formula: (R3 )p (R )m4 0 X9 ,X1‘\~X2 N \ \X8” .‘X1O Z/X5 \ u /N )l(7 {£01 A >\X:, wherein each symbol is as defined in patent document 2, and the following compounds: (Rm .

- Patent document 3 describes, as a odiesterase (PDE) inhibitor, a compound represented by the formula: (R2)I1(R3)px1§y(R4)m)n\l\/R1Kro\lx8X7:/|)|(1D Z’XS; x6 N ’/ 12,x11Y/L\ ;>“gN wherein each symbol is as defined in patent document 3, and the following compounds: Patent document 4 describes, as a phosphodiesterase (PDE) 10 inhibitor, a compound represented by the a: n Z is wherein each symbol is as defined in patent document 4.

[0020] Patent document 5 describes, as a phosphodiesterase (PDE) inhibitor, a compound represented by the formula:' VV()2012/176934 wherein each symbol is as defined in patent document 5.

Patent document 6 describes, as a phosphodiesterase (PDE) inhibitor, a compound represented by the a: wherein each symbol is as d in patent document 6.

[Document List] [patent documents] patent document 1 W02008/004ll7 patent document 2 W02010/057l2l patent document 3: WO20lO/057126 patent document 4 /072828 patent document 5 W02008/001182 patent document 6: W02010/090737 [non—patent documents] non—patent document 1: Nat. Rev. Drug Discov. 2006, vol. 5, p. 660—670 non—patent document 2: Circ. Res. 2007, vol. 100(7), p. 950— non—patent document 3: Proc. Natl. Acad. Sci. USA, 1999, vol. 96, p. 8991—8996 non—patent document 4: J. Biol. Chem. 1999, vol. 274, p. 18438—18445 tent docUment 5: Gene, 1999, vol. 234, p. 109—117 non—patent document 6: Eur. J. Biochem. 1999, Vol. 266, p. 1118—1127 non—patent document 7: J. Biol. Chem. 1999, vol. 274, p. 18438—18445 non—patent document 8: Eur. J. Biochem. 1999, vol. 266, p. 1118—1127 tent document 9: Brain Res. 2003, vol. 985, p. 113-126 Y OF THE INVENTION Problems to be Solved by the Invention 'The development of a compound having a superior PDElOA inhibitory action, which is useful as an agent for the treatment or laxis of phrenia etc. and the like, and has properties superior in the stability, has been desired.

Means of Solving the Problems

[0029] The present inventors have conducted intensive studies in an attempt to solve the aforementioned problems and successfully obtained l—ethyl~7—methyl—3—{4—[(3~methyl—3H— imidazo[4,5—b]pyridin—2—y1)oxy]phenyl}—1,3—dihydro—2H— imidazo[4,5-b]pyridin—2—one as a crystal which is thermodynamically, ally and physically highly stable. In addition, they have found that the crystal has a , or PDElOA inhibitory action, and is sufficiently satisfactory as a medicament for the treatment or prophylaxis of schizophrenia and the like. They have completed the present invention baSed on these findings.

Accordingly, the present ion relates to a crystal of 1-ethylmethyl{4-[(3-methyl-3H- imidazo[4,5-b]pyridinyl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5-b]pyridinone showing an X-ray powder diffraction pattern having characteristic peaks at interplaner spacings (d) of 13.59±0.2 and 6.76±0.2 Angstroms in powder X- ray diffraction nafter sometimes to be referred to as the crystal of the present invention). More specifically, the present invention provides a crystal of 1-ethylmethyl{4- [(3-methyl-3H-imidazo[4,5-b]pyridinyl)oxy]phenyl}-1,3- dihydro-2H-imidazo[4,5-b]pyridinone showing an X-ray powder diffraction pattern having characteristic peaks at lanar spacings (d) of 13.59±0.2, 9.22±0.2, 7.88±0.2, 6.76±0.2, 6.21±0.2, .2, 5.73±0.2, 4.64±0.2, 3.79±0.2 and 3.75±0.2 Angstroms in powder X-ray diffraction; the crystal of the mentioned [1], which shows an X- ray powder diffraction pattern having further characteristic peaks at interplaner spacings (d) of 9.22±0.2, .2, 6.21±0.2, 6.13±0.2, 5.73±0.2, 4.64±0.2, 3.79±0.2 and 3.75±0.2 Angstroms in powder X-ray diffraction; the crystal of the above-mentioned [2], which shows an X- ray powder diffraction pattern having further characteristic peaks at laner gs (d) of 7.48±0.2, 5.24±0.2, .13±0.2, 4.27±0.2, .2, 4.06±0.2, 3.99±0.2, 3.93±0.2, 3.60±0.2, 3.41±0.2, 3.16±0.2, 3.10±0.2, 3.06±0.2, 2.89±0.2, 2.83±0.2, 2.73±0.2 and 2.58±0.2 Angstroms in powder X-ray diffraction; the crystal of the above-mentioned [1], which shows an initial temperature of about 222 - about 224°C of an endothermic or caused by melting in DSC measurement (temperature increase rate 5°C/min); (Followed by page 8a) a medicament comprising the l of the above-mentioned the medicament of the above-mentioned [5], which is a phosphodiesterase 10A inhibitor; the medicament of the above-mentioned [5], which is a prophylactic or therapeutic agent for schizophrenia; a method of preventing or treating schizophrenia in a mammal, comprising administering an effective amount of the crystal of the mentioned [1] to the mammal; (Followed by page 9) WO 76934 V use of the crystal of the above-mentioned [1] for the production of a prophylactic or therapeutic drug for schizophrenia; the crystal of the aboye—mentioned [l] for use for the laxis or treatment of schizophrenia; and the like.

Effect of the Invention Since the crystal of the present invention shows a superior PDElOA inhibitory action, is low toxic and is. superior in stability, it is useful as a pharmaceutical product.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. I shows a powder X—ray diffraction pattern of the crystal of Reference Example l—l.

Fig. 2 shows a powder X—ray diffraction n of the crystal of Reference Example 2.

Fig. 3 shows a powder X—ray diffraction pattern of the l of Reference Example 3.

Fig. 4 shows a powder X—ray diffraction pattern of the crystal of Reference Example 4.

Fig. 5 shows a powder X—ray diffraction pattern of the crystal of Reference Example 5.

Fig. 6 shows a powder X—ray ction pattern of the crystal of Reference Example 6.

Fig. 7 shows a powder X—ray diffraction pattern of the crystal of Reference Example 7.

Fig. 8 shows a powder X—ray diffraction pattern of the crystal of Example 1(2).

Fig. 9 shows DSC thermoanalytical data of the crystal of Example 1(2).

Description of Embodiments (DETAILED DESCRIPTION OF THE INVENTION) yThe crystal of 1—ethyl—7—methyl—3—{4—[(3—methyl—3H— imidazo[4,5-b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro-2H~ imidazO[4,5—b]pyridin—2—one in the present ion may be a solvate such as e and the like, or a lvate such as nonhydrate rate) and the like.

[Examples of the “hydrate” include 0.5 e to 5.0 hydrate. Among these, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate, 2.0 hydrate and 2.5 hydrate are preferable. Particularly preferred are 0.5 hydrate, 1.0 hydrate and 1.5 hydrate. In addition, the aforementioned “hydrate” may also be a “variable hydrate” containing a variable amount of water in the crystal structure according to the humidity environment. The water content of the variable hydrate varies within the range of about 4.0 — about 14.5 wt%. l—Ethyl—7—methyl-3—{4—[(3—methyl—3H—imidazo[4,5— b]pyridin—2—yl)oxy]phenyl}~1,3-dihydro—2H—imidazo[4,5— b]pyridin—2—one in the present ion may also be a 2O deuteride thereof.

In addition, the crystal of 1—ethyl—7—methyl—3—{4—[(3— methyl—3H—imidazo[4,5—b]pyridin-2—yl)oxy]phenyl]—l,3~dihydro— 2H~imidazo[4,5—b]pyridin—2—one in the present ion may also be a solvate other than a hydrate. es of the solvate crystal of 1—ethyl—7~methyl—3—{4— [(3—methyl—3H—imidazo[4,5-b]pyridin—2—yl)oxy]phenyl}—l,3~ dihydronH—imidazo[4,5-b]pyridin—2—one include alcohol solvate crystals such as methanol solvate crystal, ethanol solvate crystal and the like (preferably Cyfi alcohol solvate crystal), organic solvent hydrate l to which water and organic solvent are added (e.g., alcohol hydrate crystals such as methanol hydrate, ethanol hydrate, etc., preferably Cbfi alcohol hydrate crystal) and the like.

The l of the present invention can be produced by crystal transformation of ous l-ethyl—7-methyl—3—{4—[(3— methyl—3H-imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro— 2H—imidazo[4,5—b]pyridin32—one or other crystals ding hydrate crystal) of l—ethyl—7—methyl~3—{4—[(3—methyl~3H— imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}-l,3—dihydro—2H~ imidazo[4,5—b]pyridin—2—one.

The crystal transformation is a phenomenon where a crystal structure changes when the temperature or pressure exceeds a certain level.

As the “crystal transformation ”, a method known per se can be ned and, for example, crystallization from a solution (e.g., concentration , slow cooling method, reaction method (diffusion method, electrolysis method), hydrothermal growth method, flux method and the like), crystallization from the above (e.g., a gasification method (sealed tube method, gas stream method), a gas phase reaction method, a chemical transportation method), crystallization from molten form (e.g., a normal freezing method ng—up method, temperature gradient method, Bridgman method), a zone melting method (zone leveling method, float zone method), a special growth method (VLS method, liquid phase epitaxis method), a transpiration method (a method ing dissolving a crystal in a solvent, filtering and evaporating the solvent under ambient conditions), a slurry method (a method including adding a crystal to a solvent such that an excess solid s to give a suspension, stirring the suspension at ambient temperature or under heating or cooling, and collecting the solid), drying under reduced pressure, ng, pulverization, pressurization and the like can be mentioned.

To obtain the crystal of the present invention, a slurry method is preferable from among the above.

[0040] For analyzing the l obtained, X—ray diffraction crystallographic analysis is commonly used. In.addition, crystal orientation can also be determined by a mechanical method, an optical method (e.g., FT—Raman um, solid— (J1 state NMR spectrum), etc. In addition, crystal thermoanalysis (Differential Scanning Calorimetry (DSC)), infrared absorption spectrum is (KBr) and the like can also be performed according to conventional methods.

The peak of the spectrum obtained by the above—mentioned analysis method inevitably contains a certain measurement error by its nature. A crystal with a spectrum peak within the error range is also encompassed in the crystal of the present invention. For e, “i0.2” or “i0.l” in the interplanar spacing (d) of powder X—ray diffraction means that the error is ble.

The crystal of the present invention produced by the aforementioned method is a novel crystal showing an X—ray powder diffraction n having characteristic peaks at interplanar spacings (d) of l3.59i0.2 and 6.76i0.2 Angstroms, by powder X—ray diffraction, and is preferably a crystal of non— solvate (e.g., anhydrate).

The crystal of the t invention is preferably a crystal showing an X—ray powder diffraction pattern having [characteristic peaks at interplanar gs (d) of 13.59i0.2, 9.22i0.2, .2, 6.76i0.2, 6.21i0.2, 6.13i0.2, 5.73i0.2, 4.64i0.2, 3.79i0.2 and 3.75i0.2 Angstroms, by powder X—ray diffraction, and is preferably a crystal of non—solvate (e.g., anhydrate).

The crystal of the present invention is more preferably a crystal g an X—ray powder diffraction pattern having Characteristic peaks at lanar spacings (d) of 13.59i0.2, 9.22i0.2, 7.88i0.2, 7.48i0.2, 6.76i0.2, 6.21i0.2, 6.13i0.2, .73i0.2, 5.24i0.2, 5.13i0.2, .2, 4.27i0.2, 4.l6i0.2, 3.99i0.2, 3.93i0.2, 3;79i0.2, .2, 3.60i0.2, 3.4li0.2, 2.89i0.2, 2,73i0.2 and 2.58i0.2 Angstroms, by powder X—ray action, and is preferably a crystal of non—solvate (e.g., anhydrate).

The crystal of the present invention is further more preferably a crystal showing an X—ray powder diffraction pattern having characteristic peaks at interplanar spacings (d) of l3.59i0.2, .2, 7.88i0.2, .2, 6.76i0.2, 6.21i0.2, 6.13i0.2, 5.73i0.2, 5.24i0.2, 5.13i0.2, 4.64i0.2, 4.27i0.2, 4.16i0.2, 4.06i0.2, 3.99i0.2, 3.93i0.2, 3.79:0.2, 3.75i0.2, .2, 3.4li0.2, 3.16i0.2, 3.10i0.2, 3.06i0.2, 2.89i0.2, 2.83i0.2, 2.73i0.2 and 2.58i0.2 Angstroms, by powder X—ray diffraction, and is preferably a crystal of non—solvate (e.g., anhydrate).

As another embodiment, the crystal of the present invention produced by the aforementioned method is a novel crystal showing an X—ray powder diffraction pattern having characteristic peaks at interplanar spacings (d) of l3.59i0.l and 6.76i0.l Angstroms, by powder X-ray ction, and is preferably a crystal of non~solvate (e.g., anhydrate).

] The crystal of the present invention is preferably a crystal showing an X~ray powder diffraction pattern having characteristic peaks at interplanar spacings (d) of 13.59i0.l, .l, 7.88i0.l, 6.76i0.l, 6.21i0.l, 6.13i0.l, 5.73i0.l, 4.64i0.l, .l and 3.75i0.l Angstroms, by powder X-ray diffraction, and is preferably a crystal of non—solvate (e.g., anhydrate).

The crystal of the t invention is more preferably a l g an X—ray powder diffraction pattern having characteristic peaks at interplanar spacings (d) of l3.59i0.l, 9.22i0.l, 7.88i0.l, 7.48i0.1, 6.76i0.l, 6.21i0.l, 6.13i0.l, .73i0.l, 5.24f0.l, 5.13i0.l, 4.64i0.1, 4.27i0.1, 4.16i0.1, 3.99i0.l, 3.93i0.l, .l,'3.75i0.l, 3.60i0.l, 3.41i0.l, 2.89i0.l, 2.73i0.l and 2.58i0.l Angstroms, by powder X—ray diffraction, and is preferably a crystal of lvate (e.g., anhydrate).

The crystal of the t invention is further more preferably a l showing an X—ray powder ction pattern having characteristic peaks at interplanar spacings (d) of l3.59i0.1, 9.22i0.l, 7.88i0.l, .l, 6.76i0.l, 6.21i0.l, 6.13i0.l, 5.73i0.l, 5.24i0.l, 5.13i0.l,°4.64f0.l, 4.27i0.l, 4.16i0.l, 4.06i0.l, 3.99i0.l, 3.93i0.l, .1, 3.75i0.l, .l, .l, 3.l6iO.l, 3.l0i0.l, 3.06i0.l, 2.89i0.l, 2.83i0.l, 2.73i0.l and 2.58i0.l Angstroms, by powder X-ray diffraction, and is preferably a crystal of non-solvate (e.g., anhydrate). The crystal of the present invention is preferably anhydrous crystal.

[0050] The crystal of the present invention shows an initial temperature of about 222 — about 224°C, preferably about 223°C, of an endothermic behavior caused by melting in DSC ement under the conditions of temperature increase rate n, wherein the “about” here means il°C.

The crystal of the present invention shows a peak temperature of about 223°C — about 225°C, preferably about 224°C, of an endothermic behavior caused by melting in DSC measurement under conditions of ature increase rate °C/min, wherein the “about” here means il°C. The peak temperature of an endothermic behavior is higher than the initial temperature.

The crystal of the present invention does not have two or W0 2012/176934 more endothermic behaviors between room temperature and about 240°C (it has only a peak of an ermic behavior caused by one melting) in DSC measurement under conditions of temperature increase rate 5°C/min, wherein the ” here means il°C.

The purity of the crystal of the t invention is about 95% — 100%, preferably about'97% — 100%, more preferably [about 99% — 100%.

[0054] AThe thus—obtained crystal of the present invention has a or PDElOA inhibitory action, is low toxic and is useful as a pharmaceutical product. Moreover, since the crystal of the present invention is superior in stability, it can be handled easily and can be processed into a solid pharmaceutical composition with good reproducibility.

The crystal of the present ion is useful for the prophylaxis and/or treatment of, for example, the following es or symptoms, in mammals (e.g., , cows, horses, dogs, cats, monkeys, mice, rats, etc. ularly humans): psychotic disorder (e.g., brief psychotic disorder, shared psychotic disorder); psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opioids, or phencyclidine; delusional er; anxiety disorder; movement disorder; mood disorder; major depressive disorder; a major depressive disorder superimposed on a psychotic disorder comprising a delusional disorder or schizophrenia; major depressive episode of the mild, moderate or severe type; W0 2012/176934 manic or mixed mood episode; hypomanic mood episode; depressive episode with atypical features; depressive episode with melancholic features; depressive e with catatonic features; mood episode with postpartum onset; post—stroke depression; mic disorder; minor depressive disorder; autism; drug addiction; neurodegenerative er; neurodegeneration associated with cerebral ; neurodegeneration associated with ; neurodegeneration ated with cerebral infarct; hypoglycemia—induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; multi—system atrophy; Alzheimer’s disease; dementia; infarct dementia; alcoholic dementia or other drug—related dementia; dementia associated with ranial tumors or cerebral trauma; dementia associated with Huntington’s disease or Parkinson’s disease; AIDS—related dementia; frontotemporal dementia; delirium; amnestic disorder; post—traumatic stress disorder; mental ation; learning disorder (e.g., reading disorder, mathematics disorder, or a disorder of written expression); attention—deficit/hyperactivity disorder; age—related cognitive decline; Ipremenstrual dysphoric disorder; post-psychotic depressive er of phrenia; bipolar disorders comprising r I disorder and bipolar II disorder; cyclothymic‘disorder; Parkinsonis disease; Huntington’s disease; paranoid; schizophrenia (e.g., id schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated phrenia, residual schizophrenia); schizophreniform disorder; affective er of the delusional type or the' depressive type; personality disorder of the paranoid type; personality disorder of the schizoid type; obesity; metabolic syndrome; non—insulin ent diabetes mellitus (NIDDM); glucose intolerance; and the like, particularly for the prophylaxis and/or treatment of schizophrenia.

[0056] The crystal of the present invention is of low toxicity and can be safely stered orally or non—orally (e.g., l, rectal and intravenous administration, etc.), as such or in the form of pharmaceutical compositions formulated with a pharmacologically acceptable carrier, e.g., tablets (including sugar—coated tablets and film—coated tablets), powders, granules, capsules (including soft capsules), orally disintegrating tablets, orally disintegrating films, liquids, injectable preparations, suppositories, sustained—release preparations and patches, in accordance with a commonly known W0 2012/176934 method.

The content of the crystal of the present invention in the pharmaceutical composition is about 0.01 to 100% by weight of the entire composition. While the dose varies depending on the subject of administration, administration route, target disease, symptom and the like, for example, for oral administration to a patient with schizOphrenia (adult, about 60 kg body weight), a single dose is generally within the range of about 0.1 — about 20 mg/kg body weight, preferably about 0.2 — about 10 mg/kg body , more preferably about 0.5 — about 10 mg/kg body weight. Such dose is preferably administered one - several times (e.g., 3 times) per day.

Pharmacologically acceptable carriers that may be used to produce the ceutical composition of the present invention include various c or inorganic carrier substances in common use as pharmaceutical materials, including ents, lubricants, binders, disintegrants, water—soluble rs and basic inorganic salts for solid preparations; and solvents, lizing agents, ding agents, isotonizing agents, buffers and soothing agents for liquid preparations. Other ordinary pharmaceutical ves such as preservatives, antioxidants, colorants, sweetening agents, souring agents, bubbling agents, flavorings and the like may also be used as necessary.

Such “excipients” include, for example, lactose, sucrose, itol, starch, cornstarch, crystalline cellulose, light anhydrous silicic acid, titanium oxide and the like.

Such “lubricants” include, for example, magnesium stearate, e ester of fatty acids, polyethylene glycol, talc and stearic acid.

[0061] Such “binders” include, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, crystalline cellulose, d-starch, nylpyrrolidone, gum arabic powder, gelatin, pullulan, low—substituted hydroxypropyl cellulose and_ the like.

Such “disintegrants” e (1) crospovidone, (2) what is called super—disintegrants such as croscarmellose sodium (FMC—Asahi Chemical) and carmellose calcium (GOTOKU CHEMICAL CO., LTD.), (3) sodium ymethyl starch (e.g., product of Matsutani Chemical), (4) bstituted hydroxypropyl ose (e.g., product of Shin-Etsu Chemical),_(5)" cornstarch, and so forth. Said “crospovidone” may be any crosSlinked r having the chemical name l—ethenyl42— pyrrolidinone homopolymer, including polyvinylpolypyrrolidone (PVPP) and l—vinyl—Z—pyrrolidinone homopolymer, and is exemplified by Colidon CL (produced by BASF), Polyplasdon XL (produced by ISP), Polyplasdon XL—lO (produced by ISP), Polyplasdon INF—10 (produced by ISP) and the like.

[0063] Such “water—soluble polymers” e, for example, ethanol—soluble water—soluble polymers and the like [e.g., cellulose derivatives such as hydroxypropyl cellulose (hereinafter also referred to as HPC), polyvinylpyrrolidone] and ethanol—insoluble water—soluble polymers [e.g., ose derivatives such as hydroxypropyl methylcellulose nafter also referred to as HPMC), methyl cellulose and carboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like].

[0064] Such “basic inorganic salts” include, for example, basic nic salts of sodium, potassium, magnesium and/or calcium.

Preferred are basic inorganic salts of magnesium and/or calcium. More preferred are basic inorganic salts of magnesium.

Such basic inorganic salts of sodium include, for example, sodium carbonate, sodium hydrogen carbonate, disodium hydrogenphosphate, etc. Such basic inorganic salts of potassium include, for example, potassium carbonate, potassium hydrogen carbonate, etc. Such basic nic salts of magnesium include, for example, heavy magnesium carbonate, magnesium ate, magnesium oxide, magnesium hydroxide, magnesium aluminometasilicate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [MgJUQ(OH)m-CO3HMQO] and aluminum magnesium hydroxide. Among others, red is heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, etc. Such basic inorganic salts of calcium include, for eXample, precipitated calcium carbonate, calcium hydroxide, etc.

Such nts" include, for example, water for injection, alcohol, propylene , macrogol, sesame oil, corn oil, olive oil, etc.

Such “solubilizing agents” e, for example, polyethylene glycol, propylene glycol, D—mannitol, benzylbenzoate, ethanol, tris—aminomethane, terol, triethanolamine, sodium carbonate, sodium citrate and the like.

Such “suspending agents” include, for example, tants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl ose etc. and the like.

Such “isotonizing agents” include, for example, glucose, itol, sodium chloride, glycerol, D—mannitol and the like.

[0069] Such “buffers” include, for example, buffer solutions of phosphates, acetates, ates, citrates, etc.

Such “soothing agents” include, for example, benzyl alcohol and the like.

Such “preservatives” include, for example, p—oxybenzoic acid esters, butanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

[0072] Such “antioxidants” include, for example, sulfites, ascorbic acid, d-tocopherol and the like.

Such “colorants” include, for example, food colors such as Food Color Yellow No. 5, Food Color Red No. 2 and Food Color Blue No. 2; and food lake colors, red ferric oxide and the like.

Such “sweetening agents” include, for example, saccharin , dipotassium glycyrrhetinate, aspartame, stevia, thaumatin and the like.

Such “souring agents” include, for example, citric acid (anhydrous citric acid), tartaric acid, malic acid and the like.

Such ing ” include, for example, sodium bicarbonate and the like.

Such “flavorings” may be synthetic substances or naturally occurring substances, and include, for example, lemon, lime, , menthol, strawberry and the like.

The crystal of the present invention may be prepared as a preparation for oral administration in accordance with a commonly known method, by, for example, Ssion—shaping it in the presence of an excipient, a disintegrant, a binder, a ant, or the like, and subsequently coating it as necessary by a commonly known method for the purpose of taste masking, c dissolution or sustained release. For an enteric preparation, an intermediate layer may be provided by a commonly known method between the enteric layer and the drug—containing layer for the purpose of separation of the two layers.

[0079] For preparing the crystal of the present ion as an orally disintegrating tablet, available methods include, for example, a method in which a core containing crystalline cellulose and e is coated with the crystal of the present ion and a basic inorganic salt, and is further coated with a coating layer containing a water—soluble polymer to give a ition, which is coated with an enteric coating layer containing polyethylene glycol, further coated with an c coating layer containing triethyl citrate, still further coated with an enteric coating layer containing polyethylene glycol, and still yet further coated with mannitol to give fine granules, which are mixed with additives and shaped, and the like. The above—mentioned “enteric coating layer” includes, for example, aqueous enteric polymer substrates such as cellulose acetate phthalate (CAP), hydroxypropyl cellulose phthalate, ymethyl cellulose acetate succinate, methacrylic acid copolymers [e.g., Eudragit L3OD—55 (trade name; produced by Rohm), Colicoat MAEBODP (trade name; produced by BASF), d PA3O (trade name; produced by Sanfyo Chemical) and the like], carboxymethyl ethyl ose, shellac and the like; sustained~release substrates such as methacrylic acid copolymers [e.g., Eudragit NEBOD (trade name), Eudragit RL3OD (trade name), Eudragit RSBOD (trade name), etc.] and the like; water—soluble polymers; plasticizers such as triethyl citrate, polyethylene glycol, acetylated monoglycerides, triacetine, castor oil and the like; and mixtures thereof, and the like.

The above-mentioned “additive” includes, for example, watersoluble sugar alcohols (e.g., sorbitol, mannitol, maltitol, reduced starch rides, xylitol, reduced palatinose, erythritol, etc.), crystalline cellulose [e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591 (crystalline cellulose carmellose sodium) and the like], low-substituted ypropyl cellulose [e.g., LH- 22, LH-32, LH-23, LH-33 (Shin-Etsu Chemical) and mixtures thereof and the like] and the like; binders, souring , ng agents, sweetening agents, flavorings, ants, colorants, stabilizers, excipients, disintegrants etc. are also used.

[0080] The crystal of the present invention can be administered as the sole active agent or in combination with other medicaments such as other agents used in the treatment of psychosis, especially schizophrenia and bipolar disorder, obsessive-compulsive disorder, major depression, Parkinson’s disease, Alzheimer’s disease, cognitive impairment and/or memory loss [e.g., nicotinic ?7 agonists, nicotinic ?7 partial ts, nicotinic ?7 positive allosteric modulators, PDE2 inhibitors, PDE4 inhibitors, PDE5 inhibitors, other PDE inhibitors, calcium channel rs, muscarinic m1 and m2 modulators, adenosine receptor modulators, ampakines, Glycine transporter 1 inhibitors, NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin modulators, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, norepinephrine and dopamine ke inhibitors, triple reuptake inhibitors, cannabinoid modulators, and esterase tors (e.g., donepezil, rivastigmine, and galanthamine)]. In such ations, each active ient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range, and can be administered either simultaneously or sequentially.

Drugs suitable in combination with the crystal of the present ion include, but are not limited to, other suitable schizophrenia drugs such as Haloperidol, Clozapine, Olanzapine, Risperidone, razole, Ziprasidone, Paliperidone, and Quetiapine fumarate; bipolar disorder drugs, including, but not limited to, Lithium, Olanzapine, Aripiprazole, and ic acid; Parkinson’s disease drugs, ing, but not limited to, Levodopa, Bromocriptine, Pergolide, exole, Tolcapone, Procyclidine, Trihexyphenidyl, and Benztropine; agents used in the treatment of major depression, including, but not limited to, Amitriptyline, Protriptyline, Desipramine, Nortriptyline, Paroxetine, Fluoxetine, Sertraline, Bupropion, Escitalopram, Mirtazapine, Venlafaxine, Duloxetine; agents used in the treatment of Alzheimer’s disease, including, but not limited to, Galanthamine, Tacrine, Donepezil, Rivastigmine, Memantine, pin, Selegiline, Estrogen and Iodoquinol; agents used in the treatment of ia, including, but not limited to, Thioridazine, Haloperidol, Risperidone, Tacrine, Donepezil, and igmine; agents used in the treatment of epilepsy, including, but not limited to, Phenytoin, Phenobarbital, Carbamazepine, ic acid, Ethosuximide, Gabapentin, Phenobarbital, Solfeton and Felbatol; agents used in the treatment of multiple sclerosis, including, but not limited to, Tolterodine, Oxybutynin, Oxycodone, Interferon ?-1b, Interferon ?-1a, Azathioprine, Methotrexate and Glatiramer; agents used in the treatment of Huntington’s disease, including, but not limited to, Amitriptyline, Protriptyline, Desipramine, Nortriptyline, Paroxetine, Fluoxetine, Sertraline, Tetrabenazine, Haloperidol, Chlorpromazine, Thioridazine, Sulpiride, Quetiapine, Clozapine, and Risperidone; agents used in the ent of es, including, but not limited to, PPAR ligands (e.g., agonists, antagonists, such as Rosiglitazone, Troglitazone and Pioglitazone), insulin secretagogues (e.g., sulfonylurea drugs, such as Glyburide, Glimepiride, Chlorpropamide, amide, and Glipizide, and non-sulfonyl secretagogues), ?-glucosidase inhibitors (e.g., Acarbose, Miglitol, and ose), insulin sensitizers (such as the PPAR-? agonists, e.g., glitazones; biguanides, PTP-1B inhibitors, DPP-IV inhibitors, and 11?-HSD inhibitors), hepatic glucose output lowering compounds (such as glucagon antagonists and metformin, e.g., Glucophage and Glucophage XR), insulin and n derivatives (both long and short acting forms and formulations of insulin); and antiobesity drugs, including, but not limited to, ?-3 agonists, CB-1 agonists, eptide Y5 inhibitors, Ciliary Neurotrophic Factor and derivatives (e.g., e), appetite suppressants (e.g., Sibutramine), and lipase inhibitors (e.g., Orlistat).

[0081] The form of administration of concomitant drugs with the crystal of the t invention is not particularly limited and is acceptable as long as the l of the t invention is combined with concomitant drugs at the time of administration. Examples of such forms of administration are as follows: (1) administration of a single formula obtained by simultaneous formulation of the crystal of the present ion with a concomitant drug, (2) aneous administration via the same administration route for two kinds of formulas obtained by independent formulations of the crystal of the present invention and a concomitant drug, (3) administrations at different times via the same administration route for two kinds of formulas obtained by independent formulations of the crystal of the present invention and a concomitant drug, (4) simultaneous stration via different administration routes for two kinds of formulas obtained by independent formulations of the crystal of the present invention and a concomitant drug, (5) administrations at different times via different stration routes for two kinds Of formulas obtained by independent formulations of the crystal of the present ion and a itant drug (e.g., administration in the order of the crystal of the present invention and then a concomitant drug, or administration in the reversed order).

These forms of administration are summarized below and abbreviated as a itant agent of the present invention.

When administering the concomitant agent of the t invention, a itant drug_and the crystal of the present inventiOn can be stered at the Same time, but the crystal of the present invention can be administered after a concomitant drug is administered or after the crystal of the present invention is administered, a concomitant drug can be administered. When administering at different times, the time difference depends upon the active ingredients to be administered, drug forms and methods of administration. For example, when a itant drug is administered first, the crystal of the present invention can be administered within 1 min to 3 days, preferably within 10 min to 1 day and more preferably within 15 min to 1 hour after the concomitant drug is administered. However, if the crystal of the present invention is administered first, a concomitant drug can be administered within 1 min to 1 day, preferably within 10 min to 6 hours and more preferably within 15 min to 1 hour after the crystal of the present invention is administered.

If there are no problems with side effects of the concomitant drugs, any dosages can be set. A daily dosage as a concomitant drug depends upon dosages, administration subjects, administration , target diseases, symptoms, etc. For example, in the case of oral administration in patients with schizophrenia s, bodyweight of approximately 60 kg), a normal daily dosage ranges from about 0.1 to about 20 mg/kg bodyweight, preferably from about 0.2 to about 10 mg/kg bodyweight and more ably from about 0.5 to about 10 mg/kg bodyweight. It is preferable that this dosage is administered once daily to l times daily (e.g., 3 .

If the crystal of the present invention is used in combination with a concomitant drug, the respective s can be d within a safe range with consideration of the opposite effects of the respective drugs.

The concomitant agent of the present invention exhibits low toxicity. For e, the crystal of the present invention or(and) the aforementioned concomitant drug can be combined with a pharmaceutically acceptable carrier according to the known method to prepare a pharmaceutical composition such as tablets (including sugar—coated tablets and film— coated tablets), powder agents, granular , capsules (including soft capsules), liquids, injection solutions, suppositories, sustained—release agents, etc. These compositions can be administered safely orally or non—orally (e.g., including topical, rectal and enous routes). _[OO84] The pharmaceutically acceptable carriers that can be used for manufacturing the concomitant agent of the present invention can be the same as those used in the pharmaceutical composition of the present invention as mentioned above.

A mixing ratio n the crystal of the present invention and a concomitant drug in the concomitant agent of the t invention can be selected appropriately based on the administration subjects, administration routes and diseases.

The aforementioned concomitant drugs can be combined at an appropriate ratio if two or more drugs are combined.

A dosage of the concomitant drug can be selected appropriately based on the dosages used clinically. In addition, a mixing ratio n the crystal of the present invention and a concomitant drug can be selected appropriately based on the administration subjects, administration routes, target diseases, ms, combinations, etc. For example, if the administration subject is humans, a concomitant drug can be used in an amount ranging from 0.01 tb 100 parts by weight relative to 1 part by weight of the crystal of the present ion.

For example, the content of the crystal of the present invention in the concomitant agent of the present invention varies with the form of formulations. lly, it is present in a range from about 0.01 to 99.9 wt%, preferably from about 0.1 to 50 wt% and more preferably from about 0.5 to 20 wt% relative to the entire formula.

The content of a concomitant drug in the concomitant agent of the present invention varies with the form of .formulations. Generally-it is present in a range from about 0.01 to 99.9 wt%, preferably from about 0.1 to 50 wt% and more preferably from about 0.5 to 20 wt% relative to the entire formula.

The content of an ve such as carriers in the concomitant agent of the present ion varies with the form of formulations. lly it is present in a range from about 1 to 99.99 wt% and preferably from about 10 to 90 wt% relative to the entire formula.

When the crystal of the present invention and a concomitant drug are formulated independently, the same contents can be applied.

Since the s may fluctuate under various conditions as mentioned above, a dosage less than the aforementioned s may be sufficient or it may be ary to administer at a dosage exceeding the range.

Examples IThe present ion is explained in detail by referring to the following Reference Examples, Examples, Formulation Examples, and Experimental es. These examples are mere embodiments, which do not limit the present invention, and can be modified within the range not deviating from the scope of the present invention.

The “room temperature” in the following Reference Examples and-Examples is generally about 10°C to about 35°C. 0 in the yield means mol/mol%, O 6 of solvent used for chromatography means % by volume, and % used for others means wt%. In proton NMR spectrum, OH and NH protons and the like that cannot be identified since they are broad bands are not recorded in the data. In silica gel chromatography, silica gel 60 (230—400 mesh) manufactured by Merk & Co., Inc. was used, and aminopropylsilane—bonded silica gel atorex NH manufactured by Fuji SilySia Chemical Ltd.) was used for basic silica gel chromatography described as “NH silica gel”.

Other abbreviations used in the text mean the following. : singlet d: doublet dd: doublet of doublets dt: t of triplets t: triplet tt: triplet of triplets td: t of doublets q: quartet septet: septet m: multiplet br: broad J: coupling constant Hz: Hertz WC 2012/176934 CDCl3: deuterated chloroform DMSO—d6: deuterated dimethyl sulfoxide 1H NMR: proton r magnetic resonance HPLC: high performance liquid chromatography THF: tetrahydrofuran DMF: N,N*dimethylformamide DMSO: dimethyl ide IPE: isopropyl ether DMA: N,N—dimethylacetamide DIPEA: N,N—diisopropylethylamine Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0) LC—MS: liquid chromatography—mass spectrometry spectrum ESI: electrospray—ionization method API: atmospheric pressure ionization method

[0092] All reagents and solvents were of commercial y and used without further cation. The compounds and/or intermediates were purified by preparative high performance liquid chromatography (prep. HPLC) using a Gilson High through Put purification system.

The columns Were reversed phase YMC CombiPrep Pro C18, S- um, 19 x 50 mm. A gradient elution was used (flow rate 20 ), typically starting with 5% acetonitrile/95% water and progressing to 100% acetonitrile over a Period of 7 minutes.

All solvents contained 0.1% trifluoroacetic acid (TFA).

Mass ometric analysis was performed according to liquid chromatography/mass spectroscopy (LCMS) methods. The method employed a Waters LC—MS System (Agilent HPllOO HPLC and a Micromass ZMD mass spectrometer for the LCMS instrument, a CAPCELL PAK C18, UGlZO, s—3 m, 1.5 x 35 mm for the chromatography ), and a solvent system that was a 5-95% gradient of acetonitrile in water with 0.04% TFA (flow rate 0.5 mL/min; molecular weight range 200—800; cone Voltage 20 V; column temperature 40°C). All masses were reported as those of the protonated parent ions.

Powder X—ray diffraction analysis was measured Using RINT Ultima—IV (manufactured by Rigaku Corporation).

Differential ng calorimetry (DSC) was measured using a differential scanning calorimeter (DSCl (manufactured by r-Toledo)) at a temperature rise rate 5°C/min within the range of 25°C to 240°C.

Heating was performed by Heatblock (manufactured by TAITEC CO., Ltd.).

Reference Example 1—1j Crystal of l-7—methyl—3—{4—I(3~methyl—3H—imidazo[4,5? b]pyridin—2-yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5— bprridinf2—one (Form A) a)3—[4—(benzyloxy)phenyl]—7-methy1—1,3—dihydro—2H—imidazo[4,5— in—Z—one N fi\% 6%,,,,,,,,,hf as. %..........4}"NkrNH A mixture of tertvbutyl (2—chloro—4~methylpyridin—3— yl)carbamate (2.00 g), 4—(benzyloxy)aniline hydrochloride (2.91 g), 9,9—dimethyl—4,5—bis(diphenylphosphino)xanthene (381 mg), sodium tert—butoxide (1.90 g) and Pd2(dba)3 (302 mg) in 2~ propanol (6 mL) and toluene (24 mL) was stirred under a nitrogen atmosphere at 100°C for 24 hr. The reaction mixture was concentrated under reduced re. The residue was dissolved in methanol, and the precipitates were filtered off.

The filtrate was concentrated, and the residue was purified by column chromatography (NH silica gel, eluted with 15% — 50% ethyl acetate in hexane) to give 3;[4—(benzyloxy)phenyl]—7§ methyl—1,3—dihydro—2H—imidazo[4,5—b]pyridin~2—one (988 mg) as a colorless solid.

MS (API+): [M+H]+ 332.3. 1H NMR (300 MHz, 00013) 5 2.39 (3H, s), 5.12 (2H, s), 6.87 (1H, d, J = 5.3 Hz), 7.12 (2H, d,‘J = 9.0 Hz), 7.28—7.50 (5H, m), 7.57 (2H, d, J z 8.7 Hz), 7.96 (1H, d, J =’5.3 Hz), 9.93 (1H, brs). b) 3—[4—(benzyloxy)phenyl]—1—ethyl—7—methyl—1,3*dihydro—2H- imidazo[4,5—b]pyridin—2—one Iodoethane (0.289 mL) was added to a mixture of 3—[4— (benzyloxy)pheny1]—7—methyl—1,3—dihydro-2H-imidazo[4,5— b]pyridin52—one (998 mg) and cesium carbonate (1.96 g) in DMF (10 mL) at room temperature. The mixture was d at 50°C for 4 hr. The mixture was diluted with water at room temperature, and the mixture was extracted with ethyl acetate.

The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 15% — 30% ethyl acetate in ) to give 3—[4—(benzyloxy)phenyl]—1—ethyl—7— methyl—1,3-dihydro—2H—imidazo[4,5—b]pyridin—2—one(801 mg) as a white solid.

MS (API+): [M+H]+ 360.4. 1H NMR (300 MHz, c0c13) 5 1.41 (3H, t, J = 7.2 Hz), 2.61 (3H, s), 4.19 (2H, q, J'= 7.2 Hz), 5.11 (2H, s), 6.81 (1H, d, J = .3 Hz), 7.10 (2H, d, J = 8.7 Hz), 7.30—7.47 (5H, m), 7.53 (2H, d, J = 9.1 Hz), 7.91 (1H, d, J = 5.3 Hz).

[0100] c) 1—7—methyl—3—{4—[(3—methyl~3H—imidazo[4,5-b]pyridin— 2—yl)oxy]phenyl}~1,3—dihydro—2H—imidazo[4,5—b]pyridin—2—one w") __\ ’fi N’”“O~<J~ll 57/ \ o r A mixture of 3—[4—(benzyloxy)phenyl]—l—ethyl—7—methyl- 1,3—dihydro—2H—imidazo[4,5—b]pyridin—2—one (800 mg) and 10% Pd—C (118 mg) in ethanol (20 mL) was hydrogenated overnight under a balloon pressure at room temperature. The catalyst was filtered off, and the filtrate was concentrated in vacuo to give l—B—(4-hydroxyphenyl)—7—methyl~1,3—dihydro—2H— imidazo[4,5—b]pyridin-2—one as a colorless solid. To a mixture of this solid and 3—methyl—2-(methylsulfonyl)—3H—imidazo[4,5— bprridine (480 mg) in DMF (10 mL) was added 60% sodium hydride (58.9 mg) at 100°C. The mixture was heated under microwave irradiation at 180°C for 30 min. The on mixture was diluted with methanol and concentrated in vacuo.

The e was purified by column chromatography (NH silica gel, eluted with 30% — 50% ethyl acetate in hexane, and silica gel, eluted-with 15% — 30% ethyl acetate in hexane). The crude nce was purified by HPLC (C18, eluted with water/acetonitrile containing 0.1% trifluoroacetic acid). To the obtained solution was added aqueous ted sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and then trated in vacuo to give l~ethyl—7-methyl—3—{4—[(3— methyl—3H—imidazo[4,5—b]pyridin—2~yl)oxy]phenyl}—l,3*dihydro— 2H—imidazo[4,5—b]pyridin—2—one (119 mg) as colorless crystals (Form A).

MS (API+): [M+H]+ 401.3.

Reference Example 1-2 Crystal of l—ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5- b] pyridin—Z-yl) oxy] phenyl } —1, 3—dihydro—2H—imidazo [4, 5— din—2—one (Form A) a) 1~ethyl—3-(4—hydroxyphenyl)~7—methyl~1,3-dihydro—2H— imidazo[4,5-b]pyridin~2—one‘

[0105] m— {in21:» ”our________x;x N :5 o i A mixture of 3—[4—(benzyloxy)pheny1]—1—ethy1—7—methyl— 1,3—dihydro—2H—imidazo[4,5—b]pyridin—2—one (21.4 g) and 10% Pd—C (3.17 g) in ethanol (400 mL) was hydrogenated under a n pressure at room temperature for 2 hr. The catalyst was ed off, and the filtrate was concentrated in vacuo.

The solid was washed with THF—hexane to give 1—ethy1—3—(4- hydroxyphenyl)—7-methyl-1,3-dihydro—2H-imidazo[4,5—b]pyridinf 2—one (10.90 g) as a solid.

Ms (API+): [M+H]+ 270.4. _b) 1*ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5tb]pyridin— 2—y1)oxy]pheny1}—1,3—dihydro-2H—imidazo[4,5—b]pyridin—2—one

[0108] Q"? '—"\ ”firl“ «frag 1 2; I?” 7 To a solution of 3—methyl—2—(methylsulfony1)—3H— imidazo[4,5—b]pyridine (1.0 g) and 1-ethyl-3—(4— hydroxyphenyl)—7—methy1—1,3—dihydro—2H~imidazo[4,5—b]pyridin— 2—0ne (1.3 g) in DMF (10 mL) was added 60% sodium hydride (0.23 g) at room temperature, and the mixture was stirred under microwave irradiation at 180°C for 30 min. To the mixture was added ethanol (10 mL). The formed crystals were collected by filtration, and washed with ethanol. This microwave reaction was repeated two additional times using the same amount of starting materials. The combined crystals were recrystallized from ethanol containing 5% distilled water (270 m1) and dried under reduced pressure to give l-7—methyl— 3—{4-[(3—methyl—3H—imidazo[4,5-b]pyridin—2—y1)oxy]pheny1)—1,3— dihydro—ZH—imidazo[4,5-b]pyridin—2—one (3.3 g) as white crystals (Form A).

MS (API+): [M+H]+ 401.3. 1H NMR (300 MHZ, DMSO—de) 5 1.32 (311, t, J = 7.2 Hz), 2.61 (3H, s), 3.77 (3H, s), 4.12 (2H, q, J = 7.2 Hz), 7.00 (1H, d, J = .7 Hz), 7.20 (1H, dd, J ='.7.>'9, 4.9 Hz), 7.58—7.66 (2H, m), 7.71-7.78 (2H, m), 7.80 (1H, dd, J = 7.9, 1.1 Hz), 7.87 (1H, d, J = 4.9 Hz), 8.22 (1H, dd, J = 4.9, 1.5 Hz).

Anal. Calcd for C3H2&%02: C, 65.99; H, 5.03; N, 20.99. Found: C, 65.76; H, 5.07; N, 20.85.

The ement s of powder X—ray diffraction of Form A crystals obtained in Reference Example 1—1 are shown in '20 the following Table 1 and Fig. 1.

[Table 1] Powder X~ray diffraction data (Form A crystals) 2 9 (O ) d value CA) relative intenSit§ _ (%71 7.88 3 5 9-5 9.302 26 .9 8.1102 38 14.06 6.2937 8 14.58 6.0704 11 .74 5.6255 . 57 16.14 5.487 22 16.76 5.2854 . 10 18.3 4.8439 _ 81 19.6 4.5255 6 -3 4.371 61 21.22 .4.1835 6 21.84 4.0661 12 22.3 3.9833 10 22.76 3.9038 14 23.72 3.7479 19 24.68 3.6043 58 .36 3.5092 23 26.32 3.3833 11 27.1 3.2877 6 27.7 3.2178 100 28.36 3.1444 12 29.94 2.982 3 .48 2.9304 3 .9 2.8915 5 31.7 2.8203 5 32.84 2.725 3 33.14 ,2-701 3 33.94 2.6391 4 J Reference Example 2 Crystal of l—ethy1—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5— b]pyridin*2—yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5— b]pyridin—2—one (Form B) The crystals of l~ethyl—7—methyl—3—{4—[(3—methyl—3H— imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}-l,3—dihydro—2H— imidazo[4,5~b]pyridin~2—one (Form A) (20 mg, 0.05 mmol) obtained in Reference Example 1—1 were mixed with acetonitrile (3 mL), and dissolved at an inside temperature of 60°C. This solution was filtered through a filter with 0.22 pm pore size, and cooled to 0 ~ 5°C with stirring. The e was stirred for 8 hr in a cooled state at O — 5°C. The crystals were collected by tion to give l—ethyl—7*methyl—3-{4~[(3— methyl—3H—imidaio[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro— 2H—imidazo[4L5-b]pyridin—2—one als of Form B).

The measurement results of powder X—ray diffraction of the obtained crystals are shown in the following Table 2 and Fig. 2.

[Table 2] Powder X—ray diffraction data (Form B crystals) r—-— 2 6 (o ) d value (A) relative ity (%) 4.82 18.3182 ' 37 .12 » 17.2455 19 .5 . 15.7584 12 .7 15.492 11 .08 1 14.5245 7 9.25 9.5425 20 9.52 9.1852 17 .22 8.5482 13 11.34 ‘ 7.7955 96 11.35 7.7828 100 11.92 7.4184 23 .7 5.5398 15_9 5.5593 5 17.18 5.1571 4 18.54 4.7553 6 22.88 3.8835 12 24.58 3.5187 7 24.72 3.5985 11 3.5589 5 .02 3.4215 6 29.85 2.9898 6 29.98 2.9781 6 .1 2.9555 5 .25 2.9512 7 Reference Example 3 Crystal of l—ethyl—7—methyl—3—{4—[(3-methyl-3H-imidazo[4,5— b]pyridin—2—yl)oxy]phenyl}—l,3*dihydro—2H—imidazo[4,5— in—Z—one (Form D) The crystals of l—ethyl—7—methyl—3—{4~[(3—methyl—3H— imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H— imidazo[4,5—b]pyridin—2—one (Form A) (20 mg, 0.05 mmol) obtained in Reference Example l~l were mixed with trifluoroethanol (0.5 mL) and dissolved at room temperature. oroethanol was evaporated under a nitrogen stream while cooling to O — 5°C. The crystals were collected by filtration to give l—ethyl—7—methyl—3—{4—[(3—methyl~3H-imidazo[4,5— b]pyridin—2—yl)oxy]phenyl}~l,3—dihydro—2H—imidazo[4,5— b]pyridin—2~one (crystals of Form D).- The measurement results of powder X~ray diffraction of the obtained crystals are shown in the following Table 3 and Fig. 3.

[Table 3] Powder X—ray diffraction data (Form D ls) 2 9 (o ) d value (A) relative intensity (%) L_—_i ,72 15.4378 12 11.52 7.6757 100 11.96 7.3937 13 12,4 7.1323 24 .62 5.6685 14 16.26 5.4468 8 16.52 5.3616 11 19.28 4.5999 7 23.26' 3.821 18 24.18 3.6777 ’ 29 24.56 3.6216 11 24.68 3.6043 10 .54 3.4848 10 26.28 3.3884 13 26.5 3.3607 18 28.14 3.1685 10 29.82 2.9937 8 29.92 2.9839 7 .2 2.9569 9 31.18 2.8661 4 __J Reference Example 4 l of l—7—methyl~3—{4w[(3—methyl—3H—imidazo[4,5— b]pyridin-2+yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5~ b]pyridin—2—one (Form E) The crystals of lrethyl—7—methyl—3—{4-[(3—methyl—3H— imidazo[4,5—b]pyridin—2-yl)oxylphenyl}—l,3—dihydro—2H— imidazo[4,5—b]pyridin—2—one (Form A) (20 mg, 0.05 mmol) obtained in Reference Example 1—1 were mixed with acetone (4 mL) and dissolved at inside temperature 50°C. This solution was filtered through a filter with 0.22 um pore size, water (3' mL) heated to 50°C was added, and cooled to"0 e 5°C with stirring. The mixture was stirred for 8 hr in a cooled state at O — 5°C. The crystals were collected by filtration to give l-ethyl—7—methyl—3-{4—[(3—methyl—3H—imidazo[4,5—b]pyridin—2— yl)oxy]phenyl}—l,3-dihydro~2H—imidazo[4,5—b]pyridin~2—one (crystals of Form E). - The measurement results of powder X—ray ction of the obtained crystals are shown in the following Table 4 and Fig. 4.

[Table 4] WO 76934 Powder Xeray diffraction data (Form E crystals) 2 6 (o ) d value (21) ve intensity (%) ,64 15.6566 15 11.32 7.8102 100 11_9 7.4308 4 ,4 5.749 1 17.02 5.2052 3 .06 4.4227 1 .32 4.3667 1 22.76 3.9038 4 23.92 3.7171 1 24.5 3.6304 1 .52 3.4875 2 26.04 3.419 1 28.6 3.1186 1 29.96 2.98 3 .26 2.9512 2 30_9 2.8915 2 34.48 2.599 2 Reference Example 5 Crystal of l—ethyl—7—methyl~3—{4—[(3Fmethyl—3H—imidazo[4,5— b]pyridin—2~yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5— b]pyridin—2—one (Form F) The crystals of l—ethyl—7-methyl-3—{4—[(3—methyl—3H— imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro-2H— imidazo[4,5-b]pyridin—2—one (Form A) (20 mg, 0.05 mmol) obtained in Reference Example 1—1 were mixed with anol (10 mL) and dissolved at inside temperature 60°C. This solution was filtered through a filter with 0.22 um pore size, n—heptane (10 mL) heated to 60°C was added, and cooled to 0 - °C with stirring. The mixture was stirred for 8 hr in a cooled state at 0 — 5°C. The crystals were collected by filtration to give l—ethyl—7-methyl—3-{4—[(3-methyle3H— imidazo[4,5-b]pyridin~2—yl)oxy]phenyl}-l,3—dihydro—2H— imidazo[4,5—b]pyridin—2*one (crystals of Form F).

The measurement results of powder X—ray diffraction of the obtained crystals are shown in the following Table 5 and Fig. 5.

[Table 5] Powder X—ray diffraction data (Form F crystals) 2 6 (0 ) d value (A) relativelintensity (%) 7_33 11 9687 5 *ii .42 8 4827 100 14.32. , 6.18 3 14.86 6.9666 2 16.66 6.3488 3 .92 4.2428 6 .98 4.2308 5 22.28 3.9868 2 23_5 3.7826 6 23.78 3.7386 4 ,5 3.4902 2 26.98 3.4268 2 26.82 3.3214 18 27.62 3.2269 2 31.66 2.8238 12 33.44 2.6774 2 Reference Example 6 Crystal of l—ethyl—7—methyl—3-{4—[(3-methyl—3H—imidazo[4,5— in—Z-yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5— b]pyridin—2—one variable hydrate (Form H) The crystals of l—ethyl—7—methyl—3—{4—[(3—methyl-3H— imidazo[4,5—b]pyridin—2~yl)oxy]phenyl}—l,3-dihydro~2H— o[4,5-b]pyridin—2—one (Form A) (20 mg, 0.05 mmol) obtained in Reference Example 1—1 were mixed with acetonitrile/water (9:1) (1 mL) and the mixture was stirred at room temperature for a week. The crystals were collected by filtration to give 1—ethyl—7—methyl—3~{4—[(3—methyl—3H— imidazo[4,5—b]pyridin—Z—ylfoxy]phenyl}—1,3-dihydro—2H— o[4,5—b]pyridin-2—one variable hydrate (water content of the variable hydrate varied within the range of about 4 — about 14 wt%) (crystals of Form H).

The measurement results of powder X—ray diffraction of the obtained ls are shown in the following Table 6 and Fig. 6.

[Table 6] Powder X—ray diffraction data (Form H crystals} relative intensity (%) 6.06 14.5724 23 7.9 11.182 ' 4 9.24 9.5631 18 .96 8.0659 28 .86 5.5832 29 16.2 5.4668 5 17.14 ' 5.1691 17.76 4.99 4 18.62 4.7614 ~ 9 .42 4.3456 12 24.04 3.6988 8 24.8 3.5871 100 26.54 3.3558 29 27.2 3.2758 .24 27.54 3.2361 6 29.28 3.0477 3 29.6 3.0154 9 31.46 2.8413 6 33.48 2.6743 5 nce Example 7 Crystal of l-ethyl—7—methyl—3—{4~[(3—methyl—3H-imidazo[4,5— bprridin—Z—yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5— b]pyridin—2-one monohydrate (Form I) The crystals of l—ethyl—7—methyl—3—{4—[(3—methyl—3H- imidazo [4 , 5—b] pyridin—2—yl) oxy] phenyl } ~l , 3—dihydro—2H— imidazo[4,5—b]pyridin—2-one (Form A) (20 mg, 0.05 mmol) obtained in Reference Example 1—1 were mixed with ethanol/water (9:1) (1 mL) and the mixture was stirred at room ature for a week. The crystals were collected by filtration to give l—ethyl—7—methyl—3-{4—[(3—methyl—3H— imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H— imidazo[4,5—b]pyridin—2~one monohydrate (crystals of Form I).

The measurement results of powder X—ray diffraction of the obtained ls are shown in the following Table 7 and Fig. 7.

[Table 7] VV()2012/176934 Powder X—ray diffraction data (Form I ls) 2 9 (° ) d value (A) relative intensity (%) 8.24 10.7213 11 .6 8.339 41 11.44 7.7285 33 12.64 6.9974 5 13.72 6.4489 17 13.94 6.3476 12 14.7 6.0211 16 .64 5.6613 50 17.68 5.0124 20 18.46 . 4.8023 31 18.96 4.6768 6 .62 4.3039 19 » 20.92 4.2428 6 22.62 3.9277 12 22.92 3.8769 8 23.16 3.8373 5 24.5 3.6304 10 .52 3.4875 100 26.1 3.4113 37 27.72 3.2155 42 29.6 3.0154 8 29.78 2.9976 22 Example 1 l of l—ethyl—7—methyl*3~{4—[(3—methyl—3H—imidazo[4,5— b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H~imidazo[4,5— b]pyridin—2—one (Form G) (l) The crystals of l—ethyl—7-methyl—3—{4—[(3-methyl—3H— imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}~1,3—dihydro—2H- imidazoI4,5—b]pyridin—2—one (Form A: 100 mg) were dissolved in ethanol (20 mL) at 80°C, and the solution was allowed to cool to room temperature. The mixture was stirred at room- W0 2012/176934 temperature for 350 hr. The solids were collected by filtration to give l~7*methyl-3—{4-[(3~methyl—3H- imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3~dihydro—2H— o[4,5~b]pyridinone (50 mg) as crystals (Form G). (2) The crystals of l—ethyl-7~methyl—3—{4—[(3—methyl—3H— imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro~2H~ imidazo[4,5—b]pyridin—2-one (Form A: 40.0 g) were dissolved in DMSO (400 mL) at 95°C, and the solution was allowed to cool to 85°C. To the solution was slowly added ethanol (400 mL) at 85°C, and the mixture was allowed to cool to 80°C. To the solution was added a seed l (Form G, 50 mg) at 80°C. The mixture was stirred and maintained at 73°C for 20 hr. Thef' solids were collected by filtration, and washed with ethanol (500 mL) to give l—7-methyl-3—{4—[(3—methyl-3H* 'imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H— imidazo[4,5—b]pyridin—2—one (19.5 g) as white crystals (Form Example 2 Crystal of l—ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5- bprridin—Z-yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5— b]pyridin—2~one (Form G) The crystals of l—ethyl-7—methyl—3—{4—[(3—methyl—3H— imidazo[4,5—b]pyridin-2—yl)oxy]phenyl}—l,3—dihydro-2H— o[4,5—b]pyridin—2—one (Form A: 600 mg) were d in ethanol (60 mL) at room temperature for 168 hr. The solids were collected by filtration to give l—ethyl—7—methyl—3—{4— [(3—methyl—3H—imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3— dihydro—2H-imidazo[4,5—b]pyridin—2—one (350 mg) as crystals, (Form G).

M8 (APl+): [M+H]+ 401.1. 1H NMR (400 MHz, DMSO—d6) 5 1.25—1.38 (3H, m), 2.61 (3H, s), 3.78 (3H, s), 4.04—4.18.(2H, m), 6.96—7.04 (1H, m), 7.17—7.25 (1H, m), 7.59—7.66 (2H, m), 7.71—7.77 (2H, m), 7.78—7.83 (1H, m), 7.85—7.91 (1H, m), 8.16—8.28 (1H, m).

Anal. Calcd for Cszfikozz C, 65.99; H, 5.03; N, 20.99. Found: C, 65.73; H, 5.12; N, 20.85.

Example 3 Crystal of 1—ethyl—7—methyl~3—{4—[(3-methyl—3H—imidazo[4,5— b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5— b]pyridin—2;one (Form G) The crystals (3.0 g) of l—ethyl*7—methyl—3—{4~[(3—methyl— 3H-imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H— imidazo[4,5—b1pyridin—2—one obtained in Example 7 a) were dissolved in DMSO (33 mL) at 90°C. To the solution was slowly added ethanol (30 mL) at 80 — 90°C. The l (Form G) obtained in Example 2 was added as a seed crystal at 80 — 90°C.

The mixture was stirred at 60 — 65°C for 6 hr, and at room temperature for 18 hr. The solids were collected by filtration, and washed with ethanol (15 mL) to give l—7—methyl—3-{4- [(3—methyl—3H—imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—1,3— dihydro-2H—imidazo[4,5-b]pyridin-2—one (1.3 g) as white crystals (Form G).

[0127] Example 4 Crystal of l—ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5— b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5- b]pyridin—2—one (Form G) The crystals (3.0 g) of l—ethyl—7—methyl—3—{4—[(3—methyl— 3H—imidazo[4,5-b]pyridin~2—yl)oxy]phenyl}—1,3fdihydro-2H— imidazo[4,5—b]pyridin~2—one obtained in Example 7 a) were dissolved in DMSO (33 mL) at 90 — 95°C. To the on was slowly added ethyl acetate (30 mL) at 70 — 90°C. The crystal (Form G) obtained in e 3 was added as a seed crystal at 80 — 90°C. The mixture was d at 45 — 50°C for 25 min and at 70 — 75°C for 3 hr. The mixture was cooled to O — 5°C, and stirred for 1 hr. The solids were collected by filtration and washed with ethyl acetate (15 mL) to give l~ethyl—7—methyl—3— {4—[(3—methyl—3H—imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3— dihydro—ZH—imidazo[4,5—b]pyridin-2—one (2.6 g) as crystals (Form G).

Example 5 l of l-ethyl~7-methyl—3—{4—[(3—methyl-3H—imidazo[4,5- b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5— bprridin—Z—one (Form G) A solution of 3—methyl—2-(methylsulfonyl)—3H—imidazo[4,5- b]pyridine (20.4 g, 96.55 mmol) in DMA (117 mL) was added to a solution of l—ethyl—3—(4—hydroxyphenyl)—7—methyl—l,3—dihydro— 2H~imidazo[4,5—b]pyridin—2—one (26.0 g, 96.55 mmol) and potassium tert—butoxide (11.4 g) in DMA (96 mL) at room temperature. The mixture was stirred at 95 - 100°C for 1.5 hr.

Water (221 mL) was added at 80 — 100°C. The precipitates were collected at room temperature and dried under d pressure to give 1—ethylmethy1-3—{4—[(3—methyl-3H—imidazo[4,5— b]pyridin—2*yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5— b]pyridin—2—one (35.8 g) as a crude t.

The crude 1-ethyl—7—methyl—3—{4—[(3—methyl—3H— imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H— imidazo[4,5—b]pyridin—2—one (10.0 g) was dissolved in DMSO (150 mL) at 90 — 100°C. The solution was filtered through a ipaper filter, and washed with DMSO (10 mL). The combined filtrate was slowly added to a e of the crystals (Form GE 100 mg) (as a seed l) obtained in Example 4 in ethyl acetate (100 mL) at 5 — 30°C. The mixture was stirred at room temperature for 17 hr and at 70°C for 1 hr. The mixture was slowly cooled to 25°C and stirred for 2 hr. The mixture was stirred at O — 10°C for 1 hr, and at room temperature for 1 hr.

The solids were ted by filtration, and dried under reduced pressure at 50°C to give l~ethyl—7—methyl~3—{4—[(3— methyl+3H-imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro— 2H—imidazo[4,5—b]pyridin~2—one (8.0 g) as white crystals (Form

[0129] Example 6 Crystal of 1-ethyl-7~methyl-3—{4~[(3—methyl—3H—imidazo[4,5— b]pyridin—2—yl)oxy]phenyl}~1,3—dihydro—2H—imidazo[4,5— b]pyridin—2—one (Form G) A solution of 3—methyl—2—(methylsulfonyl)-3H—imidazo[4,5— b]pyridine (40.8 g, 193.09 mmol) in DMA (234 mL) was added to a solution of 1—ethy1—3—(4—hydroxyphenyl)—7—methyl—1,3— dihydro—ZH—imidazo[4,5—b]pyridin—2—one (52.0 g, 193.09 mmol) and potassium tert—butoxide (22.8 g) in DMA (192 mL) at room temperature. The mixture was stirred at 90 — 100°C for 1 hr.

Water (442 mL) was added at 80 — 100°C. The precipitates were collected at room temperature and dried under reduced pressure to give 1—ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5— b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5— b]pyridin—2—one (72.4 g) as a crude product.

The crude 1—7—methyl—3—{4-[(3—methyl—3H— o[4,5-b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H— imidazo[4,5—b]pyridin—2—one (60.0 g) was dissolved in DMSO (900 mL) at 90 ~ 100°C. The solution was filtered through a paper , and washed with DMSO (60 mL). The combined filtrate was slowly added to a mixture of the crystals (Form G: 600 mg) (as a seed l) obtained in Example 5 in ethyl acetate (600 mL) at 0 — 30°C. The mixture was stirred at 70°C for 0.5 hr and cooled to room temperature. The mixture was stirred at room ature for 1 hr, at 0 — 10°C for 1 hr, and at room ature for 1 hr. The solids were collected by filtration, and dried under reduced pressure at 50°C to give 1— ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5—b]pyridin—2- yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5—b]pyridin—2—one (47.9 g) as white crystals (Form G).

MS 0351+): [M+H]+ 401.2. 1H NMR (500 MHZ, CDCl3) 5 1.42 (3H, t), 2.62 (3H, s), 3.84 (3H, s), 4.15—4.27 (2H, m), 6.81~6.92 (1H, m), 7.10-7.18 (1H, m), 7.52—7.61 (2H, m), 7.7377.80 (1H, m), 7.82—7.87 (2H, m), 7.91— 7.95 (1H, m), 8.20~8.29 (1H, m).

Example 7 Crystal of 1—ethyl~7—methy1—3—{4—[(3—methyl—3H—imidazo[4,5~ b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro-2H-imidazo[4,5— blpyridin—2—one (Form G) a) A solution of 3—methy1—2—(methylsulfonyl)—3H—imidazo[4,5— b]pyridine (78.4 g, 371.33 mmol) in DMA (420 mL) was added to a solution of l—3—(4—hydroxyphenyl)—7—methyl—1,3- dihydro—ZH—imidazo[4,5—b]pyridinone (100.0 9, 371.33 mmol) and potassium tert—butoxide (51.5 g) in DMA (370 mL) at room temperature. The e was stirred at 90 — 100°C for 1 hr.

Water (780 mL) was added at 90 — 100°C. The precipitates were collected at room ature and dried under reduced pressure to give 1-ethyl—7—methyl—3-{4-[(3—methyl—3H—imidazo[4,5— b] pyridin—Z-yl) oxy] phenyl } —1 , 3—dihydro—2H—imidazo [4 , 5— b]pyridin—2—one (127.7 g) as crystals. The ed crystals (125.0 g) were dissolved in DMSO (1375 mL) at 90 - 95°C. To the solution was slowly added ethanol (1250 mL) at 80 — 95°C, and the mixture was d to cool to room temperature. The solids were collected by filtration, washed with ethanol (625 mL) to give l—7-methyl—3-{4—[(3—methyl—3H-imidazo[4,5— b]pyridin—2—y1)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5— b]pyridin—2-one (103.9 g) as crystals. b) A mixture of the obtained crystals (55.0 g) in a on of DMSO (275 mL) and ethanol (275 mL) was stirred at 70 — 75°C for 0.5 hr, and the mixture was allowed to cool to room temperature. The solids were collected by filtration, and washed with ethanol (165 mL) to give 1—ethy1—7—methy1—3—{4— [(3—methyl-3H—imidazo[4,5—b1pyridin—2eyl)oxy]phenyl}—1,3— dihydro—ZH—imidazo[4,5—b]pyridin—2—one (52.2 g) as crystals.

The obtained crystals (5.0 g) were dissolved in DMSO (50 mL) at 95°C. The solution was filtered through a paper filter and washed with DMSO (5 mL). To the combined filtrate was slowly added ethanol (50 mL) at 73 — 95°C. To the solution were added the crystals obtained in Example 4 (Form G: 5 mg) as a seed crystal at 73°C. The mixture was allowed to cool to room ature. The mixture was stirred at 70 - 75°C for 7 hr, and allowed to cool to room temperature. The mixture was stirred at 70 ~ 75°C for 8 hr, and cooled to room ature.

The mixture was stirred at 70 — 75°C for 2 hr, and the e was stirred at room temperature for 1 hr, and 0 — 10°C for 1 hr.

The solids were collected by tion, and dried under reduced pressure at 50°C to give l—7—methyl—3—{4—[(3— methyl—3H—imidazo[4,5~b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro— 2H—imidazo[4,5—b]pyridin—2~one (4.5 g) as white crystals (Form Example 8 Crystal of 1—ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4.5— bprridin—2—yl)oxy]phenyl}—1,3-dihydro—2H—imidazo[4,5— b]pyridin—2—one (Form G) 3—Methyl—2—(methylsulfonyl)—3H—imidazo[4,5—b1pyridine_ (8.62 g, 40.8 mmol) was added to a mixture of 1—ethyl—3—(4— hydroxyphenyl)-7—methyl—1,3—dihydro—2H—imidazo[4,5—b]pyridin~ 2—one (10.0 g, 37.1 mmol), potassium carbonate (6.15 g) and water (4.25 mL) in DMA (75 mL) at room temperature. The mixture was stirred at 80 - 90°C for 1 hr. Water (135 mL) was added at 45°C. The precipitates were collected at room temperature, and dried under reduced pressure to give 1—ethyl— 7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5—b]pyridin—2— yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5—b]pyridin—2—one (14.13 g) as a crude product.

The crude l—ethyl—7—methyl—3—{4~[(3—methyl—3H— imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H— imidazo[4,5-b]pyridin—2—one (12.0 g) was dissolved in DMSO (228 mL) at 90°C. The solution was filtered through glass filter. The filtrate was heated to 90°C and stirred at 30°C for 1 hr. Ethanol (72 mL) was added and the e was stirred for 1 hr. After stirring at 60°C for 4.5 hr, the mixture was cooled to room temperature. After stirring at 10°C W0 2012/176934 for 4.5 hr, the precipitates were collected and dried under reduced pressure to give 1~ethyl—7—methyl—3—{4—[(3—methyl—3H- imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H— imidaio[4,5—b]pyridin—2—one (10.32 g) as white crystals (Form Example 9 Crystal of 1'ethy1—7-methyl—3—{4—[(3—methyl—3Heimidazo[4,5— din—2~yl)oxy]phenyl}~1,3—dihydro—2H-imidazo[4,5- b]pyridin—2—one (Form G) 3—Methyl—2—(methylsulfonyl)—3H—imidazo[4,5—b]pyridine (258.9 g, 1.22 mmol) was added tofa mixture of 1—ethy1—3—(4— hydroxyphenyl)—7—methyl-1,3—dihydro42H—imidazo[4,5—b]pyridin— 2—one (300.0 g, 1.11 mmol), potassium carbonate (184.7 g) and water (127.5 mL) in DMA (1950 mL) at room temperature. DMA (300 mL) was further added and the mixture was stirred at 86 — 87°C for 1 hr. Water (4050 mL) was added at 45°C. The precipitates were collected at 25°C, and dried under reduced pressure to give 1-ethy1—7~methyl-3—{4—[(3—methyl—3H— imidazo[4,5—b]pyridin—2—y1)oxy]phenyl}—1,3—dihydro—2H— imidazo[4,5—b]pyridin—2—one (435.87 g) as a crude product.

The crude 1-ethy1—7—methyl—3—{4—[(3—methy1—3H— imidazo[4,5-blpyridinyl)oxy]phenyl}—1,3-dihydro—2H— imidazo[4,5—b]pyridin—2—one (400.0 g) was dissolved in DMSO (7600 mL) at 80 — 90°C. The solution was filtered through a glass . The filtrate was heated to 80 ~ 90°C, and the crystals (Form G: 4 g) obtained in e 8 were added to the solution at 50°C as a seed crystal. After cooling to 30°C, l (2400 mL) was added. The mixture was heated to 60 ~ 70°C and cooled to room ature. After stirring under ice— cooling, the precipitates were collected and dried under reduced pressure to give l—7—methy1—3—{4—[(3—methyl~3H— imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—1,3-dihydro—2H— imidazo[4,5—b]pyridin~2-one (344.04 g) as white crystals (Form G).

The measurement results of powder X—ray diffraction of the Form G crystals ed in Example 1(2) are shown in the following Table 8 and Fig. 8. In addition, the DSC thermoanalytical data of the crystals are shown in Fig. 9.

[Table 8] ‘Powder X~ray diffraction data (Form G Crystals) 2 9 (° ) 01 value (A) relative intensity (‘3) 6.5 13.5869 8 9.58 9.2245 38 11.22 7.8796 82 11.82 7.4809 17 13.08 6.763 25 14.26 6.2059 47 14.44 6.1289 49 .46 5.7268 58 16.9 5.2419 12 17.28 5 29 19.12 4.638 45 .8 4.267 25 21.32 4.1641 16 21.88 4.0588 5 22.24 3.9939 30 22. 58 3.9345 44 23.44 3.7921 100 23.27 3.7479 100 24.74 3.5957 15 26.12 3.4088 17 28.24 . 3.1575 5 28. 82 3. 0953 10 29.18 3.0579 20 .88 2.8933 13 31. 64 2. 8255 6 32.78 2.7298 7 34. 68 2. 5845 7 Formulation Example 1 (1) Crystal of Example 1 10.0 g (2) Lactose 70.0 g (3) Cornstarch 50.0 g 2012/066461 (4) Soluble starch 7.0 g (5) Magnesium stearate 3.0 g After 10.0 g of the crystal of Example 1 and 3.0 g of -magnesium te are granulated in 70 mL of aqueous solution of soluble starch (7.0 g as soluble starch) and then dried, the ing mixture is mixed with 70.0 g of lactose and 50.0 g of cornstarch (lactose, cornstarch, soluble starch and magnesium stearate are all products in compliance with ~ Japanese Pharmacopoeia). The mixture is compressed to obtain a tablet.

Experimental Example 1 Study of crystallization from various solvents The crystals of l—ethyl—7—methyl—3—{4—[(3—methyl—3H— imidazo[4,5—b]pyridin—2-yl)oxy]phenyl}—l,3—dihydro—2H— imidazo[4,5—b]pyridin—2—one (Form A) (20 mg, 0.05 mmol) obtained in Reference Example 1—1 were maintained at 55°C, and various ts were added until almost the whole amount was dissolved. This solution was filtered through a filter with 0.22 um pore size, and cooled to O — 5°C with stirring. The mixture was stirred for 8 hr under cooling at O — 5°C. The crystals of l—ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5— bprridin—Z—yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5~ din—2~one formed were collected by filtration, and the l form of the crystalline products was confirmed. The results are shown in Table 9.

[Table 9] LSOlVGDt solubility at 55°C (mg/mL) _LEryStal form methanol 5.6 . Form A l 2.6 Form A F2_propano 1 <2 . 7 L— A [acetone ' 6.5' VA Lmethylethylketone 6.8 —J A ethyl acetate 3.4 A a ton1tr i le ~r ce 8.1 B rtoluene 5.2 G chloroform 1‘ >200 A Ltetrahydrofuran 26 A Ltrifluoroethanol >200 D L__ _J As shown above, in the crystallization from various solvents, Form A crystals were preferentially crystallized, and Form G crystals were crystallized only under the toluene condition where use for the production of a drug substance for pharmaceutical products is limited from the aspect of residual solvent.

Experimental e 2 Solvent suspending test of crystal form mixture Crystal form mixtures containing the same weight of each crystal form of l—ethyl—7—methyl—3e{4—[(3~methyl—3H— imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H— imidazo[4,5-b]pyridin—2-one obtained in nce Examples 1—1, 3 and 4, and Example 1 were ed to the total amount of 20 mg. The crystal form mixtures were mixed with ethanol (1 mL), and the mixtures were stirred at room temperature. After stirring for one week, and after stirring for 2 weeks, the crystals of l—7—methyl—3~{4—[(3-methyl—3H—imidazo[4,5— b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5- din—2—one formed were collected by filtration, and the crystal form of the crystalline products was confirmed. The . 2012/066461 results are shown in Table 10.

[Table 10] crystal form crystal form mixture 1 week later 2 weeks later Form A+Form G Form G Form G Form A+Form E Form A + Form G Form G Form A+Form D+Form E+Form G [ Form G Form G As shown above, the mixtures of various crystal forms transformed into Form G l 2 weeks later at room temperature and under suspending in ethanol. The results have clarified that the crystal (Form G) of the present invention is dynamically stable under suspending in ethanol at room temperature.

Experimental Example 3 Solvent suspending test of Form A crystal in various solvents The crystals of l—ethyl—7—methyl—3—{4—[(3-methyl—3H- imidaZo[4,5—b]pyridinyl)oxy]phenyl}-l,3—dihydro—2H— imidazo[4,5—b]pyridin-2—one (Form A) (20 mg, 0:05 mmol) obtained in Reference Example 1—1 were mixed with various solvents (1 mL) and the mixture was stirred at room temperature. After stirring for one week, and after ng for 2 weeks, the crystals of lsethyl—7~methyl—3-[4—[(3—methyl— dazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H— imidazo[4,5—b]pyridin—2—one formed were collected by filtration, and the crystal form of the crystalline products was confirmed. The results are shown in Table 11.

[0143] WO 76934 [Table 11] t crystal form 1 week later 2 weeks later methanol Form G Form G “—1 isopropyl alcohol Form A *——T_ Form A acetone Form G Form G methylethylketone Form G Form G ethyl e Form AfForm G Form G toluene ‘[—__ Form G Form G __J tetrahydrofuran Form G —_—T Form G 1—butanol‘ As shown above, Form A crystal was transformed into Form G crystal when suspended in many of the solvents. The results have revealed that the crystal (Form G) of the present invention is thermodynamically more stable when suspended in various solvents at room temperature than Form A preferentially ed by crystallization from a solution.

[0145] Experimental Example 4 Preservation stability test The crystals of l—ethyl-7—methyl—3—{4—[(3—methyl—3H- imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H— o[4,5—b]pyridin—2—one (Form G, 5 — 10 mg) obtained in Example 1 were placed in a glass bottle, sealed with a metal cap and preserved at 80°C. The sample was taken out 1 week and 2 weeks later, dissolved in a water/acetonitrile mixed solution at a concentration of 0.2 mg/mL and analogs were measured by Alliance HPLC 2695 (Waters Corporation). The results are shown in Table 12.

[Table 12] area tage storage crystal appearance (%) of HPLC peak condition . form area of main form h' . w lte crystalline prestorage 99.7 Form G powder 80°C, 1 week no change 99.7 ::r Form G [80°C, 2 weeks no change 99.6 _L_Form G From the above—mentioned results, it has been clarified that the crystal (Form G) of the present invention has very high al and al stability. mental Example 5 PDE enzyme inhibition Human PDElOA enzyme was generated from Sf9 or COS—7 cells transfected with the full—length gene. The cloned enzyme was extracted from homogenized cell pellets. The extracted enzyme from Sf9 cells was partially purified using His—tag affinity column. The enzyme was stored at —70°C until use. PDE activity was measured using an SPA illation Proximity Assay) (GE Healthcare). To evaluate the inhibitory activity, 10 uL of serially diluted l—ethyl-7—methyl—3—{4—[(3—methyl—3H~ imidazo[4,5—b]pyridin-2—yl)oxy]phenyl}~l,3—dihydro—2H— imidazo[4,5—b1pyridin—2—one was incubated with 20 uL of PDE enzyme in an assay buffer (50 mM HEPES—NaOH, 8.3 mM MgClz, 1.7 mM EGTA, 0.1% BSA (pH 7.4))_for 30 min at room temperature.

The final concentration of DMSO in the assay was 1 percent as compounds were tested in duplicate in 96-well half—area plates (Corning). To start the reaction, 10 uL of substrate [3H] cGMP (25 or 50 nM; enclosed in SPA kits from GE Healthcare or purchased from PerkinElmer, respectively) was added to a final assay volume of 40 uL. After 60 min of tion at room temperature, yttrium SPA beads containing zinc sulphate were added (6 mg/mL, 20 uL) to terminate the PDE reaction. After standing still for 60 min, the assay plates were counted on a scintillation counter (PerkinElmer) and the tion rate was calculated. The tion rate was calculated based on the control wells containing DMSO as 0% and control wells without enzyme as 100%. The s are shown in Table 13.

[Table 13] Inhibition rate (%) (10 uM] Inhibition rate (%) (1 pM) 106 109 INDUSTRIAL APPLICABILITY Since the crystal of the present invention shows a superior PDElOA inhibitory action, it can provide a prophylactic or therapeutic drug ally useful for a disease such as schizophrenia and the like. In addition, since the crystal of the present invention is superior in the efficacy, low toxicity, stability, in vivo kinetics etc. (particularly, stability), it is useful as a medicament.

[0151] While some of the ments of the present invention‘ have been described in detail in the above, it is, however,‘ possible for those of ordinary skill in the art to make various modifications and changes to the particular embodiments shown t substantially departing from the teaching and ages of the present invention. Such modifications and changes are encompassed in the spirit and scope of the t invention as set forth in the appended claims.

This application is based on patent application No. 2011-138920 filed in Japan, the contents of which are incorporated in full herein by this reference}

Claims (12)

1. A crystal of lmethyl{4-[(3-methyl-3H- imidazo[4,5-b]pyridinyl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5-b]pyridinone showing an X-ray powder diffraction pattern having characteristic peaks at interplanar spacings (d) of 13.59±0.2, 9.22±0.2, 7.88±0.2, 6.76±0.2, 6.21±0.2, 6.13±0.2, 5.73±0.2, 4.64±0.2, .2 and 3.75±0.2 Angstroms in powder X-ray ction.

2. The crystal according to claim 1, which shows an X-ray powder diffraction pattern having further characteristic peaks at interplanar spacings (d) of 7.48±0.2, 5.24±0.2, 5.13±0.2, 4.27±0.2, 4.16±0.2, 4.06±0.2, 3.99±0.2, 3.93±0.2, 3.60±0.2, .2, 3.16±0.2, .2, 3.06±0.2, 2.89±0.2, 2.83±0.2, 2.73±0.2 and 2.58±0.2 Angstroms in powder X-ray diffraction.

3. The crystal according to claim 1, which shows an initial temperature of about 222 - about 224 °C of an endothermic behavior caused by melting in DSC ement (temperature increase rate n).

4. A medicament comprising the crystal according to claim

5. The medicament according to claim 4, which is a phosphodiesterase 10A inhibitor.

6. The ment according to claim 4, which is a prophylactic or therapeutic agent for schizophrenia.

7. A method of preventing or treating schizophrenia in a mammal, comprising administering an effective amount of the crystal according to claim 1 to the mammal, wherein the mammal is a non-human subject.

8. Use of the crystal according to claim 1 for the production of a prophylactic or therapeutic drug for schizophrenia.

9. The crystal according to claim 1 for use for the prophylaxis or treatment of schizophrenia.

10. The crystal according to claim 1, substantially as herein described with reference to any one of the examples and/or s.

11. The medicament according to claim 4, substantially as herein described with reference to any one of the examples and/or figures.

12. The use according to claim 8, substantially as herein described with nce to any one of the examples and/or figures.